3 3 8 U N I T I I Diseases of Organ Systems
38 A 71-year-old African American man visits his physician 39 A 45-year-old man comes to the physician for a rou-
for a checkup because he is worried about his family history tine health maintenance examination. On physical examina-
of prostate cancer. Physical examination does not indicate any tion, there are no remarkable findings. Laboratory findings
abnormalities. Because of the patient’s age and family history, include serum creatinine, 1.1 mg/dL; urea nitrogen, 17 mg/
his prostate-specific antigen (PSA) level is measured and is dL; glucose, 76 mg/dL; alkaline phosphatase, 89 U/L; and
8 ng/mL. Six months later, the PSA level is 10 ng/mL. A urolo- prostate-specific antigen (PSA), 16 ng/mL. Prostate biopsies
gist obtains transrectal biopsy specimens, and microscopic are performed and the high power microscopic appearance of
examination shows multifocal areas of glandular hyperplasia a biopsy specimen is shown in the figure. Which of the follow-
and the appearance shown in the figure. Which of the fol- ing is the most likely risk factor for his disease?
lowing statements applies best to this clinical and pathologic A Epigenetic hypermethylation of GSTP1 gene
scenario? B Exposure to naphthylamine compounds
A Associated with increased risk for invasive cancer C Overproduction of dihydrotestosterone
B Chronic inflammation from urinary tract D Prolonged use of smoking tobacco
E Recurrent bacterial urinary tract infections
obstruction
C Normal microscopic finding of the peripheral zone
D Related to an inherited tumor suppressor gene
mutation
E Responsive to 5α-reductase inhibitor therapy
ANSWERS hypertrophy, and predispose to urinary stasis with infection;
they are not true diverticula. Interstitial cystitis is a compli-
1 D The features of vesicoureteral reflex from uretero- cation of recurrent bladder infection, most often in women,
pelvic junction (UPJ) obstruction are described. This is the and characterized by chronic pain. Malakoplakia is a rare
most common cause for hydronephrosis in infants and chil- response to bacterial infection in which collections of macro-
dren. Obstructed tubules do not reabsorb β2-microglobulin. phages filled with degraded bacterial products elicit forma-
Other anomalies, such as contralateral renal agenesis, may tion of intracellular laminated, calcified concretions called
be present. Surgical correction of the abnormal UPJ restores Michaelis-Gutmann bodies. True papillomas are uncommon
proper peristaltic urine flow. Bladder exstrophy is an open urothelial proliferations and asymptomatic. Schistosomia-
abdominal wall defect. Urinary diverticula may predispose sis leads to hematuria and inflammation with bladder wall
to infection, but not obstruction. All or part of one or both fibrosis.
ureters may be duplicated, but this is usually an incidental
finding; granulomatous inflammation in the urinary tract is PBD9 969, 982 BP9 668–669 BPD8 981, 994 BP8 696
uncommon. Urachal remnants (embryologic allantois) may
predispose to infection but not hydronephrosis; adenocarci- 3 C Bilateral hydronephrosis, without hydroureter or
noma may arise in a urachal cyst. bladder dilation, suggests that the problem involves both
ureters. Obstructive uropathy has led to chronic renal failure
PBD9 961 BP9 668 PBD8 940 BP8 561 with uremia. The elevated IgG4 suggests a fibroinflammatory
process with IgG4-secreting plasma cells in the retroperito-
2 A He has findings consistent with nodular prostatic neum; this process is part of autoimmune pancreatitis and
hyperplasia with bladder outlet obstruction. Diverticula
may develop in the setting of obstruction and bladder wall
C H A P T E R 2 1 The Lower Urinary Tract and Male Genital System 3 3 9
may also involve biliary tract, salivary glands, and lungs, is a low risk for adenocarcinoma. Obesity increases the risk
but is not associated with the other listed choices. Nephro- for malignancy, but correlation with a specific malignancy
lithiasis could cause ureteropelvic junction obstruction, but is difficult to draw. Schistosomiasis can lead to squamous
bilaterality would be uncommon. Polypoid cystitis results metaplasia and increased risk for squamous carcinoma of
from inflammation but may mimic a tumor mass, and could the bladder.
obstruct one or both ureteral orifices with hydroureter. Renal
cell carcinoma is likely to be unilateral, but may cause only PBD9 964–967 BP9 669–670 PBD8 976–979 BP8 576
focal obstruction. Urothelial carcinomas may be multifocal,
but are unlikely to obstruct both ureters simultaneously. 8 E Exposure to arylamines markedly increases the risk of
urothelial carcinoma shown the in figure, which can occur
PBD9 960–961 BP9 668 BPD8 973 BP8 572–573 decades after the initial exposure. After absorption, aromatic
amines are hydroxylated into an active form, which is detox-
4 C The embryologic urachus may not become obliter- ified by conjugation with glucuronic acid and then excreted.
ated, leaving a fistulous tract or a cyst between the bladder Urinary glucuronidase splits the nontoxic conjugated form
and abdominal wall at the umbilicus. Congenital diverticula into the active carcinogenic form. Adenocarcinoma is a com-
result from either focal failure in formation of bladder muscu- plication of the congenital condition known as exstrophy of
lature or bladder outlet obstruction, and there is no fistulous the bladder. Rhabdomyosarcoma of the pelvis is typically
tract. Exstrophy refers to failure in development of the lower a pediatric neoplasm, and not associated with chemical
abdominal wall, leaving an open defect to the bladder. Abnor- exposures. Renal cell carcinomas also may manifest as
mal reflux of bladder contents into the ureter defines vesico- painless hematuria, but exposure to aniline dyes is not a
ureteral reflux, which may be due to congenital abnormalities risk factor. Squamous cell carcinoma is the most common
of bladder development, but there is no fistulous tract. A vitel- malignancy of the urethra, but it is rare and has no relation
line duct remnant may account for a Meckel diverticulum, or to carcinogens.
rarely a fistulous tract from small intestine to umbilicus.
PBD9 964–965 BP9 669–670 PBD8 979–980 BP8 575–576
PBD9 962 PB9 668 PBD8 974
9 C Bladder hypertrophy can result from outlet obstruc-
5 D This woman has a peculiar form of cystitis known tion. In an older man, this type of obstruction is most often
as malakoplakia, when macrophages have reduced phago- caused by prostatic enlargement caused by hyperplasia or
cytic function, and the concretions within macrophages carcinoma. Mild elevations in the prostate-specific antigen
are known as Michaelis-Gutmann bodies. Malakoplakia is a (PSA) level may occur in patients with prostatic hyper-
reaction to chronic bacterial infections, usually Escherichia plasia, and greater increases in PSA suggest carcinoma.
coli and Proteus species, and often in the setting of immu- Autoimmune conditions may be associated with interstitial
nosuppression. The most common organism associated with cystitis, but cystitis does not cause bladder neck obstruc-
cases of acute cystitis is E. coli. The other organisms listed are tion. Polycythemia can be the result of a paraneoplastic syn-
uncommon causes for cystitis and for malakoplakia. drome, but urothelial malignancies are unlikely to produce
this finding; renal cell carcinoma is a more likely cause.
PBD9 963 BP9 668 PBD8 975–976 Schistosomiasis leads to chronic inflammation and scarring.
Bladder outlet obstruction can increase the risk of infection,
6 B Local resection may suffice for lower grade urothelial typically with bacterial organisms such as Escherichia coli,
carcinomas that are minimally invasive and localized. The not Mycobacterium tuberculosis.
risk for recurrence may be reduced with BCG installation into
the bladder. Once the muscular wall is invaded, radical cys- PBD9 969, 982 BP9 668 PBD8 981 BP8 571–573
tectomy is needed. Chemical carcinogens such as aniline dyes
increase the risk for developing urothelial carcinoma, but 1 0 A She has a urethral caruncle, which is most common in
do not dictate therapy. An inverted urothelial papilloma is postmenopausal women as a result of urethral prolapse with
benign, but a papillary urothelial neoplasm of low malignant atrophy from decreased estrogen. Topical estrogen creams
potential (PUNLAP) is a precursor to urothelial carcinomas, and anti-inflammatory agents may shrink the lesion. It is not
which can have TP53 mutations regardless of stage. an infectious process, so multinucleated cells (herpes sim-
plex virus) or plasma cell infiltrates (syphilis) are unlikely. It
PBD9 964–967 BP9 669–671 PBD8 976–979 BP8 576 is not malignant or premalignant. Lichen sclerosus occurs at
this age, but not produce a mass lesion.
7 E Urothelial carcinoma in situ is shown in the figure.
Smokers are at increased risk, and China has a third of the PBD9 969 BP9 668 PBD8 981
world’s smokers. Urothelial malignancies can be recurrent
and multifocal; they are far more likely to be sporadic than 11 E Carcinoma of the urethra is uncommon. It tends to
familial, although gene mutations such those in TP53 may be occur in older women and is locally aggressive. A clear cell
the same. Familial malignancies often present much earlier carcinoma occurs on the cervix and may be related to in utero
in life. The embryologic allantois extends from the develop- exposure to diethylstilbestrol. An embryonal rhabdomyo-
ing bladder and may persist as a urachal remnant forming sarcoma (sarcoma botryoides) is a rare tumor that occurs in
a diverticulum, cyst, or fistula to the umbilicus, and there children. Benign tumors, such as a leiomyoma, are typically
3 4 0 U N I T I I Diseases of Organ Systems
well circumscribed and do not ulcerate. Condyloma lata infiltrate. Circumcision generally reduces risks for infec-
may appear in association with secondary syphilis, but are tions. Phimosis is a nonretractile prepuce, and paraphimosis
flat and typically do not ulcerate. Condyloma accuminata are refers to forcible retraction of the prepuce that produces pain
papillary lesions with acanthosis, related to HPV infection, and urinary obstruction.
and usually do not ulcerate.
PBD9 970–971 BP9 678 PBD8 982–983 BP8 709
PBD9 969 BP9 668 PBD8 982 BP8 575–577
16 D Penile squamous carcinomas such as this large ulcer-
1 2 D Hypospadias is a congenital condition seen in about ated mass are likely invasive, and this lowers the 5-year sur-
1 in 300 male infants. The inguinal hernia and the cryptorchi- vival to less than 70%; if there is nodal involvement, 5-year
dism are abnormalities that may accompany this condition. survival is less than 30%. Prior phimosis and human papil-
Epispadias is a congenital condition in which the urethra lomavirus infection, more likely in uncircumcised men, are
opens abnormally on the dorsal aspect of the penis. Bowen risk factors. Candidiasis is not a risk factor. Angiokeratomas
disease, which is squamous cell carcinoma in situ of the appear as localized, benign, red or blue papules. Urothelium
penis, occurs in adults. Phimosis is a constriction preventing extends to the urethral orifice and development of urothelial
retraction of the prepuce. It can be congenital, but more likely carcinoma is theoretically possible at this site, but is far less
is the result of inflammation of the foreskin of the penis (e.g., common than squamous carcinomas. Adenocarcinomas are
balanitis, a form of local inflammation of the glans penis). rare at this site.
PBD9 970 BP9 658 PBD8 982 BP8 687–688 PBD9 971–972 BP9 657–658 PBD8 983–984 BP8 688–689
13 E Phimosis can be congenital, but is more often a con- 1 7 B Bowen disease is the in situ form of squamous cell
sequence of multiple episodes of balanitis (inflammation carcinoma of the penis. Similar to carcinoma in situ else-
of the glans penis or foreskin). Balanitis leads to scarring where, it has a natural history of progression to invasive
that prevents retraction of the foreskin. Forcible retraction cancer if untreated. Poor hygiene and infection with human
may result in vascular compromise, with further inflamma- papillomavirus (particularly types 16 and 18) are factors that
tion and swelling (paraphimosis). Bowenoid papulosis is a favor development of dysplasias and cancer of the genital
premalignant lesion of the penile shaft resulting from viral epithelia. Balanitis is an inflammatory condition without
infection. Epispadias is a congenital condition in which the dysplasia. Condylomas are raised, whitish lesions. Syphilis
penile urethra opens onto the dorsal surface of the penis. is a sexually transmitted disease that produces a hard chan-
Candidiasis is most likely to produce shallow ulcerations cre, which heals in a matter of weeks. A soft chancre may be
that are intensely pruritic. seen with Haemophilus ducreyi infections.
PBD9 970 BP9 657 PBD8 982 BP8 688 PBD9 971 BP9 658 PBD8 983–984 BP8 688–689
14 B Genital candidiasis can occur in individuals without 18 A Cryptorchidism results from failure of the testis to
underlying illnesses, but it is far more common in individu- descend from the abdominal cavity into the scrotum during
als with diabetes mellitus. Warm, moist conditions at these fetal development. One or both testes may be involved. It
sites favor fungal growth. Scabies mites are more likely to is associated with an increased risk of testicular cancer. An
be found in linear burrows in epidermis scraped from the undescended testis eventually atrophies during childhood.
extremities. Neoplasms with atypical cells may ulcerate, but Unilateral cryptorchidism may lead to infertility, because
such lesions are unlikely to be shallow or multiple without it may be associated with atrophy of the contralateral
a mass lesion present. Intranuclear inclusions suggest a viral descended testis. Isolated cryptorchidism is a developmen-
infection; however, diabetes is not a risk factor for genital tal defect that is usually sporadic and is not inherited in the
viral infections. These lesions are too large and numerous to germline. Mumps infection tends to produce patchy bilateral
be syphilitic chancres. testicular atrophy, usually without infertility.
PBD9 970 BP9 657 PBD8 982 BP8 688 PBD9 972–973 BP9 658–659 PBD8 984–984 BP8 689–690
1 5 C Condyloma acuminatum is a benign, recurrent 1 9 A This is acute epididymitis/orchitis, and most of
squamous epithelial proliferation resulting from infection these infections are secondary to ascending infections from
with human papillomavirus (HPV) infection, one of many the urinary tract. The time course suggests bacterial infec-
sexually transmitted diseases that can occur in sexually tion. Human papillomavirus affects squamous epithelium.
active individuals. Koilocytosis is particularly character- Mumps orchitis is likely to be bilateral, and not associated
istic of HPV infection. Candidiasis can be associated with with urinary tract infection. Tuberculosis can produce tes-
inflammation, such as balanoposthitis, but not condylomata. ticular infection, but the time course is likely to be weeks to
Recurrent gonococcal infection indicates that the patient is months, and with preceding respiratory disease. Syphilis
sexually active and at risk for additional infections, but is not can lead to orchitis, but is unlikely to be preceded by urinary
the cause for the condylomata. Gonococcal infection causes tract infection.
suppurative lesions in which there may be liquefactive
necrosis and a neutrophilic exudate or mixed inflammatory PBD9 973–974 BP9 658 PBD8 986 BP8 690
C H A P T E R 2 1 The Lower Urinary Tract and Male Genital System 3 4 1
2 0 D Mumps is a common childhood infection that can tend not to be antecedents for neoplasia. Hydrocele is a
produce orchitis as well as parotitis. Adults who have benign fluid collection.
this infection more often develop orchitis. The orchitis in
children is usually not severe, and its involvement of the PBD9 975–976 BP9 659 PBD8 988 BP8 690
testis is patchy or unilateral so that infertility is not a com-
mon outcome. Mumps orchitis may be more severe in 2 4 C Seminoma is the most common form of “pure” tes-
adults. Cryptorchidism results from failure of the testis to ticular germ cell tumor that may remain confined to the testis
descend into the scrotum normally; the abnormally posi- (stage I). The figure shows a homogenous mass lesion. The
tioned testis becomes atrophic throughout. A hydrocele is prognosis is good in most cases, even with metastases, because
a fluid collection outside the body of the testis that does seminomas are radiosensitive. Human chorionic gonadotropin
not interfere with spermatogenesis. Klinefelter syndrome (hCG) levels may be slightly elevated in about 15% of patients
and estrogen therapy can cause tubular atrophy, although with seminoma. Elevated hCG levels suggest a component
it is generalized in both cases. Patchy loss of seminiferous of syncytial cells; very high levels suggest choriocarcinoma.
tubules indicates a local inflammatory process. Radiation α-Fetoprotein levels are elevated in testicular tumors with a
as well as many chemotherapeutic agents are particularly yolk sac component, and many tumors with an embryonal cell
harmful to rapidly and continuously proliferating testicu- component also contain yolk sac cells. Testosterone is a prod-
lar germ cells, but the effect would be diffuse within the uct of Leydig cells, not germ cells. Fragile X syndrome is asso-
testicular parenchyma. Radiotherapy is typically targeted ciated with bilaterally enlarged testes and mental retardation.
to malignancies to prevent damage to normal surrounding Klinefelter syndrome is associated with bilaterally decreased
tissues. Patients who wish to father children may want to testicular size and reduced fertility.
store sperm in a sperm bank before undergoing radiation
or chemotherapy. PBD9 976–977 BP9 660–663 PBD8 988–989 BP8 690–695
PBD9 972–973 BP9 659 PBD8 986 BP8 690 2 5 D Leydig cell tumors of the testis are most often small,
benign masses that may go unnoticed. Some patients have
2 1 D The markedly hemorrhagic appearance in the figure gynecomastia caused by androgenic or estrogenic hormone
results from testicular torsion that obstructs venous outflow to production (or both) by the tumor. Most patients are young
a greater extent than the arterial supply. Doppler ultrasound to middle-aged men; sexual precocity may occur in the few
shows reduced or no vascular flow in the affected testis. An boys who have such tumors. Choriocarcinomas are grossly
abnormally positioned or anchored testis in the scrotum is soft and hemorrhagic masses that have large bizarre syncy-
a risk factor for this condition. Testicular carcinomas do not tiotrophoblast and cytotrophoblast cells and are aggressive.
obstruct the blood flow, and are not likely to produce an acute Embryonal carcinomas are large, aggressive tumors that
event. Parasitic infestation, typically filariasis, obstructs the have a variegated gross appearance and primitive cells with
flow of lymph, leading to gradual enlargement of the scrotum large, hyperchromatic nuclei. Gonadoblastomas are rare tes-
with thickening of the overlying skin. Tuberculosis can spread ticular tumors that arise in the setting of gonadal dysgenesis.
from the lung through the bloodstream, producing miliary A pure seminoma can be uniformly brown on cut surface,
tuberculosis, seen as multiple pale, millet-sized lesions, most but often has a lymphoid stroma, and is not likely to secrete
often involving the epididymis. A previous vasectomy may androgens or estrogens. Pure teratomas are rare and contain
lead to a small leakage of fluid and sperm, producing a local- elements of three germ layers. Yolk sac tumors have cells
ized sperm granuloma. that organize into primitive endodermal sinuses (Schiller-
Duval bodies).
PBD9 974–975 BP9 659 PBD8 987
PBD9 980 BP9 659 PBD8 982–983 BP8 690
22 E Tuberculosis with mycobacterial infection is uncom-
mon in the testes, but it can occur with disseminated disease. 2 6 E Although a modest elevation of the human chori-
The infection typically starts in the epididymis and spreads onic gonadotropin (hCG) concentration can occur when a
to the body of the testis. Chancroid caused by Haemophilus seminoma contains some syncytial giant cells, significant
ducreyi leads to ulcerated nodules of the external genitalia. elevation of the α-fetoprotein (AFP) level never occurs
Mumps produces patchy orchitis with minimal inflamma- with pure seminomas. Elevated levels of AFP and hCG
tion, which heals with patchy fibrosis. Syphilis involves the effectively exclude the diagnosis of a pure seminoma and
body of the testis, and there can be gummatous inflamma- indicate the presence of a nonseminomatous tumor of the
tion with neutrophils, necrosis, and some mononuclear cells. mixed type. The most common form of testicular neoplasm
Gonococcal infections produce acute inflammation. combines multiple elements; the term teratocarcinoma is
sometimes used to describe tumors with elements of tera-
PBD9 974 BP9 659 PBD8 986 BP8 690 toma, embryonal carcinoma, and yolk sac tumor. The yolk
sac element explains the high AFP level. Mixed tumors may
23 A Mutations involving SRY or other genes involved in include seminoma. Choriocarcinomas secrete high levels
testicular differentiation may increase the risk for testicular of hCG, but no AFP. It is unusual for a tumor to metasta-
cancer. Another risk factor is cryptorchidism. Infections of size to the testis; this patient is of an age at which a primary
the testis are not generally known to be associated with neo- cancer of the testis should be considered when a testicular
plasia. Mechanical problems, such as torsion with ischemia, mass is present. Lymphomas may involve the testis, usually
3 4 2 U N I T I I Diseases of Organ Systems
when there is systemic involvement by a high-grade lesion. differentiation of the glandular epithelium are not mark-
Prostatic adenocarcinoma and lymphomas do not elaborate ers of malignancy. On examining more histologic sections
hormones. Leydig cell tumors are non–germ cell tumors from the mass, the pathologist would find the malignant
derived from the interstitial (Leydig) cells; they may elabo- elements.
rate androgens.
PBD9 978–979 BP9 660–663 PBD8 990–991 BP8 690–695
PBD9 979 BP9 660–663 PBD8 992 BP8 690–695
31 B Hydrocele is one of the most common causes of scro-
27 F α-Fetoprotein (AFP) is a product of yolk sac cells that tal enlargement. It consists of a serous fluid collection within
can be shown by immunohistochemical testing. Pure yolk sac the tunica vaginalis. Most cases are idiopathic, although
tumors are rare in adults, but yolk sac components are com- some may result from local inflammation. Elephantiasis is
mon in mixed nonseminomatous tumors. Cytotrophoblasts a complication of parasitic filarial infections involving the
do not produce a serum marker, but they may be present in inguinal lymphatics; it is typically bilateral. Orchitis involves
a choriocarcinoma along with syncytiotrophoblasts, which do the body of the testis without marked enlargement, but with
produce human chorionic gonadotropin. Embryonal carci- tenderness. A seminoma is typically a firm unilateral mass.
noma cells by themselves do not produce any specific marker. A varicocele is a collection of dilated veins (pampiniform
Embryonal carcinoma cells are common in nonseminomatous plexus) that may produce increased warmth, which inhibits
tumors, however, and are often mixed with other cell types. spermatogenesis.
Leydig cells produce androgens. Lymphoblasts may be seen in
high-grade non-Hodgkin lymphomas, which do not produce PBD9 980 BP9 658 PBD8 993 BP8 689
hormones. Pure seminomas do not produce AFP.
32 B The patient has more than 10 leukocytes per high-
PBD9 977–979 BP9 660–663 PBD8 989–990 BP8 690–695 power field, indicating prostatitis. Chronic abacterial pros-
tatitis is the most common form of the disorder. Patients
2 8 D Choriocarcinoma is the most aggressive testicular typically do not have a history of recurrent urinary tract
carcinoma. It often metastasizes widely. The primitive syn- infections. Patients with acute bacterial prostatitis, most
cytial cells mimic the syncytiotrophoblast of placental tissue often caused by Escherichia coli infection, have fever, chills,
and stain for human chorionic gonadotropin. α-Fetoprotein and dysuria; on rectal examination, the prostate is very ten-
is a marker that is more likely to be found in mixed tumors der. Prostate carcinomas generally do not have a significant
with a yolk sac component. Carcinoembryonic antigen (CEA) amount of acute inflammation, and metastases are most
is found in a variety of epithelial neoplasms, particularly ade- often associated with pain; most prostatic conditions causing
nocarcinomas. CD20 is a lymphoid marker for B cells. Testos- dysuria are benign. Nodular prostatic hyperplasia by itself
terone is found in Leydig cells. Vimentin is more likely to be is not an inflammatory process. Syphilis is a disease of the
seen in sarcomas, which are rare in the testicular region. external genitalia, although the testis may be involved.
PBD9 978 BP9 660–663 PBD8 990 BP8 690–695 PBD9 981–982 BP9 663–664 PBD8 993–994 BP8 695–696
29 E Yolk sac tumors are typically seen in boys younger 33 B Of the diseases listed, prostatic nodular hyperplasia
than 3 years. The primitive glomeruloid structures are is the most common in older men. When it causes obstruc-
known as Schiller-Duval bodies. The cells are strongly positive tion of the prostatic urethra, it can predispose to bacterial
for AFP. Embryonal carcinomas with yolk sac cells contain urinary tract infections. Epispadias is a congenital condition,
AFP, but they are seen in adults. They are composed of cords observed at birth. Phimosis can occur in uncircumcised men.
and sheets of primitive cells. Choriocarcinomas contain It may be congenital or acquired from inflammation, usually
large, hyperchromatic, syncytiotrophoblastic cells. Semino- at a much younger age. Posterior urethral valves produce
mas have sheets and nests of cells resembling primitive germ bladder outlet obstruction in utero, with oligohydramnios.
cells, often with an intervening lymphoid stroma. Leydig cell Prostatic adenocarcinomas are less likely than hyperplasia to
tumors act in a benign fashion and may produce androgens cause obstructive symptoms. Vesicoureteral reflux is more
or estrogens or both. Teratomas contain elements of mature likely to be present at an earlier age, and it does not account
cartilage; bone; or other endodermal, mesodermal, or ecto- for the obstructive symptoms the patient has on urination.
dermal structures.
PBD9 982–984 BP9 664–665 PBD8 994–996 BP8 696–697
PBD9 977 BP9 660–663 PBD8 989–990 BP8 690–695
34 E Androgens are the major hormonal stimuli of glan-
30 B The tumor has elements of all three germ layers and dular and stromal proliferation resulting in nodular prostatic
is a teratoma. It is uncommon for teratomas in men to be hyperplasia. Although testosterone production decreases
completely benign. The most common additional histologic with age, prostatic hyperplasia increases, probably because
component is embryonal carcinoma. The elevated levels of of an increased expression of prostatic hormonal recep-
human chorionic gonadotropin and α-fetoprotein indicate tors that enhance the effect of any DHT that is present.
that this is a mixed tumor with elements of choriocarcinoma The 5α-reductase inhibitors, such as finasteride, diminish
and yolk sac cells. The size of the tumor, age of the patient, the prostate volume, specifically the glandular component,
location of the tumor (e.g., right, left, cryptorchid), and leading to improved urine flow. The α1-adrenergic receptor
C H A P T E R 2 1 The Lower Urinary Tract and Male Genital System 3 4 3
blockers, such as tamsulosin, cause smooth muscle in the tumors or spread of the disease inside or outside of the pri-
bladder neck and prostate to relax, which relieves symptoms mary organ site. Grading schemes also start with the lowest,
and improves urine flow immediately. The other listed con- most well-differentiated tumor, as seen with the microscope.
ditions are not amenable to therapy with these drugs. Higher grade tumors have increasingly abnormal-appearing
cells and structures so poorly differentiated that they hardly
PBD9 982–983 BP9 664–665 PBD8 994–995 BP8 696–698 resemble their site of origin. In this case, the prostate cancer
has the highest grade (it does not have glandular structures)
3 5 B The clinical features are typical of nodular prostatic and the highest stage (it has metastasized to the spine).
hyperplasia causing a slight elevation of the PSA level. A
PSA level that remains unchanged for 1 year, as in this case, PBD9 987–989 BP9 665–667 PBD8 997–1000 BP8 698–700
is less likely to be found with a prostate cancer. Finasteride
is a 5α-reductase inhibitor that decreases formation of dihy- 3 8 A Prostatic intraepithelial neoplasia (PIN) shown
drotestosterone (DHT) that binds to androgen receptors in here has dysplastic features including hyperchromatic
prostatic stromal and epithelial cells, driving proliferation cells crowded into a pseudo-multilayer appearance, with
with prostate gland enlargement. However, α1-adrenergic preservation of gland architecture. PIN is a potential pre-
blockers that diminish smooth muscle tone are somewhat cursor of prostatic adenocarcinoma. By itself, it does not
more effective in treating nodular hyperplasia. Estrogen warrant therapy because only about one third of patients
therapy has been used as antihormonal therapy in pros- diagnosed with PIN develop invasive cancer within 10
tate cancer. Mitoxantrone is a chemotherapy agent that, years. Conversely, in about 80% of cases in which prostate
when given with prednisone, has been shown to be effec- cancer is present, PIN can be found in the surrounding tis-
tive in treating advanced prostate cancers. Nitrofurantoin sue. PIN usually does not increase the PSA levels. In this
is an antibiotic that is often used in treating urinary tract case, the elevation in PSA levels may have been caused
infections. in part by the coexistent hyperplasia. Although prostati-
tis may increase PSA levels, no inflammation is seen here.
PBD9 982–983 BP9 664–665 PBD8 994–996 BP8 696–698 Although PIN can be found in the peripheral zone, it is not
a normal finding. Although there is a family history, spe-
3 6 B The prostate-specific antigen (PSA) level is signifi- cific risk factors are difficult to identify; BRCA2 mutations
cantly elevated in this patient. The large increase is likely to account for a small number of prostate cancers. Prostatic
be indicative of carcinoma. Typically, prostatic carcinomas hyperplasia may respond to inhibition of DHT synthesis,
are adenocarcinomas that form small glands packed back to but not PIN or cancer.
back. Many adenocarcinomas of the prostate do not produce
obstructive symptoms and may not be palpable on digital PBD9 985–986 BP9 666 PBD8 999 BP8 699
rectal examination. Inflammation and nodular hyperplasias
can increase the PSA level, although not to a high level that 3 9 A The figure shows prostatic adenocarcinoma with
increases significantly over time. Prostatic intraepithelial back-to-back glands, prominent nucleoli, and perineural
neoplasia, although an antecedent to adenocarcinoma, is not invasion. Alterations of the glutathione S-transferase (GSTP1)
likely to increase the PSA significantly over time. gene allow damage from carcinogens. TMPRSS2-ETS fusion
gene and PTEN mutations are common. Other genetic abnor-
PBD9 988–989 BP9 667 PBD8 1001–1002 BP8 698–700 malities in prostate cancer include variations in CAG repeats
in the androgen receptor gene, BRCA2 mutations, and trans-
3 7 E The presence of a hard irregular nodule, along with location of ETS family transcription genes. His prostate-
the extremely high prostate-specific antigen (PSA) level, specific antigen (PSA) level is four times the upper limit of
points most clearly to prostate carcinoma. Modest elevations normal. This is worrisome, but not an absolute indication of
of the PSA concentration can occur in nodular hyperplasia prostate cancer. Elevated PSA levels can occur with nodu-
of the prostate and prostatitis. Symptoms of urinary obstruc- lar hyperplasia or prostatitis. A higher level, a level that
tion are more prominent in nodular hyperplasia because the increases over time, or an increased free PSA is more sug-
nodules are in the periurethral region; but this sign is insuffi- gestive of carcinoma. Naphthylamine compounds are linked
cient to distinguish cancer from hyperplasia. Similarly, renal to urothelial carcinomas. Increased dihydrotestosterone out-
failure owing to obstruction or infiltration is most common put from prostatic stromal cells drives nodular hyperplasia.
with nodular hyperplasia, but can occur with cancer as well. Tobacco use is associated with many other cancers, includ-
Levels of alkaline phosphatase are elevated when prostate ing urothelial carcinoma and renal cell carcinoma. Recurrent
carcinoma gives rise to osteoblastic metastases. Although urinary tract infections and hydronephrosis are complica-
staging and grading schemes for malignant disease seem tions of obstruction more commonly from nodular prostatic
daunting, they are applied intuitively. The lowest stage is the hyperplasia.
smallest, most localized tumor; higher stages represent larger
PBD9 984–988 BP9 665–667 PBD8 1001–1002 BP8 698–700
22C H A P T E R
Female Genital Tract
PBD9 Chapter 22 and PBD8 Chapter 22: The Female Genital Tract
BP9 Chapter 18 and BP8 Chapter 19: Female Genital System and Breast
1 A 31-year-old, sexually active woman has had a muco- 4 A 25-year-old woman has experienced discomfort dur-
purulent vaginal discharge for 1 week. On pelvic examination, ing sexual intercourse for the past month. On physical exami-
the cervix appears reddened around the os, but no erosions or nation, there are no lesions of the external genitalia. Pelvic
mass lesions are present. A Pap smear shows numerous neu- examination shows a focal area of swelling on the left postero-
trophils, but no dysplastic cells. A cervical biopsy specimen lateral inner labium that is very tender on palpation. A 3-cm
shows marked follicular cervicitis. Which of the following in- cystic lesion filled with purulent exudate is excised. In which of
fectious agents is most likely to produce these findings? the following structures is this lesion most likely to develop?
A Candida albicans A Bartholin gland
B Chlamydia trachomatis B Gartner duct
C Gardnerella vaginalis C Hair follicle
D Herpes simplex virus D Urogenital diaphragm
E Human papillomavirus E Vestibular bulb
F Neisseria gonorrhoeae
G Trichomonas vaginalis 5 A 53-year-old postmenopausal woman is concerned
about pale areas on her labia that have been slowly enlarging
2 A 31-year-old woman has had vulvar pruritus along for the past year. The areas cause discomfort and become easily
with a thick, whitish, odorless, globular vaginal discharge for irritated. Physical examination shows pale gray to parchment-
the past week. On pelvic examination, the cervix appears ery- like areas of skin that involve most of the labia majora, labia
thematous, but there are no erosions or masses. A Pap smear minora, and introitus. The introitus is narrowed. A biopsy
shows budding cells and pseudohyphae. No dysplastic cells specimen is taken and microscopically shows thinning of the
are present. Which of the following infectious agents is most squamous epithelium, a dense band of upper dermal hyaline
likely to produce these findings? collagen, and scattered upper dermal mononuclear inflamma-
A Candida albicans tory cells. What is the most likely diagnosis?
B Chlamydia trachomatis A Extramammary Paget disease
C Neisseria gonorrhoeae B Human papillomavirus infection
D Trichomonas vaginalis C Lichen sclerosus et atrophicus
E Ureaplasma urealyticum D Pelvic inflammatory disease
E Vulvar intraepithelial neoplasia
3 A 17-year-old sexually active girl has had pelvic pain for
1 week. A pelvic examination shows mild erythema of the ec- 6 A 40-year-old woman has noted pruritic patches on her
tocervix and pain on palpation of right adnexa. A Pap smear vulva for the past 4 months. On physical examination there are
shows many neutrophils, but no dysplastic cells. A cervical multiple 1.5- to 3-cm white, scaly plaques on the vulva. A bi-
culture grows Neisseria gonorrhoeae. If the infection is not ad- opsy of one lesion is taken, and on microscopic examination, it
equately treated, she will be at increased risk for which of the shows epidermal thickening with hyperkeratosis and intense
following complications? dermal inflammation. Mitoses are seen in keratinocytes, but
A Cervical carcinoma they exhibit no atypia. What is the most likely diagnosis?
B Dysfunctional uterine bleeding A Condyloma acuminatum
C Ectopic pregnancy B Contact dermatitis
D Endometrial hyperplasia C Psoriasis
E Endometriosis D Squamous cell hyperplasia
F Placenta previa E Vulvar intraepithelial neoplasia
344
C H A P T E R 2 2 Female Genital Tract 3 4 5
7 A 36-year-old sexually active woman has noticed that 10 An 18-year-old sexually active woman has had dyspa-
warty vulvar lesions have been increasing in size and num- reunia followed by vaginal bleeding for the past month. On
ber over the past 5 years. On physical examination, there are pelvic examination, a red, friable, 2.5-cm nodular mass is seen
multiple 0.5- to 2-cm, red-pink, flattened lesions with rough on the anterior wall of the upper third of the vagina. The mi-
surfaces present on the vulva and perineum. One of the larger croscopic appearance of a biopsy specimen is shown in the
lesions is excised; its microscopic appearance is shown in the figure. Which of the following conditions is likely to have con-
figure. Which of the following infectious agents is most likely tributed most to the origin of this neoplasm?
to produce these lesions? A Congenital adrenal hyperplasia
A Candida albicans B Diethylstilbestrol (DES) exposure
B Chlamydia trachomatis C Human papillomavirus infection
C Haemophilus ducreyi D Polycystic ovary syndrome (PCOS)
D Human papillomavirus E Trichomonas vaginitis
E Treponema pallidum
11 A 4-year-old girl is brought to the physician by her par-
8 A 57-year-old woman recently noticed a pale area of dis- ents, who noticed bloodstained underwear and “something”
coloration on the labia. Pelvic examination shows the presence protruding from her external genitalia. On physical examina-
of a 0.7-cm flat, white area on the right labia majora. A biopsy tion, there are polypoid, grapelike masses projecting from the
specimen is obtained and on microscopic examination shows vagina. Histologic examination of a biopsy specimen from the
dysplastic cells that occupy half the thickness of the squamous lesion shows small, round tumor cells, some of which have eo-
epithelium, with minimal underlying chronic inflammation. sinophilic straplike cytoplasm. Immunohistochemical staining
In situ hybridization shows human papillomavirus type 16 shows desmin, vimentin, and myogenin in these cells. What is
DNA in the epithelial cells. What is the most likely diagnosis? the most likely diagnosis?
A Chronic vulvitis A Clear cell carcinoma
B Condyloma acuminatum B Infiltrating squamous cell carcinoma
C Lichen sclerosus et atrophicus C Neuroblastoma
D Squamous hyperplasia D Sarcoma botryoides
E Vulvar intraepithelial neoplasia E Vulvar intraepithelial neoplasia
12 A healthy 30-year-old woman comes to the physician for
9 A 52-year-old woman has noted increasing size of a red, a routine health maintenance examination. No abnormalities
pruritic lesion on her left labium over the past 7 months. On are found on physical examination. A screening Pap smear
physical examination, this rough, scaly lesion is 0.4 × 0.9 cm. shows cells consistent with a low-grade squamous intraepithe-
The perineum appears normal; there is no lymphadenopa- lial lesion (LSIL). Subsequent cervical biopsy specimens con-
thy, and there are no rectal lesions. A Pap smear shows no firm the presence of cervical intraepithelial neoplasia (CIN) I.
abnormal findings. The lesion is excised and on microscopic Which of the following risk factors is most likely related to her
examination shows large atypical cells lying singly or in small Pap smear findings?
clusters within the epidermis. These cells have abundant cyto- A Diethylstilbestrol (DES) exposure
plasm that stains with periodic acid–Schiff (PAS). What is the B Multiple sexual partners
most likely diagnosis? C Oral contraceptive use
A Condylomata acuminata D Prior treatment for a malignancy
B Extramammary Paget disease E Vitamin B12 (cobalamin) deficiency
C Lichen sclerosus et atrophicus
D Lichen simplex chronicus
E Vulvar intraepithelial neoplasia
3 4 6 U N I T I I Diseases of Organ Systems 16 A 34-year-old woman has a routine Pap smear for the
first time. The results indicate that dysplastic cells are present,
13 A 33-year-old woman comes to her nurse practitioner consistent with a high-grade squamous intraepithelial lesion
for a routine health maintenance examination. On physical (HSIL), also called cervical intraepithelial neoplasia (CIN) III. She
examination, there are no abnormal findings. A Pap smear is referred to a gynecologist, who performs colposcopy and
shows abnormalities; colposcopy and a biopsy are performed. takes multiple cervical biopsy specimens that all show CIN III.
The figure shows the microscopic appearance of the biopsy Conization of the cervix shows a focus of microinvasion at the
specimen. Which of the following is the best strategy to pre- squamocolumnar junction. Based on these findings, what is
vent the development of this lesion? the next most likely step in treating this patient?
A Avoidance of tobacco products A Bone scan for metastatic lesions
B Consumption of a diet rich in vegetables B Course of radiation therapy
C Maintenance of an ideal body weight C No further therapy
D Use of oral contraceptives D Pelvic exenteration
E Vaccination for human papillomavirus E Vaginal hysterectomy
14 A 42-year-old woman has a Pap smear as part of a rou-
tine health maintenance examination. There are no remarkable
findings on physical examination. The Pap smear shows cells 17 A 45-year-old woman has had a small amount of vaginal
consistent with a high-grade squamous intraepithelial lesion bleeding and a brownish, foul-smelling discharge for the past
(HSIL) with human papillomavirus type 18. Cervical biopsy month. On pelvic examination, there is a 3-cm lesion on the
specimens are obtained, and microscopic examination con- ectocervix, shown in the figure. Microscopic examination of
firms the presence of extensive moderate dysplasia (CIN II) the lesion is most likely to show which of the following?
along with intense chronic inflammation with squamous A Adenocarcinoma
metaplasia in the endocervical canal. What is the most likely B Cervical intraepithelial neoplasia
explanation for proceeding with cervical conization for this C Chronic cervicitis
patient? D Clear cell carcinoma
A Her reproductive years are over E Extramammary Paget disease
B HPV infection cannot be treated F Squamous cell carcinoma
C Perimenopausal state
D Presence of chronic cervicitis
E Risk for invasive carcinoma
15 A 28-year-old sexually active woman comes to her phy-
sician’s assistant for a routine health maintenance examina-
tion. There are no abnormal findings on physical examination.
She has been taking oral contraceptives for the past 10 years.
A Pap smear shows a high-grade squamous epithelial lesion
(HSIL), also termed moderate dysplasia, or cervical intraepit helial
neoplasia (CIN) II. What is the most likely molecular pathogen-
esis for this finding?
A Estrogenic stimulation of cell proliferation
B Inheritance of a tumor suppressor gene mutation
C Recurrent gonococcal cervicitis
D Up-regulation of antiapoptosis genes
E Viral inactivation of the RB1 gene product
18 A 43-year-old woman has had postcoital bleeding for 6 C H A P T E R 2 2 Female Genital Tract 3 4 7
months. She experienced menarche at age 11 years and has 22 A 36-year-old woman has had menorrhagia and pelvic
had 12 sexual partners during her life. She continues to have pain for six months. She had a normal, uncomplicated preg-
regular menstrual cycles without abnormal intermenstrual nancy 10 years ago but has failed to conceive since then. She
bleeding. Pelvic examination shows a focal, slightly raised has been sexually active with one partner for the past 20 years
area of erythema on the cervix at the 5 o’clock position. A Pap and has had no dyspareunia. On pelvic examination she has a
smear shows a high-grade squamous intraepithelial lesion symmetrically enlarged uterus, with no apparent nodularity
(HSIL), also termed severe cervical intraepithelial neoplasia (CIN or palpable mass. A serum pregnancy test result is negative.
III). Analysis of cells from the cervix shows the presence of What is the most likely diagnosis?
human papillomavirus type 16. Which of the following malig- A Adenomyosis
nancies is she at greatest risk of developing if the lesion is not B Chronic endometritis
treated? C Endometrial hyperplasia
A Clear cell carcinoma D Endometriosis
B Immature teratoma E Leiomyoma
C Krukenberg tumor 23 A 32-year-old woman has cyclic abdominal pain that co-
D Leiomyosarcoma incides with her menses. Attempts to become pregnant have
E Sarcoma botryoides failed over the past 5 years. There are no abnormal findings
F Squamous cell carcinoma on physical examination. Laparoscopic examination shows
numerous hemorrhagic 0.2- to 0.5-cm lesions over the perito-
19 A 13-year-old girl began menstruation 1 year ago. She neal surfaces of the uterus and ovaries. Which of the follow-
now has abnormal uterine bleeding, with menstrual periods ing ovarian lesions is most likely to be associated with her
that are 2 to 7 days long and 2 to 6 weeks apart. The amount findings?
of bleeding varies from minimal spotting to a very heavy flow. A Fibroma
On physical examination, there are no remarkable findings. A B Brenner tumor
pelvic ultrasound scan shows no abnormalities. Which of the C Endometriotic cyst
following is most likely to produce these findings? D Krukenberg tumor
A Anovulatory cycles E Metastatic choriocarcinoma
B Ectopic pregnancy F Mucinous cystadenocarcinoma
C Endometrial carcinoma
D Endometrial polyp
E Uterine leiomyomata 24 A 49-year-old perimenopausal woman has had meno-
metrorrhagia for the past 3 months. On physical examination,
20 A 41-year-old G5, P5 woman has noticed lower abdomi- there are no remarkable findings. The microscopic appearance
nal pain with fever for the past 2 days. She delivered a normal of an endometrial biopsy specimen is shown in the figure. The
term infant 1 week ago. On examination, she has a temper- patient undergoes a dilation and curettage, and the bleeding
ature of 37.4° C. There is a foul-smelling vaginal discharge. stops, with no further problems. What condition is most likely
Which of the following pathologic findings is she most likely to produce these findings?
to have? A Chronic endometritis
A Cervical intraepithelial neoplasia B Ovarian mature cystic teratoma
B Endometrial neutrophilic infiltrates C Pregnancy with missed abortion
C Myometrial smooth muscle neoplasm D Repeated failure of ovulation
D Ovarian endometrioma E Use of oral contraceptives
E Tubal granulomatous inflammation
F Vaginal trichomoniasis
21 A 35-year-old woman presents with infertility. She has
had dysmenorrhea, dyspareunia, and pelvic pain on defeca-
tion for 4 years. Laparoscopic examination reveals red-blue
nodules on the surface of the uterus and extensive adhesions
between ovaries and the fallopian tubes. Histologic examina-
tion of a biopsy from one of the nodules shows hyperplastic
endometrial glands and hemorrhage in the stroma. Molecular
analysis of the biopsy material reveals hypomethylation of the
promoter regions of the genes that encode steroidogenic factor
1 and estrogen receptor beta. There are no mutations in the
PTEN, KRAS, and MLH1 genes. Which of the following is an
appropriate treatment modality in this case?
A Aromatase inhibitors
B Chemotherapy
C Estrogen
D Antitubercular therapy
E Total abdominal hysterectomy
3 4 8 U N I T I I Diseases of Organ Systems 29 A 62-year-old obese, nulliparous woman has an episode
of vaginal bleeding, which produces only 5 mL of blood. On
25 A 52-year-old perimenopausal woman has had vaginal pelvic examination, there is no enlargement of the uterus, and
bleeding for a week. She has no medical problems and takes the cervix appears normal. A Pap smear shows cells consistent
no medications. Hysteroscopy is performed and there is a sin- with adenocarcinoma. Which of the following preexisting con-
gle, 2-cm, smooth, soft mass protruding into the endometrial ditions is most likely to have contributed to the development
cavity. Biopsies are taken. What is microscopic examination of of this malignancy?
this lesion most likely to show? A Adenomyosis
A Endocervical glands with squamous metaplasia B Chronic endometritis
B Endometrial glands resembling stratum basalis C Endometrial hyperplasia
C Papillae with marked cellular atypia D Human papillomavirus infection
D Smooth muscle cells in bundles E Use of oral contraceptives
E Tubular glands lined by clear cells with glycogen 30 A 40-year-old nulliparous woman has had menorrha-
gia for the past 6 months. On physical examination, her blood
26 A 42-year-old woman has had menometrorrhagia for the pressure is 154/93 mm Hg, there are no cervical lesions or
past 2 months. She has no history of prior irregular menstrual adnexal masses, and the uterus is normal in size. She is 155 cm
bleeding, and she has not yet reached menopause. On physi- (5 feet 1 inch) tall and weighs 74.5 kg (body mass index 38).
cal examination, there are no vaginal or cervical lesions, and A Pap smear shows atypical glandular cells of uncertain sig-
the uterus appears normal in size, but there is a right adnexal nificance. Hemoglobin A1c concentration is 9.8%. Endometrial
mass. An abdominal ultrasound scan shows the presence of biopsy shows complex hyperplasia with atypia; molecu-
a 7-cm solid right adnexal mass. Endometrial biopsy shows lar analysis detects loss of PTEN gene heterozygosity and
hyperplastic endometrium, but no cellular atypia. What is the enhanced AKT phosphorylation. Which of the following met-
most likely lesion that underlies her menstrual abnormalities? abolic pathways is most likely to be activated in this tumor?
A Corpus luteum cyst A Decreased glucose uptake
B Endometrioma B Decreased prostaglandin synthesis
C Granulosa-theca cell tumor C Increased aerobic glycolysis
D Mature cystic teratoma D Increased glycogen storage
E Metastasis E Increased oxidative phosphorylation
F Polycystic ovarian syndrome
27 A 62-year-old childless woman noticed a blood-tinged 31 A healthy 59-year-old woman has had a feeling of pelvic
vaginal discharge twice during the past month. Her last men- heaviness for the past 11 months. There is no history of abnor-
strual period was 10 years ago. Bimanual pelvic examination mal bleeding, and her last menstrual period was 8 years ago.
shows that the uterus is normal in size, with no palpable ad- Her physician palpates an enlarged nodular uterus on biman-
nexal masses. There are no cervical erosions or masses. Her ual pelvic examination. A Pap smear shows no abnormalities.
body mass index is 33. Her medical history indicates that for Pelvic CT scan shows multiple solid uterine masses; there is
the past 30 years she has had hypertension and type 2 diabe- no evidence of necrosis or hemorrhage. A total abdominal hys-
tes mellitus. An endometrial biopsy specimen is most likely to terectomy is performed. Based on the gross appearance of the
show which of the following? mass shown in the figure, what is the most likely diagnosis?
A Adenocarcinoma A Adenomyosis
B Choriocarcinoma B Endometriosis
C Leiomyosarcoma C Leiomyomas
D Malignant müllerian mixed tumor D Metastases
E Squamous cell carcinoma E Tuberculosis
28 A study of patients with postmenopausal uterine bleed-
ing reveals that some of them have malignant neoplasms
that arise from prior atypical hyperplastic lesions. The peak
incidence is between 55 and 65 years of age in women who
have obesity, hypertension, and/or diabetes mellitus. Molec-
ular analysis reveals mutations of the PTEN tumor suppres-
sor gene in most of them. Their malignancies tend to re main
localized for years before spreading to local lymphatics.
Which of the following neoplasms is most likely to have these
characteristics?
A Clear cell carcinoma
B Endometrioid carcinoma
C Leiomyosarcoma
D Müllerian mixed tumor
E Serous carcinoma
F Stromal sarcoma
32 A 53-year-old woman whose last menstrual period was C H A P T E R 2 2 Female Genital Tract 3 4 9
3 years ago notes vaginal bleeding for a week. On physical
examination, her uterus is markedly enlarged, but there are no 36 A 21-year-old woman experienced menarche at age 14
adnexal masses. CT imaging reveals an irregular 8-cm mass in years and had regular menstrual cycles for the next 3 years.
the body of the uterus. A total abdominal hysterectomy is per- For the past year, she has had oligomenorrhea and has de-
formed, and microscopic examination of the soft, hemorrhagic veloped hirsutism. She has noticed a 10-kg weight gain in the
mass shows spindle cells with atypia and numerous mitoses. past 4 months. On pelvic examination, there are no vaginal or
There is coagulative necrosis of tumor cells. Which of the fol- cervical lesions, the uterus is normal in size, and the adnexa
lowing is the most likely cell of origin for this mass? are prominent. A pelvic ultrasound scan shows that each ova-
A Cytotrophoblastic cells ry is twice normal size, whereas the uterus is normal in size.
B Endometrial glandular cells Magnetic resonance imaging is shown in the figure. Which of
C Germ cells the following conditions is most likely to be present in this
D Smooth muscle cells woman?
E Squamous epithelial cells A Immature teratomas
B Krukenberg tumors
33 A 69-year-old woman has passed blood per vagina for C Ovarian cystadenocarcinomas
a month. On pelvic examination no abnormal findings are D Polycystic ovarian syndrome
noted. Which of the following diagnostic procedures should E Tubo-ovarian abscesses
be performed next? 37 A 35-year-old woman has had increasing abdominal
A Endometrial biopsy enlargement for the past 6 months. She states that she feels
B Magnetic resonance imaging like she is pregnant, but results of a pregnancy test are nega-
C Microbiologic culture tive. On physical examination, there is abdominal distention
D Pap smear with a fluid wave. A pelvic ultrasound scan shows bilateral
E Pregnancy test cystic ovarian masses, 10 cm on the right and 7 cm on the left.
The masses are surgically removed. On gross examination,
34 A 28-year-old woman has had fever, pelvic pain, and a the excised masses are unilocular cysts filled with clear flu-
feeling of pelvic heaviness for the past week. Pelvic examina- id, and papillary projections extend into the central lumen of
tion shows a palpable painful left adnexal mass. Laparoscopy the cyst. Microscopic examination shows that the papillae are
shows an indistinct left fallopian tube that is part of a 5-cm covered with atypical cuboidal cells that invade underlying
circumscribed, red-tan mass involving the left adnexal region. stroma. Psammoma bodies are present. What is the most likely
Which of the following infectious agents is most likely to pro- diagnosis?
duce these findings? A Endometrioid tumor
A Chlamydia trachomatis B Cystadenocarcinoma
B Haemophilus ducreyi C Dysgerminoma
C Herpes simplex virus D Granulosa cell tumor
D Mycobacterium tuberculosis E Mature cystic teratoma
E Treponema pallidum F Sertoli-Leydig cell tumor
35 A 19-year-old woman has the sudden onset of abdomi-
nal pain. On physical examination, there is pelvic pain on pal-
pation. Her stool is negative for occult blood. The serum and
urine pregnancy tests are negative. Transvaginal ultrasound
shows no intrauterine gestational sac, and uterus and adnexa
are normal in size. Culdocentesis yields a small amount of
blood-tinged fluid. Which of the following has most likely led
to these findings?
A Ectopic pregnancy
B Endometriosis
C Follicle cyst
D Invasive mole
E Pelvic inflammatory disease
3 5 0 U N I T I I Diseases of Organ Systems
38 A 40-year-old woman has noticed progressive enlarge- 40 A 42-year-old woman has noted dull lower abdominal
ment of the abdomen over the past 5 months, although her pain for the past year. She reports no abnormal bleeding. On
diet has not changed, and she has been exercising more. Physi- physical examination there is a large left adnexal mass. The
cal examination shows no palpable masses, but a fluid wave pregnancy test is negative. Transvaginal ultrasound shows a
is present. Paracentesis yields 500 mL of slightly cloudy fluid. right adnexal 10-cm cystic mass filled with fluid. The mass is
Cytologic examination of the fluid shows malignant cells. An removed and has the microscopic appearance shown in the
abdominal ultrasound scan shows a 15-cm multilobular mass figure. Which of the following is most likely to be associated
that involves the right adnexal region. The uterus is normal with this lesion?
in size. The mass is surgically removed; the figure shows the A Brain metastases
gross features of a section of the excised mass. What is the B Endometrial hyperplasia
most likely diagnosis? C Masculinization
A Choriocarcinoma D Peritoneal implants
B Dysgerminoma E Sarcomatous transformation
C Granulosa cell tumor
D Mucinous cystadenocarcinoma
E Teratoma with malignant transformation 41 A 33-year-old woman has had dull, constant abdominal
pain for 6 months. On physical examination, the only finding
39 A 56-year-old woman has had weight loss accompanied is a right adnexal mass. CT scan of the pelvis shows a 7-cm
by abdominal enlargement for the past 5 months. There is a circumscribed cystic mass on the right ovary, and it contains
family history of breast and ovarian carcinoma. On physi- irregular calcifications. The right fallopian tube and ovary
cal examination, there are no lesions of the cervix, and the are surgically excised. The gross appearance of the ovary,
uterus is normal in size, but there is a left adnexal mass. An which has been opened, is shown in the figure. Microscopic
a bdominal ultrasound scan shows a 10-cm cystic mass in the examination of this lesion is most likely to show which of the
left adnexal region, with scattered 1-cm peritoneal nodules, following?
and ascites. Cytologic studies of peritoneal fluid show malig- A Mature squamous epithelium
nant cells. Which of the following mutated genes is most likely B Papillary structures with psammoma bodies
a factor in the development of this neoplasm? C Primitive neuroepithelium
A BRCA1 D Rhabdomyoblasts in a cellular stroma
B ERBB2 (HER2) E Sheets of trophoblasts and syncytial cells
C MYC
D KRAS
E RB1
42 A 23-year-old woman has had pelvic discomfort for 4 C H A P T E R 2 2 Female Genital Tract 3 5 1
months. On pelvic examination, there is a large, nontender,
right adnexal mass. An abdominal CT scan shows the 11-cm 46 A 36-year-old woman has had an uneventful preg-
mass to be solid and circumscribed. On surgical removal, the nancy for the past 37 weeks. Over the past 12 hours, she has
mass is solid and white, with small areas of necrosis. Micro- developed lower abdominal pain. On examination, there is
scopically, it contains mostly primitive mesenchymal cells suprapubic tenderness. Her temperature is 37.4° C. Pelvic ex-
along with some cartilage, muscle, and foci of neuroepithelial amination reveals a purulent cervical discharge. The infant is
differentiation. What is the most likely diagnosis? delivered 12 hours later. Which of the following organisms is
A Brenner tumor most likely responsible for her premature labor?
B Dysgerminoma A Group B streptococcus
C Granulosa cell tumor B Herpes simplex virus
D Immature teratoma C Rubella virus
E Leiomyosarcoma D Toxoplasma gondii
F Malignant müllerian mixed tumor E Treponema pallidum
43 A 52-year-old woman has had dull pain in the lower 47 A 22-year-old woman experiences sudden onset of severe
abdomen for the past 6 months and minimal vaginal bleed- lower abdominal pain. Physical examination shows no masses,
ing on three occasions. Her last menstrual period was 2 years but there is severe tenderness in the right lower quadrant. A
ago. Pelvic examination shows a right adnexal mass, and the pelvic examination shows no lesions of the cervix or vagina.
uterus appears normal in size. An abdominal ultrasound scan Bowel sounds are detected. An abdominal ultrasound scan
shows an 8-cm solid mass, a small amount of ascites, and a shows a 4-cm focal enlargement of the proximal right fallopian
right pleural effusion. A total abdominal hysterectomy is per- tube. A dilation and curettage procedure shows only decidua
formed, and the mass is determined to be an ovarian fibroth- from the endometrial cavity. Which of the following laboratory
ecoma. Which of the following additional lesions is most likely findings is most likely to be reported for this patient?
to be found in the excised specimen? A Cervical culture positive for Neisseria gonorrhoeae
A Bilateral chronic salpingitis B Detection of human chorionic gonadotropin in serum
B Cervical condylomata acuminata C 69,XXY karyotype on decidual tissue cells
C Endometrial hyperplasia D Pap smear showing pseudohyphae of Candida
D Metastases to the uterine serosa E Positive result of serologic testing for syphilis
E Partial mole of the uterus
48 A 36-year-old primigravida develops peripheral edema
44 A clinical study of women diagnosed with ovarian neo- late in the second trimester. On physical examination, her
plasms reveals that 1 in 200 develop masculinizing signs and blood pressure is 155/95 mm Hg. Urinalysis shows 2+ pro-
symptoms, including hirsutism, acne, breast atrophy, and amen- teinuria, but no blood, glucose, or ketones. At 36 weeks, she
orrhea. These women are found to have well-circumscribed, gives birth to a normal viable but low-birth-weight infant. Her
lobulated, firm, yellow mass lesions averaging 5 cm. Micro- blood pressure returns to normal, and she no longer has pro-
scopically they have plump pink cells that show positive im- teinuria. Which of the following pathologic findings is most
munohistochemical staining for inhibin. Which of the following likely to be found on examination of the placenta?
neoplasms are most likely to have these features? A Chorioamnionitis
A Brenner tumor B Chronic villitis
B Dysgerminoma C Hydropic villi
C Endometrioid carcinoma D Multiple infarcts
D Granulosa-theca cell tumor E Partial mole
E Sertoli-Leydig cell tumor
49 A 35-year-old primigravid woman at 30 weeks' gesta-
45 A 17-year-old girl missed a menstrual period, and her tion develops worsening headaches along with a 3-kg weight
pregnancy test is positive. A month later, she notes suprapubic gain over 1 week. This morning she had a generalized seizure.
pain and passing blood clots from her vagina. She passes a On physical examination, she is afebrile, but her blood pres-
small amount of tissue 3 days later. Pathologic examination of sure is 190/115 mm Hg (it was 120/80 mm Hg at a prenatal
this tissue shows products of conception. Which of the follow- visit 1 month ago). She has peripheral edema involving her
ing is the most likely cause for her pregnancy loss? head and all extremities. Fetal heart tones of 140/min and
A Bifid uterus fetal movement are present. Laboratory studies show hemo-
B Group B streptococcus infection globin, 12.5 g/dL; hematocrit, 37.6%; MCV, 92 μm3; platelet
C Polycystic ovarian syndrome count, 199,000/mm3; serum creatinine, 1 mg/dL; potassium,
D Preeclampsia 4.2 mmol/L; and glucose, 101 mg/dL. Urinalysis shows 2+
E Smoking cigarettes proteinuria, but no hematuria, RBCs, WBCs, or casts. Which of
F Fetal trisomy 16 the following is the most likely underlying factor in the causa-
tion of her disease?
A Adrenal cortical hyperplasia
B Disseminated intravascular coagulation
C Gestational trophoblastic disease
D Ovarian neoplasm producing estrogen
E Placental ischemia
F Uncontrolled gestational diabetes
3 5 2 U N I T I I Diseases of Organ Systems
50 A 21-year-old G2, P1 woman is in the early second tri- 52 A 23-year-old woman suddenly notices a bloody,
mester. She has noted a small amount of vaginal bleeding for brownish vaginal discharge. The next day she has shortness
the past week and has had marked nausea and vomiting for 3 of breath. On physical examination, a 3-cm, red-brown mass
weeks. On physical examination, the uterus measures large for is seen on the lateral wall of the vagina. A chest radiograph
dates. An ultrasound examination shows intrauterine contents shows numerous 2- to 5-cm nodules in both lungs. Laboratory
with a “snowstorm appearance,” and no fetus is identified. studies show that her serum human chorionic gonadotropin
The gross appearance of tissue obtained by dilation and curet- levels are markedly elevated. A biopsy specimen of the vagi-
tage is shown in the figure. Which of the following substances nal mass is obtained and shown in the figure. Chromosome
is most likely to be greatly increased in her serum? analysis of these cells shows a 46,XX karyotype. Which the fol-
A Acetylcholinesterase lowing cells is most likely present in this mass lesion?
B α-Fetoprotein A Amnionic
C Estradiol B Rhabdomyoblast
D Human chorionic gonadotropin C Serous epithelial
E Human placental lactogen D Smooth muscle
E Syncytiotrophoblast
51 A 23-year-old woman, G3, P2, has a spontaneous abor-
tion at 15 weeks’ gestation. The male fetus is small for ges- 53 A 26-year-old woman delivered a normal neonate a
tational age and is malformed, with syndactyly of the third month ago following an uncomplicated pregnancy. She now
and fourth digits of each hand. The placenta also is small, and has vaginal bleeding. Hysteroscopy shows a nodule in the
shows 0.5-cm grapelike villi scattered among morphologically uterine fundus. Laboratory studies show hCG level of 200
normal villi. Chromosomal analysis of placental tissue is most mIU/mL. She is given chemotherapy but the lesion does not
likely to show which of the following karyotypes? regress. Hysterectomy is performed. Microscopic examination
A 45,X of the nodule shows intermediate trophoblast cells. Immuno
B 46,XX staining for which of the following proteins is most likely to
C 47,XXY yield positive results in this nodule?
D 47,XY,+18 A α-Fetoprotein
E 69,XXY B Chromogranin
C Desmin
D Human placental lactogen
E Neuron-specific enolase
C H A P T E R 2 2 Female Genital Tract 3 5 3
ANSWERS just inferior to the fascia of the urogenital diaphragm and just
anterior to the vestibular bulb, which is not glandular and does
1 B The inflammatory cells in the cervical discharge not become cystic.
with redness (erythema), and the biopsy findings indi-
cate that the patient has cervicitis. Chlamydia trachomatis PBD9 996 BP9 682 PBD8 1011 BP8 712
is the most common cause of cervicitis in sexually active
women. Candidiasis, gonorrhea, and trichomoniasis also 5 C Lichen sclerosus et atrophicus is most common in
are common. Candidiasis often produces a scant, white, postmenopausal women. Although this lesion is not pre-
curdlike vaginal discharge; gonorrhea may have an asso- malignant, there is a 1% to 5% risk that women with this
ciated urethritis; and Trichomonas may produce a profuse condition will later develop a squamous cell carcinoma. In
homogeneous, frothy, and adherent yellow or green vagi- contrast, lichen simplex chronicus appears grossly as leu-
nal discharge. Gardnerella is found in bacterial vaginosis, koplakia from squamous hyperplasia and is not associated
a common condition caused by overgrowth of bacteria. with malignancy. Extramammary Paget disease is rare; it
Gardnerella infection produces a moderate, homogeneous, produces reddish areas of scaling and is caused by the pres-
low-viscosity, adherent vaginal discharge that is white ence of adenocarcinoma-like cells at the dermal-epidermal
or gray and has a characteristic fishy odor; clue cells are junction. Human papillomavirus infection is associated with
seen on a wet mount. Herpetic infections are more likely condylomata acuminata and with squamous epithelial dys-
to manifest as clear vesicles on the skin in the perineal plasias. Pelvic inflammatory disease results from infection
region. Infection with human papillomavirus is associated of internal genital organs with organisms such as Neisseria
with condylomata, dysplasias, and carcinoma. gonorrhoeae and Chlamydia trachomatis. Vulvar intraepithe-
lial neoplasia is marked by dysplastic squamous epithelial
PBD9 992–994 BP9 685 PBD8 1017 BP8 716–717 changes.
2 A The presence of the budding cells with pseudohyphae PBD9 996 BP9 682 PBD8 1011 BP8 712–713
indicates a fungal infection with Candida. Candidal (monili-
al) vaginitis is common; this organism is present in about 5% 6 D Squamous cell hyperplasia, formerly called lichen sim-
to 10% of women. Recurrent episodes of vaginal candidiasis plex chronicus, is most often seen in women aged 30 to 50. It
may be associated with non-albicans species. The inflamma- is not premalignant, but it may coexist with lichen sclerosus,
tion tends to be superficial, and there is typically no invasion and leukoplakia suggests the possibility of a squamous cell
of underlying tissues. Ureaplasma is a bacterial agent, as is carcinoma to be distinguished on biopsy. Human papillo-
Chlamydia, and both can produce cervicitis. Neisseria gonor- mavirus infection is associated with condylomata acuminata
rhoeae, a gram-negative diplococcus, is the causative agent of and with squamous epithelial dysplasias that show kerati-
gonorrhea. Infection with Trichomonas vaginalis can produce nocyte vacuolization and minimal inflammation. Contact
a purulent vaginal discharge, but the organisms are protozoa dermatitis produces red patches and vesicles, with intense
and do not produce hyphae. round cell infiltrates, and tends to diminish when the offend-
ing antigen (such as a skin cream) is not used. Psoriatic le-
PBD9 992–994 BP9 684 PBD8 1008–1009 BP8 712, 715–716 sions have extensive scaling, and microscopically show focal
thinning of the epidermis with marked parakeratosis. Vulvar
3 C Gonorrheal infections can lead to salpingitis and pel- intraepithelial neoplasia is marked by dysplastic squamous
vic inflammatory disease with scarring of the fallopian tube. epithelial changes.
This predisposes to ectopic pregnancy, because the fertil-
ized ovum has difficulty traversing the tube. Gonorrhea PBD9 996 BP9 682 PBD8 1011 BP8 712–713
and other genital tract infections do not cause dysfunctional
bleeding. Gonorrhea does not carry the risk of dysplasias or 7 D The epithelium shows typical features of infection
carcinomas that human papillomavirus infection does. Gon- with human papillomavirus (HPV)—specifically, prominent
orrhea and other infections do not contribute to endometrial perinuclear vacuolization (koilocytosis) and angulation of
hyperplasia. The cause of endometriosis is not known with nuclei. These lesions, called condylomata acuminata, may oc-
certainty, but infection does not seem to play a role in this cur anywhere on the anogenital surface, as single lesions or,
process. Placenta previa results from low-lying implanta- more commonly, as multiple lesions. They are not precancer-
tion of the placenta and is not related to sexually transmitted ous. Condylomata are associated with HPV infection, often
diseases. types 6 and 11. Candidal infections produce a vaginitis or
cervicitis with exudate and erythema. Chlamydial infections
PBD9 994–995 BP9 685, 701 PBD8 1009–1010 BP8 715–717, 727–728 may produce urethritis, cervicitis, and pelvic inflammatory
disease. Haemophilus ducreyi is the agent that produces the
4 A Bartholin glands may become obstructed, inflamed, soft chancre of chancroid. Treponema pallidum is the infec-
and cystic because of abscess formation, which then produces tious agent of syphilis, characterized by the gross appear-
focal pain. A Gartner duct cyst may form in the lateral vaginal ance of a hard chancre.
wall from the remnant of a wolffian (mesonephric) duct; the
cyst is filled with fluid and is usually not inflamed. Hair fol- PBD9 997 BP9 683 PBD8 1012 BP8 712–714
licles are not present at the inner labia. The Bartholin gland lies
3 5 4 U N I T I I Diseases of Organ Systems
8 E Presence of dysplastic cells occupying half of the Neuroblastomas are childhood tumors and are also small
thickness of the epithelium suggests vulvar intraepithe- blue cell tumors, but they occur in the adrenal glands or
lial neoplasia (VIN). The incidence of these lesions has extra-adrenal sympathetic chain. Clear cell carcinomas of the
been increasing, probably because of more cases of hu- vagina may be related to in utero exposure to maternal dieth-
man papillomavirus (HPV) infections. Some VIN lesions ylstilbestrol (DES), but have an onset in the second or third
may progress to invasive cancers. Chronic inflammation decades of life. Invasive squamous cell carcinomas are rare
alone does not produce dysplasia. A condyloma is usually in very young patients, and they show histologic evidence
a raised, nodular lesion. It also is caused by HPV, prin- of squamous epithelial differentiation, and are related to hu-
cipally HPV-6 and HPV-11. Lichen sclerosus is a vulvar man papillomavirus (HPV) infection. Vulvar intraepithelial
dystrophy characterized by thinning of the squamous neoplasia is a carcinoma in situ of the vulvar skin, squamous
epithelium and sclerosis of the dermis. Similar to VIN, in origin, and related to HPV infection.
squamous hyperplasia, another form of vulvar dystrophy,
can appear as an area of leukoplakia, but no dysplastic PBD9 1001 BP9 685 PBD8 1017 BP8 716
changes are present.
12 B Cervical intraepithelial neoplasia (CIN) I represents
PBD9 997–999 BP9 683 PBD8 1012–1014 BP8 714 minimal (mild) dysplasia (low-grade squamous intraepithe-
lial lesion, or LSIL) and is a potentially reversible p rocess.
9 B Extramammary Paget disease is a rare condition that Dysplasias are preneoplastic and may progress to carcinomas
is usually not associated with an underlying malignancy, in if not treated. Risk factors for cervical dysplasias and carci-
contrast to Paget disease of the breast. In many cases, the ex- noma include early age at first intercourse, multiple sexual
tramammary Paget cells remain in the epithelium, often for partners, and a male partner with multiple previous sexual
years, creating an annoying itchy red lesion. However, in a partners. These factors all increase the potential for infection
fourth of cases there may be an underlying neoplasm, so that with human papillomavirus. Diethylstilbestrol (DES) expo-
local invasion and even metastases are possible. A condy- sure is a factor in the development of clear cell carcinomas
loma is the result of human papillomavirus (HPV) infection of the vagina and cervix. Use of oral contraceptives, which
and leads to koilocytotic atypia, but the cells of a condyloma contain very low amounts of hormonally active compounds,
are not malignant. Lichen sclerosis is a white patch of epithe- does not cause cervical dysplasia or carcinoma. Treatment
lial thinning with dermal fibrosis and chronic inflammation of cancers does not typically result in dysplasias, although
that can be extensive enough to constrict the vaginal orifice; the atypical changes in epithelial cells from radiation and/or
it may have an autoimmune basis, and there is an increased chemotherapy may be challenging to distinguish from can-
risk for future development of a squamous carcinoma. Li- cer. A vitamin B12 deficiency may produce some megaloblas-
chen simplex chronicus is an area of epithelial hyperpla- tic epithelial changes, but not dysplasia.
sia that has no atypia and no association with malignancy.
Vulvar intraepithelial neoplasia has neoplastic cells extend- PBD9 1002–1004 BP9 685–688 PBD8 1020–1021 BP8 717–719
ing the full thickness of the epithelium; it is related to HPV
infection. 13 E The figure shows a high-grade squamous intraepi-
thelial lesion (HSIL) termed cervical intraepithelial neoplasia
PBD9 999–1000 BP9 683–684 PBD8 1015 BP8 714–715 (CIN) III because the dysplasia involves the full thickness of
the cervical epithelium. Such lesions arise more frequently in
1 0 B The microscopic appearance is that of a malignant women who have had first intercourse at an early age, have
tumor containing cells with a clear cytoplasm. Vaginal clear multiple sexual partners, or have a male partner with mul-
cell carcinomas are associated with exposure of the patient’s tiple sexual partners. These factors are believed to increase
mother to diethylstilbestrol (DES) during pregnancy. These the risk of infection with human papillomavirus (HPV), par-
tumors are generally first diagnosed in the late teenage ticularly types 16 and 18, which have high risk for dysplasias
years. Congenital adrenal hyperplasia can produce mascu- and carcinomas of the cervix. Because of the causal relation-
linization in girls, manifesting in early childhood. Infection ship with HPV infection, the use of HPV vaccines has been
with human papillomavirus is associated with squamous shown to prevent disease progression. Cervical squamous
epithelial dysplasias and malignancies, not with clear cell neoplasia has not been shown to be associated with s moking,
adenocarcinomas. Polycystic ovary disease can lead to hor- diet, body weight, or hormonal influences.
monal imbalances from excess androgen production, but
vaginal neoplasms do not arise in this setting. Trichomonal PBD9 1002–1004 BP9 685–687 PBD8 1019–1021 BP8 718–719
infections do not give rise to neoplasia.
14 E This patient’s cervical intraepithelial neoplasia (CIN)
PBD9 1000 BP9 685 PBD8 1016–1017 BP8 716 II is a high-grade squamous intraepithelial lesion (HSIL)
that may progress to invasive carcinoma in several years
11 D Embryonal rhabdomyosarcoma is an uncommon if not treated, particularly because she has a high-risk sub-
vaginal tumor that can be found in girls younger than 5 years. type of HPV. Infection with HPV often drives this process,
Because it forms polypoid, grapelike masses, it is sometimes but the presence of HPV alone does not determine therapy.
called sarcoma botryoides. Histologically, it is a small round HPV infection cannot be eradicated with antibiotics, but pa-
blue cell tumor that shows skeletal muscle differentiation tients may clear the virus. Chronic cervicitis with squamous
in the presence of muscle-specific proteins such as desmin. metaplasia is not a malignant lesion and does not determine
C H A P T E R 2 2 Female Genital Tract 3 5 5
therapy in this case. The conization can preserve fertility in to the ovary. Leiomyosarcomas are rare and typically arise
women who are of childbearing age. in the myometrium, although they can occur in the cervix.
Sarcoma botryoides is a vaginal lesion that typically occurs
PBD9 1002–1004 BP9 686–688 PBD8 1020–1021 BP8 718–719 in young girls.
1 5 E Dysplasias of the cervix should not be ignored be- PBD9 1002–1003, 1006–1007 BP9 685–688 PBD8 1018 BP8 719–721
cause they naturally progress to more severe dysplasias and
to invasive carcinomas. Although not all cases progress, 19 A Anovulatory cycles are a common cause of dysfunc-
the physician should not take this chance. Dysplasias are tional uterine bleeding in young women who are beginning
strongly related to human papillomavirus (HPV) infections, menstruation and in women approaching menopause. There
and HPV DNA can be found in up to 90% of cases. Viral E6 is prolonged estrogenic stimulation that is not followed by
and E7 proteins bind to Rb to up-regulate cyclin E. In about secretion of progesterone. An ectopic pregnancy has acute
10% to 15% of cases, there is no evidence of HPV, and other findings and does not have a prolonged course. Endometrial
factors may play a role in the development of the dysplasia. carcinomas are rare in patients this age. Polyps are more
With such HPV infection, the Pap smear may show changes common in older women. Submucosal leiomyomas are a
of cervical intraepithelial carcinoma (CIN) I (low-grade squa- cause of less variable bleeding and are more likely to be seen
mous intraepithelial lesion, or LSIL). Oral contraceptives in older women.
with low-dose estrogens and progestins do not increase the
risk of dysplasia significantly. Though the RB1 gene is in- PBD9 1007–1010 BP9 690–691 PBD8 1026–1027 BP8 723
volved, this is not an inherited problem, and retinoblastomas
are not seen with HPV infection. Cervicitis usually is due to 2 0 B Acute endometritis in this case is the result of retained
bacterial or fungal organisms and is not a significant risk for products of conception after delivery. Endometritis may also
dysplasia or carcinoma. Antiapoptosis genes such as BCL2 follow premature rupture of membranes with ascending in-
do not play a role in cervical carcinogenesis. fection to the uterine cavity. There is often polymicrobial in-
fection with organisms found in the vagina. Some cases of
PBD9 1002–1004 BP9 685–688 PBD8 1018–1019 BP8 717–719 chronic endometritis may be associated with Neisseria and
Chlamydia infections and produce lymphoplasmacytic infil-
16 C Microinvasive squamous cell carcinomas of the cer- trates within the endometrium. Cervical dysplasias are con-
vix are stage I lesions that have a survival rate similar to that fined to the epithelium and are usually asymptomatic so that
of in situ lesions. Such minimal invasiveness does not war- detection is by Pap smear. A myometrial neoplasm is unlikely
rant more aggressive therapies. The likelihood of metastasis to produce acute inflammation. An ovarian endometrioma
or recurrence is minimal. is a mass lesion resulting from continued hemorrhage into a
focus of endometriosis; but this mass lesion is not associated
PBD9 1004–1006 BP9 686–688 PBD8 1022–1023 BP8 719–720 with pregnancy, and endometriosis may be a cause for infer-
tility. Mycobacterium tuberculosis infection may spread to the
17 F The cervical lesion shown in the figure is large and female genital tract, most often the fallopian tube, but acute
ulcerative and projects into the vagina. It is most likely an signs are unlikely to be present, and inflammation of the tube
invasive squamous cell carcinoma that has infiltrated the sub- can be a cause for infertility. Vaginitis may produce acute in-
epithelial region. Dysplastic changes confined to the epithe- flammation with discharge, but trichomonal infections typi-
lium represent cervical intraepithelial neoplasia and do not cally are associated with a watery gray-to-green discharge.
form mass lesions. Glandular invasive lesions indicate an ad-
enocarcinoma, which is much less common than squamous PBD9 1010 BP9 689 PBD8 1027 BP8 721
cell carcinoma of the cervix. Chronic cervicitis has erythema,
but no mass effect. Clear cell carcinomas are uncommon and 2 1 A In 30% to 40% of cases, endometriosis presents with
most likely found arising in the vagina. Extramammary Paget infertility, menstrual irregularities, and pelvic pain. The pres-
disease usually arises on the vulva, producing an eczematous ence of endometrial tissue in the nodules confirms this diag-
lesion, not a mass, because the neoplastic cells are confined to nosis. The glands in the nodules are hyperplastic but show
the epithelium and to adjacent skin adnexa. no evidence of malignancy; in addition, all the genes impli-
cated in endometrial cancer are normal. Hypomethylation
PBD9 1004–1006 BP9 684 PBD8 1021–1023 BP8 719–721 of the two genes, NR5A1 (steroidogenic factor 1) and ESR2
(estrogen receptor beta) is found in endometriosis. These lead
18 F This woman has several risk factors for the devel- to overproduction of prostaglandins and estrogens. Aroma-
opment of cervical squamous cell carcinoma, including tase inhibitors are used to suppress estrogen production. Le-
multiple sexual partners, documented infection of the cer- sions of endometriosis are not neoplastic and chemotherapy
vix with high-risk human papillomavirus (HPV) type 16, or major surgery with organ removal is not indicated. Endo-
and diagnosis of a high-grade squamous intraepithelial le- metriosis is not infectious, so antibiotics are not indicated.
sion (HSIL). The remaining choices are not related to HPV
infection. Clear cell carcinomas of the cervix are uncom- PBD9 1010–1012 BP9 689–690 PBD8 1028–1029 BP8 722
mon; some are associated with maternal use of diethylstil-
bestrol (DES) in pregnancy. An immature teratoma arises 22 A In adenomyosis, endometrial glands extend from the
in the ovary. A Krukenberg tumor is a form of metastasis endometrium down into the myometrium. The process may
3 5 6 U N I T I I Diseases of Organ Systems
be superficial, but occasionally it is extensive, and the uterus granulosa-theca cell tumor or a thecoma-fibroma, the former
becomes enlarged two to four times its normal size because of more often being functional. Teratomas can contain various
a reactive thickening of the myometrium. Chronic endometri- histologic elements, but not estrogen-producing tissues. En-
tis does not extend to the myometrium and does not increase dometriosis can give rise to an adnexal mass called an endo-
uterine size. Endometrial hyperplasias do not increase the metrioma, which enlarges over time. Endometrial glands are
size of the uterus because the process is limited to the endo- hormonally sensitive, but they do not produce hormones.
metrium. In endometriosis, endometrial glands and stroma Corpus luteum cysts are common, but they are unlikely to
are found outside the uterus in such sites as peritoneum, produce estrogens. Metastases to the ovary do not cause in-
ovaries, and ligaments. A leiomyoma is a myometrial tumor creased estrogen production. Polycystic ovarian syndrome
mass that, if large, produces an asymmetric uterine mass. would involve both ovaries.
PBD9 1010–1012 BP9 689–690 PBD8 1028–1029 BP8 721 PBD9 1012–1013 BP9 691–692 PBD8 1050–1051 BP8 723, 732
2 3 C Endometriosis is a condition in which functional en- 27 A Postmenopausal vaginal bleeding is a red flag for
dometrial glands are found outside the uterus. Common sites endometrial carcinoma. Such carcinomas often arise in the
include ovaries, uterine ligaments, rectovaginal septum, and setting of endometrial hyperplasia. Increased estrogenic
pelvic peritoneum. These endometrial glands can respond stimulation is thought to drive this process, and risk factors
to ovarian hormones so that cyclic abdominal pain coincides include obesity, type 2 diabetes mellitus, hypertension, and
with menstruation. Recurrent hemorrhages may incite scar- infertility. Choriocarcinomas are gestational in origin. A
ring and the formation of fibrous adhesions in the pelvic re- submucosal leiomyosarcoma could produce vaginal bleed-
gion. This may cause distortion of the ovaries and fallopian ing, but the uterus would be enlarged because leiomyosar-
tubes and may lead to infertility. One common variation is comas tend to be large masses. Malignant müllerian mixed
formation of an endometrioma, or chocolate cyst, which rep- tumors are much less common than endometrial carcino-
resents a focus of endometriosis that becomes an expanding mas, but they could produce similar findings. Malignant
cystic lesion as its center becomes filled with chocolate-brown müllerian mixed tumors are typically uterine neoplasms
sludge from the recurrent hemorrhage. The remaining choices that have glandular and stromal elements; the malignant
are not associated with endometriosis, although endometrioid stromal component can be heterologous and may resem-
tumors may form in foci of endometriosis. ble mesenchymal cells that are not ordinarily found in the
myometrium, such as cartilage. Squamous carcinomas of
PBD9 1010–1012 BP9 689–690 PBD8 1028–1029 BP8 722–723 the endometrium are rare, and more likely to arise in the
cervix.
24 D Endometrial hyperplasia with numerous crowded
glands as shown in the figure results from excessive estro- PBD9 1014–1018 BP9 692–693 PBD8 1031–1034 BP8 725–727
genic stimulation. This lesion often occurs with failure of
ovulation about the time of menopause. Hyperplasias do not 28 B Most endometrial cancers have the endometrioid
develop from endometritis. Estrogen-secreting ovarian tu- pattern and are classified as type I endometrial carcinomas.
mors also may produce endometrial hyperplasia, but terato- They arise in the setting of unopposed estrogen stimulation
mas are not known for this phenomenon. A secretory pattern and may also have PTEN mutations as well as microsatel-
of the endometrium is seen in pregnancy, not the prolifera- lite instability. In contrast, type II endometrial carcinomas
tive pattern shown in the figure. Oral contraceptives contain occur at an older age in the background of atrophic endo-
small doses of estrogenic compounds that do not lead to metrium; they usually have a serous carcinoma pattern, but
hyperplasia. may also exhibit clear cell and müllerian mixed patterns, and
TP53 mutations are common. Leiomyosarcomas and stromal
PBD9 1012–1013 BP9 691–692 PBD8 1030–1031 BP8 723–724 sarcomas are far less common than endometrial carcinomas,
and they have no known risk factors.
2 5 B She has an endometrial polyp, seen most often in
perimenopausal and postmenopausal women. The lesion PBD9 1016–1018 BP9 692–693 PBD8 1031–1034 BP8 726
can lead to abnormal bleeding, but rarely gives rise to a ma-
lignancy. Endocervical glands with squamous metaplasia are 29 C Endometrial carcinomas can be associated with es-
seen most often with chronic cervicitis. Papillae with marked trogenic stimulation from anovulatory cycles, nulliparity,
cellular atypia are seen with the serous type of endometrial obesity, and exogenous estrogens (in higher amounts than
carcinoma. Smooth muscle cells in bundles characterize a found in birth control pills). These risks may initially give
leiomyoma, which may be submucosal. Tubular glands lined rise to endometrial hyperplasia that can progress to endo-
by clear cells with glycogen are seen with the rare clear cell metrial carcinoma if the estrogenic stimulation continues.
carcinoma. Atypical endometrial hyperplasias progress to endometrial
cancer in about 25% of cases. Adenomyosis increases the size
PBD9 1012 BP9 693 PBD8 1029–1030 BP8 724 of the uterus and is not a risk for endometrial carcinoma.
Chronic endometritis and human papillomavirus infection
2 6 C The mass is probably producing estrogen, which (associated with squamous epithelial dysplasias and neopla-
has led to endometrial hyperplasia. Estrogen-producing sia) do not cause cancer.
tumors of the ovary are typically sex cord tumors, such as a
PBD9 1014–1016 BP9 692–693 PBD8 1031–1034 BP8 725–727
C H A P T E R 2 2 Female Genital Tract 3 5 7
30 C She has obesity, diabetes mellitus, and nulliparity— not be missed. Even if the MRI is normal, a biopsy is still
factors that contribute to development of endometrial hy- indicated. Infections are uncommon at this age and unlikely
perplasias and carcinomas caused by hyperestrinism. She to cause bleeding. A Pap smear is insensitive for detection
has complex endometrial hyperplasia with atypicality of of endometrial lesions. She is postmenopausal and neither
cells, which is a precursor for type I endometrial carcinoma. pregnancy nor gestational trophoblastic disease is probable.
These lesions often have loss of PTEN tumor suppressor
genes. In many if not all cancers, there is activation of aero- PBD9 1009, 1018 BP9 690–692 PBD8 1027, 1034 BP8 723, 726
bic glycolysis (i.e., glycolysis even in the presence of enough
oxygen)—the so-called Warburg effect. This is linked to 3 4 A Sexually transmitted diseases are the most common
loss of PTEN and offers a growth advantage to tumor cells. cause of inflammation of the fallopian tube. When the inci-
When aerobic glycolysis is stimulated there is a reciprocal dence of gonorrhea caused by Neisseria gonorrhoeae decreases
decrease in oxidative phosphorylation. Tumors are meta- in a population, the proportion of cases of salpingitis caused
bolically active, so glucose uptake and glycogen utilization by Chlamydia and Mycoplasma increases. The fallopian tube
is enhanced and not reduced. This uptake is the basis for can become distended and adherent to the ovary and may
positron emission tomography (PET) scans, where positron- form a tubo-ovarian abscess. These are features of pelvic in-
emitting fludeoxyglucose F 18 is preferentially taken up into flammatory disease. Haemophilus ducreyi causes chancroid,
foci of malignancy. In many cancers the COX-2 enzyme is which can produce erythematous papules of the external
up-regulated (e.g., colon cancer), and this leads to increased genitalia or vagina, but grossly visible lesions may not be
prostaglandins, but this is not related to PTEN loss. present in women. Herpes simplex virus most often involves
the external genitalia, but it may produce vaginal or cervi-
PBD9 1013–1015 BP9 692–693 PBD8 1031–1032 BP8 725–727 cal lesions; it is unlikely to advance farther. Mycobacterium
tuberculosis is an uncommon cause of salpingitis. Treponema
31 C The masses shown are well circumscribed, suggest- pallidum infection causes syphilis, which does not produce
ing the presence of multiple benign tumors. Leiomyomas florid inflammation with mass effect, just a chancre.
(fibroids) can be present in one third to one half of all wom-
en. They tend to enlarge during the reproductive years, and PBD9 1021 BP9 695 PBD8 1008, 1038 BP8 727–728
then stop growing or involute after menopause. Although
leiomyomas are often asymptomatic, leiomyomas that are 35 C Follicle cysts and lutein cysts of the ovary are so
submucosal may produce menometrorrhagia and chronic common that they are virtually normal findings and inci-
blood loss, leading to iron deficiency anemia. About 10% of dentalomas in diagnostic studies. Though most of them are
complete moles are complicated by invasive mole, which is less than 2 cm and asymptomatic, occasionally they can be
unlikely to produce a large, circumscribed mass. A leiomyo- larger (4 to 5 cm) and even enlarge a little more in response to
sarcoma arises de novo, not from a leiomyoma, and is usually midcycle hormones, occasionally rupturing to produce pain
a larger, more irregular mass composed of more pleomorphic and bleeding. The negative pregnancy test helps to eliminate
spindle cells with many mitoses. Decreased ovarian function intrauterine or ectopic pregnancy. Endometriosis tends to
after menopause accelerates bone loss, which may be severe produce more chronic pain, and though there is hemorrhage
enough to be termed osteoporosis, but this process is not re- in the lesions, it tends to be contained within the lesions. The
lated to female genital tract neoplasia. Preeclampsia with pregnancy test would be positive with an invasive mole,
hypertension and proteinuria is associated with abnormal with uterine enlargement from the mass of grapelike villi.
decidual vascularization and placental ischemia. Pelvic inflammatory disease tends to produce chronic pain,
and there is unlikely to be bleeding.
PBD9 1019–1020 BP9 693–694 PBD8 1036–1037 BP8 724–725
PBD9 1022 BP9 695 PBD8 1039 BP8 728
32 D Leiomyosarcomas arising in the uterine corpus ac-
count for about 5% of all GYN malignancies, and is most often 36 D Polycystic ovarian syndrome (PCOS) is a disorder of
present in postmenopausal women. The cellular atypia, coag- unknown origin that is typically associated with oligomen-
ulative necrosis, and numerous mitoses distinguish this neo- orrhea, obesity, and hirsutism. The MR image shows an en-
plasm from the much more common leiomyoma (which does larged ovary with multiple round cysts of increased signal
not give rise to leiomyosarcoma), both derived from smooth intensity. It is thought to be caused by abnormal regulation of
muscle. Anaplastic cytotrophoblasts are seen with choriocar- androgen synthesis. Teratomas are mass lesions that can be bi-
cinomas. Cross striations are seen with rhabdomyosarcomas. lateral, but usually are not symmetric, and aside from struma
Adenocarcinomas arise from glandular epithelium. Germ ovarii not known for hormonal abnormalities. Krukenberg tu-
cells give rise to ovarian tumors such as teratoma and dys- mors represent metastatic disease involving the ovaries, usu-
germinoma. Squamous carcinomas are much more common ally from a primary site in the gastrointestinal tract, and are
but arise in the cervical portion of the uterus. rare among patients of this age. Cystadenocarcinoma can be
bilateral; however, androgen production by ovarian tumors
PBD9 1020–1021 BP9 694 PBD8 1037–1038 BP8 724–725 is except by the Sertoli-Leydig cell tumors. Abscesses are usu-
ally unilateral and do not account for the hormonal changes
3 3 A Causes for postmenopausal uterine bleeding include seen in this patient.
endometrial atrophy, carcinoma, hyperplasia, and polyps.
An early potentially curable endometrial carcinoma should PBD9 1022 BP9 695–696 PBD8 1039–1040 BP8 728
3 5 8 U N I T I I Diseases of Organ Systems
3 7 B Cystadenocarcinomas are common ovarian tumors carcinomas do not transform to sarcomas, and sarcomas at this
that are often bilateral. The serous type occurs more fre- site are rare.
quently than the mucinous type and is typically unilocular,
whereas mucinous tumors are multilocular. Serous cystad- PBD9 1023–1025 BP9 696–697 PBD8 1042–1043 BP8 729–730
enocarcinomas account for more than half of ovarian can-
cers. As the name indicates, they are cystic in appearance. 41 A A cystic tumor with a mass of hair in the lumen is
They may be benign, borderline, or malignant. Benign the typical appearance of a mature cystic teratoma. This tu-
tumors have a smooth cyst wall with small or absent papil- mor also is known as a dermoid cyst because it is cystic and
laryprojections.Borderlinetumorshaveincreasingamounts filled with hair and sebum derived from well-differentiated
of papillary projections. Endometrioid tumors resemble ectodermal structures. Teratomas with mature tissue ele-
endometrial carcinomas and may arise in foci of endo- ments are benign tumors of germ cell origin, and they can
metriosis. Dysgerminomas are solid tumors of germ cell contain various ectodermally, endodermally, and meso-
origin. Granulosa cell tumors can be solid and cystic and dermally derived tissues. Papillary structures with psam-
may produce estrogens. Mature cystic teratomas typically moma bodies would characterize a cystadenocarcinoma.
contain abundant hair and gooey sebaceous fluid within Primitive neuroepithelium in a more solid and less cystic
the cystic cavity; surrounding tissues are formed from mass would be consistent with an immature teratoma. Sar-
various germ layers. Sertoli-Leydig cell tumors are rare, comas of the ovary are uncommon; a rhabdomyosarcoma
yellow-brown, solid masses; they may secrete androgens element could be part of a uterine malignant mixed mul-
or estrogens. lerian tumor. A choriocarcinoma with trophoblastic cells
is usually gestational in origin and has a hemorrhagic
PBD9 1023–1026 BP9 696–697 PBD8 1042–1044 BP8 730 appearance.
38 D Mucinous tumors of the ovary are of epithelial or- PBD9 1029–1030 BP9 698–700 PBD8 1047–1048 BP8 733
igin, are less common than serous tumors, and tend to be
multiloculated. The appearance of ascites suggests metas- 4 2 D Immature teratomas are not cystic like mature tera-
tases, which is most common with surface epithelial neo- tomas. Tissues derived from multiple germ cell layers are
plasms of the ovary. Choriocarcinomas rarely reach this size present, as in all teratomas, but at least one immature tissue
because they metastasize early; they are typically hemor- element is present. Often that immature element is neuroecto-
rhagic. Granulosa cell tumors and dysgerminomas tend to be dermal tissue. The less differentiated and more numerous the
solid masses. Teratomas are germ cell tumors differentiating neuroepithelial elements, the higher the grade and the worse
into three germ layers; malignant transformation is rare, and the prognosis. Adjuvant chemotherapy and radiotherapy
is usually an element of squamous cell carcinoma from the yield a high response rate. Brenner tumors of the ovary are un-
ectodermal component. common solid tumors that contain epithelial nests resembling
transitional cells of the urinary tract; most are benign. Dysger-
PBD9 1026–1027 BP9 697–698 PBD8 1044–1045 BP8 730–731 minomas are the female equivalent of male testicular semino-
mas. Granulosa cell tumors have cells that resemble those in
3 9 A Some familial cases of ovarian carcinoma (usually ovarian follicles and may secrete estrogens. Leiomyosarcomas
serous cystadenocarcinoma) are associated with the ho- are solid tumors of smooth muscle origin that are found most
mozygous loss of the BRCA1 gene. This tumor-suppressor often in the myometrium. Malignant müllerian mixed tumors
gene also plays a role in the development of familial breast are typically uterine neoplasms that have glandular and stro-
cancers. Familial syndromes account for less than 5% of all mal elements; the malignant stromal component can be heter-
ovarian cancers, however. The ERBB2 gene may be overex- ologous and may resemble mesenchymal cells not ordinarily
pressed in ovarian cancers; however, mutations of this gene found in the myometrium, such as cartilage.
do not give rise to familial tumors, and it is best known for
an association with breast carcinomas. Mutations of the RAS PBD9 1029–1030 BP9 700 PBD8 1048 BP8 733
and MYC oncogenes occur sporadically in many types of
cancer. The RB1 gene, a tumor suppressor, can be involved 43 C Fibromas and thecomas are sex cord–stromal tumors
in familial malignancies, including retinoblastoma and that may be hormonally active and secrete estrogens that can
osteosarcoma. lead to endometrial hyperplasia or even carcinoma. Fibro-
mas can be associated with Meigs syndrome (ovarian tumor
PBD9 1024–1025 BP9 697 PBD8 1042 BP8 729–730 with ascites and right pleural effusion). Most of these tumors
also are benign and do not metastasize. In most cases, chron-
40 D This is a borderline serous tumor of the ovary, and ic salpingitis is related to sexually transmitted infections,
the figure shows a complex papillary projection into the cyst such as gonorrhea. A condyloma acuminatum is related to
lumen. This is the most common serous ovarian tumor, and infection with human papillomavirus and is more likely to
though most act in a benign fashion even when peritoneal occur in younger, sexually active women on external geni-
implants are present, some tend to recur, particularly when talia and perineum. A partial mole is an uncommon form
KRAS or BRAF mutations are present, and the implants are in- of gestational trophoblastic disease with a triploid karyotype
vasive. Distant metastases are unlikely. Serous tumors do not and occurs only in reproductive-age women.
have hormonal effects, either estrogenic to drive endometrial
hyperplasia, or androgenic to drive masculinization. Ovarian PBD9 1033 BP9 699 PBD8 1050–1051 BP8 732
C H A P T E R 2 2 Female Genital Tract 3 5 9
44 E The Sertoli cell group of ovarian neoplasms mimics insufficiency; infarcts and retroplacental hemorrhages can oc-
testicular differentiation and may produce androgens. These cur. Microscopically, the decidual arterioles may show acute
neoplasms tend to be better differentiated and act in a more atherosis and fibrinoid necrosis. Chorioamnionitis is most of-
benign fashion. Brenner tumors are uncommon solid mass- ten due to ascending bacterial infections and leads to, or fol-
es, usually act in a benign manner, and may be associated lows, premature rupture of membranes. A chronic villitis is
with endometrial hyperplasia, though they may not directly characteristic of a congenital infection such as cytomegalovi-
produce estrogenic hormones unless there are thecalike cells rus. Placental hydrops often accompanies fetal hydrops in con-
present. Dysgerminomas and endometrioid carcinomas tend ditions such as infections and fetal anemias. In a partial mole, a
not to produce hormonal effects. Granulosa-theca cell tu- fetus is present, but it is malformed and rarely live-born.
mors are known for association with estrogenic effects.
PBD9 1037–1039 BP9 703–704 PBD8 1055–1057 BP8 737–738
PBD9 1033–1034 BP9 699 PBD8 1051–1052 BP8 732
49 E Classic features of eclampsia are defined by hyperten-
45 F Spontaneous abortion (miscarriage) may occur in sion, edema, and proteinuria, typically with onset in the third
at least a third of pregnancies, and most occur in the first trimester. The addition of seizures defines eclampsia. Primi-
trimester. Fetal problems are the most likely cause for early gravid women are at greater risk. There is no evidence in this
losses, whereas maternal problems account for most late case that primary renal disease could cause her hyperten-
fetal losses. Half of early abortuses have a chromosomal ab- sion, and the onset was sudden. Although the precise cause
normality, many of which are incompatible with prolonged of preeclampsia/eclampsia is unknown, placental ischemia
survival, such as trisomy 16. If there is recurrent early preg- is believed to be the underlying mechanism. This is associ-
nancy loss, a parental germline chromosomal anomaly may ated with shallow placentation and incomplete conversion of
be suspected. Infections, uterine anomalies, masses such as decidual vessels into high-volume channels required to per-
leiomyomas, and toxemia are more likely to cause fetal loss fuse the placenta adequately. Untreated patients may go on to
later in pregnancy. Polycystic ovarian syndrome is more disseminated intravascular coagulation. Cushing syndrome
likely to be a cause for infertility. Maternal smoking is most with adrenal cortical hyperplasia could lead to hypertension
likely to affect fetal weight, and less likely to cause early with sodium retention, but she does not have hypokalemia or
fetal loss. hyperglycemia. Gestational trophoblastic disease predisposes
patients to preeclampsia, but hydatidiform mole is excluded
PBD9 1035–1036 PBD8 1053 by the presence of a fetus, and a partial mole would be un-
likely to persist into the third trimester. Functional ovarian
4 6 A Placental infections are most likely to ascend from tumors, most commonly estrogen secreting, such as a granu-
the vagina, and they are not usually hematogenous. Pre- losa cell tumor or thecoma, do not produce hypertension and
term premature rupture of membranes may predispose to proteinuria. Gestational diabetes may increase the risk for fe-
ascending infection, or it may be caused by prostaglandins tal loss, but in this case the glucose is normal.
released from acute inflammatory cells in the infection as
suggested by the purulent exudate. Premature labor with de- PBD9 1037–1039 BP9 703–704 PBD8 1055–1057 BP8 737–738
livery is likely to occur over the next 24 hours. Of the TORCH
infections, the one most likely in this case is the O, including 5 0 D The figure shows a hydatidiform mole, or complete
bacteria, such as group B streptococcus, whereas Listeria mole, with enlarged, grapelike villi that form the tumor mass
monocytogenes may produce more chronic inflammation. in the endometrial cavity. These trophoblastic tumors secrete
large amounts of human chorionic gonadotropin (hCG). Mo-
PBD9 1036–1037 BP9 701 PBD8 1055 BP8 734 lar pregnancies result from abnormal fertilization, with only
paternal chromosomes present. Neural tube defects can be
47 B Conditions predisposing to ectopic pregnancy in- distinguished from other fetal defects (e.g., abdominal wall
clude chronic salpingitis (which may be caused by gonor- defects) by use of the acetylcholinesterase test on amniotic
rhea, but a culture would be positive only with acute infec- fluid obtained by amniocentesis. If acetylcholinesterase and
tion), intrauterine tumors, and endometriosis. In about half maternal serum α-fetoprotein are elevated, a neural tube
of cases, there is no identifiable cause. Gestational tropho- defect is likely. If the acetylcholinesterase is not detectable,
blastic disease associated with a triploid karyotype with another fetal defect is suggested. α-Fetoprotein is a marker
partial mole developing outside the uterus is rare. Candida for some germ cell tumors that contain yolk sac elements.
produces cervicitis and vaginitis and is rarely invasive or ex- Estrogens can be elaborated by various ovarian stromal tu-
tensive in immunocompetent patients. Syphilis is not likely mors, including thecomas and granulosa cell tumors. More
to produce a tubal mass with acute symptoms (a gumma is a ominously, a decrease in maternal serum estriol suggests in-
rare finding). cipient abortion. Human placental lactogen is produced in
small quantities in the developing placenta, and serum levels
PBD9 1036 BP9 701 PBD8 1053–1054 BP8 734–735 typically are not measured.
48 D Toxemia of pregnancy in this case is best classified PBD9 1039–1040 BP9 701–702 PBD8 1057–1059 BP8 735–736
as preeclampsia, because she has hypertension, proteinuria,
and edema, but no seizures. The placenta tends to be small 5 1 E Partial hydatidiform mole develops from triploidy
because of reduced maternal blood flow and uteroplacental (69 chromosomes). In contrast to a complete mole with only
3 6 0 U N I T I I Diseases of Organ Systems
paternal chromosomes, in which no fetus is present, a partial cyclophosphamide, and vincristine can often lead to remis-
mole has a fetus because maternal chromosomes are present. sion and cure. Amnionic cells do not give rise to neoplasms.
Survival of the triploid fetus to term is rare. A partial mole Rhabdomyoblasts are present in embryonal rhabdomyosar-
may contain some grapelike villi, or none. The fetus is usu- comas of the vagina of young girls. Serous epithelium does
ally malformed, often with 3,4 syndactyly. A 46,XX karyo- not give rise to gestational trophoblastic disease. Smooth
type could be present in a complete mole or a normal female muscle cells give rise to leiomyomas, and rarely leiomyosar-
fetus. A fetus with Turner syndrome (monosomy X) has a comas, typically arising in the uterus.
45,X karyotype. Most female fetuses with loss of an X chro-
mosome undergo spontaneous abortion, but some survive. PBD9 1041 BP9 703 PBD8 1059–1061 BP8 736–737
Klinefelter syndrome has a 47,XXY karyotype, and male in-
fants are live-born, with no placental problems. A 47,XY,+18 5 3 D This is a placental site trophoblastic tumor (PSTT),
karyotype of trisomy 18 is associated with multiple congeni- the rarest of all forms of gestational trophoblastic disease.
tal malformations, but not with a partial mole. The intermediate trophoblastic cells do not produce large
amounts of hCG, but do produce human placental lactogen
PBD9 1040 BP9 702 PBD8 1058–1059 BP8 735–736 (hPL). Most of these lesions are treated surgically and are
controlled, but some recur and respond minimally to chemo-
5 2 E Choriocarcinomas are aggressive, malignant tro- therapy and radiation. α-Fetoprotein is produced by some
phoblastic tumors. Some of these tumors can arise without testicular neoplasms and by hepatocellular carcinomas.
evidence of pregnancy. Metastases in the vaginal wall and Chromogranin is a marker for neuroendocrine tumors. Des-
lungs and a hemorrhagic appearance are characteristic. The min is likely to be seen in tumors of mesenchymal origin.
large pleomorphic and hyperchromatic syncytiotrophoblas- Neuron-specific enolase can be seen with tumors of neural
tic cells produce human chorionic gonadotropin. Treatment and neuroendocrine differentiation.
with agents such as etoposide, methotrexate, actinomycin D,
PBD9 1041–1042 BP9 703 PBD8 1061 BP8 737
23C H A P T E R
The Breast
PBD9 Chapter 23 and PBD8 Chapter 23: The Breast
BP9 Chapter 18 and BP8 Chapter 19: Female Genital System and Breast
1 A 21-year-old woman delivered a normal term infant a region near the nipple becomes erythematous and tender. Pu-
week ago and is now nursing the infant. She now notes a lump rulent exudate from a small abscess drains through a fissure.
in her right axilla that has increased in size over the past week. Which of the following organisms is most likely to be cultured
On physical examination there is a rubbery, mobile, 1.5-cm from the exudate?
mass beneath the skin at the right anterior axillary line. The A Candida albicans
mass is excised and the microscopic appearance is shown in B Lactobacillus acidophilus
the figure. Which of the following hormones most likely pro- C Listeria monocytogenes
duced the greatest effect upon this tissue? D Staphylococcus aureus
A Cortisol E Viridans streptococci
B Growth hormone
C Oxytocin 3 A 30-year-old woman sustained a traumatic blow to
D Prolactin her right breast. Initially, there was a 3-cm contusion beneath
E Testosterone the skin that resolved within 3 weeks, but she then felt a firm,
painless lump that persisted below the site of the bruise 1
2 A 24-year-old woman is breastfeeding 3 weeks after month later. What is the most likely diagnosis for this lump?
giving birth to a normal term infant. She notices fissures in A Abscess
the skin around her left nipple. Over the next 3 days, a 5-cm B Fat necrosis
C Fibroadenoma
D Inflammatory carcinoma
E Sclerosing adenosis
4 A study of mammographic findings on women of
reproductive years is performed. The study identifies mam-
mograms showing 1- to 5-cm cysts with focal microcalcifi-
cations and surrounding densities. Subsequent fine-needle
aspiration yielded turbid fluid with few cells. Which of the
following microscopic changes is most likely to be present in
these lesions?
A Apocrine metaplasia
B Ductal carcinoma in situ
C Fat necrosis
D Papillomatosis
E Sclerosing adenosis
361
3 6 2 U N I T I I Diseases of Organ Systems hyperplasia. She has been on postmenopausal estrogen-
progesterone therapy for the past 10 years. She has smoked 1
5 A 27-year-old woman feels a lump in her right breast. pack of cigarettes per day for the past 35 years. Which of the
She has normal menstrual cycles, she is G3, P3, and her last following is the most significant risk factor for the develop-
child was born 5 years ago. On examination a 2-cm, irregular, ment of lobular carcinoma in patients with such lesions?
firm area is palpated beneath the lateral edge of the areola. A Atypical cytologic changes
This lumpy area is not painful and is movable. There are no B History of smoking
lesions of the overlying skin and no axillary lymphadenop- C Hormone replacement therapy
athy. A biopsy specimen shows microscopic evidence of an D Postmenopausal age
increased number of dilated ducts surrounded by fibrous con- E Underlying BRCA1 gene mutation
nective tissue. Fluid-filled ducts with apocrine metaplasia also
are present. What is the most likely diagnosis?
A Fibroadenoma 10 A 25-year-old Jewish woman sees her physician after
B Fibrocystic changes finding a lump in her right breast. On physical examination,
C Infiltrating ductal carcinoma a 2-cm, firm, nonmovable mass is palpated in the upper outer
D Mammary duct ectasia quadrant. No overlying skin lesions and no axillary lymph-
E Traumatic fat necrosis adenopathy are present. The figure shows an excisional bi-
opsy specimen. The family history indicates that the patient’s
6 A 47-year-old woman has a routine health examination. mother, maternal aunt, and maternal grandmother have had
There are no remarkable findings except for a barely palpable similar lesions. Her 18-year-old sister has asked a physician
mass in the right breast. A mammogram shows an irregular, to determine whether she is genetically at risk of developing
1.5-cm area of density with scattered microcalcifications in the a similar disease. A mutated gene encoding for which of the
upper outer quadrant. A biopsy specimen from this area is ob- following is most likely to be found in her sister?
tained and microscopically shows ductal hyperplasia. Which A BRCA1
of the following is the most appropriate option for follow-up B Estrogen receptor (ER)
of this patient? C HER2/neu
A Cessation of smoking cigarettes D TP53
B Continued screening for breast cancer E Progesterone receptor (PR)
C Performing a simple mastectomy F RB1
D Testing for the BRCA1 oncogene 11 A clinical study is performed on postmenopausal wom-
E Prescribing broad-spectrum antibiotic therapy en living in Paris, France, who are between the ages of 45 and
70 years. All have been diagnosed with infiltrating ductal car-
7 A 34-year-old woman has noticed a bloody discharge cinoma positive for estrogen receptor (ER) and progesterone
from the nipple of her left breast for the past 3 days. On physi- receptor (PR), but negative for HER2 expression, which has
cal examination, the skin of the breasts appears normal, and been confirmed by biopsy and microscopic examination of tis-
no masses are palpable. There is no axillary lymphadenopa- sue. None has the BRCA1 or BRCA2 mutation. Which of the
thy. She has regular menstrual cycles and is using oral contra- following is most likely to indicate the highest relative risk of
ceptives. Excisional biopsy is most likely to show which of the developing the carcinomas seen in this group of women?
following lesions in her left breast? A Age at menarche older than 16 years
A Acute mastitis B Age at menopause younger than 45 years
B Fibroadenoma C First-degree relative with breast cancer
C Intraductal papilloma D Multiparity
D Phyllodes tumor E Prior diagnosis of mastitis
E Sclerosing adenosis
8 A 57-year-old man has developed bilateral breast en-
largement over the past 2 years. On physical examination,
the enlargement is symmetric and is not painful to palpation.
There are no masses. He is not obese and is not taking any
medications. Which of the following underlying conditions
best accounts for his findings?
A ACTH-secreting pituitary adenoma
B Choriocarcinoma of the testis
C Chronic glomerulonephritis
D Diabetes mellitus
E Micronodular cirrhosis
F Rheumatoid arthritis
9 A 58-year-old woman sees her naturopathic health
care provider for a routine health examination. There are no
remarkable findings on physical examination. A screening
mammogram shows a 0.5-cm irregular area of increased den-
sity with scattered microcalcifications in the upper outer quad-
rant of the left breast. Excisional biopsy shows atypical lobular
C H A P T E R 2 3 The Breast 3 6 3
12 A 54-year-old woman feels a lump in her left breast. On 14 A 63-year-old woman has a screening mammogram that
examination there is a firm, irregular mass in the lower outer shows an irregular density with microcalcifications. On physi-
quadrant. A mammogram shows a 2-cm density with focal cal examination, there are no lesions of the overlying skin, and
microcalcifications. Excisional biopsy shows intraductal and there is no axillary lymphadenopathy. An excisional biopsy
invasive carcinoma. Immunohistochemical staining is negative specimen shows no mass on sectioning. Microscopic examina-
for estrogen receptor (ER). FISH analysis (green = HER2; red = tion shows the findings in the figure. What is the most likely
chromosome 17 centromere) shows the findings in the figure. diagnosis?
When combined with doxorubicin, which of the following drugs A Colloid carcinoma
is most likely to be useful in treating this patient? B Ductal carcinoma in situ
A Hydroxyurea C Infiltrating ductal carcinoma
B Letrozole D Infiltrating lobular carcinoma
C Raloxifene E Medullary carcinoma
D Tamoxifen F Papillary carcinoma
E Trastuzumab
13 A 66-year-old nulliparous woman received hormone re- 15 A 48-year-old woman has noticed a red, scaly area of
placement therapy for 7 years following menopause at age 53 skin on her left breast that has grown slightly larger over the
years. Her BMI is 33. She now undergoes screening mammog- past 4 months. On physical examination, there is a 1-cm area
raphy, and an irregular mass is identified in the right breast. An of eczematous skin adjacent to the areola. The figure shows the
excisional biopsy yields a 1.5-cm mass that microscopically has microscopic appearance of the skin biopsy specimen. What is
invasive cells that are positive for estrogen receptor but negative the most likely diagnosis?
for HER2, with low proliferation markers and mutated PIK3CA A Apocrine metaplasia
gene. Following surgical removal of the mass, which of the fol- B Fat necrosis
lowing clinical courses will most likely occur over the next year? C Inflammatory carcinoma
A Detection of cancer in the left breast D Lobular carcinoma in situ
B Need for chemotherapy E Paget disease of the breast
C Very low likelihood of recurrence
D Need for treatment with trastuzumab
E Occurrence of widespread metastases
3 6 4 U N I T I I Diseases of Organ Systems
16 A 54-year-old woman noticed a lump in her right breast. 18 A 57-year-old woman has felt a lump in her left breast for 4
On examination, she has an ill-defined, 1-cm mass in the upper months. She has had new onset headaches associated with nau-
outer quadrant. The mass is cystic on ultrasound. An excision sea for the past month. Her physician palpates a firm but irregu-
is done, and microscopically the mass shows predominantly lar 2-cm mass in her left breast. CT imaging of her brain shows
fibrocystic changes, but the lesion shown in the figure also is leptomeningeal enhancement. A lumpectomy with axillary node
present. Fine-needle aspirates of both breasts reveal additional sampling is performed. Immunohistochemical staining of these
foci of similar cells. Which of the following breast lesions is cells shows absence of E-cadherin and HER2, but presence of es-
most likely to produce these findings? trogen receptor (ER) and progesterone receptor (PR). An H and
A Infiltrating ductal carcinoma E stained section is shown in the figure. No nodal metastases are
B Lobular carcinoma in situ present. Which of the following is the most likely diagnosis?
C Malignant phyllodes tumor A Lobular carcinoma
D Medullary carcinoma B Medullary carcinoma
E Mucinous (colloid) carcinoma C Metaplastic carcinoma
D Metastatic glioblastoma
E Phyllodes tumor
17 A 49-year-old woman felt a lump in her left breast 1
week ago. On examination, a firm, irregular mass is palpable 19 A 39-year-old woman has noticed an enlarging mass
in the upper outer quadrant of her left breast. There are no in her left breast for the past 2 years. The physician palpates
overlying skin lesions. The gross appearance of the excisional a 4-cm firm mass. Following biopsy, a simple mastectomy is
biopsy specimen is shown in the figure. Which of the follow- performed with axillary lymph node sampling. On gross sec-
ing additional findings is she most likely to have on physical tioning, the mass has a soft, tan, fleshy surface. Histologically,
examination? the mass is composed of large cells with vesicular nuclei and
A Axillary lymphadenopathy prominent nucleoli. There is a marked lymphocytic infiltrate
B Bloody discharge from the nipple within the tumor, and the tumor has a discrete, noninfiltrative
C Chest wall tenderness border. No axillary node metastases are present. The tumor
D Cushingoid facies cells are triple negative, for HER2, estrogen receptor (ER), and
E Mass in the opposite breast progesterone receptor (PR). What is the most likely diagnosis?
A Colloid carcinoma
B Infiltrating ductal carcinoma
C Infiltrating lobular carcinoma
D Medullary carcinoma
E Papillary carcinoma
F Phyllodes tumor
20 An epidemiologic study is conducted with male subjects
who have been diagnosed with breast carcinoma. Their demo-
graphic data, medical histories, family histories, and labora-
tory data are examined to identify factors that increase the risk
of cancer. Which of the following factors is most likely to be as-
sociated with the greatest number of male breast carcinomas?
A Age older than 70 years
B Asian ancestry
C ATM gene mutation
D Chronic alcoholism
E Gynecomastia
21 A study of women with breast carcinoma is done to de- C H A P T E R 2 3 The Breast 3 6 5
termine the presence and amount of estrogen receptor (ER) 25 A 51-year-old woman has noticed an area of swelling
and progesterone receptor (PR) in the carcinoma cells. Large with tenderness in her right breast that has worsened over the
amounts of ER and PR are found in the carcinoma cells of past 2 months. On physical examination, the 7-cm area of ery-
some patients. These receptors are not present in the cells of thematous skin is tender with a rough, firm surface resembling
other patients. The patients with positivity for ER and PR are an orange peel. There is swelling of the right breast, nipple re-
likely to exhibit which of the following traits? traction, and right axillary nontender lymphadenopathy. Ex-
A Greater immunogenicity cisional biopsy of skin and breast is most likely to show which
B Greater likelihood of metastases of the following lesions?
C Greater risk of familial breast cancer A Acute mastitis
D Higher response to therapy B Atypical epithelial hyperplasia
E Higher tumor stage C Fat necrosis
F Higher tumor grade D Infiltrating ductal carcinoma
E Sclerosing adenosis
22 A 26-year-old woman has felt a breast lump for the past
month and is worried because she has a family history of early
onset and bilateral breast cancers. On physical examination, A
there is a firm, 2-cm mass in the upper outer quadrant of her
left breast. A biopsy is done, and the specimen microscopically B
shows carcinoma. Genetic analysis shows that she is a carrier 26 A 26-year-old woman has noticed a lump in her right
of the BRCA1 gene mutation, as are her mother and sister. breast for the past year. A 2-cm, firm, circumscribed, mov-
Which of the following histologic types of breast carcinoma able mass is palpated in the lower outer quadrant. The figure
has the highest incidence in families such as hers? shows the excised mass (A) and the mammogram (B). What is
A Lobular carcinoma the most likely diagnosis?
B Medullary carcinoma A Fat necrosis
C Metaplastic carcinoma B Fibroadenoma
D Papillary carcinoma C Fibrocystic changes
E Tubular carcinoma D Infiltrating ductal carcinoma
E Mastitis
23 A 79-year-old, previously healthy woman feels a lump F Phyllodes tumor
in her right breast. The physician palpates a 2-cm firm mass in
the upper outer quadrant. Nontender right axillary lymphade-
nopathy is present. A lumpectomy with axillary lymph node
dissection is performed. Microscopic examination shows that
the mass is an infiltrating ductal carcinoma. Two of 10 axillary
nodes contain metastases. Flow cytometry on the carcinoma
cells shows a small aneuploid peak and high S-phase. Immu-
nohistochemical tests show that the tumor cells are positive
for estrogen and progesterone receptor (ER/PR), negative for
HER2/neu expression, and positive for cathepsin D expression.
What is the most important prognostic factor for this patient?
A Age at diagnosis
B DNA content in the carcinoma
C Estrogen receptor positivity
D Expression of stromal proteases in the carcinoma
E Histologic subtype of carcinoma
F Lack of HER2/neu expression in the carcinoma
G Presence of lymph node metastases
24 A study of gene expression profiling involving breast bi-
opsies showing invasive carcinoma of no specific type (NST)
is performed. A subset of these cases, comprising about 15%
of all cases, has the following characteristics: estrogen receptor
(ER) and progesterone receptor (PR) negative, HER2/neu nega-
tive, basal keratin positive, flow cytometry showing aneuploi-
dy and high proliferation rate, and association with BRCA1
mutations. Which of the following therapies is most likely to
be effective in women with this subset of NST breast cancer?
A Chemotherapy
B Radiation
C Surgery alone
D Tamoxifen
E Trastuzumab
3 6 6 U N I T I I Diseases of Organ Systems 29 A 48-year-old woman has felt a poorly defined lump in
her right breast for the past year. On examination, she has a
27 A 27-year-old woman in the third trimester of her third nontender, firm, 6-cm mass in the upper inner quadrant of her
pregnancy discovers a lump in her left breast. On physical ex- right breast. There are no lesions of the overlying skin and no
amination, a 2-cm, discrete, freely movable mass beneath the axillary lymphadenopathy. A biopsy is performed, and mi-
nipple is palpable. After the birth of a term infant, the mass croscopic examination of the specimen shows the findings in
appears to decrease in size. The infant is breastfed without dif- the figure. The mass is excised with a wide margin, but recurs
ficulty. What is the most likely diagnosis? 1 year later. After further excision, the lesion does not recur.
A Fibroadenoma What is the most likely diagnosis?
B Intraductal papilloma A Fibroadenoma
C Lobular carcinoma in situ B Fibrocystic changes
D Medullary carcinoma C Lobular carcinoma
E Phyllodes tumor D Phyllodes tumor
28 A 24-year-old woman notes a lump in her right breast E Tubular carcinoma
for the past month. She is concerned because her sister was di-
agnosed with a poorly differentiated “triple negative” breast
cancer at age 31. Ultrasonography of the breast shows a solid
mass. Fine needle aspiration is attempted but no diagnostic
cells are obtained. Mammography is performed and there is
a single 1-cm density with small clustered calcifications in the
right breast but no lesions of the opposite breast. Which of the
following is the best course of action for this patient?
A Biopsy to obtain tissue from the lesion
B Continued monthly breast self-examination
C Genetic testing for BRCA1 mutations
D Hormonal therapy with tamoxifen
E Radiologic imaging to detect metastases
ANSWERS 3 B Fat necrosis is typically caused by trauma to the
breast. The damaged, necrotic fat is phagocytosed by mac-
1 D This is accessory breast tissue with lactational change. rophages, which become lipid laden. The lesion resolves as a
Prolactin secretion from the adenohypophysis increases in collagenous scar within weeks to months. The firm scar can
postpartum women to support milk production in breast mammographically and grossly resemble a carcinoma. An
lobules. Oxytocin released from the posterior pituitary abscess may form a palpable but painful mass lesion, and
stimulates myoepithelial cells to contract during nursing. often from Staphylococcus aureus infection when localized. A
The remaining hormones listed do not have a direct effect fibroadenoma is a neoplasm, and tumors are not induced by
upon breast tissue. The presence of the breast tissue in the trauma. Inflammatory carcinoma refers to dermal lymphatic
axilla represents accessory breast tissue, and can explain invasion by an underlying breast carcinoma, giving a rough
the origins of breast cancer in women following simple red-to-orange appearance to the skin. Sclerosing adenosis is
mastectomy. a feature of fibrocystic changes, a common cause of nontrau-
matic breast lumps.
PBD9 1045 BP9 705 PBD8 1067 BP8 739
PBD9 1047 BP9 707 PBD8 1070 BP8 742
2 D Staphylococcal acute mastitis typically produces lo-
calized abscesses, whereas streptococcal infections tend to 4 A Nonproliferative cysts are quite common in the breast.
spread throughout the breast, because streptococci often When they are fluid-filled, they are unlikely to contain prolif-
produce streptolysins. Acute mastitis can be associated with erative elements. The cells lining these cysts may be flattened
the first few months of breastfeeding. Candida may cause cuboidal to atrophic, but often have abundant pink cyto-
some local skin irritation, but is likely to become invasive plasm resembling apocrine change. Microcalcifications may
only in immunosuppressed patients. Lactobacillus acidophilus be seen in both benign and malignant breast lesions, but in
is the organism used to produce fermented nonhuman milk. the case of cysts they represent calcified secretions. If excised,
Listeriosis can be spread by contaminated food, including the intact cysts may have a blue to brown color. Ductal carci-
milk products, not by human milk.
PBD9 1046 BP9 707 PBD8 1069 BP8 742
C H A P T E R 2 3 The Breast 3 6 7
nomas are likely to be solid lesions. Fat necrosis may contain that would not remain indolent for 2 years. Chronic renal
many macrophages, but also connective tissue, producing a failure is unlikely to have this consequence. Diabetes mel-
firm lesion. Papillomatosis is a proliferative feature in fibro- litus slightly increases the risk for breast cancer in women.
cystic changes that tends to form a solid lesion. Sclerosing Rheumatoid nodules can appear in various locations along
adenosis produces a firm, fibrous lesion. with rheumatoid arthritis, but they rarely occur in the breast
and are unlikely to be bilateral.
PBD9 1048 BP9 705–706 PBD8 1071 BP8 739–740
PBD9 1049–1050 BP9 714 PBD8 1093 BP8 750
5 B Nonproliferative (fibrocystic) changes account for the
largest category of breast lumps. These lesions are probably 9 A Atypical lobular hyperplasia and atypical ductal hy-
related to cyclic breast changes that occur during the men- perplasia increase the risk of breast cancer fivefold; the risk
strual cycle. In about 30% of cases of breast lumps, no specific affects both breasts and is higher in premenopausal women
pathologic diagnosis can be made. Fibrocystic changes include or women who have a family history of breast cancer. Smok-
ductal proliferation, ductal dilation (sometimes with apocrine ing and exogenous estrogen therapy are not well-established
metaplasia), and fibrosis. A fibroadenoma is a discrete mass risk factors for breast cancer. The BRCA1 mutation accounts
formed by a proliferation of fibrous stroma with compressed for about 10% to 20% of familial breast carcinomas and only
ductules. Carcinomas have proliferations of atypical neoplas- a few percent of all breast cancers.
tic cells that fill ducts and can invade stroma. Inspissated duct
secretions may produce duct ectasia with a surrounding lym- PBD9 1050–1051 BP9 706 PBD8 1073 BP8 740–741
phoplasmacytic infiltrate. Trauma with subsequent fat necrosis
may produce a localized, firm lesion that mimics carcinoma, 1 0 A The biopsy specimen shows an invasive breast can-
but microscopically shows macrophages and neutrophils sur- cer. Given the young age of the patient and the strong family
rounding necrotic adipocytes, and healing leaves a fibrous scar. history of breast cancer, it is reasonable to assume that she
has inherited an altered gene that predisposes to breast can-
PBD9 1048 BP9 705–706 PBD8 1071 BP8 739–741 cer. There are two known breast cancer susceptibility genes:
BRCA1 and BRCA2. Both are cancer suppressor genes. Spe-
6 B Fibrocystic changes without epithelial hyperplasia do cific mutations of BRCA1 are common in some ethnic groups,
not suggest a significantly increased risk of breast cancer. such as Ashkenazi Jews. Estrogen receptors are expressed
Moderate to florid hyperplasia increases the risk twofold, in 50% to 75% of breast cancers. Their presence bodes well
and atypical ductal or lobular hyperplasias increase the risk for therapy with hormone receptor antagonists. There is no
fivefold. The risk in this patient is not great enough to sug- known relationship between the structure of the estrogen
gest radical or simple mastectomy at this time, but follow-up receptor gene and susceptibility to breast cancer. Likewise,
is needed. Breast cancers are not associated with tobacco use. presence of progesterone receptors in the cancer cells indi-
The BRCA1 gene accounts for a small percentage of breast cates potential response to hormonal therapy, not risk for
cancers, primarily in families in which cancer onset occurs breast cancer. HER2/neu is a growth factor receptor gene that
at a young age, and genetic testing of all persons at risk for is amplified in certain breast cancers and is a marker of poor
breast cancer is not warranted. These proliferative changes prognosis, not susceptibility. There is alteration of TP53 in
are not the result of infection. many cancers, typically acquired and not familial, including
breast carcinomas, but it does not have predictive value for
PBD9 1048–1049 BP9 705–706 PBD8 1071–1073 BP8 739–741 risk. Inheritance of RB1 mutations increases the risk for reti-
noblastoma and osteosarcomas, but not breast carcinomas.
7 C Intraductal papillomas are usually solitary and small-
er than 1 cm. They are located in large lactiferous sinuses PBD9 1051–1055 BP9 708–709 PBD8 1077–1078 BP8 744
or large ducts, and have a tendency to bleed, though they
are benign. Abscesses complicating mastitis organize with 11 C The relative risk of breast cancer increases with
a fibrous wall. Fibroadenomas contain ducts with stroma various factors, but family history is one of the strongest. A
and are not highly vascular; these lesions are not located in history of bilateral breast disease and earlier age of onset of
ducts. Phyllodes tumors also arise from intralobular stroma cancer increase the risk. The earlier age of onset increases the
and can be malignant, but they do not invade ducts to cause risk of identifying a BRCA1 or BRCA2 mutation. A longer re-
bleeding. Sclerosing adenosis, a lesion occurring with fibro- productive life, with early menarche (<11 years old) and late
cystic changes, has abundant collagen, not vascularity. menopause (>55 years old), and nulliparity increase the risk
of breast cancer, probably because of increased estrogen ex-
PBD9 1049–1050 BP9 708 PBD8 1072–1073 BP8 743 posure. “Soft” risk factors include exogenous estrogens and
obesity. Mastitis does not affect the risk of breast cancer.
8 E Micronodular cirrhosis is most often a consequence of
chronic alcoholism and impairs hepatic estrogen metabolism, PBD9 1052–1053 BP9 708–709 PBD8 1076–1077 BP8 743–745
which can lead to bilateral gynecomastia. ACTH-secreting
pituitary adenomas cause truncal obesity because of Cushing 1 2 E The expression of HER2/neu, an epidermal growth
syndrome. Choriocarcinomas of the testis produce human factor receptor, suggests that biotherapy with trastuzumab
chorionic gonadotropin and may cause some breast enlarge- may have some effectiveness. Drug names with the suf-
ment. Choriocarcinomas are highly malignant neoplasms fix -mab are monoclonal antibodies that target a specific
3 6 8 U N I T I I Diseases of Organ Systems
biochemical component of cells. This form of biotherapy change. The macrophages in fat necrosis do not infiltrate the
is useful because normal breast cells do not express HER2/ skin and do not have the atypical nuclei seen in the figure.
neu. Doxorubicin is a standard chemotherapeutic agent that Inflammatory carcinoma does not refer to a specific histologic
is part of various multiagent protocols. Hydroxyurea is type of breast cancer; rather, it describes the involvement of
a cycle-acting agent that is not useful in breast cancer. Le- dermal lymphatics by infiltrating carcinoma, and there may
trozole is an aromatase inhibitor that is useful for treating be thickening and a reddish-orange appearance to the skin.
ER-positive breast cancers. Raloxifene is a selective estrogen In lobular carcinoma in situ, terminal ducts or acini within
receptor modulator (SERM) that reduces risk for breast can- the breast are filled with neoplastic cells.
cer and reduces osteoporosis. Tamoxifen is an antiestrogenic
compound that has effectiveness in the treatment of breast PBD9 1057, 1059 BP9 710 PBD8 1080–1081 BP8 745–746
cancers positive for ER/PR.
16 B Among primary malignancies of the breast, lobular
PBD9 1055–1057 BP9 709–713 PBD8 1090 BP8 745, 747, 749 carcinoma in situ (LCIS) is most likely to be bilateral. LCIS
may precede invasive lesions by several years. Lobular car-
13 C This luminal A form comprises over half of all in- cinoma may be mixed with ductal carcinoma, and it may be
vasive breast cancers, and it tends to be low grade, and lack difficult to distinguish them histologically. The other neo-
BRCA1, BRCA2, TP53, and CHEK2 familial gene mutations. plasms listed are less likely to be bilateral and more likely to
It is often responsive to antiestrogen hormonal therapy, al- produce a single mass effect.
though surgery alone can be curative. Even with metastases,
the course is prolonged. This patient has multiple risks for PBD9 1059–1060 BP9 710–711 PBD8 1082–1083 BP8 745–747
breast cancer, including nulliparity, obesity, and hormone
replacement therapy. Breast cancer at her age is less likely to 1 7 A This irregular, infiltrative mass is an infiltrating (in-
be familial. Trastuzumab is useful for HER2-positive breast vasive) ductal carcinoma, the most common form of breast
cancers. cancer. Breast carcinomas are most likely to metastasize to
regional lymph nodes. By the time a breast cancer becomes
PBD9 1055–1056 BP9 709–713 PBD8 1084–1085 BP8 745 palpable, lymph node metastases are present in more than
50% of patients. A bloody discharge from the nipple most
14 B An intraductal carcinoma, or ductal carcinoma in often results from an intraductal papilloma. Pain in the chest
situ (DCIS), may not produce a palpable mass. The figure wall could be bone metastases, but less likely local invasion,
shows ducts that contain large, atypical cells in a cribriform and there is a margin of adipose tissue around the mass in
pattern. If grossly soft, white material is extruded from small the specimen shown. Breast cancers are associated in rare
ducts when pressure is applied, then there is necrosis of the cases with ectopic corticotropin secretion or Cushing syn-
neoplastic cells in the ducts (that leads to dystrophic calci- drome. Lobular carcinomas are more often bilateral, but they
fication), and the term comedocarcinoma is applicable. Intra- are less common than infiltrating ductal carcinomas.
ductal carcinomas represent about one fourth of all breast
cancers. If not excised, such lesions become invasive. Intra- PBD9 1060–1064 BP9 708–711 PBD8 1083–1085 BP8 743–749
ductal carcinoma has several other histologic patterns, in-
cluding noncomedo DCIS and Paget disease of the nipple, 18 A In this lobular carcinoma, note the pleomorphic cells
in which extension of the malignant cells to the skin of the infiltrating single file through the stroma. The metastatic
nipple and areola produces the appearance of a seborrheic profile of this cancer includes the carcinomatous meningitis
dermatitis. Colloid carcinomas occur about as frequently suggested by her leptomeningeal enhancement, as well
as medullary carcinomas, but they are often positive for as intra-abdominal metastases. E-cadherin is an adhesion
estrogen receptor and progesterone receptor, and the prog- m olecule that serves as a tumor suppressor, and its loss
nosis is better than average. Infiltrating ductal carcinomas characterizes another infiltrating carcinoma—signet ring
tend to produce irregular, firm, mass lesions because they carcinoma of the stomach. Medullary carcinomas are sol-
are more invasive. Infiltrating lobular carcinomas can have id masses of cells with little desmoplasia, but prominent
a diffuse pattern without significant mass effect. Medullary lymphoid infiltrates. Metaplastic carcinomas are rare in
carcinomas tend to be large masses; microscopically, they humans and have a component resembling another tissue,
have nests of large cells with a surrounding lymphoid in- such as squamous carcinomas. In the setting of a malignant
filtrate. True papillary carcinomas are rare, although a pap- breast mass, any brain lesion is a suspected metastatic le-
illary component may be present in other types of breast sion; although glioblastoma is capable of extracranial me-
carcinoma. tastases, this is rare, and there should be a bulky cerebral
mass present. Phyllodes tumors can be malignant, with a
PBD9 1057–1058 BP9 710 PBD8 1080–1081 BP8 745–748 stromal component, but these are typically bulky masses,
and there is a microscopic leaflike pattern of cystic spaces
1 5 E Paget cells are large cells that have clear, mucinous lined by epithelium.
cytoplasm and infiltrate the skin overlying the breast. They
are malignant and extend to the skin from an underlying PBD9 1065 BP9 711–712 PBD8 1085–1087 BP8 747
breast carcinoma, which may be occult, so that Paget disease
may be the first sign of malignancy. Apocrine metaplasia af- 1 9 D Medullary carcinomas account for about 1% to 5%
fects the cells lining the cystically dilated ducts in fibrocystic of all breast carcinomas. They tend to occur in women at
C H A P T E R 2 3 The Breast 3 6 9
younger ages than do most other breast cancers. Despite the elderly can be successful. An increased DNA content with
poor prognostic indicators (such as absence of HER2, ER, aneuploidy and a high S-phase suggests a worse prognosis,
and PR), medullary carcinomas have a better prognosis than but staging is still a more important determinant of prognosis.
most other breast cancers. Perhaps the infiltrating lympho- Estrogen receptor positivity suggests a better response to hor-
cytes are a helpful immune response. Colloid carcinomas oc- monal manipulation of the tumor, whereas expression of HER2/
cur about as frequently as medullary carcinomas, but they neu suggests responsiveness to biotherapy with the monoclonal
are often positive for ER, and the prognosis is better than av- antibody trastuzumab. Some histologic types of breast cancer
erage. Infiltrating ductal and infiltrating lobular carcinomas have a better prognosis than others, but staging is a more im-
tend not to produce large, localized lesions because they are portant factor than histologic type. The expression of stromal
more invasive, and they lack a distinct lymphoid infiltrate. proteases, such as cathepsin D, predicts metastases, but in this
True papillary carcinomas are quite rare, although other case “the horse is out of the barn,” and metastasis has occurred.
types of breast carcinoma may have a papillary component.
The phyllodes tumor is typically large, but it has stromal and PBD9 1066–1068 BP9 712–713 PBD8 1089–1090 BP8 748–749
glandular components.
24 A This is the basal-like subset of NST breast cancers
PBD9 1065–1066 BP9 712 PBD8 1087 BP8 747–748 that is triple negative for the usual immunohistochemical
markers. Hence, lack of ER positivity predicts that antihor-
2 0 A Male breast cancers are rare, and they occur primar- monal therapy with tamoxifen will not be of benefit, and
ily among the elderly. Additional risk factors include first- lack of HER2/neu indicates that trastuzumab will be inef-
degree relatives with breast cancer, decreased testicular fective. The basal-like cancers are highly aggressive and tend
function, exposure to exogenous estrogens, infertility, obe- to metastasize early, so containment with surgery or radia-
sity, prior benign breast disease, exposure to ionizing radia- tion is unlikely. However, some of them are cured by chemo-
tion, and residency in Western countries. Of cases in men, therapy. This emphasizes the importance of gene expression
4% to 14% are attributed to germline BRCA2 mutations, less profiling, so that treatment is individualized to each cancer
frequently for BRCA1, and ATM mutations in less than 1%. patient for the best chance of success.
Gynecomastia does not seem to be a risk factor.
PBD9 1062 BP9 713 PBD8 1084–1085 BP8 745
PBD9 1066 BP9 714 PBD8 1093–1094 BP8 750
25 D The gross appearance of the skin is consistent with
2 1 D The estrogen receptor and progesterone receptor invasion of dermal lymphatics by carcinoma—the so-called
(ER and PR) status helps predict whether chemotherapy inflammatory carcinoma, which is not a histologic type of
with antiestrogen compounds such as tamoxifen would be breast cancer, but a descriptive phrase based upon the gross
effective; however, the correlation is not perfect. ER and appearance (peau d’orange) resembling an inflammatory
PR do not affect immunogenicity and are not targets for process. Nipple retraction and nontender axillary lymphade-
immunotherapy. In contrast, immunotherapy targeted nopathy also suggest invasive ductal carcinoma. Atypical
to the overexpressed HER2/neu gene is being used. The ductal hyperplasia may increase the risk of carcinoma, but it is
overall prognosis may be predicted from several factors, not capable of invasion and does not produce visible surface
including histologic type, histologic grade, presence of skin changes. Acute mastitis may produce pain and swelling,
metastases, degree of aneuploidy, and tumor stage. A but it is more likely to occur in association with breastfeed-
family history and the presence of specific mutations such ing, and as an inflammatory process would be more likely to
as BRCA1 or BRCA2 correlate with familial risk of breast produce painful lymphadenopathy. Fat necrosis on pal-
cancer. pation can mimic that of carcinoma, but the skin is not
involved. Sclerosing adenosis is a feature of benign fibro-
PBD9 1066–1068 BP9 713 PBD8 1076 BP8 745 cystic changes producing breast lumps, but it has no skin
involvement.
2 2 B Patients with the BRCA1 gene mutation have a high
incidence of carcinomas with medullary features that are PBD9 1066–1067 BP9 712 PBD8 1083, 1089 BP8 747
poorly differentiated and triple negative (do not express the
HER2/neu protein, and are negative for estrogen and pro- 2 6 B Grossly and radiographically, this patient has a dis-
gesterone receptors). crete mass that in a woman her age is most likely a fibroad-
enoma. Fat necrosis and infiltrating cancers are masses with
PBD9 1065 BP9 712 PBD8 1087 BP8 747 irregular outlines. Fibrocystic changes are generally irregu-
lar lesions, not discrete masses. Mastitis has a more diffuse
2 3 G Many factors affect the course of breast cancer. The involvement, without mass effect. Phyllodes tumors are typi-
involvement of axillary lymph nodes is the most important cally much larger and are far less common.
prognostic factor listed. If there is no spread to axillary nodes,
the 10-year survival rate is almost 80%. It decreases to 35% to PBD9 1069 BP9 707–708 PBD8 1091–1092 BP8 742–743
40% with 1 to 3 positive nodes, and to 15% with more than 10
positive nodes. Increasing age is a risk for breast cancer, but age 2 7 A Fibroadenomas are common and may enlarge during
alone does not indicate a prognosis, and treatment of cancers in pregnancy or late in each menstrual cycle. Most intraductal
3 7 0 U N I T I I Diseases of Organ Systems
papillomas are smaller than 1 cm and are not influenced by then be instituted that may include additional studies and
hormonal changes. Lobular carcinoma in situ is typically an pharmacologic therapies.
ill-defined lesion without a mass effect. Medullary carcinomas
tend to be large; they account for only about 1% of all breast PBD9 1045–1046, 1069 BP9 705–708 PBD8 1068, 1091 BP8 739, 742
carcinomas. Phyllodes tumors are uncommon and tend to be
larger than 4 cm. 2 9 D Phyllodes tumors, although grossly and microscopi-
cally similar to fibroadenomas, occur at an older age, are
PBD9 1069 BP9 707–708 PBD8 1091–1092 BP8 742–743 larger, and are more cellular than fibroadenomas; they can
recur locally following excision, but rarely metastasize. The
2 8 A Her age would suggest the lesion is probably benign, figure shows cellular stroma protruding into spaces lined by
and even fibroadenomas and fibrocystic changes can have a single layer of cuboidal epithelium. In contrast, fibrocystic
calcifications. The fibrous component of a fibroadenoma or changes can produce a breast lump, but usually not as large
fibrocystic changes can make it difficult to aspirate cells from as 6 cm, and without firm areas of cellular stroma. A lobular
them. However, the family history and the mammographic carcinoma has malignant-appearing epithelial cells in clus-
appearance of small clustered calcifications are concerning ters and rows and may not even produce a significant mass
for carcinoma. A delay in diagnosis and treatment of breast effect. Tubular carcinomas of the breast are uncommon, most
cancer decreases survival. Although BRCA1 mutations are are less than 1 cm in diameter, and most have small tubular
associated with HER2 and ER- and PR-negative breast can- structures in a noncellular stroma.
cers, the lesion must still be diagnosed. Based upon the his-
tologic findings and molecular markers, a treatment plan can PBD9 1069–1070 BP9 707 PBD8 1092–1093 BP8 743
CHAPTER
24The Endocrine System
PBD9 Chapter 24 and PBD8 Chapter 24: The Endocrine System
BP9 Chapter 19 and BP8 Chapter 20: The Endocrine System
1 A 25-year-old woman has noted breast secretions for the 4 A 41-year-old woman notices that her gloves from the
past month. She is not breastfeeding and has never been preg- previous winter no longer fit her hands. Her facial features
nant. She has not menstruated for the past 5 months. Physi- have become coarse in the past year, and her voice seems deeper.
cal examination yields no abnormal findings. MRI of the brain On physical examination, her blood pressure is 140/90 mm
shows a 0.7-cm mass within the sella turcica. Which of the fol- Hg. There is decreased sensation to pinprick over the palms
lowing additional complications is she most likely to have? in the distribution of her thumb and first two fingers. A radio-
A Acromegaly graph of the foot shows an increased amount of soft tissue be-
B Cushing disease neath the calcaneus. A chest radiograph shows cardiomegaly.
C Hyperthyroidism Laboratory studies indicate a fasting serum glucose level of
D Infertility 138 mg/dL and hemoglobin A1c level of 8.6%. Which of the
E Neurologic dysfunction following additional test results is most likely to indicate the
cause of her physical and laboratory findings?
2 A 20-year-old man’s closest friends tell him he looks dif- A Abnormal glucose tolerance test result
ferent now than a year ago, with coarse features. He bought B Failure of growth hormone suppression
new shoes with his usual size and they do not fit. A year later C Hyperprolactinemia
his 23-year-old brother has similar problems. Both of them D Increased serum TSH level
have hyperglycemia. Which of the following genetic altera- E Loss of diurnal serum cortisol levels
tions is most likely present in both brothers? 5 A 39-year-old G2, P2 woman, whose last pregnancy was
A Germline mutation of AIP 14 years ago, has had absent menstrual cycles for 6 months.
B Overexpression of cyclin D1 She also reports expression of milk from her breasts. On physi-
C Fusion of PAX8-PPARG cal examination, she is normotensive. She is 150 cm tall and
D Loss of function mutation in PTEN weighs 63 kg (body mass index 28). Secondary sex character-
E Loss of VHL heterozygosity istics are normal. Laboratory testing indicates that β-human
chorionic gonadotropin level is normal. She has a normal
3 A 39-year-old woman has had no menstrual periods for growth hormone stimulation test. CT scan of the head shows
the past year, along with malaise, cold intolerance, and loss of no abnormalities of bone and no hemorrhage. Brain MRI
body hair. She has had headaches for the past 5 months. On shows fluid density within a normal-sized sella turcica. What
physical examination her lateral visual fields are reduced. She is the most likely diagnosis?
is most likely to have a neoplasm composed of which of the A Craniopharyngioma
following cell types? B Empty sella syndrome
A Beta C Hereditary hemochromatosis
B Chief D Prader-Willi syndrome
C Chromaffin E Prolactinoma
D Chromophobe F Sheehan syndrome
E Glomerulosa
F Parafollicular 371
3 7 2 U N I T I I Diseases of Organ Systems 9 A 23-year-old man has experienced headaches, polyuria,
and visual problems for the past 3 months. On physical exami-
6 A 21-year-old woman delivers a term infant after an nation, he has bilateral temporal visual field deficits. CT scan
uncomplicated pregnancy. The placenta cannot be deliv- of the head shows a large, partially calcified, cystic mass oc-
ered, however, and there is substantial hemorrhage, requir- cupying the sellar and suprasellar areas. Laboratory findings
ing transfusion of 10 U of packed RBCs. She must undergo a show a serum prolactin concentration of 60 ng/mL and serum
hysterectomy. Over the next 3 months, she is unable to pro- sodium level of 152 mEq/L. Serum calcium, phosphate, and
duce sufficient milk to breastfeed her infant, and she becomes glucose levels are normal. The mass is excised, and histologic
increasingly fatigued. Laboratory studies show Na+, 134 examination shows a mixture of squamous epithelial elements
mmol/L; K+, 5.2 mmol/L; Cl–, 88 mmol/L; CO2, 23 mmol/L; and lipid-rich debris containing cholesterol crystals. Which of
glucose, 59 mg/dL; calcium, 9.3 mg/dL; phosphorus, 3.5 mg/ the following lesions is most consistent with the clinical and
dL; and creatinine, 0.9 mg/dL. Over the next 5 months, her laboratory findings in this patient?
menstrual cycles do not return. Which of the following labora- A Craniopharyngioma
tory findings is now most likely to be reported in this woman? B Metastases from a lung neoplasm
A Decreased corticotropin-releasing hormone C Multiple endocrine neoplasia type 1
B Decreased oxytocin D Multiple endocrine neoplasia type 2
C Failure of antidiuretic hormone release E Prolactinoma
D Failure of growth hormone stimulation
E Increased corticotropin 10 A 42-year-old woman has a sudden onset of fever with
F Increased dopamine headache, nausea, diaphoresis, and palpitations. On physical
examination her temperature is 39.2° C; pulse, 115/min; irreg-
7 A 42-year-old man has had polyuria and polydipsia for ular respiratory rate, 30/min; and blood pressure, 150/85 mm
the past 4 months. His medical history shows that he fell off Hg. Deep tendon reflexes are 4+ bilaterally. Her outstretched
a ladder and hit his head just before the onset of these prob- hands exhibit a high frequency tremor. Which of the following
lems. On physical examination, there are no specific findings. drugs should she receive emergently?
Laboratory findings include serum Na+, 155 mmol/L; K+, 3.9 A Aspirin
mmol/L; Cl–, 111 mmol/L; CO2, 27 mmol/L; glucose, 84 mg/ B Hydrocortisone
dL; creatinine, 1 mg/dL; and osmolality, 350 mOsm/mL. The C Insulin
urine specific gravity is 1.002. This patient is most likely to D Propranolol
have a deficiency of which of the following hormones? E Tetracycline
A Corticotropin
B Melatonin 11 A 47-year-old woman has had increasing fatigue with
C Oxytocin dyspnea and reduced exercise tolerance for the past year. On
D Prolactin examination she has nonpitting edema of the lower extremi-
E Vasopressin ties. Laboratory studies show a serum TSH level of 10 mU/L
and T4 level of 2 μg/dL. She is most likely to have pathologic
8 A 69-year-old man has become progressively obtunded findings affecting which of the following cells?
over the past week. He has an 80 pack-year history of smoking A Hypophyseal basophils
cigarettes. On physical examination, he is afebrile and normo- B Hypophyseal pituicytes
tensive. A head CT scan shows no intracerebral hemorrhag- C Hypothalamic glial cells
es. Laboratory findings include serum Na+ of 115 mmol/L, D Hypothalamic neurons
K+ of 4.2 mmol/L, Cl– of 85 mmol/L, and bicarbonate of 23 E Thyroid C cells
mmol/L. The serum glucose is 80 mg/dL, urea nitrogen is 19 F Thyroid follicular cells
mg/dL, and creatinine is 1.7 mg/dL. Which of the following
neoplasms is most likely to be present in this man? 12 A 2-year-old child has failure to thrive since infancy.
A Adenohypophyseal adenoma Physical examination shows that the child is short and has
B Adrenocortical carcinoma coarse facial features, a protruding tongue, and an umbilical
C Pheochromocytoma hernia. As the child matures, profound intellectual disability
D Small cell lung carcinoma becomes apparent. A deficiency of which of the following hor-
E Renal cell carcinoma mones is most likely to explain these findings?
A Cortisol
B Insulin
C Norepinephrine
D Somatostatin
E Thyroxine (T4)
C H A P T E R 2 4 The Endocrine System 3 7 3
is enlarged but painless; there are no other remarkable find-
ings. Laboratory studies show a serum T4 level of 12 μg/dL
and a TSH level of 0.4 mU/L. A year later she is euthyroid.
Which of the following is most indicative of the pathogenesis
of this patient’s disease?
A Activational mutations in the RET proto-oncogene
B Anti–thyroid peroxidase antibodies
C Irradiation of the neck during childhood
D Prolonged iodine deficiency
E Recent viral upper respiratory tract infection
13 A 43-year-old woman has had increasing lethargy and 16 A 20-year-old woman and her twin sister both experi-
weakness over the past 3 years. She has cold intolerance and ence increasing diplopia. Their conditions develop within
wears a sweater in the summer. One year ago, she had men- 3 years of each other. On physical examination, they have
orrhagia, but now she has oligomenorrhea. She has difficulty exophthalmos and weak extraocular muscle movement. The
concentrating, and her memory is poor. She has chronic con- thyroid gland is diffusely enlarged but painless in each sister,
stipation. On physical examination, her temperature is 35.5° C, and there is no lymphadenopathy in either woman. Which of
pulse is 54/min, respirations are 13/min, and blood pres- the following serum laboratory findings is most likely to be
sure is 110/70 mm Hg. She has alopecia, and her skin ap- reported in these sisters?
pears coarse and dry. Her face, hands, and feet appear puffy, A Decreased free thyroxine level
with doughlike skin. Laboratory findings show hemoglobin, B Decreased thyroid-stimulating hormone level
13.8 g/dL; hematocrit, 41.5%; glucose, 73 mg/dL; and creati- C High titer thyroid peroxidase autoantibodies
nine, 1.1 mg/dL. The representative microscopic appearance D Increased thyrotropin-releasing hormone level
of her causative disease is shown in the figure. Which of the E Increased triiodothyronine level
following serologic test findings is most likely to be positive
in this woman?
A Anticentromere antibody 17 A 21-year-old woman has noted increasing fatigue and
B Anti–double-stranded DNA antibody a 7-kg weight loss without dieting over the past 4 months.
C Anti–Jo-1 antibody She also has increasing anxiety and nervousness with diarrhea.
D Antimitochondrial antibody Physical examination shows a diffusely enlarged thyroid
E Antiribonucleoprotein antibody gland. Her temperature is 37.5° C, pulse is 103/min, respi-
F Anti–thyroid peroxidase antibody rations are 28/min, and blood pressure is 140/75 mmHg. A
radionuclide scan of the thyroid shows a diffuse increase in
14 A 37-year-old woman has had difficulty swallowing uptake. The figure shows the representative microscopic ap-
and a feeling of fullness in the anterior neck for the past week. pearance of the thyroid gland. What is most likely to produce
She is recovering from a mild upper respiratory tract infection these findings?
1 month ago. On physical examination, her temperature is A Antibodies against TSH receptor
37.4° C, pulse is 74/min, respirations are 16/min, and blood B Dietary deficiency of iodine
pressure is 122/80 mm Hg. Palpation of her diffusely enlarged C Irradiation of the neck
thyroid elicits pain. Laboratory studies show an increased se- D Maternal deficiency in T4
rum T4 level and a decreased TSH level. Two months later, she E Mutation in the RET proto-oncogene
no longer has these complaints. The T4 level is now normal.
Which of the following conditions is most likely to have pro-
duced these findings?
A Hashimoto thyroiditis
B Medullary thyroid carcinoma
C Subacute granulomatous thyroiditis
D Toxic follicular adenoma
E Toxic multinodular goiter
15 A 30-year-old woman has given birth to her second child.
She develops heat intolerance and loses more weight than ex-
pected postpartum. On physical examination, her thyroid gland
3 7 4 U N I T I I Diseases of Organ Systems 22 A 38-year-old woman felt a small bump on the right side
of her neck 1 month ago, and it has not changed since then.
18 A 40-year-old man notes weight loss, increased appetite, Physical examination shows a 1-cm painless nodule palpable
and double vision for 6 months. On physical examination, his in the right lower pole of the thyroid gland. There is no lymph-
temperature is 37.7° C, pulse is 106/min, respirations are adenopathy. Radionuclide scanning shows that the nodule
20/min, and blood pressure is 140/80 mm Hg. A fine tremor does not absorb radioactive iodine, and no other nodules are
is observed in his outstretched hands. He has bilateral prop present. A fine-needle aspiration biopsy of the nodule is done,
tosis and corneal ulceration. Laboratory findings include a and the cytologic features are those of a follicular neoplasm.
serum TSH level of 0.1 mU/L. A radioiodine scan indicates Which of the following laboratory findings is most likely to be
increased diffuse uptake throughout the thyroid. He receives present in this patient?
propylthiouracil therapy, and his condition improves. Which A Anti–TSH receptor immunoglobulins
of the following best describes the microscopic appearance of B High free T4
his thyroid gland before therapy? C Low T3
A Destruction of follicles, lymphoid aggregates, and D Normal TSH
E Anti–thyroid peroxidase antibodies
Hürthle cell metaplasia
B Enlarged thyroid follicles lined by flattened epithe- 23 A 30-year-old woman has a 6-month history of weight
loss (3 kg), hand tremors, mild watery diarrhea, and heat intol-
lial cells erance. On physical examination, vital signs are temperature,
C Follicular destruction with inflammatory infiltrates 37.3° C; pulse, 103/min with sinus rhythm; respirations, 20/
min; and blood pressure, 125/85 mm Hg. She has a 1-cm firm,
containing giant cells painless nodule palpable on the left side of her neck. There is
D Nodules with nests of cells separated by hyaline no lymphadenopathy. No other abnormal findings are noted.
Laboratory findings include a total serum T4 of 11.6 μg/dL
stroma that stains with Congo red with TSH of 0.2 mU/L. A scintigraphic scan shows more
E Papillary projections in thyroid follicles and lym- uptake of radioactive iodine into the nodule than the sur-
rounding thyroid. A partial thyroidectomy is performed, and
phoid aggregates in the stroma microscopic examination of the excised nodule shows well-
differentiated thyroid follicles without vascular or capsular
19 A 45-year-old woman from Kathmandu, Nepal, reports invasion. Molecular analysis of this nodule is most likely to
a feeling of fullness in her neck, but has no other concerns. reveal which of the following genetic changes?
The enlargement has been gradual and painless for more than A Activating missense mutation of GNAS1 gene
1 year. Physical examination confirms diffuse enlargement of B Fusion gene formed by PAX8 and PPARG genes
the thyroid gland without any apparent masses or lymphade- C Gain of function mutation of TSH receptor gene
nopathy. Laboratory studies of thyroid function show a nor- D Mutational activation of RET tyrosine kinase
mal free T4 level and a slightly increased TSH level. What is
the most likely cause of these findings? receptor
A Diffuse nontoxic goiter E Overexpression of cyclin D1 (CCND1) gene
B Follicular adenoma F Stop codon mutation of autoimmune receptor
C Hashimoto thyroiditis
D Papillary carcinoma (AIRE) gene
E Subacute granulomatous thyroiditis
F Toxic multinodular goiter 24 A 44-year-old, otherwise healthy woman feels a small
lump on the left side of her neck. A firm, painless, 1.5-cm
20 A 14-year-old girl noticed gradual neck enlargement cervical lymph node is palpable. The thyroid gland is not en-
during the past 8 months. On physical examination her larged. A chest radiograph is unremarkable. Laboratory find-
thyroid gland is diffusely enlarged. Her serum TSH level is ings include serum glucose, 83 mg/dL; creatinine, 1.2 mg/
normal. A dietary history is most likely to reveal that she has dL; calcium, 9.1 mg/dL; phosphorus, 3.3 mg/dL; thyroxine,
begun eating more of which of the following foods? 8.7 μg/dL; and TSH, 2.3 mU/L. The hemoglobin is 14 g/dL,
A Cabbage platelet count is 240,400/mm3, and WBC count is 5830/mm3.
B Fava beans A fine-needle aspiration biopsy of the thyroid gland is done.
C Fish What is the most likely diagnosis?
D Plantains A Anaplastic carcinoma
E Rye bread B Follicular carcinoma
C Medullary carcinoma
21 A 70-year-old man has had greater difficulty swallow- D Papillary carcinoma
ing for the past 2 years. Over the past 6 months, he has lost E Parathyroid carcinoma
3 kg. On physical examination, his temperature is 37.3° C, and F Small lymphocytic lymphoma
pulse is 102/min. There is fullness to the anterior neck, with
a 5 × 10 cm irregular mass on palpation. Laboratory studies
show serum TSH of 0.2 mU/L. A thyroid scintigraphic scan
shows a 1.5-cm nodule with increased uptake in the right thy-
roid lobe, and decreased uptake into the remaining enlarged
thyroid. What is the most likely diagnosis?
A Follicular adenoma
B Graves disease
C Hashimoto thyroiditis
D Papillary carcinoma
E Toxic multinodular goiter
25 A 45-year-old man has felt a lump on the left side of his C H A P T E R 2 4 The Endocrine System 3 7 5
neck for 4 months. Physical examination shows a nontender
nodule on the left lobe of the thyroid gland. An adjacent cervi- 27 A 44-year-old man with no previous illnesses has been
cal lymph node is enlarged and nontender. Laboratory studies bothered by progressive hoarseness, shortness of breath, and
show no thyroid autoantibodies in his serum, and the T4 and stridor for the past 3 weeks. On physical examination, he has a
TSH levels are normal. A thyroidectomy is performed; the fig- firm, large, tender mass involving the entire right thyroid lobe.
ure shows the microscopic appearance of the nodule. Which of CT scan shows extension of this mass posterior to the trachea
the following etiologic factors is most likely to be involved in and into the upper mediastinum. A fine-needle aspiration
the pathogenesis of the thyroid nodule in this patient? biopsy of the mass is done, and microscopically shows pleo-
A Autoimmunity morphic spindle cells. The mass is noted at surgery to have
B Chronic dietary iodine deficiency infiltrated the adjacent skeletal muscle. Four of seven cervical
C Consumption of goitrogens lymph nodes have metastases. Pulmonary metastases also are
D RET gene mutation identified on a chest radiograph. Which of the following neo-
E Viral infection plasms is most likely to be present in this man?
A Anaplastic carcinoma
B Follicular carcinoma
26 A 62-year-old woman has felt a lump on the right side C Medullary carcinoma
of her neck for 5 months. On physical examination, she has no D Non-Hodgkin lymphoma
palpable lymphadenopathy. A fine-needle aspiration biopsy is E Papillary carcinoma
done, and she undergoes a thyroidectomy. A 3-cm solid mass
within the right thyroid lobe has the microscopic appearance 28 A 42-year-old woman has noted increasing fullness in
shown in the figure. Six months later, she has pain in the right her neck for the past 7 months. On physical examination, her
thigh. A radiograph shows a fracture of the right femur in an thyroid gland is diffusely and asymmetrically enlarged and
area of lytic bone destruction. A radioiodine scan shows up- nodular. There is no lymphadenopathy. She undergoes thy-
take localized to the region of the fracture. Which of the fol- roidectomy. Gross examination of the thyroid shows a mul-
lowing is the most likely diagnosis? ticentric thyroid neoplasm; microscopically, the neoplasm is
A Papillary carcinoma composed of polygonal- to spindle-shaped cells forming nests
B Follicular carcinoma and trabeculae. There is a prominent, pink hyaline stroma that
C Granulomatous thyroiditis stains positively with Congo red. Electron microscopy shows
D Hashimoto thyroiditis varying numbers of intracytoplasmic, membrane-bound,
E Non-Hodgkin lymphoma electron-dense granules. Immunohistochemical staining for
which of the following antigens is most useful for diagnosis of
this neoplasm?
A Calcitonin
B CD3
C Cytokeratin
D Estrogen receptor
E Parathyroid hormone
F Vimentin
29 A 40-year-old man experiences weakness and easy fati-
gability of 2 months’ duration. Physical examination yields no
remarkable findings. Laboratory studies show serum calcium
of 11.5 mg/dL, inorganic phosphorus of 2.1 mg/dL, and se-
rum parathyroid hormone of 58 pg/mL, which is near the top
of the reference range. A radionuclide bone scan fails to show
any areas of increased uptake. What is the most likely cause of
these findings?
A Chronic renal failure
B Hypervitaminosis D
C Medullary thyroid carcinoma
D Parathyroid adenoma
E Parathyroid carcinoma
F Parathyroid hyperplasia
3 7 6 U N I T I I Diseases of Organ Systems 34 A 27-year-old man has controlled his diabetes mellitus
for the past 10 years with insulin injections. This morning, his
30 A 63-year-old woman had frequent headaches for 1 roommate is unable to awaken him. The man is unconscious
month. She now suddenly experiences a generalized seizure when brought to the emergency department. On physical
and becomes obtunded. She is taken to the emergency depart- examination, his temperature is 37° C, pulse is 91/min, res-
ment, where a physical examination reveals an irregular heart pirations are 30/min, and blood pressure is 90/65 mm Hg.
rate. Laboratory findings include serum calcium of 15.4 mg/ Laboratory findings include a high plasma level of insulin
dL, serum phosphorus of 1.9 mg/dL, and albumin of 4.2 g/ and a lack of detectable C peptide. Urinalysis shows no blood,
dL. A chest radiograph shows multiple lung masses and lytic protein, or glucose, but 4+ ketonuria. Which of the following
lesions of the vertebral column. Which of the following condi- conditions is most likely to be present?
tions best accounts for these findings? A Acute myocardial infarction
A Chronic renal failure B Bacteremia
B Disseminated tuberculosis C Hepatic failure
C Metastatic breast carcinoma D Hyperosmolar syndrome
D Parathyroid carcinoma E Hypoglycemic coma
E Vitamin D toxicity F Ketoacidosis
31 A 40-year-old woman notes lethargy, weakness, and 35 Blood relatives of individuals diagnosed with type 1 or
constipation for the past 6 months. On physical examination, type 2 diabetes mellitus are studied for 10 years. Laboratory
she is afebrile and normotensive, and her heart rate is irregu- testing for glucose and insulin levels and autoantibody forma-
lar. There is pain on palpation of the left third proximal finger. tion is performed on a periodic basis. The HLA types of the
An ECG shows a prolonged QT (corrected) interval. Labora- subjects are determined. A cohort of the subjects who are 8 to
tory studies show glucose, 73 mg/dL; creatinine, 1.2 mg/dL; 22 years old has no overt clinical illnesses and no hyperglyce-
calcium, 11.6 mg/dL; phosphorus, 2.1 mg/dL; total protein, 7.1 mia; however, autoantibodies to glutamic acid decarboxylase
g/dL; albumin, 5.3 g/dL; and alkaline phosphatase, 202 U/L. are present. Many subjects in this cohort have the HLA-DR3 and
A radiograph of the left hand shows focal expansion by a HLA-DR4 alleles. Which of the following pancreatic abnormali-
cystic lesion of the third proximal phalanx. A technicium ra- ties is most likely to be found in this cohort of study subjects?
dionuclide scan shows a 1-cm area of increased uptake in the A Acinar acute inflammation and necrosis
right lateral neck. A mutation in which of the following genes B Acinar fibrosis and fatty replacement
is most likely present in this woman? C Islet amyloid deposition
A GNAS1 D Islet hyperplasia
B MEN1 E Insulitis
C TP53 F Normal islets in a fibrous stroma
D RET
E VHL 36 A 23-year-old woman has a routine health status exami-
nation. Her body mass index is 22. Laboratory studies show
32 A 68-year-old man has experienced increasing malaise fasting plasma glucose is 130 mg/dL. Urinalysis shows mild
for 3 years. Physical examination shows no remarkable find- glucosuria, but no ketonuria or proteinuria. She has no detect-
ings. Laboratory findings include a serum creatinine level of able insulin autoantibodies. Her father was similarly affected
4.9 mg/dL and urea nitrogen level of 45 mg/dL. Abdominal at age 20 years. She is most likely to have a mutation in a gene
CT scan shows small kidneys. Which of the following endo- encoding for which of the following?
crine glandular lesions has developed secondary to the under- A Glucagon
lying disease in this patient? B Glucokinase
A Adrenal atrophy C GLUT4
B Islet cell hyperplasia D Insulin
C Multinodular goiter E MHC DR
D Parathyroid hyperplasia
E Pituitary microadenoma 37 A 13-year-old girl collapses while playing basketball.
On arrival at the emergency department, she is obtunded. On
33 A 47-year-old woman noticed a lump in her neck 1 week physical examination, she is hypotensive and tachycardic with
ago. On physical examination, there is a 2-cm nodule in the deep, rapid, labored respirations. Laboratory studies show
right lobe of the thyroid gland. A fine-needle aspiration biopsy serum Na+, 151 mmol/L; K+, 4.6 mmol/L; Cl–, 98 mmol/L;
is performed, and microscopic examination of the specimen CO2, 7 mmol/L; and glucose, 521 mg/dL. Urinalysis shows
shows cells consistent with a follicular neoplasm. She under- 4+ glucosuria and 4+ ketonuria levels, but no protein, blood,
goes a subtotal thyroidectomy. Which of the following labora- or nitrite. Which pathologic abnormality is most likely to be
tory tests should be performed on this patient in the immediate present in her pancreas at the time of her collapse?
postoperative period? A Loss of islet beta cells
A Antithyroglobulin antibody B Acute inflammation of islets
B Calcitonin C Amyloid replacement of islet beta cells
C Calcium D Chronic inflammation of islets
D Parathyroid hormone E Hyperplasia of alpha cells
E TSH F Pancreatic neuroendocrine tumor
38 A study of patients more than 25 years of age with body C H A P T E R 2 4 The Endocrine System 3 7 7
mass index above 30, dyslipidemia, hypertension, and fast- C Hypokalemia
ing glucose averaging 115 mg/dL is performed. They have D Leukopenia
adipose tissue abnormalities including increased nonesterified E Steatorrhea
fatty acid release, altered adipokines with decreased adiponec- F Uricosuria
tin, greater proinflammatory cytokine release, and diminished 43 A 52-year-old man has been concerned about a gradual
peroxisome proliferator-activated receptor gamma (PPARγ) weight gain over the past 30 years. He is 174 cm (5 feet 7 inch-
function. Which of the following is the best initial therapeutic es) tall and weighs 91 kg (body mass index 30). He is taking no
intervention for these patients? medications. On physical examination, he has decreased sen-
A Adrenalectomy sation to pinprick and light touch over the lower extremities.
B Caloric restriction Patellar reflexes are reduced. Motor strength seems to be nor-
C Insulin injection mal in all extremities. Laboratory studies show blood glucose
D l-Thyroxine of 169 mg/dL, creatinine of 1.9 mg/dL, total cholesterol of
E Liposuction 220 mg/dL, HDL cholesterol of 27 mg/dL, and triglycerides
of 261 mg/dL. A chest radiograph shows mild cardiomegaly.
39 An infant is born following premature delivery. Multi- Five years later, he has claudication in the lower extremities
ple external congenital anomalies are noted. The infant exhibits a when he exercises. Based on these findings, which of the fol-
seizure soon after birth. The blood glucose is 19 mg/dL. Which lowing complications is most likely to occur in this man?
of the following maternal diseases is the most likely cause for A Gangrene
the observed findings in this infant? B Hypoglycemic coma
A Cystic fibrosis C Ketoacidosis
B Diabetes mellitus, type 2 D Mucormycosis
C Gestational diabetes E Pancreatitis
D Maturity onset diabetes of the young F Systemic amyloidosis
E Pancreatic neuroendocrine tumor
40 A clinical study is conducted in patients diagnosed with 44 A 45-year-old woman has had angina pectoris, polyuria,
either type 1 or type 2 diabetes mellitus. Persons with either and polydipsia for the past 5 years. On physical examination,
type develop complications of accelerated and advanced ath- she has a body mass index of 32. Laboratory studies show
erosclerosis. All untreated patients have an elevated hemoglobin her hemoglobin A1c is 10%. Urinalysis shows proteinuria, but
A1c. Which of the following features common to patients with no ketonuria. The representative microscopic appearance of
either type 1 or type 2 diabetes mellitus is most likely to be her kidneys is shown in the figure. Which of the following is
found by this study? the most likely mechanism leading to the disease causing her
A Association with certain MHC class II alleles findings?
B High concordance rate in monozygotic twins A Chronic pancreatitis
C Marked resistance to the action of insulin B Glucokinase gene mutation
D Nonenzymatic glycosylation of proteins C Insulin resistance
E Presence of islet cell antibodies D Systemic amyloidosis
E T-cell mediated B-cell destruction
41 A 50-year-old man with fasting blood glucose >140
mg/dL on two occasions is put on a restricted caloric diet
and started on a glucagon-like peptide-1 (GLP-1) receptor ago-
nist. Which of the following laboratory studies is most likely
to afford the best method of monitoring disease control in
this man?
A Cholesterol, total
B Fasting plasma glucose
C Glycosylated hemoglobin
D Microalbuminuria
E Random plasma glucose
F Serum fructosamine
42 A 50-year-old man has had a nonhealing ulcer on the
bottom of his foot for 2 months. On examination, the 2-cm ul-
cer overlies the right first metatarsal head. There is reduced
sensation to pinprick in his feet. His visual acuity is reduced
bilaterally. Laboratory studies show serum creatinine is 2.9
mg/dL. Which of the following laboratory test findings is he
most likely to have?
A Glucosuria
B Hypoalbuminemia
3 7 8 U N I T I I Diseases of Organ Systems injections normalizes their Hgb A1c levels. Which of the fol-
lowing is the most likely mechanism leading to their disease?
45 A 50-year-old man has a 35-year history of diabetes A Chloride ion channel abnormality
mellitus. During this time, he has had hemoglobin A1c val- B Chromosome 21 trisomy
ues between 7% and 10%. He now has problems with sexual C Glucokinase gene mutation
function, including difficulty attaining an erection. He also is D Peripheral insulin resistance
plagued by mild but recurrent low-volume diarrhea and dif- E Loss of T-cell tolerance
ficulty with urination. He has delayed gastric emptying. These
problems are most likely to originate from which of the fol-
lowing mechanisms of cellular injury? 49 A 33-year-old woman has had several “fainting spells”
A Cross-linking of extracellular matrix proteins over the past 6 months. Each time, she has a prodrome of light-
B Production of vascular endothelial growth factor headedness followed by a brief loss of consciousness. After
C Abnormal transforming growth factor-beta each episode, she awakens and on examination has no loss of
motor or sensory function. Physical examination after the cur-
signaling rent episode shows that she is afebrile, with a pulse of 72/min,
D Increased endothelial procoagulant activity respirations of 17/min, and blood pressure of 120/80 mm Hg.
E Nonenzymatic glycosylation Imaging studies reveal a 0.5-cm lesion in the head of the pan-
F Polyol-induced susceptibility to oxidative stress creas. The microscopic appearance of this lesion is shown in
46 A 74-year-old woman is admitted to the hospital in an the figure. Which of the following pancreatic disorders is most
obtunded condition. Her temperature is 37° C, pulse is 95/ likely to be present in this patient?
min, respirations are 22/min, and blood pressure is 90/60 mm A Acute necrotizing pancreatitis
Hg. She appears dehydrated and has poor skin turgor. Her se- B Adenocarcinoma
rum glucose level is 872 mg/dL. Urinalysis shows 4+ glucos- C Cystic fibrosis
uria, but no ketones, protein, or blood. Which of the following D Neuroendocrine tumor
factors is most important in the pathogenesis of this patient’s E Pseudocyst
condition? 50 A 43-year-old man from Stockholm, Sweden, has had
A Autoimmune insulitis low-volume watery diarrhea for the past 3 months. He now
B Glucokinase gene mutation has midepigastric pain. Over-the-counter antacid medica-
C HLA-DR3/HLA-DR4 genotype tions do not relieve the pain. On physical examination, he is
D Peripheral insulin resistance afebrile; on palpation, there is no abdominal tenderness and
E Virus-induced injury to beta cells in islets no masses. An upper gastrointestinal endoscopy shows mul-
47 A 40-year-old woman has experienced chest pain on ex- tiple 0.5- to 1.1-cm, shallow, sharply demarcated ulcerations
ertion for the past 2 months. A month ago, she had pneumonia in the first and second portions of the duodenum. He is given
with Streptococcus pneumoniae cultured from her sputum. On omeprazole. Three months later, repeat endoscopy shows that
physical examination, she has a body mass index of 35. A ran- the ulcerations are still present. Which of the following ana-
dom blood glucose value is 132 mg/dL. The next day, a fasting lytes is most likely to be increased in his in serum or plasma?
blood glucose is 120 mg/dL, followed by a value of 122 mg/ A Gastrin
dL on the following day. She is given an oral glucose tolerance B Glucagon
test, and her blood glucose is 240 mg/dL 2 hours after receiv- C Insulin
ing the standard 75-g glucose dose. On the basis of these find- D Somatostatin
ings, she is prescribed an oral thiazolidinedione (TZD) drug. E Vasoactive intestinal polypeptide (VIP)
After 2 months of therapy, her fasting blood glucose is 90 mg/
dL. The beneficial effect of TZD in this patient is most likely
related to which of the following processes?
A Activation of PPARγ nuclear receptor in adipocytes
B Decreased production of insulin autoantibodies
C Greater density of insulin receptors in adipocytes
D Increased half-life of circulating plasma insulin
E Reduced secretion of glucagon by a cell in islets of
Langerhans
F Regeneration of beta cells in islets of Langerhans
48 A family is followed longitudinally for two generations.
Four of eight children develop hyperglycemia by age 18 years.
They are found to have serum islet autoantibodies. They
have similar MHC I and MHC II loci. Treatment with insulin
51 A 39-year-old man has had headache, weakness, and a C H A P T E R 2 4 The Endocrine System 3 7 9
5-kg weight gain over the past 3 months. He has experienced
mental depression during the same period. On physical exam- 54 A 28-year-old, otherwise healthy man has had head-
ination, his face is puffy. His temperature is 36.9° C and blood aches for the past 2 weeks. Physical examination yields no
pressure is 160/75 mm Hg. He has cutaneous striae over the remarkable findings except for a blood pressure of 174/116
lower abdomen and ecchymoses scattered over the extremi- mm Hg. An abdominal CT scan shows an enlarged right ad-
ties. A radiograph of the spine shows a compressed fracture of renal gland. A right adrenalectomy is done; the figure shows
T11. Laboratory findings show fasting plasma glucose level of the gross appearance of the specimen. Which of the following
200 mg/dL, serum Na+ of 150 mmol/L, and serum K+ of 3.1 laboratory findings in his blood was most likely reported in
mmol/L. The plasma cortisol level is 38 μg/dL at 8:00 am and this patient before surgery?
37 μg/dL at 6:00 pm. Administration of low and high doses of A Hyperglycemia
dexamethasone fails to suppress the plasma cortisol level and B Hyperkalemia
excretion of urinary 17-hydroxycorticosteroids. The plasma C Hyponatremia
corticotropin level is 0.8 pg/mL. Which of the following le- D Low corticotropin level
sions is most likely to be present in this man? E Low insulin level
A Adenohypophyseal adenoma F Low renin level
B Adrenal cortical adenoma 55 A 40-year-old woman has experienced increasingly fre-
C Extra-adrenal pheochromocytoma quent episodes of weakness accompanied by numbness and
D Small cell carcinoma of the lung tingling in her hands and feet for the past year. On examina-
E Thyroid medullary carcinoma tion her blood pressure is 168/112 mm Hg. Laboratory studies
show sodium, 142 mmol/L; potassium, 2.9 mmol/L; chloride,
52 A 43-year-old woman has had absent menstrual cycles 104 mmol/L; HCO3–, 28 mmol/L; and glucose, 74 mg/dL. Her
along with increasing weakness and weight gain over the past plasma renin activity is low. Which of the following radiologic
5 months. She notes low back pain for the past week. On physi- findings is most likely to be present in this woman?
cal examination, vital signs include blood pressure of 155/95 A Adrenal nodular enlargement
mm Hg. She has a prominent fat pad in the posterior neck B Pancreatic mass
and back. Facial plethora, hirsutism, and abdominal cutane- C Retroperitoneal mass
ous striae are present. Laboratory findings include Na+, 139 D Thyroid nodular enlargement
mmol/L; K+, 4.1 mmol/L; Cl–, 96 mmol/L; CO2, 23 mmol/L; E Mediastinal mass
glucose, 163 mg/dL; creatinine, 1.3 mg/dL; calcium, 8.9 mg/
dL; and phosphorus, 4.1 mg/dL. Her serum ACTH level is
low. A radiograph of the spine shows decreased bone density
with a compression fracture at T9. Which of the following ra-
diographic findings is most likely to be present in this patient?
A Adrenal 10-cm solid mass with abdominal CT scan
B Decreased radionuclide uptake in a thyroid gland
nodule
C Pulmonary 6-cm hilar mass on chest radiograph
D Retroperitoneal 5-cm mass at the aortic bifurcation
on pelvic MRI scan
E Sella turcica enlargement with erosion on head CT
scan
53 A 73-year-old woman has experienced malaise and a
10-kg weight loss over the past 4 months. She also has devel-
oped a chronic cough during this time. She has a 100 pack-year
history of smoking cigarettes. Physical examination shows
muscle wasting and 4/5 motor strength in all extremities. Ab-
dominal CT scan shows bilaterally enlarged adrenal glands. A
chest radiograph shows a 6-cm perihilar mass on the right and
prominent hilar lymphadenopathy. Laboratory studies show
Na+, 118 mmol/L; K+, 6 mmol/L; Cl–, 95 mmol/L; CO2, 21
mmol/L; and glucose, 49 mg/dL. Her 8:00 am serum cortisol
level is 9 ng/mL. What is the most likely diagnosis?
A Amyloidosis
B Ectopic corticotropin syndrome
C Meningococcemia
D Metastatic carcinoma
E Pituitary adenoma
3 8 0 U N I T I I Diseases of Organ Systems hyperpigmentation of the skin. Vital signs include tempera-
ture of 36.9° C, pulse of 70/min, respirations of 14/min, and
56 A 5-year-boy has developed features that suggest puber- blood pressure of 95/65 mm Hg. Laboratory studies include a
ty over the past 6 months. On physical examination, the boy serum cortisol level of 3 μg/mL at 8:00 am with a serum cor-
has secondary sex characteristics, including pubic hair and en- ticotropin level of 65 pg/mL. Which of the following diseases
largement of the penis. Which of the following morphologic most often occurs in patients with this disorder?
features is most likely to be seen in his adrenal glands? A Type 2 diabetes mellitus
A Cortical atrophy B Classic polyarteritis nodosa
B Cortical hyperplasia C Hashimoto thyroiditis
C Cortical nodule D Systemic lupus erythematosus
D Medullary atrophy E Ulcerative colitis
E Medullary hyperplasia
F Medullary nodule 61 A 44-year-old woman has become increasingly listless
and weak and has had chronic diarrhea and a 5-kg weight loss
57 A female infant is born at term to a 41-year-old Yupik over the past 7 months. She also notices that her skin seems
woman after an uncomplicated pregnancy. Soon after birth, darker, although she rarely goes outside because she is too
the neonate develops hypotension. Physical examination tired for outdoor activities. On physical examination, she is
shows ambiguous genitalia with a prominent clitoris. Labo- afebrile, and her blood pressure is 85/50 mm Hg. A chest ra-
ratory studies show Na+, 131 mmol/L; K+, 5.1 mmol/L; Cl–, diograph shows no abnormal findings. Laboratory findings
93 mmol/L; CO2, 18 mmol/L; glucose, 65 mg/dL; creatinine, include serum Na+, 120 mmol/L; K+, 5.1 mmol/L; glucose,
0.4 mg/dL; testosterone, 50 mg/dL (normal <30 mg/dL); and 58 mg/dL; urea nitrogen, 18 mg/dL; and creatinine, 0.8 mg/
cortisol, 2 μg/dL. An abdominal ultrasound scan shows bi- dL. The serum corticotropin level is 82 pg/mL. Which of the
laterally enlarged adrenal glands. Which of the following en- following is most likely to account for these findings?
zyme deficiencies is most likely to be present in this infant? A Adenohypophyseal adenoma
A Aromatase B Autoimmune destruction of the adrenals
B 11-Hydroxylase C Pancreatic neuroendocrine tumor
C 21-Hydroxylase D Metastatic carcinoma with lung primary
D 17α-Hydroxylase E Neisseria meningitidis infection of the adrenals
E Oxidase F Sarcoidosis of the lung and adrenals
58 A 19-year-old, previously healthy woman collapsed 62 A 37-year-old woman states that, although most of
after complaining of a mild sore throat the previous day. On the time she feels fine, she has had episodes of palpitations,
examination she is hypotensive and febrile with purpuric tachycardia, tremor, diaphoresis, and headache over the past
skin lesions. Her peripheral blood smear shows schistocytes. 3 months. When her symptoms are worse, her blood pressure
Imaging studies show her adrenal glands are enlarged, and is measured in the range of 155/90 mm Hg. She collapses sud-
there are extensive bilateral cortical hemorrhages. Infection denly one day and is brought to the hospital, where her ven-
with which of the following organisms best accounts for these tricular fibrillation is converted successfully to sinus rhythm.
findings? On physical examination, there are no remarkable findings.
A Cytomegalovirus Which of the following laboratory findings is most likely to be
B Histoplasma capsulatum reported in this patient?
C Mycobacterium tuberculosis A Decreased serum cortisol level
D Neisseria meningitidis B Decreased serum glucose level
E Streptococcus pneumoniae C Decreased serum potassium level
D Increased serum free T4 level
59 A 29-year-old woman with systemic lupus erythema- E Increased urinary free catecholamines
tosus has been treated with corticosteroid therapy for several F Increased urinary homovanillic acid (HVA) level
years because of recurrent lupus nephritis. She undergoes an
emergency appendectomy for acute appendicitis. On postop- 63 A 25-year-old woman gives birth to a term infant fol-
erative day 2, she becomes somnolent and develops severe lowing an uncomplicated pregnancy. On physical examina-
nausea and vomiting. She then becomes hypotensive. Blood tion, the newborn is found to have an enlarged abdomen, but
cultures are negative, and laboratory studies now show Na+ of there are no other abnormal findings except for slightly ele-
128 mmol/L, K+ of 4.9 mmol/L, Cl– of 89 mmol/L, CO2 of 19 vated blood pressure. An abdominal ultrasound scan shows a
mmol/L, glucose of 52 mg/dL, and creatinine of 1.3 mg/dL. right retroperitoneal mass in the adrenal gland. An increase in
Which of the following morphologic findings in the adrenal which of the following substances is most likely to be associ-
gland cortex is most likely to be present in this patient? ated with the lesion in this neonate?
A Adenoma A Serum corticotropin (ACTH) level
B Atrophy B Serum cortisol level
C Carcinoma C Serum growth hormone level
D Caseating granulomas D Serum prolactin level
E Hemorrhagic necrosis E Urinary free catecholamine level
F Nodular hyperplasia F Urinary homovanillic acid (HVA) level
60 A 55-year-old man has experienced increasing leth-
argy for the past 7 months. Physical examination shows
64 A 27-year-old man has headaches that have occurred C H A P T E R 2 4 The Endocrine System 3 8 1
frequently for the past 3 months. On physical examination, he
is afebrile, and his blood pressure is 140/85 mm Hg. There are serum calcium concentration returned to normal. Three years
no neurologic abnormalities and no visual defects; however, later, he had an episode of upper gastrointestinal hemorrhage.
he has an enlarged thyroid. Laboratory studies show that his An endoscopy and biopsy specimen showed multiple benign
serum calcitonin level is elevated. A total thyroidectomy is gastric ulcerations. Abdominal MRI indicated multiple 1- to
performed, and on sectioning, the thyroid has multiple tumor 2-cm mass lesions in the pancreas. He underwent surgery, and
nodules in both lobes. Microscopically, the thyroid nodules are multiple tumors were found. Which of the following additional
composed of nests of neoplastic cells separated by amyloid- neoplasm lesions is he most likely to have?
rich stroma. The endocrinologist says that the patient’s family A Adrenal pheochromocytoma
members could be at risk for development of similar tumors B Endometrial carcinoma
and advises that they undergo genetic screening. Which of the C Pituitary adenoma
following morphologic findings in the adrenal glands is most D Pulmonary small cell anaplastic carcinoma
likely to be present in this patient? E Thyroid medullary carcinoma
A Bilateral 4-cm medullary masses
B Bilateral cortical atrophy 66 A 10-year-old boy has been bothered by frequent head-
C Bilateral cortical nodular hyperplasia aches for the past 5 months. Physical examination yields no
D Solitary caseating granuloma specific findings. Laboratory studies show normal electrolyte
E Solitary 1-cm cortical mass with contralateral corti- levels. CT scan of the head shows no bony abnormalities and
no intracranial hemorrhage. MRI of the brain shows a 2-cm
cal atrophy solid mass without calcifications or cystic change in the area
F Solitary 12-cm hemorrhagic cortical mass inferior to the splenium of the corpus callosum, superior to
the collicular plate, and between the right and left thalamic
65 A 26-year-old man developed sudden severe abdomi- pulvinar regions. Because of the location, the mass is difficult
nal pain. On physical examination, he had marked abdominal to remove completely. Which of the following neoplasms is
tenderness and guarding. Laboratory studies showed serum most likely to be present in this child?
glucose, 76 mg/dL; calcium, 12.2 mg/dL; phosphorus, 2.6 A Craniopharyngioma
mg/dL; creatinine, 1.1 mg/dL; and parathyroid hormone, 62 B Hypothalamic glioma
pg/mL (normal range 9 to 60 pg/mL). During surgery, four C Lymphoblastic lymphoma
enlarged parathyroid glands were found and excised, with re- D Metastatic carcinoma
implantation of one half of one gland. After the surgery, his E Pineoblastoma
F Prolactinoma
ANSWERS younger persons in familial cases. GH opposes insulin, and
excesses can lead to secondary diabetes mellitus. In adults
1 D Prolactinomas are more common than other hormone- with closed epiphyses, gigantism does not occur, but acro-
secreting pituitary adenomas. In addition to her galactorrhea megaly of soft tissues does. Cyclin D1 mutations may be
and infertility, this patient also may have decreased libido, found in some parathyroid adenomas. The PAX8-PPARG fu-
and her amenorrhea is secondary to the excessive prolactin sion gene may be found in some follicular thyroid neoplasms.
secretion. Microadenomas might not have pressure effects The tumor suppressor gene PTEN may be mutated in some
on surrounding structures such as optic chiasm, but they can pancreatic neuroendocrine tumors. The VHL tumor suppres-
be discovered because of their hormonal effects. Acromegaly sor gene may be associated with some pheochromocytomas.
results from a growth hormone–secreting pituitary adenoma
in an adult. Cushing disease occurs when there is an ACTH- PBD9 1076–1077 BP9 718–719 PBD8 1101
secreting pituitary adenoma. A thyroid-stimulating hor-
mone (TSH)−secreting pituitary adenoma is uncommon, but 3 D She has a nonfunctioning (null-cell) pituitary adeno-
it could account for elevated levels of T4 and TSH in a hyper- ma that has enlarged to compress and obliterate the nor-
thyroid patient. Neurologic dysfunction with hyponatremia mal adenohypophyseal cells resulting in hypopituitarism;
from the syndrome of inappropriate diuretic hormone lead- the adenoma also presses on the optic chiasm, producing
ing to neurologic dysfunction is most often a paraneoplastic bitemporal hemianopsia. About a fourth of all pituitary tu-
syndrome caused by a small cell anaplastic lung carcinoma, mors are nonfunctioning. Beta cells of the pancreatic islets of
but may also be due to head trauma that damages the nerve Langerhans produce insulin. Chief cells in the parathyroids
tracts and neurohypophysis with uncontrolled release of produce parathormone that increases serum calcium. Chro-
vasopressin (antidiuretic hormone, ADH). maffin cells in the adrenal medulla produce catecholamines.
Glomerulosa cells of the adrenal cortex produce corticoste-
PBD9 1074–1076 BP9 717–719 PBD8 1103–1104 BP8 754–755 roids. Parafollicular cells (C cells) of the thyroid interstitium
produce calcitonin.
2 A The aryl hydrocarbon receptor–interacting protein (AIP)
gene mutations account for a minority of growth h ormone PBD9 1076, 1080 BP9 720 PBD8 1105 BP8 756
(GH)–producing pituitary adenomas, but may be present in
3 8 2 U N I T I I Diseases of Organ Systems
4 B Failure to suppress growth hormone (GH) levels by follicle-stimulating hormone and luteinizing hormone lev-
glucose infusion suggests autonomous GH production. The els are deficient. If she were to have primary adrenal failure,
patient’s symptoms suggest acromegaly, and a GH-secreting the corticotropin (ACTH) level would be increased, but in
adenoma is most likely. Acromegaly causes an overall increase her case, ACTH is low because of anterior pituitary failure.
in soft tissue in adults because of the anabolic effects of the Because the hypothalamus is unaffected, corticotropin-re-
increase in GH. Because the epiphyses of the long bones are leasing hormone would still be present. Oxytocin release
closed in adults, there is not the increase in height, or gigan- from the posterior pituitary is probably not affected. She
tism, that would be seen in children with a pituitary adenoma does not have diabetes insipidus from lack of antidiuretic
that is secreting excessive GH. Instead, the increase in soft hormone, because the posterior pituitary is less likely to be
tissue mass manifests as increasing shoe or glove size, carpal involved. Dopamine production in the hypothalamus is not
tunnel syndrome, and coarse facial features. This woman affected.
probably has an abnormal glucose tolerance test result, but
this does not indicate the underlying cause of diabetes mel- PBD9 1081 BP9 720–721 PBD8 1105 BP8 757
litus, which in this case is secondary to acromegaly. A pro-
lactinoma would cause amenorrhea and galactorrhea in a 7 E Diabetes insipidus ensues from lack of antidiuretic
woman. A thyroid-stimulating hormone (TSH)−secreting hormone (ADH), also called arginine vasopressin. There is
adenoma of the pituitary can give rise to hyperthyroidism failure of resorption of free water in the renal collecting
with an increased metabolic rate that would most likely to tubules—hence the increased dilute urine with higher serum
lead to weight loss, and glucose intolerance is not a feature of osmolality and hypernatremia. Corticotropin stimulates the
hyperthyroidism. Functional pituitary tumors can be detected adrenal glands, mainly with the effect of increasing cortisol
clinically before they become large enough to cause pressure secretion. Oxytocin is involved in lactation. Prolactin and
symptoms such as visual disturbances. Cushing syndrome melatonin deficiencies have no identifiable specific clinical
from an adrenal cortical neoplasm producing cortisol could effects in men.
be accompanied by glucose intolerance, hypertension, and
truncal obesity, but there is no overall increase in soft tissues. PBD9 1081 BP9 721 PBD8 1106 BP8 757
PBD9 1079 BP9 719 PBD8 1100–1103 BP8 755–756 8 D The syndrome of inappropriate antidiuretic hormone
(SIADH) secretion results in increased free water resorption
5 B Empty sella syndrome is a rare condition, seen most by the kidney and subsequent hyponatremia. SIADH is most
frequently in obese women, and results from herniation of often a paraneoplastic effect, and small cell (oat cell) ana-
the arachnoid through the diaphragma sellae. Although the plastic carcinoma of the lung (of neuroendocrine derivation
increased pressure can lead to reduction in pituitary tissue and seen almost exclusively in smokers) is the most likely
through compression atrophy, there is typically adequate candidate among probable malignant neoplasms. Anterior
functional anterior pituitary to prevent hypopituitarism. pituitary adenomas do not produce antidiuretic hormone
This herniation can cause a “stalk section” effect, however, (ADH), which is released from the posterior pituitary. Ad-
with loss of prolactin inhibition and hyperprolactinemia. A renal cortical carcinomas can secrete cortisol or sex steroids,
craniopharyngioma is a destructive tumor mass that is usu- but not ADH. Pheochromocytomas secrete catecholamines.
ally seen at a younger age. Hemochromatosis can interfere Renal cell carcinomas are known for various paraneoplastic
with organ function, including hypopituitarism; onset usu- effects, but SIADH is not a high probability.
ally occurs later in women than in men (in the 60s in women
compared with the 40s in men), owing to differences in phys- PBD9 1081–1082 BP9 721 PBD8 1106 BP8 757
iologic iron losses (e.g., menstrual blood loss). Prader-Willi
syndrome is an example of genomic imprinting with hypo- 9 A Craniopharyngiomas are uncommon, usually suprasel-
thalamic dysfunction seen in prepubertal boys. A prolacti- lar neoplasms; they are typically found in young individuals.
noma could be a microadenoma, but MRI in this case rules They are thought to arise from embryologic remnants of the
this out because of the fluid density in the sella (seen with Rathke pouch in the region of the pituitary. These are aggres-
T2 weighting). If she had Sheehan syndrome after her preg- sive neoplasms that infiltrate and destroy surrounding tissues,
nancy, she would have manifested hypopituitarism within making complete excision difficult. Despite their aggressive
months, not years. behavior, they are composed of benign-appearing squamoid
or primitive tooth structures. The increase in prolactin occurs
PBD9 1081 BP9 720–721 PBD8 1105 as a “stalk section” effect, and the hypernatremia results from
diabetes insipidus caused by destruction of the hypothala-
6 D Sheehan syndrome, or postpartum pituitary necrosis, mus, posterior pituitary, or both. A metastasis to this location
is caused by pituitary enlargement during pregnancy, caus- in a young individual is highly unlikely. Multiple endocrine
ing its blood supply to be more tenuous so that intrapartum neoplasia (MEN) type 1 includes pituitary adenomas, but not
hypotension with obstetric bleeding complications (e.g., the craniopharyngiomas. MEN 2 does not involve the pituitary.
placenta accreta in this patient) predisposes to infarction. Prolactinomas, similar to pituitary adenomas, can enlarge the
The anterior pituitary is at greater risk than the posterior sella when they are macroadenomas, but are not typically su-
pituitary. The laboratory findings in this patient suggest ad- prasellar or destructive of surrounding structures.
renal insufficiency, and her inability to breastfeed is caused
by lack of prolactin; loss of menstrual cycles suggests that PBD9 1082 BP9 716 PBD8 1106–1107
C H A P T E R 2 4 The Endocrine System 3 8 3
1 0 D Thyroid storm is a medical emergency. There is is suspected, the TSH level is decreased. Anticentromere an-
not enough time to wait for confirmatory laboratory thy- tibody is characteristic of limited scleroderma (CREST syn-
roid testing. There are increased catecholamine levels, drome). Anti–double-stranded DNA antibody is very specific
and the β-blocker propranolol will help prevent emergent for systemic lupus erythematosus. Anti–Jo-1 antibody can be
death from cardiac failure. Acetaminophen and ice packs seen in polymyositis. Increased antimitochondrial antibody
are better choices to treat fever alone. Propylthiouracil indicates primary biliary cirrhosis. Antiribonucleoprotein an-
(PTU) is the antithyroid medication with the fastest onset tibodies are seen in some collagen vascular diseases, such as
of action (hours), along with iodine to help reduce pre- mixed connective tissue disease.
formed thyroid hormone output. The fever and ancillary
findings here go beyond what would be expected with an PBD9 1086–1087 BP9 724–725 PBD8 1111–1113 BP8 760–762
acute infection.
14 C Subacute granulomatous thyroiditis (de Quervain
PBD9 1084 BP9 722–723 PBD8 1109 BP8 759 thyroiditis) is a self-limited condition that can be of viral ori-
gin because many cases are preceded by an upper respira-
11 F The normal feedback loop of peripheral thyroid hor- tory infection. The transient hyperthyroidism results from
mones (T3 and T4) onto the basophils (thyrotrophs) of the inflammatory destruction of the thyroid follicles and release
adenohypophysis regulates TSH release (under tropic control of thyroid hormone. The released colloid acts as a foreign
of TRH from the hypothalamus). When patients with primary body, producing florid granulomatous inflammation in the
thyroid failure, the most common cause for hypothyroidism thyroid. Hashimoto thyroiditis can enlarge the thyroid tran-
with myxedema in adults, do not have sufficient residual siently, but there is usually no pain or hyperthyroidism. Thy-
functioning thyroid follicular cells producing thyroid hor- roid neoplasms are not typically associated with signs and
mones, then the TSH will rise, as in this case, in conjunction symptoms of inflammation and are rarely functional. A toxic
with a low T4 level. The levels of TRH from the hypothala- multinodular goiter likewise produces no signs of inflamma-
mus are much lower and harder to measure for correlation tion, and does not reverse functionality.
with thyroid gland function. The measurement of TSH is
also the most useful screening test for hyperthyroidism. PBD9 1088 BP9 725–726 PBD8 1113 BP8 762
Neurohypophyseal axons release ADH and oxytocin pro-
duced in the hypothalamus, whereas modified glial cells 1 5 B The presence of autoantibodies in the serum in
called pituicytes do not release hormones. Thyroid parafol- this patient with transient hyperthyroidism would suggest
licular, or “C” cells, produce calcitonin. Hashimoto thyroiditis (“hashitoxicosis”), but the variant
called subacute lymphocytic painless thyroiditis may affect 1 in
PBD9 1083–1086 BP9 721–724 PBD8 1108–1111 BP8 758–760 20 postpartum women, and a minority progress to hypothy-
roidism. Mutations in the RET proto-oncogene are associ-
12 E Cretinism is a condition that is uncommon whenever ated with papillary carcinoma and medullary carcinoma of
routine newborn screening is available for testing and treat- the thyroid. Irradiation of the thyroid gland can give rise to
ment at birth for hypothyroidism. Hypothyroidism that de- hypothyroidism, but it is unlikely that irradiation in child-
velops in older children and adults is known as myxedema. hood would give rise to hypothyroidism at age 60 years. Irra-
A lack of cortisol from primary adrenal failure leads to Ad- diation also can predispose to the development of papillary
dison disease, or a 21-hydroxylase deficiency could produce carcinoma, but these tumors usually do not affect thyroid
congenital adrenal hyperplasia. An absolute deficiency of in- hormone secretion. An iodine deficiency can lead to hypo-
sulin leads to type 1 diabetes mellitus, but this is more likely thyroidism, but a goiter would be present. A history of a
to develop in childhood or later, and there would be weight viral infection sometimes precedes subacute granulomatous
loss. There is no deficiency state caused by a lack of norepi- thyroiditis, which is typically a self-limited disease that lasts
nephrine or somatostatin. for weeks to 2 months.
PBD9 1085–1086 BP9 723–724 PBD8 1110 BP8 759–760 PBD9 1086–1087 BP9 724–725 PBD8 1113–1114 BP8 760–762
13 F The lymphoid follicles and the large, pink nodules of 1 6 B Exophthalmos is a feature seen in about 40% of indi-
Hürthle cells in this photomicrograph are typical for Hashi- viduals with Graves disease. The hyperfunctioning thyroid
moto thyroiditis. The anti–thyroid peroxidase (antimicro- gland leads to an increased T4 level, with positive feedback
somal) and antithyroglobulin antibody titers typically are in- from the pituitary to decrease thyroid-stimulating hormone
creased in patients with Hashimoto thyroiditis when thyroid (TSH) secretion. There is about 50% concordance of Graves
enlargement is still present. In the later, “burnt-out” phase of disease among identical twins. The autoimmune character of
Hashimoto thyroiditis, the antibodies are sometimes undetect- this disorder is evidenced by an association with HLA-DR3
able—only the hypothyroidism is. The thyroid-stimulating and by the presence of an autoantibody against TSH receptor
hormone (TSH) level is an indication of whether there is a pri- that activates T4 secretion. An increased thyrotropin-releasing
mary disease in the thyroid. If the patient appears hypothyroid hormone (TRH) level would increase the TSH level and in-
and a primary thyroid disease (e.g., Hashimoto thyroiditis) is crease the T4, but feedback typically occurs at the level of the
suspected, the TSH level is elevated. If the patient appears hy- pituitary and the hypothalamus, and abnormal increases in
perthyroid and a primary thyroid disease (e.g., Graves disease) TRH are uncommon. Anti–thyroid peroxidase antibodies
3 8 4 U N I T I I Diseases of Organ Systems
can be seen in Hashimoto thyroiditis and in Graves disease, 20 A She has developed a sporadic goiter. Vegetables of
but the highest titers occur in Hashimoto thyroiditis. T3 lev- the Brassicaceae family, including cabbage, turnips, and
els are less likely to be elevated than T4 levels. Brussels sprouts, contain glucosinolate, which can decom-
pose to release thiocyanate, a by product that interferes with
PBD9 1089–1090 BP9 726–727 PBD8 1114–1115 BP8 763–764 thyroid hormone synthesis. Thus such substances are known
as goitrogens. Young persons with increased demand for
17 A The tall columnar epithelium with papillary infold- thyroid hormone are at increased risk. Fava beans contain
ings and scalloping of the colloid is characteristic of Graves oxidizing agents that incite hemolysis in persons with glucose-
disease, which leads to hyperthyroidism. This disease is 6-phosphate dehydrogenase (G6PD) deficiency. In addition,
caused by autoantibodies that bind to the thyroid-stimulating beans contain long-chain sugars that are indigestible with
hormone (TSH) receptor and mimic the action of TSH. Di- human intestinal enzymes, leaving them to be fermented by
etary iodine deficiency can cause diffuse compensatory en- colonic bacteria that release gas (flatus). Fish have omega-3
largement of thyroid, but it does not cause hyperthyroidism. fatty acids that protect against atherogenesis. Plantains are
Irradiation of the neck is a predisposing factor for papillary starchy, as anyone mistaking them for sweet bananas soon
carcinoma of the thyroid. Maternal thyroid hormone deficien- discovers; rare food allergy develops to them. Fungus grow-
cy may affect childhood mental development. Mutations in ing on moldy rye produces ergot poisoning.
the RET proto-oncogene occur in papillary carcinoma of the
thyroid and in medullary carcinomas of the thyroid. These PBD9 1091 BP9 728 PBD8 1116–1117 BP8 764–765
neoplasms do not cause diffuse enlargement of the gland, hy-
perthyroidism, or diffuse increase in radioiodine uptake. Tu- 2 1 E A long-standing diffuse goiter can evolve into a mul-
mors usually produce “cold nodules” on radioiodine scans. tinodular goiter, and one of the nodules can begin hyper-
functioning to cause so-called Plummer disease. This “toxic”
PBD9 1089–1090 BP9 726–727 PBD8 1114–1115 BP8 763–764 nodule has acquired growth and functional characteristics
similar to a benign neoplasm, such as a follicular adenoma,
18 E The clinical findings in this case point to hyperthy- but one that is functional. Rare toxic follicular adenomas can
roidism, and the increased, diffuse uptake corroborates function and produce “hot” nodules, but the remaining gland
Graves disease as a probable cause because the thyroid- is often atrophic, not enlarged. In Graves disease, the thy-
stimulating hormone (TSH) level is quite low. The thyroid- roid is enlarged, but usually diffusely, without pronounced
stimulating immunoglobulins that appear in this autoim- nodularity, so that there is increased uptake into the entire
mune condition result in diffuse thyroid enlargement and gland. In addition, clinical features such as dermopathy and
hyperfunction, and papillary projections lined by tall co- ophthalmopathy that are lacking with Plummer disease are
lumnar epithelial cells. Destruction of thyroid follicles with associated with Graves disease. There may be initial diffuse
lymphoid aggregates and Hürthle cell metaplasia is charac- thyroid enlargement with Hashimoto thyroiditis and tran-
teristic of Hashimoto thyroiditis. A goiter has enlarged fol- sient hyperfunction, but over time the thyroid atrophies, and
licles and flattened epithelial cells; most of these patients are hypothyroidism ensues. It is extremely rare for a papillary
euthyroid. Follicular destruction and the presence of giant carcinoma to function, and although this would be a hot nod-
cells occur in granulomatous thyroiditis. Nests of cells in a ule, the remaining thyroid would not be enlarged.
Congo red–positive hyaline stroma characterize a medullary
carcinoma, which can be multifocal, but is not diffuse and PBD9 1091–1092 BP9 728–729 PBD8 1116–1118 BP8 764–765
does not lead to hyperthyroidism.
22 D Solitary “cold” and solid (not cystic) thyroid nodules
PBD9 1089–1090 BP9 726–727 PBD8 1114–1116 BP8 758–759 are likely to be neoplastic, and most are benign follicular ad-
enomas that do not affect thyroid function. If the nodule was
19 A Diffuse nontoxic goiter is most often caused by di- hyperfunctioning, and produced hyperthyroidism, it would
etary iodine deficiency. This condition is endemic in regions appear “hot” on the scan, and suppress thyroid-stimulating
of the world where there is a deficiency of iodine (e.g., in- hormone (TSH). Anti-TSH receptor immunoglobulins can
land mountainous areas); it also may occur sporadically. As be seen in Graves disease, as may high T4 and low TSH lev-
in this case, patients are typically euthyroid. A follicular ad- els, but this is a diffuse disease of the thyroid. T3 levels are
enoma rarely functions to produce excess thyroid hormone; rarely measured. Antimicrosomal and antithyroglobulin
most are “cold,” nonfunctioning nodules that do not involve antibodies are seen in Hashimoto thyroiditis (and Graves
the thyroid diffusely. A chronic lymphocytic thyroiditis, disease), but thyroiditis is a diffuse process and unlikely to
such as Hashimoto thyroiditis, initially can produce thyroid produce a solitary nodule. As Hashimoto thyroiditis pro-
enlargement, but atrophy eventually occurs with resulting gresses, decreasing function of the thyroid can lead to de-
hypothyroidism. Papillary carcinomas most often produce creasing T4 level and increasing TSH level, typical of primary
a mass effect or metastases and do not affect thyroid func- thyroid failure.
tion. Subacute granulomatous thyroiditis can lead to dif-
fuse enlargement, and transient hyperthyroidism can occur, PBD9 1092–1094 BP9 729–730 PBD8 1118–1119 BP8 767
but the disease typically runs a course of no more than 6 to
8 weeks. Plummer disease, or toxic multinodular goiter, oc- 23 C A thyroid nodule that is well differentiated, nonin-
curs when there is a hyperfunctioning nodule in a goiter. vasive, and hyperfunctioning suggests a “toxic” follicular
adenoma, and a large proportion of these adenomas have
PBD9 1090–1091 BP9 728–729 PBD8 1116 BP8 764–765
C H A P T E R 2 4 The Endocrine System 3 8 5
activating mutations of the thyroid-stimulating hormone and then are easily distinguished from follicular adenomas.
(TSH) receptor–signaling pathway involving the TSH recep- Follicular carcinomas are much less likely than papillary car-
tor or associated G protein. Mutation of the GNAS1 gene is cinomas to involve lymph nodes, but they are more likely to
seen in McCune-Albright syndrome and some pituitary ad- metastasize to distant sites, such as bone, lung, and liver. If
enomas. A PAX8-PPARG fusion gene is found in certain fol- the metastatic lesions are functional, they absorb radioactive
licular carcinomas of the thyroid. Activation of the RET gene iodine. Thyroiditis is unlikely to manifest as a mass because
occurs in papillary thyroid carcinomas. Overexpression of the entire gland is typically involved. Medullary carcinoma is
the cyclin D1 gene (CCND1) is characteristic of parathyroid less common than follicular carcinoma. There is an increased
adenomas. The AIRE gene regulates expression of self-antigens risk of non-Hodgkin B-cell lymphoma in patients with Hashi-
in the thymus, and mutation in this gene causes autoim- moto thyroiditis, but lymphomas are unlikely to destroy bone,
mune polyendocrinopathy affecting adrenals, parathyroids, although they can be present in the marrow.
gonads, and gastric parietal cells with destruction of these
tissues and consequent hypofunction. PBD9 1097–1098 BP9 733–734 PBD8 1123–1124 BP8 768–769
PBD9 1093 PBD8 1116–1118 BP8 729–730 2 7 A The large size, histologic features, and aggressive
nature of this neoplasm are consistent with anaplastic
2 4 D Papillary thyroid carcinomas may present initially carcinoma. The prognosis is poor. Other thyroid malignan-
with metastases, and local lymph nodes are the most com- cies tend to form solitary or multifocal (in papillary and
mon sites for metastases. The primary site may not be detect- medullary carcinomas) masses without spindle cells; they
able as a palpable nodule. Papillary carcinoma is the most are less likely to be extensively invasive, although metasta-
common thyroid malignancy. Metastases to the thyroid ses can occur, particularly to local lymph nodes in the case of
are uncommon. Anaplastic carcinomas are uncommon, but papillary carcinomas or lung in the case of follicular carcino-
are very aggressive, locally invasive lesions. Follicular and mas. Malignant lymphomas do not have spindle cells and do
medullary carcinomas tend to spread hematogenously. A not tend to be infiltrative.
parathyroid carcinoma is a locally infiltrative mass, and the
serum calcium level is usually quite high in such patients. PBD9 1098–1099 BP9 734 PBD8 1124 BP8 771
A small lymphocytic lymphoma, which is the tissue form of
chronic lymphocytic leukemia, is uncommon at this patient’s 28 A Medullary carcinomas are derived from the C cells,
age, usually involves multiple nodes, and is accompanied by or parafollicular cells, of the thyroid, with embryologic origin
an elevated WBC count. from neural crest. Therefore they have neuroendocrine func-
tion, including synthesis of calcitonin. An amyloid stroma is
PBD9 1094–1097 BP9 730–733 PBD8 1121–1122 BP8 768–769 a common feature of this tumor. These tumors occur sporad-
ically in about 70% of cases, but they can be familial and part
25 D The papillary architecture in this nodule, with cells of multiple endocrine neoplasia types 2A and 2B. CD3 is a
that have clear nuclei, is a pattern typical for papillary carci- useful marker for some lymphoid neoplasms. Although vari-
noma. There is no such thing as a papillary adenoma. These ous tissues may show positivity for estrogen receptors, this
nuclear changes, even if the pattern is follicular, confirm the di- finding has no clinical significance in thyroid. Staining for
agnosis of papillary carcinoma. About 30% of all papillary thy- parathyroid hormone is useful to determine if a parathyroid
roid carcinomas have mutational activation of RET or NTRK1 carcinoma is present. Vimentin is a marker for sarcomatous
proto-oncogenes, which belong to the family of receptor tyro- neoplasms, and cytokeratin is a useful marker to determine
sine kinases that transduce extracellular signals for cell growth if a neoplasm is epithelial.
and differentiation and exert many of their downstream effects
through the ubiquitous MAP kinase signaling pathway. Iodine PBD9 1099–1100 BP9 734–735 PBD8 1124–1126 BP8 769–771
deficiency gives rise to uniform thyroid enlargement because
the secretion of thyroid-stimulating hormone (TSH) increases 29 D When a patient develops hypercalcemia, a disorder
when there is reduced synthesis of T4. Autoimmunity plays a of the parathyroid glands or a malignancy at a visceral loca-
role in Hashimoto thyroiditis and Graves disease, and these tion must be considered. The elevated parathyroid hormone
do not progress to carcinoma, although non-Hodgkin lym- (PTH) suggests primary hyperparathyroidism. The most
phoma may develop in the former. Goitrogens interfere with common cause of primary hyperparathyroidism is a para-
thyroid hormone synthesis and have an effect similar to that thyroid adenoma. Secondary hyperparathyroidism, most
of iodine deficiency, with potential hypothyroidism, but not commonly resulting from renal failure, is excluded when the
malignancy. Viral infections can cause a subacute thyroiditis, serum inorganic phosphate level is low because phosphate is
not carcinoma. retained with chronic renal failure. Hypervitaminosis D can
cause hypercalcemia because of increased calcium absorp-
PBD9 1096–1097 BP9 731–732 PBD8 1121–1122 BP8 767–768 tion, but in these cases, the PTH levels are expected to be
near the low end of the reference range because of feedback
2 6 B Follicular carcinoma can be difficult to differentiate suppression. Serum PTH levels near the high end of the ref-
from follicular adenoma, unless there is microscopic evidence erence range indicate autonomous PTH secretion unregulated
of invasion, as shown in the figure, so the term follicular neo- by hypercalcemia. Although medullary carcinomas of the
plasm may be given for a fine-needle aspiration specimen. Fol- thyroid often have positive immunohistochemical staining
licular carcinomas are often indolent, but they can metastasize, for calcitonin, and plasma levels are sometimes increased,
3 8 6 U N I T I I Diseases of Organ Systems
there is typically no major reduction in serum calcium as a 33 C Inadvertent removal of or damage to the parathy-
result. roid glands during thyroid surgery can cause hypocalcemia
secondary to hypoparathyroidism. This is the most common
PBD9 1100–1103 BP9 735–737 PBD8 1127–1129 BP8 774 cause of hypoparathyroidism. Individuals with hypocalcemia
exhibit neuromuscular irritability, carpopedal spasm, and
3 0 C A common cause of clinically significant hypercal- sometimes seizures. Antithyroglobulin antibody levels are of
cemia in adults is a malignancy. When a patient presents no use in diagnosing surgical diseases of the thyroid. Calcitonin
with hypercalcemia, a disorder of the parathyroid glands quantitation is not a useful measure to determine the status
or a malignancy at a visceral location must be considered. of calcium metabolism. Parathyroid hormone levels decrease
Hypercalcemia from malignancy can be caused by osteo- if the parathyroid glands are inadvertently removed during
lytic metastases or a paraneoplastic syndrome from secre- thyroid surgery, but the calcium level is the best immediate
tion of parathyroid hormone–related protein by the tumor. indicator of hypoparathyroidism, and this test is more readily
Metastatic disease from common primary sites, such as the available in the laboratory. The thyroid-stimulating hormone
breast, lung, and kidney, is much more common than para- (TSH) concentration can increase if the patient becomes hypo-
thyroid carcinoma, which tends to be local but aggressive. thyroid after surgery and is not receiving thyroid hormone
Chronic renal failure causes phosphate retention, which replacement, but this is not an immediate problem.
tends to depress the serum calcium level and leads to sec-
ondary hyperparathyroidism; the serum calcium level is PBD9 1103–1104 BP9 738 PBD8 1129–1130 BP8 775
maintained at near-normal levels. Tuberculosis, a granulo-
matous disease, can be associated with hypercalcemia from 34 E An insulin overdose produces hypoglycemic coma.
up-regulation of 1,25-dihydrocholecalciferol in activated He does not have detectable C peptide, which indicates that
macrophages; lytic bone lesions from tuberculosis are un- there is no endogenous insulin production, typical for type
common. Parathyroid carcinomas are an uncommon cause 1 diabetes. The high insulin level is the result of the patient’s
of hyperparathyroidism, and bone metastases from parathy- use of exogenous insulin to treat his diabetes mellitus. Because
roid carcinomas are rare. Vitamin D toxicity theoretically can he has not eaten enough to maintain glucose at an adequate
lead to hypercalcemia, but this condition is uncommon. level, he has developed hypoglycemia. The ketosis in this
case results from decreased food intake, and anyone not con-
PBD9 1103 BP9 736 PBD8 1129 BP8 774 suming enough calories will develop ketosis. Ketoacidosis in
type 1 diabetes mellitus would be accompanied by hyper-
3 1 B A parathyroid neoplasm, most likely an adenoma, glycemia. Acute myocardial infarction is a complication that
is causing hypercalcemia complicated by osteitis fibrosa generally occurs later in the course of diabetes when more
cystica of her finger. Parathyroid hyperplasia involving all atherosclerosis has developed. The patient has no obvious
the glands is less likely. Parathyroid carcinomas are rare, source of sepsis. Insulin is not injected into the bloodstream,
thankfully, because they are aggressive, and serum calcium and the injections are almost never complicated by infection.
levels may be so high that cardiac arrhythmias occur. The Hepatic failure is not a typical complication of diabetes mel-
MEN1 mutation is the second most common mutation in litus. Hyperosmolar coma can complicate type 2 diabetes
parathyroid tumors, after the inversion with overexpression mellitus.
of CCND1, the gene encoding cyclin D1. MEN1 is a tumor
suppressor gene, the loss of which occurs not only in spo- PBD9 1105–1109 BP9 739–740 PBD8 1133 BP8 776–778
radic parathyroid tumors, but also in multiple endocrine
neoplasia (MEN) type 1. GNAS1 mutations are seen in 40% 35 E The presence of HLA-DR3 and HLA-DR4 alleles of
of cases of somatotroph (growth hormone–producing) pitui the MHC class II region has the strongest linkage to type 1
tary adenomas. The TP53 mutation can be seen in anaplastic diabetes mellitus. Autoantibodies to islet cell antigens such
thyroid carcinomas. The RET gene mutation is seen in cases as glutamic acid decarboxylase are present years before
of medullary thyroid carcinoma. The VHL mutation can overt clinical diabetes develops. An insulitis caused by T cell
be seen in some pheochromocytomas in patients with von infiltration occurs before the onset of symptoms or very early
Hippel−Lindau disease. in the course of type 1 diabetes mellitus. The insulitis in type
1 diabetes mellitus is associated with increased expression
PBD9 1101–1102 BP9 735–737 PBD8 1127 BP8 772–774 of class I MHC molecules and aberrant expression of class II
MHC molecules on the beta cells of the islets. These changes
3 2 D Chronic kidney injury, often leading to small end- are mediated by cytokines such as interferon-γ elaborated by
stage kidneys, with chronic renal failure can lead to secondary CD4+ cells (along with CD8+ cells). Acute neutrophilic in-
hyperparathyroidism resulting from decreased phosphate filtration with necrosis and hemorrhage are characteristic of
excretion by the kidneys. The resultant hyperphosphatemia acute pancreatitis. Extensive fibrosis and fatty replacement
depresses the serum calcium level and stimulates parathy- of the pancreas is seen in patients with cystic fibrosis surviv-
roid gland activity. Because of reduced renal parenchymal ing for decades. Islet hyperplasia occurs in infants of diabetic
function, there also is less active vitamin D, which leads to mothers. Amyloid deposition in islets may be seen in some
decreased dietary calcium absorption. Renal failure does not cases of type 2 diabetes mellitus. A fibrous stroma with mini-
lead to any of the other endocrine lesions listed. mal chronic inflammation and scattered normal islets is seen
with chronic pancreatitis.
PBD9 1103–1104 BP9 738 PBD8 1129 BP8 774
PBD9 1110 BP9 739–741 PBD8 1134 BP8 777–778
C H A P T E R 2 4 The Endocrine System 3 8 7
3 6 B This patient has maturity-onset diabetes of the of insulin with type 1 diabetes mellitus must be treated with
young (MODY), which accounts for less than 5% of cases insulin injections. There is modest weight gain with hypothy-
of diabetes mellitus and is linked to specific genetic defects roidism, but without abnormalities of adipocytes leading to
involving islet cells and inherited in an autosomal domi- insulin resistance. Liposuction is a plastic surgery technique
nant fashion. In this patient with MODY2, there is an in- used for body contouring, not weight reduction.
activating mutation in glucokinase that increases the beta
cell threshold for insulin release, and the hyperglycemia is PBD9 1111–1112 BP9 742–743 PBD8 1136–1137 BP8 778–780
mild. MODY3 is more common, results from mutations in
hepatocyte nuclear factor 1α, has severe insulin secretion 3 9 B The findings are complications of diabetes with preg-
defect in response to glucose, and results in more severe nancy, and the malformations suggest that hyperglycemia
hyperglycemia. Loss of glucagon secretion does not have preceded the pregnancy, and type 2 diabetes is quite common,
significant effects and does not lead to hyperglycemia. The even now in women of childbearing age. The neonatal hypo-
GLUT4 receptors are found on target cells for insulin, such glycemia is a consequence of excessive islet beta-cell function
as adipocytes and myocytes, but cases of diabetes related from having been in a hyperglycemic environment. Though
to mutations in GLUT receptors are rare. Mutations affecting cystic fibrosis is present from birth, the loss of pancreatic exo-
insulin itself are rare. Certain MHC alleles predispose to crine function takes years, and loss of islets is a late finding.
type 1 and type 2 diabetes mellitus, but are not involved in Gestational diabetes refers to glucose intolerance in pregnan-
pathways of insulin metabolism. cy, and newborns are likely to have hypoglycemia as a conse-
quence of their own beta cell hyperfunction, but not anomalies.
PBD9 1112 BP9 740, 743 PBD8 1137 BP8 776 Maturity-onset diabetes of the young (MODY; but not in in-
fancy) resembles type 2 diabetes and can occur from a variety
37 A Type 1 diabetes mellitus does not become overt un- of genetic defects in pathways monitoring glucose levels, but is
til the beta cells are markedly depleted, and insulin levels much less common. Pancreatic neuroendocrine tumors are un-
are greatly reduced. In this case, the girl has ketoacidosis. common but could secrete glucagon with secondary diabetes.
Amyloid replacement of islets is a feature of type 2 diabetes
mellitus; ketoacidosis is not a feature of type 2 diabetes mel- PBD9 1113 PBD8 1137
litus. Acute or chronic pancreatitis diminishes exocrine pan-
creatic function, but rarely destroys enough islets to cause 4 0 D Nonenzymatic glycosylation of proteins is a function
overt diabetes mellitus. Insulitis with inflammatory cells, of the level of blood glucose, rather than the cause of hypergly-
mostly T cells, can be seen in the islets of patients with type cemia. This is the basis for an elevated hemoglobin A1c. Type 1
1 diabetes mellitus before the diabetes is clinically overt. Eo- and type 2 diabetes mellitus are characterized by hyperglyce-
sinophils are rare, however, with insulitis, but instead may mia, but the underlying pathogenetic mechanisms are differ-
be found in the islets of diabetic infants who fail to survive ent. Type 1 diabetes mellitus is an autoimmune disease that is
the immediate postnatal period. A pancreatic neuroendo- associated with certain alleles of the MHC class II molecules. It
crine tumor may become hormonally active and can lead to is characterized by a very high concordance rate in twins and
hypoglycemia if insulin is produced in excess; production of the presence of islet autoantibodies. Insulin resistance is a key
glucagon by such an adenoma may lead to secondary dia- feature of type 2 diabetes mellitus.
betes mellitus from the insulin-opposing effect of glucagon,
but there is still insulin secretion to prevent ketoacidosis. PBD9 1115–1116 BP9 743–744 PBD8 1138 BP8 780–781
The most common finding with glucagonoma is necrolytic
migrating erythema. Alpha cell hyperplasia is quite rare. 41 C Nonenzymatic glycosylation refers to the chemical
process whereby glucose attaches to proteins without the aid
PBD9 1109–1111 BP9 741, 748–749 PBD8 1143 BP8 777–778 of enzymes. The degree of glycosylation is proportionate to
the level of blood glucose. Many proteins, including hemo-
38 B The findings are those of insulin resistance from obe- globin, undergo nonenzymatic glycosylation. Because RBCs
sity with metabolic syndrome. Insulin resistance drives beta have a life span of about 120 days, the amount of glycosylated
cell dysfunction, but other factors such as the TCF7L2 gene hemoglobin is a function of the blood glucose level over the
play a role in eventual development of overt type 2 diabetes previous 120-day period. The level of glycosylated hemo-
mellitus. Excess free fatty acids may stimulate cytokine re- globin is not appreciably affected by short-term changes in
lease from beta cells to promote inflammation and islet cell plasma glucose levels. Random glucose testing is an imme
dysfunction. Lifestyle modification with dietary modification diate way for monitoring short-term adjustments with diet
for weight reduction coupled with increased exercise will aid and medications such as insulin and oral agents. Fasting
in reversing the insulin resistance so that no drug therapy is glucose testing affords a better way to diagnose diabetes
needed to control hyperglycemia. Cushing syndrome may mellitus initially. Measurements of cholesterol and fructos-
occur from ACTH-independent adrenal cortical lesions, such amine have no value in managing diabetes mellitus. Micro-
as primary hyperplasia, adenoma, or carcinoma, and lead to albuminuria may presage the development of diabetic renal
secondary diabetes from glucocorticoid-induced insulin resis- disease. The “incretin effect” is diminished in patients with
tance, but primary adrenal lesions are less common than met- type 2 diabetes, and use of GLP-1 receptor agonists can help
abolic syndrome from obesity alone, and the study patients to restore incretin function and lead to improved glycemic
lack additional features of Cushing syndrome such as hirsuit- control and loss of weight via increased satiety.
ism, osteoporosis, and easy bruisability. The absolute decrease
PBD9 1115–1116 BP9 743–744 PBD8 1138 BP8 780–781
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Robbins and Cotran Review of Pathology ( PDFDrive ) (1)
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