Textbook of Pathology, 6th Edition

TUMOURS OF ENDOMETRIUM AND MYOMETRIUM ETIOPATHOGENESIS. The exact etiology of endometrial 735
cancer remains unknown. However, a few factors associated
Tumours arising from endometrium and myometrium may with increased frequency of its development are chronic
be benign or malignant. They may originate from different unopposed oestrogen excess, obesity, diabetes, hypertension
tissues as under: and nulliparous state. There is irrefutable evidence of
Endometrial glands—endometrial polyps, endometrial
carcinoma. relationship of endometrial carcinoma with prolonged oestrogenic
stimulation. These evidences are as under:
Endometrial stroma—stromal nodules, stromal sarcoma. 1. Endometrial carcinoma has association with endometrial
Smooth muscle of the myometrium—leiomyoma, hyperplasia (discussed above) in which there is unopposed
leiomyosarcoma. chronic hyperoestrogenism and frequent anovulatory cycles.
Mullerian mesoderm—mixed mesodermal or mullerian 2. In postmenopausal years when endometrial carcinoma
tumours. occurs characteristically, there is excessive synthesis of
Out of these, endometrial polyps, endometrial carcinoma, oestrogen in the body from adrenal as well as from ovarian
leiomyomas and leiomyosarcomas are relatively more sources.
common and are described below. 3. Women having oestrogen-secreting tumours (e.g. granu-
losa cell tumour) have increased risk of developing
Endometrial Polyps synchronous endometrial cancer.

‘Uterine polyp’ is clinical term used for a polypoid growth 4. Patients receiving prolonged exogenous oestrogen
projecting into the uterine lumen and may be composed of therapy are at higher risk of developing this cancer.
benign lesions (e.g. endometrial or mucous polyp, 5. Women of breast cancer receiving tamoxifen for prolonged
leiomyomatous polyp and placental polyp), or malignant period have 2-fold increased risk of developing uterine
polypoid tumours (e.g. endometrial carcinoma, choriocar- cancer.
cinoma and sarcoma). The most common variety, however, 6. Prolonged administration of oestrogen to laboratory
is the one having the structure like that of endometrium and animals can produce endometrial hyperplasia and
is termed endometrial or mucus polyp. They are more common carcinoma.
in the perimenopausal age group. Small endometrial polyps 7. Women with gonadal agenesis rarely develop endo- CHAPTER 24
generally remain asymptomatic and are detected metrial carcinoma.
incidentally. The larger ones may ulcerate, degenerate and Pathogenetically, papillary serous variant of endometrial
result in clinical bleeding. carcinoma is associated with mutation in p53 tumour
suppressor gene while endometrioid carcinoma has mutation
MORPHOLOGIC FEATURES. Grossly, endometrial in PTEN gene located on chromosome 10. The role of heredity
polyps may be single or multiple, usually sessile and small in pathogenesis of endometrial cancer is supported by higher
(0.5 to 3 cm in diameter) but occasionally they are large incidence in hereditary non-polyposis colon cancer (HNPCC)
and pedunculated. syndrome (having simultaneous cancers of the colon and
Histologically, they are essentially made up of mixture endometrioid adenocarcinoma) and in Cowden syndrome
of endometrial glands and stroma. The histologic pattern (having simultaneous cancers of the breast, thyroid, and
of the endometrial tissue in the polyp may resemble either endometrium). The Female Genital Tract
functioning endometrium or hyperplastic endometrium
of cystic hyperplasia type, the latter being more common. MORPHOLOGIC FEATURES. Grossly, endometrial
Rarely, a large endometrial polyp may undergo malignant carcinoma may have 2 patterns—localised polypoid tumour,
change. or a diffuse tumour; the latter being more common
(Fig. 24.14). The tumour protrudes into the endometrial
Endometrial Carcinoma cavity as irregular, friable and grey-tan mass. Extension
Carcinoma of the endometrium, commonly called uterine of the growth into the myometrium may be identified by
cancer, is the most common pelvic malignancy in females in the presence of soft, friable and granular tissue in cut
the United States and Eastern Europe but is uncommon in section. In advanced disease, the involvement may extend
Asia where cervical cancer continues to be the leading cancer beyond the physiologic limits—into the cervical canal, into
in women. Whereas the decline in the incidence of cervical the peritoneum, besides lymphatic metastases and
cancer in the developed countries is due to aggressive cervical haematogenous metastases to distant sites such as lungs,
screening programme leading to early detection and cure of liver, bones and other organs.
in situ stage, increased frequency of endometrial carcinoma Histologically, most endometrial carcinomas are
in these countries may be due to longevity of women’s life adenocarcinomas, commonly termed endometrioid
to develop this cancer of older females. It is primarily a adenocarcinomas due to their resemblance with normal
disease of postmenopausal women, the peak incidence at endometrium. Depending upon the pattern of glands and
onset being 6th to 7th decades of life and is uncommon below individual cell changes, these may be well-differentiated,
the age of 40 years. The most important presenting complaint moderately-differentiated or poorly-differentiated.
is abnormal bleeding in postmenopausal woman or excessive Well-differentiated adenocarcinoma is characterised by
flow in the premenopausal years. increase in the number of glands which are closely packed

736






















Figure 24.14 Endometrial carcinoma. A, B, Diagrammatic
representation of the common gross patterns—localised polypoid growth
and diffuse growth. C, The specimen of the uterus and cervix shows
enlarged uterus and dilated uterine cavity containing irregular, grey-white,
friable growth arising from endometrial mucosa and invading the
underlying myometrium superficially.




sometimes showing ‘back-to-back crowding’ due to G1: Well-differentiated (predominantly glandular).
obliterated intervening stroma. The glandular epithelium G2: Moderately-differentiated (glandular and partly solid
shows stratification, formation of tufting and papillae and areas).
atypical changes. Most growths are well-differentiated G3: Poorly-differentiated (predominantly solid).
(Fig. 24.15).
SECTION III
Moderately-differentiated adenocarcinoma shows all the Papillary serous carcinoma of the endometrium resembling
above features alongwith presence of some solid sheets its ovarian counterpart is distinct since it occurs in the
of malignant cells. background of atrophic endometrium and is more
Poorly-differentiated adenocarcinoma is characterised by aggressive. Uncommon histologic variants of endometrial carci-
presence of solid sheets and ribbons of malignant epithe- noma are: adenocarcinoma with squamous metaplasia
lial cells which show marked cytologic atypia and frequent (adenoacanthoma), adenosquamous carcinoma (when both
mitoses. Glandular pattern is hard to find. components are frankly malignant), clear cell carcinoma,
Cases can also be categorised as regards histologic mucinous adenocarcinoma and papillary serous carcinoma.
grade as follows: Carcinoma of the endometrium is categorised into four
stages as per FIGO classification given in Table 24.5.
Systemic Pathology


























Figure 24.15 Endometrial carcinoma. The most common histologic pattern is well-differentiated adenocarcinoma showing closely packed
(back-to-back) glands with cytologic atypia.

 TABLE 24.5: FIGO Clinical Staging of Carcinoma of the MORPHOLOGIC FEATURES. Leiomyomas are most 737
Endometrium. frequently located in the uterus where they may occur
Stage IA Tumour limited to endometrium. within the myometrium (intramural or interstitial), the
IB Invasion to less than one-half the myometrium. serosa (subserosal), or just underneath the endometrium
IC Invasion to more than one-half the myometrium. (submucosal). Subserosal and submucosal leiomyomas
Stage IIA Endocervical glandular involvement only. may develop pedicles and protrude as pedunculated
IIB Cervical stromal invasion. myomas. Leiomyomas may involve the cervix or broad
Stage IIIA Tumour invades serosa and/or adnexa and/or positive ligament.
peritoneal cytology. Grossly, irrespective of their location, leiomyomas are
IIIB Metastases to pelvic and/or para-aortic lymph nodes. often multiple, circumscribed, firm, nodular, grey-white
Stage IVA Tumour invasion of bladder and/or bowel mucosa. masses of variable size. On cut section, they exhibit
IVB Distant metastases including intra-abdominal and/or characteristic whorled pattern (Fig. 24.16, A,B).
inguinal lymph nodes.
Histologically, they are essentially composed of 2 tissue
elements—whorled bundles of smooth muscle cells
Leiomyoma admixed with variable amount of connective tissue. The
smooth muscle cells are uniform in size and shape with
Leiomyomas or fibromyomas, commonly called fibroids by abundant cytoplasm and central oval nuclei (Fig. 24.17).
the gynaecologists, are the most common uterine tumours Cellular leiomyoma has preponderance of smooth
of smooth muscle origin, often admixed with variable amount muscle elements and may superficially resemble leiomyo-
of fibrous tissue component. About 20% of women above sarcoma but is distinguished from it by the absence of
the age of 30 years harbour uterine myomas of varying size. mitoses (see below).
Vast majority of them are benign and cause no symptoms. The pathologic appearance may be altered by
Malignant transformation occurs in less than 0.5% of secondary changes in the leiomyomas; these include:
leiomyomas. Symptomatic cases may produce abnormal hyaline degeneration, cystic degeneration, infarction,
uterine bleeding, pain, symptoms due to compression of calcification, infection and suppuration, necrosis, fatty
surrounding structures and infertility. change, and rarely, sarcomatous change. CHAPTER 24
The cause of leiomyomas is unknown but the possible
stimulus to their proliferation is oestrogen. This is evidenced
by increase in their size in pregnancy (Fig. 24.16,C) and high Leiomyosarcoma
dose oestrogen-therapy and their regression following Leiomyosarcoma is an uncommon malignant tumour as
menopause and castration. Other possible factors implicated compared to its rather common benign counterpart. The
in its etiology are human growth hormone and sterility. incidence of malignancy in pre-existing leiomyoma is less The Female Genital Tract

































Figure 24.16 Leiomyomas. A, Diagrammatic appearance of common locations and characteristic whorled appearance on cut section.
B, Sectioned surface of the uterus shows multiple circumscribed, firm nodular masses of variable sizes—submucosal (white arrows) and intramural
(black arrows) in location having characteristic whorling. C, The opened up uterine cavity shows an intrauterine gestation sac with placenta (white
arrow) and a single circumscribed, enlarged, firm nodular mass in intramural location (black arrow) having grey-white whorled pattern.

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Figure 24.17 Leiomyoma uterus. Microscopy shows whorls of smooth muscle cells which are spindle-shaped, having abundant cytoplasm and
oval nuclei.

than 0.5% but primary uterine sarcoma is less common than circular smooth muscle layers, and tubal mucosa having 3
that which arises in the leiomyoma. The peak age incidence types of cells namely: ciliated, columnar and dark intercalated
is seen in 4th to 6th decades of life. The symptoms produced cells. The tubal serosal covering may contain tiny nodular
are nonspecific such as uterine enlargement and abnormal masses of mesothelial cells forming Walthard’s cell rests.
uterine bleeding. The major conditions involving the fallopian tubes are
inflammations, ectopic tubal gestation, and endometriosis.
MORPHOLOGIC FEATURES. Grossly, the tumour may
form a diffuse, bulky, soft and fleshy mass, or a polypoid
SECTION III
mass projecting into lumen. INFLAMMATIONS
Histologically, though there are usually some areas Salpingitis and Pelvic Inflammatory Disease
showing whorled arrangement of spindle-shaped smooth
muscle cells having large and hyperchromatic nuclei, the Pelvic inflammatory disease (PID) by definition is a clinical
hallmark of diagnosis and prognosis is the number of syndrome characterised by signs and symptoms of ascending
mitoses per high power field (HPF). The essential infection beginning in the vulva or vagina and spreading
diagnostic criteria are: more than 10 mitoses per 10 HPF through the entire genital tract. Although ascending route
with or without cellular atypia, or 5-10 mitoses per 10 HPF of infection is the most common mode of spread, PID may
with cellular atypia. More the number of mitoses per 10 occur following abortion and puerperium, with use of
HPF, worse is the prognosis. intrauterine contraceptive devices, or from local intra-
abdominal infections such as appendicitis with peritonitis.
Leiomyosarcoma is liable to recur after removal and In addition, haematogenous spread may occur, though this
Systemic Pathology
eventually metastasises to distant sites such as lungs, liver, route is more important in the pathogenesis of tuberculosis.
bone and brain. Most commonly, PID occurs as a venereally-transmitted
infection, chiefly caused by Chlamydia trachomatis and
FALLOPIAN TUBES Neisseria gonorrhoeae. Post-abortal and postpartum infections
are mainly caused by staphylococci, streptococci, coliform
NORMAL STRUCTURE bacteria, clostridia and pneumococci.
Patients generally complain of lower abdominal and
The fallopian tube or oviducts are paired structures, each pelvic pain which is often bilateral, dysmenorrhoea,
extending from superior angle of the uterus laterally to the menstrual abnormalities and fever with tachycardia. Long-
region of the ovaries and running in the superior border of standing chronic PID may lead to infertility and adhesions
the broad ligaments forming mesosalpinx. Each tube is between small intestine and pelvic organs.
7-14 cm long and is divided into 4 parts—interstitial portion
in the uterine cornual wall; narrow isthmic portion; wider MORPHOLOGIC FEATURES. Grossly, the fallopian
ampullary region; and funnel-like distal infundibulum. The tubes are invariably involved bilaterally. The distal end
infundibulum is fringed by fimbriae, the longest of which is blocked by inflammatory exudate and the lumina are
called fimbria ovarica is attached to the ovary. dilated. There may be formation of loculated tubo-ovarian
Histologically, the wall of tube has 4 coats—serous abscess involving the tube, ovary, broad ligament and
forming the peritoneal covering, subserous consisting of adjacent part of uterus.
fibrovascular tissue, muscular composed of longitudinal and

Microscopically, the appearance varies with the duration 739
of inflammatory process.
The process begins with acute salpingitis characterised
by oedema and intense acute inflammatory infiltrate of
neutrophils involving the tubal mucosa as well as wall.
The lumen is filled with purulent exudate consisting of
leucocytes and sloughed off epithelial cells.
The purulent process may extend to involve tube as
well as ovary causing salpingo-oophoritis and forming
tubo-ovarian abscess.
The escape of purulent exudate into the peritoneal
cavity produces pelvic peritonitis and pelvic abscess.
Pyosalpinx is distension of the fallopian tube with pus Figure 24.18 Ectopic tubal gestation. The lumen of the fallopian
due to occluded fimbrial end. tube is dilated in the middle and contains dark tan, haemorrhagic and
End-result of pyosalpinx after resorption of the puru- friable gestational tissue (sac, foetus and placenta).
lent exudate is hydrosalpinx in which the tube is thin-
walled, dilated and filled with clear watery fluid. predispose to ectopic tubal pregnancy are: PID, previous
Acute salpingitis may resolve with treatment but some tubal surgery, use of IUCD and congenital anomalies of the
cases pass into chronic salpingitis with infiltrate of female genital tract. The most frequent site of tubal pregnancy
polymorphs, lymphocytes and plasma cells and fibrosis. is the ampullary portion and the least common is interstitial
Salpingitis isthmica nodosa used to be considered pregnancy. Ectopic tubal pregnancy is a potentially
another manifestation of chronic salpingitis but currently hazardous problem because of rupture which is followed by
accepted pathogenesis of this lesion appears to be similar intraperitoneal haemorrhage.
to that of adenomyosis. Nevertheless, the appearance is
characterised by multiple nodules containing spaces TUMOURS AND TUMOUR-LIKE LESIONS
which are lined by benign tubal epithelium. Inflammatory Tumours in the fallopian tubes are rare. Relatively more CHAPTER 24
changes are scanty or absent.
common are hydatids of Morgagni or parovarian cysts which
are unilocular, thin-walled cysts hanging from the tubal
Tuberculous Salpingitis fimbriae. Rare tumours include adenomatoid tumours,
Tuberculous salpingitis is almost always secondary to focus leiomyomas, teratomas, adenocarcinomas and choriocarci-
elsewhere in the body. The tubercle bacilli reach the tube, noma all of which are similar in morphology to such tumours
most commonly by haematogenous route, generally from the elsewhere in the body.
lungs, but occasionally from the urinary tract or abdominal
cavity. Tubal tuberculosis is always present when there is OVARIES
tuberculosis of other female genital organs such as of
endometrium, cervix and lower genital tract. Though NORMAL STRUCTURE The Female Genital Tract
infrequent in developed countries of the world, the incidence The ovaries are paired bean-shaped organs hanging from
of tubal tuberculosis in developing countries like India is either tube by a mesentery called the mesovarium, the lateral
estimated to be about 5%; concomitant involvement of suspensory ligament and the ovarian ligament. The lateral
endometrium is present in about 80% cases. It affects more suspensory ligament of the ovary contains blood vessels,
commonly young women in their active reproductive life and lymphatics and plexuses of nerves. Each ovary measures 2.5-
the most common complaint is infertility. 5 cm in length, 1.5-3 cm in breadth and 0.7-1.5 cm in width
and weighs 4-8 gm.
MORPHOLOGIC FEATURES. Grossly, the tube is dila-
ted and contains purulent exudate though the fimbrial end Histologically, the ovarian structure consists of covering
is generally patent. The tubal peritoneum as well as the by coelomic epithelium, outer cortex and inner medulla
peritoneum in general is studded with yellowish tubercles. (Fig. 24.19).
Microscopically, typical caseating granulomas and Coelomic epithelium. The surface of the ovary is covered
chronic inflammation are identified in the tubal serosa, by a single layer of cuboidal epithelial cells.
muscularis and mucosa.
Cortex. During active reproductive life, the cortex is broad
and constitutes the predominant component of the ovary.
ECTOPIC TUBAL PREGNANCY
The cortex contains numerous ovarian follicles and their
The term ectopic tubal pregnancy is used for implantation derivative structures. Each follicle consists of a central germ
of a fertilised ovum in the tube. Though ectopic pregnancy cell ovum surrounded by specialised gonadal stroma. This
may rarely occur in the uterine horn, cornu, ovary and stroma consists of granulosa cells encircling the ovum, and
abdominal cavity, tubal pregnancy is by far the most common concentrically-arranged plump spindle-shaped theca cells. In
form of ectopic gestation (Fig. 24.18). Several factors which infancy, the granulosa cells form a single layer of cuboidal

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Figure 24.19 Structure of the ovary to illustrate origin of ovarian tumours.


cells around the ovum but later form several layers. Granu- Histologically, they are lined by granulosa cells.
losa cells may form Call-Exner bodies normally as well as in Occasionally, however, there may be difficulty in
certain neoplastic conditions. Call-Exner bodies have a distinguishing between a large cyst of coelomic epithelial
central small round mass of dense pink material surrounded origin (serous cyst) lined by flattened epithelial cells and a
by a rosette of granulosa cells. The granulosa component is cyst of follicular origin. Such cases are appropriately
avascular and draws its nutrition from the highly vascular designated as ‘simple cysts’.
theca component. The theca component has 2 parts—
luteinised theca layer called theca interna, and outer Luteal cysts are formed by rupture and sealing of corpus
condensed ovarian stroma called theca externa. Granulosa haemorrhagicum. The wall of these cysts is composed of
cells and follicle-associated (luteinised) theca cells produce yellowish luteal tissue (lutein = yellow pigment).
oestrogen. Fully mature ovarian follicle called graafian follicle Histologically, luteal cysts are commonly lined by
SECTION III
bursts releasing the ovum and becomes transformed into luteinised granulosa cells. Lining by predominantly lutei-
corpus luteum which is the principal source of progesterone nised theca cells may also be seen in cystic ovaries in
that brings about secretory endometrial pattern. The corpus association with hydatidiform mole and choriocarcinoma,
luteum is later replaced by corpus albicans. In addition to and rarely, in normal pregnancy. Corpus albicans cyst is a
specialised gonadal stroma and follicles, the cortex contains variant of corpus luteum cyst in which there is
unspecialised ovarian stroma consisting of spindle-shaped hyalinisation in the wall and distension of the cavity with
connective tissue cells and smooth muscle fibres. fluid.
Medulla. The ovarian medulla is primarily made up of
connective tissue fibres, smooth muscle cells and numerous Polycystic Ovary Disease (Stein-Leventhal Syndrome)
blood vessels, lymphatics and nerves. In addition, the
medulla may also contain clusters of hilus cell (or hilar- Polycystic ovary syndrome (PCOS) is a syndrome
Systemic Pathology
Leydig cells) which may have androgenic role in contrast to characterised by oligomenorrhoea, anovulation, infertility,
oestrogenic role of the ovarian cortex. hirsutism and obesity in young women having bilaterally
The major pathologic lesions of the ovary are the non- enlarged and cystic ovaries. The principal biochemical
neoplastic cysts and ovarian tumours. abnormalities in most patients are excessive production of
androgens, and low levels of pituitary follicle stimulating
hormone (FSH). These endocrinologic abnormalities were
NON-NEOPLASTIC CYSTS previously attributed to primary ovarian dysfunction as
The most common of the non-neoplastic cysts of the ovary evidenced by excellent results from wedge resection of the
are tubo-ovarian inflammatory mass (discussed above) and ovary. Current concept of pathogenesis of PCOS is the
follicular and luteal cysts. Polycystic ovarian disease of Stein- unbalanced release of FSH and LH by the pituitary. FSH is
Leventhal syndrome is another cause of cystic ovary. inhibited to low levels by testosterone but the level of LH is
sufficient to cause luteinisation of ovarian theca and
Follicular and Luteal Cysts granulosa cells which then secrete androgen inappropriately
Normally follicles and corpus luteum do not exceed a and produce an abnormal state of anovulation. A hereditary
diameter of 2 cm. When their diameter is greater than 3 cm, basis for the syndrome has been suggested in some cases.
they are termed as cysts. PATHOLOGIC CHANGES. Grossly, the ovaries are
Follicular cysts are frequently multiple, filled with clear usually involved bilaterally and are at least twice the size
serous fluid and may attain a diameter upto 8 cm. When of the normal ovary. They are grey-white in colour and
large, they produce clinical symptoms.

 TABLE 24.6: Classification of Ovarian Tumours. ovarian tumours. However, a few risk factors have been 741
identified as under:
I. TUMOURS OF SURFACE EPITHELIUM
(COMMON EPITHELIAL TUMOURS) (60-70%) 1. Nulliparity. There is higher incidence of ovarian cancer in
A. Serous tumours unmarried women and married women with low or no
1. Serous cystadenoma parity.
2. Borderline serous tumour 2. Heredity. About 10% cases of ovarian cancer occur in
3. Serous cystadenocarcinoma women with family history of ovarian or breast cancer.
B. Mucinous tumours Women with hereditary breast-ovarian cancer susceptibility
1. Mucinous cystadenoma
2. Borderline mucinous tumour have mutation in tumour suppressor BRCA gene—BRCA-1
3. Mucinous cystadenocarcinoma (located on chromosome 17q) and BRCA-2 (located on
C. Endometrioid tumours chromosome 13q). The risk in BRCA-1 carriers is higher
D. Clear cell (mesonephroid) tumours compared to that in BRCA-2 carriers. Interestingly, men in
E. Brenner tumours such families have an increased risk of prostate cancer. In
addition to BRCA mutation, other molecular abnormalities
II. GERM CELL TUMOURS (15-20%)
A. Teratomas in ovarian cancers include mutation of p53 tumour
suppressor gene and overexpression of ERBB-2 and K-RAS
1. Benign (mature, adult) teratoma
• Benign cystic teratoma (dermoid cyst) genes.
• Benign solid teratoma 3. Complex genetic syndromes. Besides the above two main
2. Malignant (immature) teratoma factors, several complex genetic syndromes are associated
3. Monodermal or specialised teratoma with ovarian tumours as follows:
• Struma ovarii
• Carcinoid tumour i) Lynch syndrome associated with increased risk of ovarian
B. Dysgerminoma cancer.
C. Endodermal sinus (yolk sac) tumour ii) Peutz-Jeghers syndrome with ovarian sex cord-stromal
D. Choriocarcinoma tumours.
E. Others (embryonal carcinoma, polyembryoma, mixed germ iii) Gonadal dysgenesis with gonadoblastoma.
cell tumours) iv) Nevoid basal cell carcinoma with ovarian fibromas. CHAPTER 24
III. SEX CORD-STROMAL TUMOURS (5-10%)
A. Granulosa-theca cell tumours CLINICAL FEATURES AND CLASSIFICATION
1. Granulosa cell tumour
2. Thecoma In general, benign ovarian tumours are more common,
3. Fibroma particularly in young women between the age of 20 and 40
B. Sertoli-Leydig cell tumours (Androblastoma, arrhenoblastoma) years, and account for 80% of all ovarian neoplasms.
C. Gynandroblastoma Malignant tumours may be primary or metastatic, ovary
IV. MISCELLANEOUS TUMOURS being a common site for receiving metastases from various
A. Lipid cell tumours other cancers. Primary malignant ovarian tumours are more
B. Gonadoblastoma common in older women between the age of 40 and 60 years. The Female Genital Tract
Although certain specific tumours have distinctive
V. METASTATIC TUMOURS (5%)
A. Krukenberg tumour features such as elaboration of hormones, most benign and
B. Others malignant ovarian tumours are discovered when they grow
sufficiently to cause abdominal discomfort and distension.
Urinary tract and gastrointestinal tract symptoms are
studded with multiple small (0.5-1.5 cm in diameter) frequently associated due to compression by the tumour.
bluish cysts just beneath the cortex. The medullary stroma Ascites is common in both benign and malignant ovarian
is abundant, solid and grey. tumours. Menstrual irregularities may or may not be present.
Histologically, the outer cortex is thick and fibrous. The Some ovarian tumours are bilateral. Malignant tumours
subcortical cysts are lined by prominent luteinised theca usually spread beyond the ovary to other sites before the
cells and represent follicles in various stages of maturation diagnosis is made.
but there is no evidence of corpus luteum. A simplified classification proposed by the WHO with
minor modifications has been widely adopted (Table 24.6).
OVARIAN TUMOURS According to this classification, ovarian tumours arise from
The ovary is third most common site of primary malignancy normally-occurring cellular components of the ovary
in the female genital tract, preceded only by endometrial and (Fig. 24.19). Five major groups have been described:
cervical cancer. Both benign and malignant tumours occur I. Tumours of surface epithelium (common epithelial
in the ovaries. tumours)
II. Germ cell tumours
ETIOPATHOGENESIS III. Sex cord-stromal tumours

Unlike the two other female genital cancers (cervix and IV. Miscellaneous tumours
endometrium), not much is known about the etiology of V. Metastatic tumours

742 I. TUMOURS OF SURFACE EPITHELIUM much better prognosis than frankly malignant tumours of
(COMMON EPITHELIAL TUMOURS) the ovary.
Based on this categorisation of biologic behaviour, groups
Tumours derived from the surface (coelomic) epithelium of surface epithelial ovarian tumours are described below:
called common epithelial tumours form the largest group of
ovarian tumours. This group constitutes about 60-70% of all Serous Tumours
ovarian neoplasms and 90% of malignant ovarian tumours. Serous tumours comprise the largest group constituting
The common epithelial tumours are of 3 major types—serous, about 20% of all ovarian tumours and 40% of malignant
mucinous and endometrioid, though mixtures of these epithelia
may occur in the same tumour. These tumours frequently ovarian tumours. They are called serous tumours because of
the presence of clear, watery, serous fluid in these
have prominent cystic component which may have a single predominantly cystic tumours. About 60% of serous tumours
or multiple loculations and hence the descriptive prefix are benign, 15% borderline and 25% malignant. Only 20% of
cystadeno- in these tumours. In addition, surface epithelial
benign tumours occur bilaterally, whereas 65% of both
tumours may differentiate along urothelium to form Brenner borderline and malignant serous tumours have bilateral
tumour, and along mesonephroid pattern forming clear cell ovarian involvement. Serous tumours occur most commonly
(mesonephroid) adenocarcinoma. in 2nd to 5th decades of life, the malignant forms being more
Depending upon the aggressiveness, the surface epithe- frequent in later life.
lial tumours are divided into 3 groups: clearly benign, clearly Histogenesis of the serous tumours is by metaplasia from
malignant, and borderline (or atypical proliferating or low-grade) the surface (coelomic) epithelium or mesothelium which
malignant tumours. In general, the criteria for diagnosis of differentiates along tubal-type of epithelium.
these 3 grades of aggressiveness are as follows (Fig. 24.20):
Clearly benign tumours are lined by a single layer of MORPHOLOGIC FEATURES. Grossly, benign,
well-oriented columnar epithelium. Papillary projections, if borderline and malignant serous tumours are large (above
present, are covered by the same type of epithelium without 5 cm in diameter) and spherical masses. Small masses are
any invasion into fibrovascular stromal stalk. generally unilocular while the larger serous cysts are
multiloculated similar to the mucinous variety, but differ
Clearly malignant tumours have anaplastic epithelial from the latter in containing serous fluid rather than the
component, multilayering, loss of basal polarity and viscid fluid of mucinous tumours. Malignant serous
unquestionable stromal invasion. The prognosis of these tumours may have solid areas in the cystic mass. Exophytic
SECTION III
tumours is very poor.
as well as intracystic papillary projections may be present
Borderline (atypical proliferating) tumours or tumours in all grades of serous tumours but are more frequent in
with low malignant potential have some morphological malignant tumours termed papillary serous cystadeno-
features of malignancy, apparent detachment of cellular carcinomas (Fig. 24.21).
clusters from their site of origin and essential absence of Histologically, the features are as follows:
stromal invasion. Morphological features of malignancy 1. Serous cystadenoma is characteristically lined by
which may be present in varying combinations include: strati- properly-oriented low columnar epithelium which is
fication (2-3 layers) of the epithelial cells but generally sometimes ciliated and resembles tubal epithelium.
maintained basal polarity of nuclei, moderate nuclear Microscopic papillae may be found.
abnormalities, and some mitotic activity. This group has a
Systemic Pathology

























Figure 24.20 Diagrammatic representation of general histologic criteria to distinguish benign, borderline (atypical proliferating) and malignant
surface epithelial tumours of the ovary.

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Figure 24.21 Papillary serous cystadenocarcinoma of the ovary. It
shows an enlarged ovary replaced with a large unilocular cyst with
intracystic papillae (arrow).



2. Borderline (atypical proliferating) serous tumour peritonei (page 579). As compared with serous tumours,
usually has stratification (2-3 layers) of benign serous type mucinous tumours are more commonly unilateral. Benign
of epithelium. There is detachment of cell clusters from mucinous tumours occur bilaterally in 5% of cases while
their site of origin and moderate features of malignancy borderline and malignant are bilateral in 20%. As per current
but there is absence of stromal invasion. concept, the diagnosis of primary ovarian mucinous
3. Serous cystadenocarcinoma has multilayered adenocarcinoma is made after excluding metastatic tumours
malignant cells which show loss of polarity, presence of to the ovary, while bilateral mucinous adenocarcinoma of
solid sheets of anaplastic epithelial cells and definite the ovary is invariably metastatic deposits to the ovary.
evidence of stromal invasion. Papillae formations are more Mucinous tumours occur principally between 2nd and 5th
frequent in malignant variety and may be associated with decades of life. Mucinous cystadenocarcinoma usually CHAPTER 24
psammoma bodies but mere presence of psammoma develops in women above the age of 40 years.
bodies is not indicative of malignancy (Fig. 24.22). Histogenesis of mucinous tumours, in line with that of
serous tumours, is by metaplasia from the coelomic
Mucinous Tumours epithelium that differentiates along endocervical type or
intestinal type of mucosa.
Mucinous tumours are somewhat less common than serous
tumours and constitute about 20% of all ovarian tumours
and 10% of all ovarian cancers. Over 80% are benign, 10- MORPHOLOGIC FEATURES. Grossly, mucinous
15% are borderline (atypical proliferating) and 5-10% are tumours are much larger than serous tumours. They are
malignant. These predominantly cystic tumours contain smooth-surfaced cysts with characteristic multiloculations
mucin which was previously described as pseudomucin. containing thick and viscid gelatinous fluid (Fig. 24.23). The Female Genital Tract
Well-differentiated borderline mucinous tumours are Benign tumours generally have thin wall and septa
associated with mucinous ascites termed pseudomyxoma dividing the loculi are also thin and often translucent, but



























Figure 24.22 Papillary serous cystadenocarcinoma of the ovary. Microscopic features include stratification of low columnar epithelium lining
the inner surface of the cyst and a few psammoma bodies. The stroma shows invasion by clusters of anaplastic tumour cells.

744
























Figure 24.23 Mucinous cystadenoma of the ovary. Cut surface
shows a very large multilocular cyst without papillae. The cyst wall shows
presence of loculi containing gelatinous mucoid material.


malignant varieties usually have thickened areas. In forming solid sheets, papillary formation, adenomatous
younger patients, an element of teratoma may be pattern and infiltration into stroma with or without pools
recognised in the firm areas of the tumour. of mucin.
Histologically, the most distinctive feature is the charac-
teristic tall columnar nonciliated epithelium lining the Endometrioid Tumours
loculi (Fig. 24.24). Other features are as under: Endometrioid tumours comprise about 5% of all ovarian
1. Mucinous cystadenoma is lined by a single layer of tumours. Most of them are malignant accounting for about
SECTION III
these cells having basal nuclei and apical mucinous vacuo- 20% of all ovarian cancers. Benign and borderline forms are
les. There is very little tendency to papillary proliferation very rare. They are called endometrioid carcinomas because
of the epithelium. of the close resemblance of histologic pattern to that of uterine
2. Borderline (atypical proliferating) mucinous tumour endometrioid adenocarcinoma. About 40% of ovarian
is identified by the same histologic criteria as for endometrioid carcinomas have bilateral involvement. About
borderline serous tumour i.e. stratification (usually 2-3 cell 15-30% of cases have coexistent endometrial adeno-
thick) of typical epithelium without stromal invasion. carcinoma.
3. Mucinous cystadenocarcinoma likewise is charac- Histogenesis of these tumours in majority of cases is
terised by piling up of malignant epithelium, at places
believed to be from ovarian coelomic epithelium differen-
Systemic Pathology


























Figure 24.24 Mucinous cystadenoma of the ovary. The cyst wall and the septa are lined by a single layer of tall columnar mucin-secreting
epithelium with basally-placed nuclei and large apical mucinous vacuoles.

tiating towards endometrial type of epithelium. In view of carcinoma i.e. clear cells having abundant eosinophilic 745
presence of endometriosis in a few cases of endometrioid cytoplasm rich in glycogen.
tumours, some authors have suggested malignant trans-
formation of endometriosis. Brenner Tumour
MORPHOLOGIC FEATURES. Grossly, these tumours Brenner tumours are uncommon and comprise about 2% of
are partly solid and partly cystic and may have foci of all ovarian tumours. They are characteristically solid ovarian
haemorrhages, especially in benign variety. tumours. Less than 10% of Brenner tumours are bilateral.
Histologically, the endometrioid adenocarcinoma is Most Brenner tumours are benign. Rarely, borderline form
distinguished from serous and mucinous carcinomas by is encountered called ‘proliferating Brenner tumour’ while
typical glandular pattern that closely resembles that of the one with carcinomatous change is termed ‘malignant
uterine endometrioid adenocarcinoma. There may be foci Brenner tumour’.
of squamous metaplasia justifying the diagnosis of Histogenesis of the tumour is from coelomic epithelium
adenoacanthoma. Papillary pattern and foci of serous and by metaplastic transformation into transitional epithelium
mucinous carcinoma may also be found. Benign variety (urothelium).
closely resembles endometriosis with cystic change. There
are no clearly defined criteria for borderline endometrioid MORPHOLOGIC FEATURES. Grossly, Brenner tumour
tumours. is typically solid, yellow-grey, firm mass of variable size.
Occasionally, a few scattered tiny cysts may be present
Clear Cell (Mesonephroid) Tumours on cut section.
Clear cell (mesonephroid) tumours are almost always Histologically, Brenner tumour consists of nests, masses
malignant and comprise about 5% of all ovarian cancers; rare and columns of epithelial cells, scattered in fibrous stroma
benign variety is called clear cell adenofibroma. They are termed of the ovary. These epithelial cells resemble urothelial cells
clear cell or mesonephroid carcinomas because of the close which are ovoid in shape, having clear cytoplasm,
histologic resemblance to renal adenocarcinoma. They have vesicular nuclei with characteristic nuclear groove called
also been called as mesonephroma or mesonephric carcinoma ‘coffee-bean’ nuclei.
because of the questionable relationship to the mesonephric CHAPTER 24
structures. II. GERM CELL TUMOURS
Ovarian germ cell tumours arising from germ cells which
MORPHOLOGIC FEATURES. Grossly, these tumours produce the female gametes (i.e. ova) account for about 15-
are large, usually unilateral, partly solid and partly cystic. 20% of all ovarian neoplasms. The neoplastic germ cells may
Less than 10% are bilateral. follow one of the several lines of differentiation as shown in
Histologically, clear cell or mesonephroid carcinoma is Fig. 24.25. Nearly 95% of them are benign and occur chiefly
characterised by tubules, glands, papillae, cysts and solid
sheets of tumour cells resembling cells of renal adeno- in young females, vast majority of them being benign cystic
teratomas (dermoid cysts). The remainder are malignant The Female Genital Tract





































Figure 24.25 Histogenetic classification of germ cell tumours of the ovary.

746
























Figure 24.26 Dermoid cyst of the ovary. The ovary is enlarged and
shows a large unilocular cyst containing hair, pultaceous material and
bony tissue.



germ cell tumours comprising a variety of morphologic forms seen (Rokitansky’s protuberance) where tissue elements
occurring chiefly in children and young adults and are highly such as tooth, bone, cartilage and various other odd tissues
aggressive tumours. Most germ cell tumours of the ovaries are present (Fig. 24.26). Less often, the cyst may contain
have their counterparts in the testis (Chapter 23) and mucoid material.
sometimes in the mediastinum but their frequency differs Microscopically, the most prominent feature is the lining
from one site to the other. For instance, benign cystic teratoma of the cyst wall by stratified squamous epithelium and its
or dermoid cyst so common in ovaries is extremely rare in adnexal structures such as sebaceous glands, sweat glands
SECTION III
the testis. and hair follicles (Fig. 24.27). Though ectodermal
derivatives are most prominent features, tissues of
Teratomas
mesodermal and endodermal origin are also commonly
Teratomas are tumours composed of different types of tissues present. Various other tissue components frequently
derived from the three germ cell layers—ectoderm, meso- found in teratomas are bronchus, intestinal epithelium,
derm and endoderm, in different combinations. In view of cartilage, bone, tooth, smooth muscle, neural tissue,
wide spectrum of tissue elements found in these teratomas, salivary gland, retina, pancreas and thyroid tissue. Thus,
their histogenesis has been a matter of speculation for a long viewing a benign cystic teratoma in different microscopic
time. Cytogenetic studies have revealed that these tumours fields reveals a variety of mature differentiated tissue
arise from a single germ cell (ovum) after its first meiotic elements, producing kaleidoscopic patterns.
division. Less than 1% of patients with a dermoid cyst develop
Systemic Pathology
Teratomas are divided into 3 types: mature (benign), malignant transformation of one of the tissue components,
immature (malignant), and monodermal or highly most commonly squamous cell carcinoma.
specialised teratomas.
IMMATURE (MALIGNANT) TERATOMA. Immature or
MATURE (BENIGN) TERATOMA. Vast majority of ovarian malignant teratomas of the ovary are rare and account for
teratomas are benign and cystic and have the predominant approximately 0.2% of all ovarian tumours. They are
ectodermal elements, often termed clinically as dermoid cyst. predominantly solid tumours that contain immature or
Infrequently, mature teratoma may be solid and benign and embryonal structures in contrast to the mature or adult
has to be distinguished from immature or malignant structures of the benign teratomas. They are more common
teratoma. Benign cystic teratomas are more frequent in young in prepubertal adolescents and young women under 20 years
women during their active reproductive life. The tumour is of age.
bilateral in 10% of cases.
Grossly, malignant teratoma is a unilateral solid mass
Grossly, benign cystic teratoma or dermoid cyst is
characteristically a unilocular cyst, 10-15 cm in diameter, which on cut section shows characteristic variegated
usually lined by the skin and hence its name. On appearance revealing areas of haemorrhages, necrosis,
sectioning, the cyst is filled with paste-like sebaceous tiny cysts and heterogeneous admixture of various tissue
secretions and desquamated keratin admixed with masses elements.
of hair. The cyst wall is thin and opaque grey-white. Gene- Microscopically, parts of the tumour may show mature
rally, in one area of the cyst wall, a solid prominence is tissues, while most of it is composed of immature tissues

747
























Figure 24.27 Benign cystic teratoma. Microscopy shows characteristic lining of the cyst wall by epidermis and its appendages. Islands of
mature cartilage are also seen.


having an embryonic appearance. Immature tissue patients with dysgerminoma have elevated hCG level in the
elements may differentiate towards cartilage, bone, plasma. All dysgerminomas are malignant and are extremely
glandular structures, neural tissue etc, and are distributed radiosensitive.
in spindle-shaped myxoid or undifferentiated sarcoma MORPHOLOGIC FEATURES. Grossly, dysgerminoma
cells. An important factor in grading and determining the is a solid mass of variable size. Cut section of the tumour CHAPTER 24
prognosis of immature teratoma is the relative amount of is grey-white to pink, lobulated, soft and fleshy with foci
immature neural tissue. Immature neural tissue can of haemorrhages and necrosis.
undergo maturation even at the site of metastases over a Histologically, their structure is similar to that of
period of years. Immature teratoma may contain areas of seminoma of the testis (Fig. 24.28). The tumour cells are
other germ cell tumours such as endodermal sinus arranged in diffuse sheets, islands and cords separated
tumour, embryonal carcinoma and choriocarcinoma.
by scanty fibrous stroma. The tumour cells are uniform
Grade I tumours having relatively mature elements and in appearance and large, with vesicular nuclei and clear
confined to the ovary have a good prognosis, whereas grade cytoplasm rich in glycogen. The fibrous stroma generally
III immature teratomas with metastases have an extremely contains lymphocytic infiltrate and sometimes may have
poor prognosis. sarcoid granulomas. The Female Genital Tract
MONODERMAL (SPECIALISED) TERATOMA. Mono-
dermal or highly specialised teratomas are rare and include
2 important examples—struma ovarii and carcinoid tumour.
Struma ovarii. It is a teratoma composed exclusively
of thyroid tissue, recognisable grossly as well as micros-
copically. Most often, the tumour has the appearance of a
follicular adenoma of the thyroid. Rarely, struma ovarii
may be hyperfunctioning and produce hyperthyroidism.
Carcinoid tumour. This is an ovarian teratoma arising
from argentaffin cells of intestinal epithelium in the
teratoma. Ovarian carcinoid may also hyperfunction and
produce 5-HT and consequent carcinoid syndrome.
Struma-carcinoid is a rare combination of struma
ovarii and ovarian carcinoid.


Dysgerminoma
Dysgerminoma is an ovarian counterpart of seminoma of
the testes (page 709). Dysgerminomas comprise about 2% of Figure 24.28 Dysgerminoma. The histologic appearance is identical
all ovarian cancers. They occur most commonly in 2nd to to that of seminoma of the testis. Masses of large uniform tumour cells
3rd decades. About 10% of them are bilateral. About 10% of are separated by scanty fibrous stroma that is infiltrated by lymphocytes.

748 Endodermal Sinus (Yolk Sac) Tumour
Endodermal sinus tumour or yolk sac tumour is the second
most common germ cell tumour occurring most frequently
in children and young women. More often, endodermal
sinus tumour is found in combination with other germ cell
tumours rather than in pure form. The tumour is rich in
alphafetoprotein (AFP) and α-1-antitrypsin. The tumour is
usually unilateral but may metastasise to the other ovary.
It is a highly aggressive and rapidly growing tumour.
MORPHOLOGIC FEATURES. Grossly, the tumour is
generally solid with areas of cystic degeneration.
Histologically, like its testicular counterpart, the endo-
dermal sinus tumour is characterised by the presence of
papillary projections having a central blood vessel with
perivascular layer of anaplastic embryonal germ cells.
Such structures resemble the endodermal sinuses of the
rat placenta (Schiller-Duval body) from which the tumour
derives its name. It is common to find intracellular and
extracelluar PAS-positive hyaline globules which are
composed of AFP (Fig. 24.29). Figure 24.29 Endodermal sinus (yolk sac) tumour ovary. The tumour
has microcystic pattern and has highly anaplastic tumour cells. Several
Choriocarcinoma characteristic Schiller-Duval bodies are present. Inset shows intra- and
extracellular hyaline globules.
Choriocarcinoma in females is of 2 types—gestational and non-
gestational. Gestational choriocarcinoma of placental origin tumours, pure thecomas, combination of granulosa-theca cell
is more common and considered separately later (page 752). tumours and fibromas.
Pure primary non-gestational choriocarcinoma of ovarian
origin is rare while its combination with other germ cell GRANULOSA CELL TUMOUR. Pure granulosa cell
SECTION III
tumours is seen more often. The patients are usually young tumours may occur at all ages. These tumours invade locally
girls under the age of 20 years. Morphologically, ovarian but occasionally may have more aggressive and malignant
choriocarcinoma is identical to gestational choriocarcinoma. behaviour. Recurrences after surgical removal are common.
Ovarian choriocarcinoma is more malignant than that of Most granulosa cell tumours secrete oestrogen which may
placental origin and disseminates widely via bloodstream be responsible for precocious puberty in young girls, or in
to the lungs, liver, bone, brain and kidneys. The marker for older patients may produce endometrial hyperplasia,
both types of choriocarcinoma is hCG. endometrial adenocarcinoma and cystic disease of the breast.
Rarely, granulosa cell tumour may elaborate androgen which
may have masculinising effect on the patient.
Other Germ Cell Tumours
Certain other germ cell tumours occasionally encountered Grossly, granulosa cell tumour is a small, solid, partly
in the ovaries are embryonal carcinoma, polyembryoma and cystic and usually unilateral tumour. Cut section of solid
Systemic Pathology
mixed germ cell tumours. All these tumours are areas is yellowish-brown (Fig. 24.30).
morphologically identical to similar tumours occurring in
the testes (Chapter 24).

III. SEX CORD-STROMAL TUMOURS

Sex cord-stromal tumours of the ovaries comprise 5-10% of
all ovarian neoplasms. They arise from specialised ovarian
stromal cells of the developing gonads. Thus, these include
tumours originating from granulosa cells, theca cells and
Sertoli-Leydig cells. Since sex cord-stromal cells have
functional activity, most of these tumours elaborate steroid
hormones which may have feminising effects or
masculinising effects.

Granulosa-Theca Cell Tumours
Granulosa-theca cell tumours comprise about 5% of all Figure 24.30 Solid ovarian tumour. Specimen of the uterus, cervix
ovarian tumours. The group includes: pure granulosa cell and adnexa shows enlarged ovarian mass (arrow) on one side which on
cut section is solid, grey-white and firm.

749

























Figure 24.31 Granulosa cell tumour showing uniform granulosa cells and numerous rosette-like Call-Exner bodies containing central amorphous
pink material surrounded by granulosa cells.


Microscopically, the granulosa cells are arranged in a combination of fibroma and thecoma is present called
variety of patterns including micro- and macrofollicular, fibrothecoma.
trabecular, bands and diffuse sheets. The microfollicular
pattern is characterised by the presence of characteristic Sertoli-Leydig Cell Tumours
rosette-like structures, Call-Exner bodies, having central (Androblastoma, Arrhenoblastoma) CHAPTER 24
rounded pink mass surrounded by a circular row of Tumours containing Sertoli and Leydig cells in varying
granulosa cells (Fig. 24.31). degree of maturation comprise Sertoli-Leydig cell tumours,
also called androblastomas or arrhenoblastomas. Charac-
Morphologic appearance alone is a poor indicator of
clinical malignancy but presence of metastases and invasion teristically, they produce androgens and masculinise the
patient. Less often, they may elaborate oestrogen. Their peak
outside the ovary are considered better indicators of incidence is in 2nd to 3rd decades of life.
aggressive behaviour.
Grossly, Sertoli-Leydig cell tumour resembles a granulosa-
THECOMA. Pure thecomas are almost always benign. They theca cell tumour.
occur more frequently in postmenopausal women. Histologically, these tumours recapitulate to some extent
Thecomas are typically oestrogenic. Endometrial the structure of the testis. Three histologic types are
hyperplasia, endometrial carcinoma and cystic disease of distinguished: The Female Genital Tract
the breast are some of its adverse effects. Occasionally a 1. Well-differentiated androblastoma composed almost
thecoma may secrete androgen and cause virilisation.
entirely of Sertoli cells or Leydig cells forming well-defined
Grossly, thecoma is a solid and firm mass, 5-10 cm in tubules.
diameter. Cut section is yellowish. 2. Tumours with intermediate differentiation have a biphasic
Microscopically, thecoma consists of spindle-shaped theca pattern with formation of solid sheets in which abortive
cells of the ovary admixed with variable amount of tubules are present.
hyalinised collagen. The cytoplasm of theca cells is lipid- 3. Poorly-differentiated or sarcomatoid variety is composed
rich and vacuolated which reacts with lipid stains. of spindle cells resembling sarcoma with interspersed
scanty Leydig cells.
GRANULOSA-THECA CELL TUMOUR. Mixture of both
granulosa and theca cell elements in the same ovarian tumour Gynandroblastoma
is seen in some cases with elaboration of oestrogen. Gynandroblastoma is an extremely rare tumour in which
FIBROMA. Fibromas of the ovary are more common and there is combination of patterns of both granulosa-theca cell
account for about 5% of all ovarian tumours. These tumours tumour and Sertoli-Leydig cell tumour. The term
are hormonally inert but some of them are associated with gynandroblastoma stands for combination of female (gyn)
pleural effusion and benign ascites termed Meig’s syndrome. and male (andro).
Grossly, these tumours are large, firm and fibrous, usually IV. MISCELLANEOUS TUMOURS
unilateral masses. LIPID CELL TUMOURS. There is a small group of ovarian
Histologically, they are composed of spindle-shaped well- tumours that appears as soft yellow or yellow-brown nodules
differentiated fibroblasts and collagen. Sometimes, which on histologic examination are composed of large lipid-

750




















Figure 24.32 Krukenberg tumour showing characteristic bilateral metastatic ovarian cancer (arrow) having firm white appearance.


laden cells. These cells resemble Leydig, lutein and adrenal carcinomas of the breast, genital tract, gastrointestinal tract
cortical cells. The examples of these tumours are: hilus cell (e.g. stomach, colon appendix, pancreas, biliary tract) and
tumours, adrenal rest tumours and luteomas. These tumours haematopoietic malignancies.
elaborate steroid hormones and are responsible for various
endocrine dysfunctions such as Cushing’s syndrome and Krukenberg Tumour
virilisation.
Krukenberg tumour is a distinctive bilateral tumour meta-
GONADOBLASTOMA. This is a rare tumour occurring static to the ovaries by transcoelomic spread. The tumour is
exclusively in dysgenetic gonads, more often in phenotypic generally secondary to a gastric carcinoma (page 557) but
females and in hermaphrodites. Dysfunctions include other primary sites where mucinous carcinomas occur (e.g.
virilism, amenorrhoea and abnormal external genitalia. colon, appendix and breast) may also produce Krukenberg
tumour in the ovary. Rarely, a tumour having the pattern of
Microscopically, gonadoblastoma is composed of mixture Krukenberg tumour is primary in the ovary.
SECTION III
of germ cell and sex cord components.
Grossly, Krukenberg tumour forms rounded or kidney-
V. METASTATIC TUMOURS shaped firm large masses in both ovaries. Cut section
shows grey-white to yellow firm fleshy tumour and may
About 10% of ovarian cancers are secondary carcinomas. have areas of haemorrhage and necrosis (Fig. 24.32).
Metastasis may occur by lymphatic or haematogenous route
but direct extension from adjacent organs (e.g. uterus, Microscopically, it is characterised by the presence of
fallopian tube and sigmoid colon) too occurs frequently. mucus-filled signet ring cells which may lie singly or in
Bilaterality of the tumour is the most helpful clue to diagnosis clusters. It is accompanied by sarcoma-like cellular prolife-
of metastatic tumour. Most common primary sites from ration of ovarian stroma (Fig. 24.33).
where metastases to the ovaries are encountered are: FIGO staging of ovarian cancer is given in Table 24.7.
Systemic Pathology


























Figure 24.33 Krukenberg tumour. Histologic features include mucin-filled signet-ring cells and richly cellular proliferation of the ovarian stroma.

 TABLE 24.7: FIGO Clinical Staging of Carcinoma of the Ovary. Certain conditions such as inflammation of the placenta and 751
chorionic membranes (placentitis and chorioamnionitis),
Stage I Growth limited to ovaries. placental abnormalities (e.g. placenta accreta, placenta
IA Growth limited to one ovary; no ascites; capsule praevia and twin placenta etc), toxaemia of pregnancy
intact.
IB Growth limited to both ovaries; no ascites; capsule (eclampsia and pre-eclampsia) and products of gestation seen
intact. in abortions need mere mention only here. However,
IC Tumour classified as either stage IA or IB but with gestational trophoblastic diseases resulting from benign
tumour in the surface of one or both ovaries, or with and malignant overgrowth of trophoblast—hydatidiform
ascites containing malignant cells. mole (complete and partial mole) and choriocarcinoma
Stage II Growth involving one or both ovaries, with pelvic respectively, are significant morphologic lessions and are
extension. discussed below and their features contrasted in Table 24.8.
IIA Extension and/or metastases to the uterus and/or
tubes. HYDATIDIFORM MOLE
IIB Extension to other pelvic tissues.
IIC Tumour either stage IIA or IIB but with tumour on the The word ‘hydatidiform’ means drop of water and ‘mole’ for
surface of one or both ovaries, or with capsule a shapeless mass. Hydatidiform mole is defined as an abnormal
ruptured, or with ascites containing malignant cells. placenta characterised by 2 features:
Stage III Tumour invading one or both ovaries with peritoneal i) Enlarged, oedematous and hydropic change of the
implants outside the pelvis. chorionic villi which become vesicular.
IIIA Tumour grossly limited to the true pelvis with negative ii) Variable amount of trophoblastic proliferation.
nodes but with microscopic seeding of abdominal Most workers consider hydatidiform mole as a benign
peritoneal surfaces.
IIIB Tumour of one or both ovaries with histologically tumour of placental tissue with potential for developing into
confirmed implants of abdominal peritoneal surfaces, choriocarcinoma, while some authors have described mole
not exceeding 2 cm in diameter; nodes are negative. as a degenerative lesion though capable of neoplastic change.
IIIC Abdominal implants greater than 2 cm in diameter The incidence of molar pregnancy is high in teenagers and
and/or positive retroperitoneal or inguinal nodes. in older women. For unknown reasons, frequency of
Stage IV Growth involving one or both ovaries, with distant hydatidiform mole varies in different regions of the world; CHAPTER 24
metastases.
the incidence in Asia and Central America is about 10 times
higher than in the United States. The incidence is higher in
PLACENTA poorer classes.
Hydatidiform mole may be non-invasive or invasive. Two
NORMAL STRUCTURE types of non-invasive moles are distinguished—complete
(classic) and partial. Pathogenesis of these 2 forms is different:
At term, the normal placenta is blue red, rounded, flattened
and discoid organ 15-20 cm in diameter and 2-4 cm thick. It Complete (classic) mole by cytogenetic studies has been
weighs 400-600 gm or about one-sixth the weight of the shown to be derived from the father (androgenesis) and has
newborn. The umbilical cord is about 50 cm long and 46, XX or rarely 46, XY chromosomal pattern. Complete mole
contains two umbilical arteries and one umbilical vein bears relationship to choriocarcinoma. The Female Genital Tract
attached at the foetal surface. The placenta is derived from Partial mole is mostly triploid (i.e. 69,XXY or 69,XXX)
both maternal and foetal tissues. The maternal portion of the and rarely tetraploid. Partial mole rarely develops into
placenta has irregular grooves dividing it into cotyledons choriocarcinoma.
which are composed of sheets of decidua basalis and Clinically, the condition appears in 4th-5th month of
remnants of blood vessels. The foetal portion of the placenta gestation and is characterised by increase in uterine size,
is composed of numerous functional units called chorionic vaginal bleeding and often with symptoms of toxaemia.
villi and comprise the major part of placenta at term. The Frequently, there is history of passage of grape-like masses
villi consist of a loose fibrovascular stromal core and a few per vaginum. About 1% of women with molar pregnancy
phagocytic (Höffbauer’s) cells. The villous core is covered develop it again in a subsequent pregnancy.
by an inner layer of cytotrophoblast and outer layer of The single most significant investigation forming the
syncytiotrophoblast. The basement membrane separating mainstay of management is the serial determination of
the foetal capillaries in the villous core and the trophoblast β-hCG which is elevated more in both blood and urine as
forms zones where nutrients and metabolites are compared with the levels in normal pregnancy. Removal of
transported between the mother and the foetus. Such zones the mole is accompanied by fall in β-hCG levels. A more
are called vasculosyncitial membranes. The placenta ominous behaviour is associated with no fall in β-hCG
secretes a number of hormones and enzymes into the levels after expulsion of the mole. About 10% of patients with
maternal blood. These include: human chorionic gonado- complete mole develop into invasive moles and 2.5% into
tropin (hCG), human placental lactogen (HPL), chorionic choriocarcinoma.
thyrotropin and adrenocorticotropin hormone which
partake in oestrogen and progesterone metabolism. MORPHOLOGIC FEATURES. The pathologic findings
Diseases related to pregnancy and placenta are numerous in non-invasive (complete and partial) and invasive mole
and form the subject matter of discussion in obstetrics. are different:

752



























Figure 24.34 Uterus containing hydatidiform mole. The specimen shows numerous, variable-sized, grape-like translucent vesicles containing
clear fluid. Tan areas of haemorrhage are also seen.

COMPLETE (CLASSIC) MOLE. Grossly, the uterus is Large, round, oedematous and acellular villi due to
enlarged and characteristically filled with grape-like hydropic degeneration forming central cisterns.
vesicles up to 3 cm in diameter (Fig. 24.34). The vesicles Decreased vascularity of villous stroma.
contain clear watery fluid. Rarely, a macerated foetus may Trophoblastic proliferation in the form of masses and
be found. sheets of both cytotrophoblast and syncytiotrophoblast,
Microscopically, the features are quite typical. These are generally circumferential around the villi.
as under (Fig. 24.35):
SECTION III

 TABLE 24.8: Comparative Features of Major Forms of Gestational Trophoblastic Disease.
Feature Complete Mole Partial Mole Choriocarcinoma

1. Karyotype 46,XX or rarely 46,XY Triploid i.e. 69,XXY or 69,XXX 46,XY or variable
2. Clinical findings
i) Diagnosis Mole Missed abortion Abortion; molar, ectopic
or normal pregnancy
ii) Vaginal bleeding Marked Mild Marked, abnormal
iii) Uterus size Large Small Generally not bulky
3. hCG levels
Systemic Pathology
i) Serum hCG High Low Persistently high
ii) hCG in tissues Marked Mild Localised in syncytiotrophoblast
only
4. Embryo Not present May be present Not present
5. Gross appearance
i) Vesicles Large and regular Smaller and irregular No vesicles
ii) Villi Present Present Always absent
6. Microscopy
i) Villous size Uniform Variable None present
ii) Hydropic villi All Some None
iii) Trophoblastic proliferation Diffuse, all three Focal, syncytiotrophoblast only Both cytotrophoblast
(cytotrophoblast, and syncytiotrophoblast
intermediate trophoblast
and syncytiotrophoblast)
iv) Atypia Diffuse Minimal Marked
v) Blood vessels Generally absent Present Present and abnormal
7. Persistence after initial 20% 7% May metastasise rapidly
therapy if not treated
8. Behaviour 2% may develop Choriocarcinoma almost Survival rate with
choriocarcinoma never develops chemotherapy 70%

753

























Figure 24.35 Hydatidiform mole characterised by hydropic and avascular enlarged villi with trophoblastic proliferation in the form of masses
and sheets.


PARTIAL MOLE. Grossly, the uterus is generally smaller brain or lungs. The diagnosis is confirmed by demonstration
than expected and contains some cystic villi, while part of persistently high levels of β-hCG in the plasma and urine.
of the placenta appears normal. A foetus with multiple Widespread haematogenous metastases are early and
malformations is often present. frequent in choriocarcinoma if not treated; these are found
Microscopically, some of the villi show oedematous chiefly in the lungs, vagina, brain, liver and kidneys. CHAPTER 24
change while others are normal or even fibrotic. MORPHOLOGIC FEATURES. Grossly, the tumour
Trophoblastic proliferation is usually slight and focal.
appears as haemorrhagic, soft and fleshy mass.
INVASIVE (DESTRUCTIVE) MOLE (CHORIO- Sometimes, the tumour may be small, often like a blood
ADENOMA DESTRUENS). Grossly, invasive mole clot, in the uterus.
shows invasion of the molar tissue into the uterine wall Microscopically, the characteristic features are as under:
which may be a source of haemorrhage. Rarely, molar Absence of identifiable villi.
tissue may invade the blood vessels and reach the lungs. Masses and columns of highly anaplastic and bizarre
Microscopically, the lesion is benign and identical to cytotrophoblast and syncytiotrophoblast cells which are
classic mole but has potential for haemorrhage. It is always intermixed.
associated with persistent elevation of β-hCG levels. Invariable presence of haemorrhages and necrosis. The Female Genital Tract
Invasion of the underlying myometrium and other
CHORIOCARCINOMA structures, blood vessels and lymphatics.
Gestational choriocarcinoma is a highly malignant and
widely metastasising tumour of trophoblast (non-gestational Gestational choriocarcinoma and its metastases
choriocarcinoma is described on page 748). Approximately respond very well to chemotherapy while non-gestational
50% of cases occur following hydatidiform mole, 25% choriocarcinoma is quite resistant to therapy and has
following spontaneous abortion, 20% after an otherwise worse prognosis. With hysterectomy and chemotherapy,
normal pregnancy, and 5% develop in an ectopic pregnancy. the cure rate of choriocarcinoma has remarkably improved
Choriocarcinoma follows the geographic pattern of from dismal 20 to 70% 5-year survival rate and almost total
hydatidiform mole, being more common in Asia and Africa cure in localised tumours. The effectiveness of treatment
than in the United States and Europe. is also monitored by serial β-hCG determinations. Death
Clinically, the most common complaint is vaginal from choriocarcinoma is generally due to fatal
bleeding following a normal or abnormal pregnancy. haemorrhage in the CNS or lungs or from pulmonary
Occasionally, the patients present with metastases in the insufficiency.



❑

754


Chapter 25 The Breast
Chapter 25








NORMAL STRUCTURE lactiferous duct subjacent to the nipple shows a small
dilatation called lactiferous sinus. Each lactiferous duct has
The breast is a modified skin appendage which is functional its own collecting duct system which has branches of smaller
in the females during lactation but is rudimentary in the diameter, ultimately terminating peripherally as terminal
males. Microanatomy of the breast reveals 2 types of tissue ducts (or TDLU) in the breast lobules.
components: epithelial and stromal (Fig. 25.1). In a fully- The entire ductal-lobular epithelial system has bilayered
developed non-lactating female breast, the epithelial lining: the inner epithelium with secretory and absorptive
component comprises less than 10% of the total volume but function, and an outer supporting myoepithelial lining, both
is more significant pathologically since majority of lesions having characteristic ultrastructure and immunoreativity.
pertain to this portion of the breast. The inner epithelium stains positive for epithelial membrane
antigen (EMA) and lactalbumin while the myoepithelium is
EPITHELIAL COMPONENT. The epithelial component of positive for smooth muscle actin (SMA) and S-100.
the breast consists of 2 major parts: terminal duct-lobular
unit (TDLU) which performs the main secretory function STROMAL COMPONENT. The supportive stroma of the
during lactation, and large duct system which performs the breast consists of variable amount of loose connective tissue
function of collection and drainage of secretions; both are and adipose tissue during different stages of reproductive
interconnected to each other. life. The stromal tissue of the breast is present at 2 locations:
The breast is divided into about 20 lobes. Each lobe intralobular and interlobular stroma. Intralobular stroma
consists of breast lobules which drain their secretions through encloses each lobule, and its acini and ducts, and is chiefly
its collecting duct system and opens into the nipple through made of loose connective tissue, myxomatous stroma and a
SECTION III
its own main excretory duct, lactiferous duct. The segment of few scattered lymphocytes. Interlobular stroma separates one












Systemic Pathology

























Figure 25.1 A, Microanatomy of the breast and major lesions at various sites. B, Normal terminal duct-lobular unit (TDLU). C, SMA-100
immunostain for myoepithelium.

lobule from the other and is composed mainly of adipose Mammary Duct Ectasia (Plasma Cell Mastitis) 755
tissue and some loose connective tissue. Mammary duct ectasia is a condition in which one or more
The most important disease of the breast is cancer.
However, there are a few inflammatory lesions, benign of the larger ducts of the breast are dilated and filled with
inspissated secretions. These are associated with periductal
tumours and tumour-like lesions which may be confused and interstitial chronic inflammatory changes. Duct ectasia
clinically with breast cancer. These pathologic lesions are affects women in their 4th to 7th decades of life. The patients
described first, followed by an account of breast cancer.
may remain asymptomatic or there may be nipple
discharge, retraction of the nipple due to fibrous scarring
NON-NEOPLASTIC CONDITIONS and clinically palpable dilated ducts in the subareolar area.
The lesion may be mistaken for carcinoma of the breast.
These conditions in the breast include inflammations,
fibrocystic change and gynaecomastia. The etiology of the condition remains unknown but it
appears to begin with periductal inflammation followed by
destruction of the elastic tissue to cause ectasia and
INFLAMMATIONS
periductal fibrosis.
Inflammation of the breast is called mastitis. Important types
of mastitis are acute mastitis and breast abscess, chronic MORPHOLOGIC FEATURES. Grossly, the condition
mastitis, mammary duct ectasia (or plasma cell mastitis), appears as a single, poorly-defined indurated area in the
traumatic fat necrosis and galactocele. breast with ropiness on the surface. Cut section shows
dilated ducts containing cheesy inspissated secretions.
Acute Mastitis and Breast Abscess Histologically, the features are as under:
Acute pyogenic infection of the breast occurs chiefly during 1. Dilated ducts with either necrotic or atrophic lining
the first few weeks of lactation and sometimes by eczema by flattened epithelium and lumen containing granular,
of the nipples. Bacteria such as staphylococci and amorphous, pink debris and foam cells.
streptococci gain entry into the breast by development of 2. Periductal and interstitial chronic inflammation,
cracks and fissures in the nipple. Initially a localised area chiefly lymphocytes, histiocytes with multinucleate histio-
of acute inflammation is produced which, if not effectively cytic giant cells. Sometimes, plasma cells are present in CHAPTER 25
treated, may cause single or multiple breast abscesses. impressive numbers and the condition is then termed
Extensive necrosis and replacement by fibrous scarring of plasma cell mastitis.
the breast with retraction of the nipple may result. 3. Occasionally, there may be obliteration of the ducts
by fibrous tissue and varying amount of inflammation and
Granulomatous Mastitis is termed obliterative mastitis.

Although chronic non-specific mastitis is uncommon, chronic
granulomatous inflammation in the breast may occur as a Fat Necrosis The Breast
result of the following: Focal fat necrosis of an obese and pendulous breast followed
1. Systemic non-infectious granulomatous disease e.g. as part by an inflammatory reaction is generally initiated by
of systemic sarcoidosis, Wegener’s granulomatosis. trauma. The condition presents as a well-defined mass with
2. Infections e.g. tuberculosis which is not so uncommon in indurated appearance.
developing countries like India and may be misdiagnosed
clinically as breast cancer owing to axillary nodal Grossly, the excised lump has central pale cystic area of
involvement. Tubercle bacilli reach the breast by haemato- necrosis.
genous, lymphatic or direct spread, usually from the lungs Histologically, there is disruption of the regular pattern
or pleura. Pathologically, typical caseating tubercles with of lipocytes with formation of lipid-filled spaces
discharging sinuses through the surface of the breast are surrounded by neutrophils, lymphocytes, plasma cells
found. ZN staining may demonstrate acid-fast bacilli. Fungal and histiocytes having foamy cytoplasm and frequent
infection of the breast may occur in immunocompromised foreign body giant cell formation. In late stage, there is
patients. replacement fibrosis and even calcification.
3. Silicone breast implants implanted on breast cancer patients
after mastectomy or as breast augmentation cosmetic surgery Galactocele
may rupture or silicone may slowly leak into surrounding A galactocele is cystic dilatation of one or more ducts
breast tissue. This incites chronic inflammatory reaction of occurring during lactation. The mammary duct is obstruc-
lymphocytes, macrophages and foreign body giant cells. ted and dilated to form a thin-walled cyst filled with milky
Eventually, a surrounding fibrous capsule forms and after a fluid. Rarely, the wall of galactocele may get secondarily
long period it may even be calcified.
infected.
4. Idiopathic granulomatous mastitis is an uncommon form of
reaction around lobules and ducts in the absence of any FIBROCYSTIC CHANGE
known etiology. Exact pathogenesis is not known but
probably it is a form of hypersensitivity reaction to luminal Fibrocystic change is the most common benign breast
secretion of the breast epithelium during lactation. condition producing vague ‘lumpy’ breast rather than

756
























Figure 25.2 Simple fibrocystic change. A, Diagrammatic view. It shows cystic dilatation of ducts and increase in fibrous stroma. There is mild
epithelial hyperplasia in terminal ducts. B, Non-proliferative fibrocystic changes—fibrosis, cyst formation, adenosis and apocrine metaplasia.
C, Proliferative fibrocystic changes showing moderate epithelial hyperplasia.

palpable lump in the breast. Its incidence has been reported usual large cyst is rounded, translucent with bluish colour
to range from 10-20% in adult women, most often between prior to opening (blue-dome cyst). On opening, the cyst
3rd and 5th decades of life, with dramatic decline in its contains thin serous to haemorrhagic fluid.
incidence after menopause suggesting the role of oestrogen Microscopically, simple fibrocystic change includes
in its pathogenesis. It was previously termed fibrocystic disease following 2 features (Fig. 25.2):
but is currently considered as an exaggerated physiologic 1. Cyst formation: The cyst lining shows a variety of
phenomena and not a disease. The entity was formerly also appearances. Often, the epithelium is flattened or atrophic.
known as benign mammary dysplasia under the mistaken belief Frequently, there is apocrine change or apocrine meta-
SECTION III
that all forms are dysplastic or precancerous conditions, and plasia in the lining of the cyst resembling the cells of
hence has attracted considerable interest. apocrine sweat glands. Occasionally, there is simultaneous
As such, fibrocystic change of the female breast is a epithelial hyperplasia (discussed below) forming tiny
histologic entity characterised by following features: intracystic papillary projections of piled up epithelium.
i) Cystic dilatation of terminal ducts. 2. Fibrosis: There is increased fibrous stroma surround-
ii) Relative increase in inter- and intralobular fibrous tissue. ing the cysts and variable degree of stromal lymphocytic
iii) Variable degree of epithelial proliferation in the terminal infiltrate.
ducts.
It is important to identify the spectrum of histologic
features by core needle biopsy or cytologic findings by FNAC B. Proliferative Fibrocystic Changes;
in fibrocystic changes since only some subset of changes has Epithelial Hyperplasia and Sclerosing Adenosis
Systemic Pathology
an increased risk of development of breast cancer. Presently, Proliferative fibrocystic change in the breasts includes 2
the spectrum of histologic changes are divided into two entities: epithelial hyperplasia and sclerosing adenosis.
clinicopathologically relevant groups: EPITHELIAL HYPERPLASIA. Epithelial hyperplasia (or
A. Nonproliferative changes: Simple fibrocystic change. epitheliosis in the British literature) is defined as increase
B. Proliferative changes: Proliferative fibrocystic change.
in the layers of epithelial cells over the basement membrane
to three or more layers in the ducts (ductal hyperplasia) or
A. Nonproliferative Fibrocystic Changes: lobules (lobular hyperplasia). The latter condition, lobular
Simple Fibrocystic Change
hyperplasia, must be distinguished from adenosis
Simple fibrocystic change most commonly includes (discussed separately) in which there is increase in the
2 features—formation of cysts of varying size, and increase number of ductules or acini without any change in the
in fibrous stroma. Cysts are formed by dilatation of number or type of cells lining them. Epithelial hyperplasia
obstructed collecting ducts, obstruction being caused by may be totally benign or may have atypical features. It is
periductal fibrosis following inflammation or fibrous the latter type of hyperplasia which is precancerous and is
overgrowth from oestrogen stimulation. associated with increased risk of developing breast cancer.
MORPHOLOGIC FEATURES. Grossly, the cysts are Microscopically, epithelial hyperplasia is characterised by
rarely solitary but are usually multifocal and bilateral. epithelial proliferation to more than its normal double
They vary from microcysts to 5-6 cm in diameter. The layer. In general, ductal hyperplasia is termed as epithelial

hyperplasia of usual type and may show various grades of risk to develop invasive breast cancer later. This risk is further 757
epithelial proliferations (mild, moderate and atypical) as more if there is a history of breast cancer in the family.
under, while lobular hyperplasia involving the ductules or
acini is always atypical: GYNAECOMASTIA (HYPERTROPHY OF MALE BREAST)
1. Mild hyperplasia of ductal epithelium consists of at Unilateral or bilateral enlargement of the male breast is
least three layers of cells above the basement membrane, known as gynaecomastia. Since the male breast does not
present focally or evenly throughout the duct. contain secretory lobules, the enlargement is mainly due to
2. Moderate and florid hyperplasia of ductal type is proliferation of ducts and increased periductal stroma.
associated with tendency to fill the ductal lumen with Gynaecomastia occurs in response to hormonal stimulation,
proliferated epithelium. Such epithelial proliferations into mainly oestrogen. Such excessive oestrogenic activity in
the lumina of ducts may be focal, forming papillary males is seen in young boys between 13 and 17 years of age
epithelial projections called ductal papillomatosis, or may (pubertal gynaecomastia), in men over 50 years (senescent
be more extensive, termed florid papillomatosis, or may fill gynaecomastia), in endocrine diseases associated with
the ductal lumen leaving only small fenestrations in it. increased oestrogenic or decreased androgenic activity e.g.
3. Of all the ductal hyperplasias, atypical ductal hyper- in hepatic cirrhosis, testicular tumours, pituitary tumours,
plasia is more ominous and has to be distinguished from carcinoma of the lung, exogenous oestrogen therapy as in
intraductal carcinoma (page 760). The proliferated carcinoma of the prostate and testicular atrophy in
epithelial cells in the atypical ductal hyperplasia partially Klinefelter’s syndrome (secondary gynaecomastia); and lastly,
fill the duct lumen and produce irregular microglandular enlargement without any obvious cause (idiopathic gynaeco-
spaces or cribriform pattern. The individual cells are mastia).
uniform in shape but show loss of polarity with indistinct
cytoplasmic margin and slightly elongated nuclei. MORPHOLOGIC FEATURES. Grossly, one or both the
4. Atypical lobular hyperplasia is closely related to male breasts are enlarged having smooth glistening white
lobular carcinoma in situ (page 761) but differs from the tissue.
latter in having cytologically atypical cells only in half of Microscopically, there are 2 main features:
the ductules or acini. 1. Proliferation of branching ducts which display CHAPTER 25
epithelial hyperplasia with formation of papillary
SCLEROSING ADENOSIS. Sclerosing adenosis is benign projections at places.
proliferation of small ductules or acini and intralobular 2. Increased fibrous stroma with, myxoid appearance.
fibrosis. The lesion may be present as diffusely scattered
microscopic foci in the breast parenchyma, or may form an
isolated palpable mass which may simulate an infiltrating BREAST TUMOURS
carcinoma, both clinically and pathologically.
Tumours of the female breast are common and clinically The Breast
Grossly, the lesion may be coexistent with other significant but are rare in men. Among the important benign
components of fibrocystic disease, or may form an isolated breast tumours are fibroadenoma, phyllodes tumour
mass which has hard cartilage-like consistency, (cystosarcoma phyllodes) and intraductal papilloma.
resembling an infiltrating carcinoma. Carcinoma of the breast is an important malignant tumour
Microscopically, there is proliferation of ductules or acini which occurs as non-invasive (carcinoma in situ) and invasive
and fibrous stromal overgrowth. The histologic cancer with its various morphologic varieties.
appearance may superficially resemble infiltrating
carcinoma but differs from the latter in having maintained FIBROADENOMA
lobular pattern and lack of infiltration into the surrounding Fibroadenoma or adenofibroma is a benign tumour of fibrous
fat. and epithelial elements. It is the most common benign
tumour of the female breast. Though it can occur at any age
Prognostic Significance during reproductive life, most patients are between 15 to 30

Since there is a variable degree of involvement of epithelial years of age. Clinically, fibroadenoma generally appears as
and mesenchymal elements in fibrocystic change, following a solitary, discrete, freely mobile nodule within the breast.
prognostic implications may occur: Rarely, fibroadenoma may contain in situ or invasive lobular
1. Simple fibrocystic change or nonproliferative fibrocystic changes or ductal carcinoma, or the carcinoma may invade the
of fibrosis and cyst formation do not carry any increased risk fibroadenoma from the adjacent primary breast cancer.
of developing invasive breast cancer. MORPHOLOGIC FEATURES. Grossly, typical fibro-
2. Identification of general proliferative fibrocystic changes are adenoma is a small (2-4 cm diameter), solitary, well-
associated with 1.5 to 2 times increased risk for development encapsulated, spherical or discoid mass. The cut surface
of invasive breast cancer. is firm, grey-white, slightly myxoid and may show slit-
3. Multifocal and bilateral proliferative changes in the breast pose like spaces formed by compressed ducts. Occasionally,
increased risk to both the breasts equally. multiple fibroadenomas may form part of fibrocystic
4. Within the group of proliferative fibrocystic changes, disease and is termed fibroadenomatosis. Less commonly,
atypical hyperplasia in particular, carries 4 to 5 times increased

758























Figure 25.3 Fibroadenoma of the breast, microscopic patterns.



a fibroadenoma may be fairly large in size, up to 15 cm in benign, borderline and malignant on the basis of histologic
diameter, and is called giant fibroadenoma but lacks the features. Local recurrences are much more frequent than
histologic features of cystosarcoma phyllodes (see below). metastases.
Microscopically, fibrous tissue comprises most of a
fibroadenoma. The arrangements between fibrous MORPHOLOGIC FEATURES. Grossly, the tumour is
overgrowth and ducts may produce two types of patterns generally large, 10-15 cm in diameter, round to oval,
which may coexist in the same tumour. These are bosselated, and less fully encapsulated than a fibro-
intracanalicular and pericanalicular patterns (Fig. 25.3): adenoma. The cut surface is grey-white with cystic
Intracanalicular pattern is one in which the stroma cavities, areas of haemorrhages, necrosis and degenerative
compresses the ducts so that they are reduced to slit-like changes (Fig. 25.4).
SECTION III
clefts lined by ductal epithelium or may appear as cords Histologically, the phyllodes tumour is composed of an
of epithelial elements surrounding masses of fibrous extremely hypercellular stroma, accompanied by
stroma. proliferation of benign ductal structures. Thus, phyllodes
Pericanalicular pattern is characterised by encircling tumour resembles fibroadenoma except for enhanced
masses of fibrous stroma around the patent or dilated stromal cellularity. The histologic criteria used to
ducts. distinguish benign, borderline and malignant categories
The fibrous stroma may be quite cellular, or there may of phyllodes tumour are as under:
be areas of hyalinised collagen. Sometimes, the stroma is frequency of mitoses;
loose and myxomatous. Occasionally, the fibrous tissue cellular atypia;
element in the tumour is scanty, and the tumour is instead cellularity; and
predominantly composed of closely-packed ductular or infiltrative margins.
Systemic Pathology
acinar proliferation and is termed tubular adenoma. If
an adenoma is composed of acini with secretory activity,
it is called lactating adenoma seen during pregnancy or
lactation. Juvenile fibroadenoma is an uncommon variant
of fibroadenoma which is larger and rapidly growing mass
seen in adolescent girls but fortunately does not recur after
excision.

PHYLLODES TUMOUR (CYSTOSARCOMA PHYLLODES)
Cystosarcoma phyllodes was the nomenclature given by
Müller in 1838 to an uncommon bulky breast tumour with
leaf-like gross appearance (phyllodes=leaf-like) having an
aggressive clinical behaviour. Most patients are between 30
to 70 years of age. Grossly, the tumour resembles a giant
fibroadenoma but is distinguished histologically from the
latter by more cellular connective tissue. Later, the WHO
classification of breast tumours has proposed the term Figure 25.4 Phyllodes tumour. Simple mastectomy specimen shows
replacement of almost whole breast with a large circumscribed, grey-
‘phyllodes tumour’ in place of misleading term of ‘cysto- white, firm, nodular mass having slit-like, compressed cystic areas (arrow)
sarcoma phyllodes’. Phyllodes tumour can be classified into and areas of haemorrhage.

About 20% of phyllodes tumours are histologically 1. Geography. The incidence of breast cancer is about six 759
malignant and less than half of them may metastasise. times higher in developed countries than the developing
countries, with the notable exception of Japan. These
INTRADUCTAL PAPILLOMA geographic differences are considered to be related to
consumption of large amount of animal fats and high caloric
Intraductal papilloma is a benign papillary tumour occurring diet by Western populations than the Asians (including
most commonly in a lactiferous duct or lactiferous sinus near Japanese) and Africans.
the nipple. Clinically, it produces serous or serosanguineous
nipple discharge. It is most common in 3rd and 4th decades 2. Genetic factors. Recently, much work has been done on
of life. the influence of family history and inherited mutations in
breast cancer:
MORPHOLOGIC FEATURES. Grossly, intraductal papil- i) Family history: First-degree relatives (mother, sister,
loma is usually solitary, small, less than 1 cm in diameter, daughter) of women with breast cancer have 2 to 6-fold
commonly located in the major mammary ducts close to higher risk of development of breast cancer. The risk is
the nipple. Less commonly, there are multiple proportionate to a few factors:
papillomatosis which are more frequently related to a Number of blood relatives with breast cancer.
papillary carcinoma. Younger age at the time of development of breast cancer.
Histologically, an intraductal papilloma is characterised Bilateral cancers.
by multiple papillae having well-developed fibrovascular High risk cancer families having breast and ovarian
stalks attached to the ductal wall and covered by benign carcinomas.
cuboidal epithelial cells supported by myoepithelial cells. ii) Genetic mutations: About 10% breast cancers have been
An intraductal papillary carcinoma is distinguished from found to have inherited mutations. These mutations include
intraductal papilloma in having severe cytologic atypia, the following, most important of which is breast cancer
pleomorphism, absence of myoepithelial cells, multi- (BRCA) susceptibility gene in inherited breast cancer:
layering and presence of mitotic figures. BRCA 1 gene located on chromosome 17, a DNA repair
gene, is implicated in both breast and ovarian cancer in
CARCINOMA OF THE BREAST inherited cases. BRCA1 deletion is seen in about two-third CHAPTER 25

Cancer of the breast is among the commonest of human of women with inherited breast cancer having family history
cancers throughout the world. Its incidence varies in different but BRCA1 mutation is uncommon in sporadic cases. The
countries but is particularly high in developed countries. In protein product of BRCA gene is a cell cycle regulated protein
the United States, carcinoma of the breast constitutes about and it can be detected by immunohistochemistry. Men who
25% of all cancers in females and causes approximately 20% have mutated BRCA1 have increased risk of developing
of cancer deaths among females. However, there has been cancer of the prostate but not of male breast.
some decline in mortality from the breast cancer in recent BRCA 2 gene located on chromosome 13, another DNA The Breast
years in North America, Western Europe and Australia due repair gene, in its mutated form, has a similarly higher
to both early diagnosis and modern therapy. Cancer of the incidence of inherited cancer of the breast (one-third cases)
male breast, on the other hand, is quite rare and comprises and ovary in females, and prostate in men.
0.2% of malignant tumours (ratio between male-female breast In both BRCA1 and BRCA2, both copies of the genes
cancer is 1:100). The incidence of breast cancer is highest in (homozygous state) must be inactivated for development of
the perimenopausal age group and is uncommon before the breast cancer.
age of 25 years. Mutation in p53 tumour suppressor gene on chromosome
Clinically, the breast cancer usually presents as a solitary, 17 as an acquired defect accounts for 40% cases of sporadic
painless, palpable lump which is detected quite often by self- breast cancer in women but rarely in women with family
examination. Higher the age, more are the chances of breast history of breast cancer. p53 mutation is also seen in Li-
lump turning out to be malignant. Thus, all breast lumps, Fraumeni syndrome having multiple cancers including
irrespective of the age of the patient must be removed breast cancer in young women; others are tumours of the
surgically. Currently, emphasis is on early diagnosis by brain, sarcomas, and adrenal cortical tumours.
mammography, xero-radiography and thermography. Other mutations seen less frequently in breast cancer
Techniques like fine needle aspiration cytology (FNAC), include ataxia telangiectasia gene, PTEN (phosphate and
stereotactic biopsy and frozen section are immensely valuable tensin) tumour suppressor gene.
to the surgeon for immediate pathological diagnosis. 3. Oestrogen excess. There is sufficient evidence to suggest
that excess endogenous oestrogen or exogenously
administered oestrogen for prolonged duration is an
Etiology
important factor in the development of breast cancer.
Though extensive clinical and experimental research as well Evidences in support of increased risk with oestrogen excess
as epidemiologic studies have been carried out in the field are as follows:
of breast cancer, its exact etiology remains elusive. However, i) Women with prolonged reproductive life, with menar-
based on current status of our knowledge, the following risk che setting in at an early age and menopause relatively late
factors are considered significant in its etiology: have greater risk.
ii) Higher risk in unmarried and nulliparous women than
in married and multiparous women.

760 iii) Women with first childbirth at a late age (over 30 years)
are at greater risk.
iv) Lactation is said to reduce the risk of breast cancer.
v) Bilateral oophorectomy reduces the risk of development
of breast cancer.
vi) Functioning ovarian tumours (e.g. granulosa cell tumour)
which elaborate oestrogen are associated with increased
incidence of breast cancer.
vii) Oestrogen replacement therapy administered to post-
menopausal women may result in increased risk of breast
cancer.
viii) Long-term use of oral contraceptives has been suspected
to predispose to breast cancer but there is no definite
increased risk with balanced oestrogen-progesterone Figure 25.5 Topographic considerations in breast cancer.
preparations used in oral contraceptives.
ix) Men who have been treated with oestrogen for prostatic invasive carcinoma) before they invade the breast stroma
cancer have increased risk of developing cancer of the male (invasive carcinoma). While only 2 types of non-invasive
breast. carcinoma have been described—intraductal carcinoma and
Normal breast epithelium possesses oestrogen and lobular carcinoma in situ, there is a great variety of
progesterone receptors. The breast cancer cells secrete many histological patterns of invasive carcinoma breast which have
growth factors which are oestrogen-dependent. In this way, clinical correlations and prognostic implications. Table 25.1
the interplay of high circulating levels of oestrogen, oestrogen presents different types of carcinoma of the breast as
receptors and growth factors brings about progression of proposed in the WHO classification with some modifications.
breast cancer. The important morphological forms are described below.
4. Miscellaneous factors. These include a host of following
environmental influences and dietary factors associated with A. NON-INVASIVE (IN SITU) BREAST CARCINOMA
increased risk of breast cancer: In general, two types of non-invasive or in situ carcinoma—
i) Consumption of large amounts of animal fats, high calorie intraductal carcinoma and lobular carcinoma in situ, are
SECTION III
foods. characterised histologically by presence of tumour cells
ii) Cigarette smoking. within the ducts or lobules respectively without evidence of
iii) Alcohol consumption. invasion.
iv) Breast augmentation surgery.
v) Exposure to ionising radiation during breast Intraductal Carcinoma
developement. Carcinoma in situ confined within the larger mammary ducts
vi) Identification of a transmissible retrovirus in early 20th is called intraductal carcinoma. The tumour initially begins
century, mouse mammary tumour virus (MMTV), also called with atypical hyperplasia of ductal epithelium followed by
Bittner milk factor transmitted from the infected mother-mice filling of the duct with tumour cells. Clinically, it produces a
to the breast-fed daughter-mice prompted researchers to look palpable mass in 30-75% of cases and presence of nipple
for similar agent in human breast cancer (Chapter 8). Though discharge in about 30% patients. Approximately a quarter
Systemic Pathology
no such agent has yet been identified, there are reports of
presence of reverse transcriptase in breast cancer cells.  TABLE 25.1: Classification of Carcinoma of the Breast.
5. Fibrocystic change. Fibrocystic change, particularly A. NON-INVASIVE (IN SITU) CARCINOMA
when associated with atypical epithelial hyperplasia, has 1. Intraductal carcinoma
about 5-fold higher risk of developing breast cancer 2. Lobular carcinoma in situ
subsequently.
B. INVASIVE CARCINOMA
General Features and Classification 1. Infiltrating (invasive) duct carcinoma-NOS (not otherwise
specified)
Cancer of the breast occurs more often in left breast than 2. Infiltrating (invasive) lobular carcinoma
the right and is bilateral in about 4% cases. Anatomically, 3. Medullary carcinoma
upper outer quadrant is the site of tumour in half the breast 4. Colloid (mucinous) carcinoma
cancers; followed in frequency by central portion, and 5. Papillary carcinoma
equally in the remaining both lower and the upper inner 6. Tubular carcinoma
7. Adenoid cystic (invasive cribriform) carcinoma
quadrant as shown in Fig. 25.5. 8. Secretory (juvenile) carcinoma
Carcinoma of the breast arises from the ductal epithelium 9. Inflammatory carcinoma
in 90% cases while the remaining 10% originate from the 10. Carcinoma with metaplasia
lobular epithelium. For variable period of time, the tumour
cells remain confined within the ducts or lobules (non- C. PAGET’S DISEASE OF THE NIPPLE

761














Figure 25.6 Morphologic patterns in non-invasive (in situ) carcinoma of breast.


of patients of intraductal carcinoma treated with excisional Lobular Carcinoma in Situ
biopsy alone develop ipsilateral invasive carcinoma during
a follow-up period of 10 years while the chance of a Lobular carcinoma in situ is not a palpable or grossly visible
contralateral breast cancer developing in patients with tumour. Patients of in situ lobular carcinoma treated with
intraductal carcinoma is far less than that associated with in excisional biopsy alone develop invasive cancer of the
situ lobular carcinoma. ipsilateral breast in about 25% cases in 10 years as in
intraductal carcinoma but, in addition, have a much higher
MORPHOLOGIC FEATURES. Grossly, the tumour may incidence of developing a contralateral breast cancer (30%).
vary from a small poorly-defined focus to 3-5 cm diameter
mass. On cut section, the involved area shows cystically MORPHOLOGIC FEATURES. Grossly, no visible tumour
dilated ducts containing cheesy necrotic material (in is identified.
comedo pattern), or the intraductal tumour may be polypoid Histologically, in situ lobular carcinoma is characterised
and friable resembling intraductal papilloma (in papillary by filling up of terminal ducts and ductules or acini by CHAPTER 25
pattern). rather uniform cells which are loosely cohesive and have
Histologically, the proliferating tumour cells within the small, rounded nuclei with indistinct cytoplasmic margins
ductal lumina may have 4 types of patterns in different (Fig. 25.6,B).
combinations: solid, comedo, papillary and cribriform
(Fig. 25.6,A): B. INVASIVE BREAST CARCINOMA
i) Solid pattern is characterised by filling and plugging
of the ductal lumina with tumour cells. Infiltrating (Invasive) Duct Carcinoma-NOS
ii) Comedo pattern is centrally placed necrotic debris Infiltrating duct carcinoma-NOS (not otherwise specified) is the The Breast
surrounded by neoplastic cells in the duct. classic breast cancer and is the most common histologic
iii) Papillary pattern has formation of intraductal papillary pattern accounting for 70% cases of breast cancer. In fact,
projections of tumour cells which lack a fibrovascular stalk this is the pattern of cancer for which the terms ‘cancer’ and
so as to distinguish it from intraductal papilloma. ‘carcinoma’ were first coined by Hippocrates. Clinically,
iv) Cribriform pattern is recognised by neat punched out majority of infiltrating duct carcinomas have a hard
fenestrations in the intraductal tumour. consistency due to dense collagenous stroma (scirrhous

























Figure 25.7 Infiltrating duct carcinoma-NOS. The breast shows a tumour extending up to nipple and areola. Cut surface shows a grey white
firm tumour extending irregularly into adjacent breast parenchyma.

762
























Figure 25.8 Infiltrating duct carcinoma-NOS. Microscopic features include formation of solid nests, cords, gland-like structures and intraductal
growth pattern of anaplastic tumour cells. There is infiltration of densely collagenised stroma by these cells in a haphazard manner.


carcinoma). They are found more frequently in the left breast, ii) Infiltration by these patterns of tumour cells into
often in the upper outer quadrant. Retraction of the nipple diffuse fibrous stroma and fat.
and attachment of the tumour to underlying chest wall may iii) Invasion into perivascular and perineural spaces as
be present. well as lymphatic and vascular invasion.
MORPHOLOGIC FEATURES. Grossly, the tumour is
irregular, 1-5 cm in diameter, hard cartilage-like mass that Infiltrating (Invasive) Lobular Carcinoma
cuts with a grating sound. The sectioned surface of the Invasive lobular carcinoma comprises about 5% of all breast
tumour is grey-white to yellowish with chalky streaks and cancers. This peculiar morphologic form differs from other
SECTION III
often extends irregularly into the surrounding fat invasive cancers in being more frequently bilateral; and
(Fig. 25.7). within the same breast, it may have multicentric origin.
Histologically, as the name NOS suggests, the tumour is
different from other special types in lacking a regular and MORPHOLOGIC FEATURES. Grossly, the appearance
uniform pattern throughout the lesion. A variety of varies from a well-defined scirrhous mass to a poorly-
histologic features commonly present are as under defined area of induration that may remain undetected
(Fig. 25.8): by inspection as well as palpation.
i) Anaplastic tumour cells forming solid nests, cords, Histologically, there are 2 distinct features (Fig. 25.9):
poorly-formed glandular structures and some intraductal i) Pattern—A characteristic single file (Indian file) linear
foci. arrangement of stromal infiltration by the tumour cells
Systemic Pathology


























Figure 25.9 Invasive lobular carcinoma. Characteristic histologic features are: one cell wide files of round regular tumour cells (‘Indian file’
arrangement) infiltrating the stroma and arranged circumferentially around ducts in a target-like pattern.

with very little tendency to gland formation is seen. Colloid (Mucinous) Carcinoma 763
Infiltrating cells may be arranged concentrically around This is an uncommon pattern of breast cancer occurring more
ducts in a target-like pattern. frequently in older women and is slow-growing. Colloid
ii) Tumour cytology—Individual tumour cells resemble carcinoma has better prognosis than the usual infiltrating
cells of in situ lobular carcinoma. They are round and duct carcinoma.
regular with very little pleomorphism and infrequent MORPHOLOGIC FEATURES. Grossly, the tumour is
mitoses. Some tumours may show signet-ring cells usually a soft and gelatinous mass with well-demarcated
distended with cytoplasmic mucin.
borders.
Histologically, colloid carcinoma contains large amount
Medullary Carcinoma
of extracellular epithelial mucin and acini filled with
Medullary carcinoma is a variant of ductal carcinoma and mucin. Cuboidal to tall columnar tumour cells, some
comprises about 1% of all breast cancers. The tumour has a showing mucus vacuolation, are seen floating in large
significantly better prognosis than the usual infiltrating duct lakes of mucin (Fig. 25.12).
carcinoma, probably due to good host immune response in
the form of lymphoid infiltrate in the tumour stroma. Other Morphologic Forms
A few other morphologic forms of invasive breast carcinoma
MORPHOLOGIC FEATURES. Grossly, the tumour is
characterised by a large, well-circumscribed, rounded having clinical significance have been recognised:
mass that is typically soft and fleshy or brain-like and PAPILLARY CARCINOMA. It is a rare variety of infiltrating
hence the alternative name of ‘encephaloid carcinoma’. duct carcinoma in which the stromal invasion is in the form
Cut section shows areas of haemorrhages and necrosis of papillary structures.
(Fig. 25.10). 1. TUBULAR CARCINOMA. Tubular carcinoma is an
Histologically, medullary carcinoma is characterised by uncommon variant of invasive ductal carcinoma which has
2 distinct features (Fig. 25.11): more favourable prognosis.
i) Tumour cells—Sheets of large, pleomorphic tumour CHAPTER 25
cells with abundant cytoplasm, large vesicular nuclei and Histologically, the tumour is highly well-differentiated
many bizarre and atypical mitoses are diffusely spread in and has an orderly pattern. The tumour cells are regular
the scanty stroma. and form a single layer in well-defined tubules. The
ii) Stroma—The loose connective tissue stroma is scanty tubules are quite even and distributed in dense fibrous
and usually has a prominent lymphoid infiltrate. stroma.
2. ADENOID CYSTIC CARCINOMA. Adenoid cystic or
invasive cribriform carcinoma is a unique histologic pattern
of breast cancer with excellent prognosis. The Breast

Histologically, there is stromal invasion by islands of cells
having characteristic cribriform (fenestrated) appearance.





























Figure 25.10 Medullary carcinoma breast. Cut surface of the breast
shows a large grey white soft fleshy tumour replacing almost whole of Figure 25.11 Medullary carcinoma breast. Microscopy shows two
the breast. The tumour is somewhat delineated from the adjacent breast characteristic features—large tumour cells forming syncytial arrangement
parenchyma (arrow) as compared to irregular margin of IDC. and stroma infiltrated richly with lymphocytes.

764 5. METAPLASTIC CARCINOMA. Rarely, invasive
ductal carcinomas may have various types of metaplastic
alterations such as squamous metaplasia, cartilagenous and
osseous metaplasia, or their combinations. Development of
squamous cell carcinoma of the breast parenchyma is
exceedingly rare and must be separated from lesions of
epidermis or nipple region.

C. PAGET’S DISEASE OF THE NIPPLE
Paget’s disease of the nipple is an eczematoid lesion of the
nipple, often associated with an invasive or non-invasive
ductal carcinoma of the underlying breast. The nipple bears
a crusted, scaly and eczematoid lesion with a palpable
subareolar mass in about half the cases. Most of the patients
with palpable mass are found to have infiltrating duct
carcinoma, while those with no palpable breast lump are
usually subsequently found to have intraductal carcinoma.
Prognosis of patients with ductal carcinoma having Paget’s
disease is less favourable than of those who have ductal
carcinoma without Paget’s disease.
Figure 25.12 Colloid (mucinous) carcinoma breast. The tumour cells
are seen as clusters floating in pools of abundant mucin. The pathogenesis of Paget’s disease of the breast is
explained by the following 2 hypotheses:
3. SECRETORY (JUVENILE) CARCINOMA. This pattern 1. The tumour cells from the underlying ductal carcinoma
is found more frequently in children and has a better have migrated up into the lactiferous ducts and invaded the
prognosis. The tumour is generally circumscribed which epidermis producing skin lesions.
on histologic examination shows abundant intra- and 2. An alternate theory, though less reliable than the former,
extracellular PAS-positive clear spaces due to secretory is that Paget’s disease represents a form of carcinoma in situ
activity of tumour cells. of the epidermis itself.
SECTION III
4. INFLAMMATORY CARCINOMA. Inflammatory MORPHOLOGIC FEATURES. Grossly, the skin of the
carcinoma of the breast is a clinical entity and does not nipple and areola is crusted, fissured and ulcerated with
constitute a histological type. The term has been used for oozing of serosanguineous fluid from the erosions
breast cancers in which there is redness, oedema, tenderness (Fig. 25.13, A).
and rapid enlargement. Inflammatory carcinoma is Histologically, the skin lesion is characterised by the
associated with extensive invasion of dermal lymphatics and presence of Paget’s cells singly or in small clusters in the
has a dismal prognosis. epidermis (Fig. 25.13, B). These cells are larger than the




Systemic Pathology
























Figure 25.13 Paget’s diseases of the breast. A, The region of nipple
and areola is crusted and ulcerated. B, There are clefts in the epidermal
layers containing large tumour cells (arrow).

epidermal cells, spherical, having hyperchromatic nuclei 765
with cytoplasmic halo that stains positively with
mucicarmine. In these respects, Paget’s cells are
adenocarcinoma-type cells. In addition, the underlying
breast contains invasive or non-invasive duct carcinoma
which shows no obvious direct invasion of the skin of
nipple.


GRADING, STAGING AND PROGNOSIS
Histologic grading and clinical staging of breast cancer
determines the management and clinical course in these
patients.
A. HISTOLOGIC GRADING. The breast cancers are
subdivided into various histologic grades depending upon Figure 25.14 Oestrogen and progesterone hormonal receptors (ER
the following parameters: and PR) in breast cancer. The tumour cells show nuclear positivity with
ER and PR antibody immunostains.
1. Histologic type of tumour. Based on classification descri-
bed in Table 25.1, various microscopic types of breast cancer
can be subdivided into 3 histologic grades: 6. HER2/neu overexpression. HER2/neu (also called erbB2),
a member of the family of epidermal growth factors, is a
i) Non-metastasising—Intraductal and lobular carcinoma in transmembrane protein having tyrosine kinase activity. It
situ.
ii) Less commonly metastasising—Medullary, colloid, papi- can be detected by immunohistochemistry or by fluorescence
llary, tubular, adenoid cystic (invasive cribriform), and in situ hybridisation (FISH) and is considered as a good
secretory (juvenile) carcinomas. predictive marker. An individual having overexpression of
iii) Commonly metastasising—Infiltrating duct, invasive HER2/neu by tumour cells is likely to respond higher dose of CHAPTER 25
herceptin therapy but is not related to other forms of
lobular, and inflammatory carcinomas.
chemotherapy.
2. Microscopic grade. Widely used system for microscopic 7. DNA content. Tumour cell subpopulations with
grading of breast carcinoma is that of Nottingham aneuploid DNA content as evaluated by mitotic markers (e.g.
modification of the Bloom-Richardson system. It is based on Ki-67) or by flow cytometry have a worse prognosis than
3 features: purely diploid tumours.
i) Tubule formation
ii) Nuclear pleomorphism B. CLINICAL STAGING. The American Joint Committee The Breast
iii) Mitotic count. (AJC) on cancer staging has modified the TNM (primary
Tumour, Nodal, and distant Metastasis) staging proposed
3. Tumour size. There is generally an inverse relationship by UICC (Union International for Control of Cancer) and is
between diameter of primary breast cancer at the time of shown in Table 25.2.
mastectomy and long-term survival.
Spread of breast cancer to axillary lymph nodes occurs
4. Axillary lymph node metastasis. Survival rate is based early. Later, however, distant spread by lymphatic route to
on the number and level of lymph nodes involved by internal mammary lymphatics, mediastinal lymph nodes,
metastasis. More the number of regional lymph nodes supraclavicular lymph nodes, pleural lymph nodes and
involved, worse is the survival rate. Involvement of the pleural lymphatics may occur. Common sites for
lymph nodes from proximal to distal axilla (i.e. level I— haematogenous metastatic spread from breast cancer are the
superficial axilla, to level III—deep axilla) is directly correlated
with the survival rate. In this regards, identification and
dissection of sentinel lymph node followed by its  TABLE 25.2: AJC Clinical Staging of Breast Cancer.
histopathologic examination has attained immense Stage TIS: In situ carcinoma (in situ lobular, intraductal, Paget’s
prognostic value (Sentinel lymph node is the first node in the disease of the nipple without palpable lump)
vicinity to receive drainage from primary cancer i.e. it stands Stage I: Tumour 2 cm or less in diameter
‘sentinel’ over the tumour). No nodal spread
5. Oestrogen and progesterone receptors (ER/PR). Stage II: Tumour > 2 cm in diameter
Oestrogen is known to promote the breast cancer. Presence Regional lymph nodes involved
or absence of hormone receptors on the tumour cells can help
in predicting the response of breast cancer to endocrine Stage III A: Tumour > 5 cm in diameter
Regional lymph nodes involved on same side
therapy (Fig. 25.14). Accordingly, patients with high levels
of ER and PR on breast tumour cells have a slightly better Stage III B: Tumour > 5 cm in diameter
prognosis. A recurrent tumour that is receptor-positive is Supraclavicular and infraclavicular lymph nodes involved
more likely to respond to anti-oestrogen therapy than one Stage IV: Tumour of any size
that is receptor-negative. With or without regional spread but with distant metastasis

766
  TABLE 25.3: Summary of Prognostic Markers and Predictive Factors for Invasive Breast Cancer.
Factor Favourable Prognosis Poor Prognosis
I. ROUTINE HISTOPATHOLOGY CRITERIA:
i) Histologic type Medullary ca., tubular ca., mucinous Inflammatory ca.
(colloid) ca.; lobular ca. of low grade
ii) Tumour size (two dimensions) Nodal metastasis 10-20% in 1 cm Size larger than 1 cm
size tumour; 10 years survival 90%
in node negative
iii) Histologic (Nottingham) grading Low grade (grade I) tumour = High grade (grade III) tumour =
(Score range of 3-9) based on degree of score 3-5, score 8-9
tubule formation-1-3 score, regularity of moderate grade (grade II) tumour =
nuclei-1-3 score, and mitoses-1-3 score score 6-7
iv) Axillary nodal status Node negative: recurrence rate after Node positive: recurrence rate after
10 years 10-30%; 10 years 70%;
Number of nodes: less than 4; number of nodes: more than 4;
sentinel node negative sentinel node positive
v) Lymphatic and/ or vascular invasion Negative for both: good Positive for one or both: poor
(both extratumoural)
vi) Others:
a) Tumour circumscription Good Poor
b) Inflammatory reaction May have some role Controversial
c) Stromal elastosis Absence good Presence poor
d) Intraductal component Presence good Absence poor
e) Skin involvement Absence good Presence poor
II. HORMONE RECEPTOR STATUS:
Oestrogen-progesterone receptors ER-PR positive cases respond ER-PR negative cases respond
(ER-PR) better to adjuvant therapy poorly to adjuvant therapy
HER-2/neu (C-erb B-2) Under expression Over expression (predictive of
response to herceptin)
III. BIOLOGICAL INDICATORS:
SECTION III
i) Mitotic index (by Ki67, MIB-1) Low mitotic count High mitotic count
ii) DNA ploidy analysis Not related Not related
(aneuploidy, diploidy)
iii) Angiogenesis (VEGF, CD31, CD34, Angiogenic activity low High angiogenic activity
microvessel density counts)
iv) Oncogene disregulation
a) BRCA1, BRCA2 BRCA negative BRCA positive
b) p53 p53 positive respond better to p53 negative respond poorly to
chemotherapy and radiotherapy chemotherapy and radiotherapy
c) BCL2 BCL2 positive good BCL2 negative poor
d) Cathepsin D Absence indicates good prognosis Presence renders poor prognosis
Systemic Pathology

lungs, liver, bones, adrenals, brain and ovaries. Breast is one iii) Fibroadenoma is a long-term risk factor (after over 20 years)
of the most suspected source of inapparent primary for invasive breast cancer, the risk being about twice
carcinoma in women presenting with metastatic carcinoma. compared to controls.
C. PROGNOSTIC FACTORS IN BREAST CANCER. 2. Breast carcinoma in situ. Following factors act as
Based on current knowledge gained by breast cancer determinants:
screening programmes in the West employing mammo- i) Ductal carcinoma in situ (comedo and non-comedo
graphy and stereotactic biopsy, various breast cancer risk subtypes) is diagnosed on the basis of three histologic
factors and prognostic factors have been described. These features—nuclear grade, nuclear morphology and necrosis,
prognostic factors are divided into following 3 groups: while lobular neoplasia includes full spectrum of changes of
1. Potentially pre-malignant lesions. These conditions are lobular carcinoma in situ and atypical lobular hyperplasia.
as under: Ductal carcinoma in situ is more important and demands
i) Atypical ductal hyperplasia is associated with 4-5 times most attention. Comedo type of in situ carcinoma has higher
increased risk than women of the same age. Such lesions are recurrence rate.
commonest in the age group of 45-55 years. ii) Breast conservative therapy is used more frequently
ii) Clinging carcinoma is a related lesion in the duct but nowadays in carcinoma in situ which requires consideration
different from carcinoma in situ and has lower risk of of three factors for management: margins, extent of disease,
progression to invasive cancer than in situ carcinoma. and biological markers. The biological markers such as p53 and

BCL-2 have low positivity in high-grade in situ ductal 1. routine histopathology criteria; 767
carcinoma and likelihood of recurrences after conservative 2. hormone receptor status; and
surgery. 3. biological indicators.
3. Invasive breast cancer. Prognostic and predictive factors A summary combining all these factors is given in
for invasive breast cancer have been extensively studied by Table 25.3.
univariate analysis (examining single factor separately) as Overall, taking the most important parameter of node-
well as by multivariate analysis (comparing the value of positive or node-negative breast cancer, the prognosis
various factors included in a study). These can be broadly varies— localised form of breast cancer without axillary
divided into 3 groups: lymph node involvement has a survival rate of 84% while
survival rate falls to 56% with nodal metastases.

❑ CHAPTER 25


































The Breast

768


Chapter 26 The Skin
Chapter 26








NORMAL STRUCTURE

The skin or the integument is the external organ that protects
against mechanical trauma, UV light and infection. In
addition, the skin is concerned with thermoregulation,
conservation and excretion of fluid, sensory perception and,
of course, has aesthetic role for appearance of the indidivdual.
The histology of normal skin shows some variation in
different parts of the body. In general, it is composed of 2
layers, the epidermis and the dermis, which are separated
by an irregular border. Cone-shaped dermal papillae extend
upward into the epidermis forming peg-like rete ridges of the
epidermis. Fig. 26.1 presents a diagrammatic representation
of the main structures identifiable in a section of the normal
skin while Fig. 26.2 shows the various layers of the epidermis.

EPIDERMIS
The epidermis is composed of the following 5 layers from
base to the surface: Figure 26.2 Different layers comprising the normal epidermis.
SECTION III
1. Basal cell layer (stratum germinatum). The basal cell
layer consists of a single layer of keratinocytes that forms by desmosomes. Interspersed in the keratinocytes are
the junction between the epidermis and dermis. The nuclei melanocytes, a type of dendritic cells, seen as every tenth cell
of these cells are perpendicular to the epidermal basement in the basal layer. These cells have small nuclei with clear
membrane. These are hyperchromatic and normally contain cytoplasm containing melanin pigment granules that
a few mitoses indicating that the superficial epidermal layers determines the appearance of an individual. They are always
originate from the basal cell layer. These cells are interconnec- positive with dopa reaction (page 40). The other type of
ted with each other and with the overlying squamous cells dendritic cells in the basal layer are Langerhans cells which
are bone marrow-derived cells of mononuclear-phagocyte
system.
Systemic Pathology
2. Prickle cell layer (Stratum spinosum, Stratum malpi-
ghii). This layer is composed of several layers of polygonal
prickle cells or squamous cells. The layers become flat as they
near the surface so that their long axis appears parallel to
the skin surface. These cells possess intercellular bridges or
tonofilaments. These intercellular cytoplasmic tonofilaments
contain PAS-positive material that is precursor of keratin.
3. Granular cell layer (stratum granulosum). This layer
consists of 1 to 3 layers of flat cells containing keratohyaline
basophilic granules which are PAS-negative. Granular cell
layer is much thicker in palms and soles.
4. Stratum lucidum. This layer is present exclusively in
palms and soles as a thin homogeneous, eosinophilic, non-
nucleate zone.
5. Horny layer (Stratum corneum). The stratum corneum
is also normally devoid of nuclei and consists of eosinophilic
Figure 26.1 Main structures identified in a section of the normal
skin. layers of keratin.

Intraepidermal nerve endings are present in the form of and connective tissue components. The hair shaft is made 769
Merkel cells which are touch receptors. up of an outer sheath and pigmented cortex and inner
medulla.
DERMIS
4. ARRECTORES PILORI. These are small bundles of
The dermis consists of 2 parts—the superficial pars papillaris smooth muscle attached to each hair follicle. When the muscle
or papillary dermis, and the deeper pars reticularis or reticular contracts, the hair becomes more erect, the follicle is dragged
dermis. The dermis is composed of fibrocollagenic tissue upwards so as to become prominent on the surface of the
containing blood vessels, lymphatics and nerves. In the skin skin producing what is known as ‘goose skin’.
of fingers, arteriovenous shunts or glomera are normally 5. NAILS. The nails are thickenings of the deeper part of
present. The specialised nerve endings present at some sites the stratum corneum that develop at specially modified
perform specific functions. These are as under: portion of the skin called nail bed. The nail is composed of
Pacinian corpuscles concerned with pressure are present
in the deep layer of skin. clear horny cells, resembling stratum lucidum but are much
more keratinised.
Meissner corpuscles are touch receptors, located in the
papillae of skin of palms, soles, tips of fingers and toes. HISTOPATHOLOGIC TERMS
Ruffini corpuscles are cold receptors found in the external
genitalia. Before describing pathology of common skin diseases, the
End-bulbs of Krause are cold receptors found in the external following pathologic terms in common use need to be defined
genitalia. for understanding of dermatopathology:
Besides these structures, the dermis contains cutaneous Acanthosis: Thickening of the epidermis due to hyperplasia
appendages or adnexal structures. These are sweat glands, of stratum malpighii.
sebaceous glands, hair follicles, arrectores pilorum and nails:
Acantholysis: Loss of cohesion between epidermal cells with
1. SWEAT GLANDS. These are of 2 types—eccrine and formation of intraepidermal space containing oedema fluid
apocrine. and detached epithelial cells.
i) Eccrine glands. They are present all over the skin but are Dyskeratosis: Abnormal development of epidermal cells CHAPTER 26
most numerous on the palms, soles and axillae. They are resulting in rounded cells devoid of their prickles and having
coiled tubular glands lying deep in the dermis. Their ducts pyknotic nuclei. Dyskeratosis is a feature of premalignant
pass through the epidermis on the surface of the skin as pores and malignant lesions and is rarely seen in benign conditions.
via which they empty their secretion i.e. sweat. The glands Hyperkeratosis: Thickening of the horny layer.
are lined by two main types of secretory cells: basal, Parakeratosis: Abnormal keratinisation of the cells so that
acidophilic, clear or chief cells, and the superficial, basophilic, the horny layer contains nucleated keratinocytes rather than
dark granular cells. The secretory cells are surrounded by the normal non-nucleate keratin layer. The Skin
myoepithelial cells.
Spongiosis: Intercellular oedema of the epidermis which may
ii) Apocrine glands. Apocrine glands are encountered in progress to vesicle formation in the epidermis.
some areas only—in the axillae, in the anogenital region, in
the external ear as modified glands called ceruminous glands, Pigment incontinence: Loss of melanin pigment from dama-
in the eyelids as Moll’s glands, and in the breast as mammary ged basal cell layer so that the pigment accumulates in the
glands. Apocrine glands are also tubular glands but have melanophages in the dermis.
larger lumina. Apocrine glands have a single layer of
secretory cells which contain acidophilic, PAS-positive, DERMATOSES
prominent granular cytoplasm. The type of secretion in
apocrine glands is decapitation secretion as if the cytoplasm Dermatosis is a common term used for any skin disorder.
of the secretory cells is pinched off (apo = off). Dermatosis may be of various types such as genetic,
inflammatory, infectious, granulomatous, connective tissue,
2. SEBACEOUS (HOLOCRINE) GLANDS. Sebaceous bullous and scaling type. A few common examples of each
glands are found everywhere on the skin except on the palms of these groups are described below.
and soles. They are often found in association with hair but
can be seen in a few areas devoid of hair as modified I. GENETIC DERMATOSES
sebaceous glands such as in the external auditory meatus,
nipple and areola of male and female breast, labia minora, 1. ICHTHYOSIS. Two important forms of ichthyosis are—
prepuce, and meibomian glands of the eyelids. Sebaceous ichthyosis vulgaris and sex-linked ichthyosis.
glands are composed of lobules of sebaceous cells containing Ichthyosis vulgaris is an autosomal dominant disorder.
small round nuclei and abundant fatty, network-like It is more common and appears a few months after birth as
cytoplasm. scaly lesions on the extensor surfaces of the extremities.
3. HAIR. The hair grows from the bottom of the follicle. It
has, therefore, an intracutaneous portion present in the hair Histologically, the characteristic feature is association of
follicle and the shaft. The hair follicle consists of epithelial hyperkeratosis with thin or absent granular layer.

770 Sex-linked ichthyosis is a sex-(X) linked recessive prone to develop infections, especially of lungs, and
disorder. It begins shortly after birth and affects extensor as lymphoma-leukaemia.
well as flexor surfaces but palms and hands are spared.
Histologically, the papillary dermis shows numerous
Histologically, there is hyperkeratosis with normal or dilated blood vessels.
thickened granular cell layer and acanthosis.
II. NON-INFECTIOUS INFLAMMATORY DERMATOSES
2. KERATOSIS PALMARIS ET PLANTARIS. The
condition occurs as both autosomal dominant and autosomal A very large number of skin diseases have acute or chronic
recessive forms. It mainly affects the palms and soles as inflammation as a prominent feature. A few selected
localised or diffuse lesions. examples of non-infectious acute and chronic inflammatory
dermatoses which have not been covered in other groups of
Histologically, there is marked hyperkeratosis, hyper- dermatoses are given below.
granulosis, acanthosis and mild inflammatory infiltrate 1. DERMATITIS (ECZEMA). The pathologic term derma-
in the upper dermis. titis is synonymous with the clinical term eczema. Both refer
to inflammatory response to a variety of agents acting on
3. XERODERMA PIGMENTOSUM. This is an autosomal the skin from outside or from within the body such as
recessive disorder in which sun-exposed skin is more chemicals and drugs, hypersensitivity to various antigens
vulnerable to damage. The condition results from decreased and haptens etc. Accordingly, clinical types such as contact
ability to repair the sunlight-induced damage to DNA. dermatitis, atopic dermatitis, drug-induced dermatitis,
Patients of xeroderma pigmentosum are more prone to photo-eczematous dermatitis and primary irritant dermatitis
develop various skin cancers like squamous cell carcinoma, are described. Many idiopathic varieties of skin disorders
basal cell carcinoma and melanocarcinoma. such as pompholyx, seborrheic dermatitis, exfoliative
dermatitis (erythroderma) and neurodermatitis (lichen
Histologically, the changes include hyperkeratosis, simplex chronica) are also included under this heading. In
thinning and atrophy of stratum malpighii, chronic general, these conditions are clinically characterised by
inflammatory cell infiltrate in the dermis and irregular itching, erythema with oedema, oozing and scaling.
accumulation of melanin in the basal cell layer. Changes However, irrespective of the clinical type of dermatitis, the
of skin cancers mentioned above may be present in histopathologic picture is similar.
advanced stage.
SECTION III
Histologically, dermatitis reaction may be acute, subacute
4. DARIER’S DISEASE (KERATOSIS FOLLICULARIS). or chronic:
The condition is either transmitted as autosomal dominant Acute dermatitis is characterised by considerable
disorder or as a mutation. In typical cases, there is extensive spongiosis (intercellular oedema) that may lead to forma-
papular eruption. tion of intraepidermal vesicles or bullae. The vesicles and
bullae as well as the oedematous epidermis are permeated
Histologically, the characteristic changes are hyper- by acute inflammatory cells. The upper dermis shows
keratosis, papillomatosis and dyskeratosis. Dyskeratosis congested blood vessels and mononuclear inflammatory
results in the formation of ‘corps ronds’ (present in the cell infiltrate, especially around the small blood vessels.
granular layer as a central homogeneous basophilic Subacute dermatitis may follow acute dermatitis.
dyskeratotic mass surrounded by a clear halo) and ‘grains’ Spongiosis and vesicles are smaller than in acute
Systemic Pathology
(having grain-shaped elongated nuclei surrounded by dermatitis. The epidermis shows moderate acanthosis and
homogeneous dyskeratotic material) and there is varying degree of parakeratosis in the horny layer with
appearance of suprabasal clefts containing acantholytic formation of surface crusts containing degenerated
cells. The dermis often shows chronic inflammatory cell leucocytes, bacteria and fibrin. The dermis contains
infiltrate. perivascular mononuclear infiltrate. The classical example
of subacute dermatitis is nummular dermatitis.
5. URTICARIA PIGMENTOSA. Urticaria pigmentosa may Chronic dermatitis shows hyperkeratosis, parakera-
occur as congenital form or may appear without any family tosis and acanthosis with elongation of the rete ridges and
history in the adolescents. Clinically, the condition presents broadened dermal papillae. Vesicles are absent but slight
as extensive pigmented macules. spongiosis may be present. The upper dermis shows
perivascular chronic inflammatory infiltrate and fibrosis
Histologically, the epidermis is normal except for an (Fig. 26.3). The most characteristic example of chronic
increase in melanin pigmentation in the basal cell layer. dermatitis is lichen simplex chronicus.
The characteristic feature is the presence of numerous
mast cells in the dermis. 2. URTICARIA. Urticaria or hives is the presence of
transient, recurrent, pruritic wheals (i.e. raised erythematous
6. ATAXIA TELANGIECTASIA. An autosomal recessive areas of oedema). Hereditary angioneurotic oedema is an
disorder, ataxia appears in infancy, while telangiectasia uncommon variant of urticaria in which there is recurrent
appears in childhood. The lesions are located on the oedema not only on the skin but also on the oral, laryngeal
conjunctivae, cheeks, ears and neck. These children are more and gastrointestinal mucosa (page 97).

Erythema nodosum, acute or chronic, is the most 771
common form. The lesions consist of tender red nodules, 1-5
cm in diameter, seen more often on the anterior surface of
the lower legs. Erythema nodosum is often found in
association with bacterial or fungal infections, drug intake,
inflammatory bowel disease and certain malignancies.
Erythema induratum is a less common variety. The
lesions are chronic, painless, slightly tender, recurrent and
found on the calves of lower legs.
Histologically, the early lesions show necrotising vascu-
litis involving the blood vessels in the deep dermis and
subcutis. In chronic stage, there is inflammatory infiltrate
consisting of lymphocytes, histiocytes and multinucleate
giant cells. The infiltrate is located in the septa separating
the lobules of fat.

5. ACNE VULGARIS. Acne vulgaris is a very common
chronic inflammatory dermatosis found predominantly in
adolescents in both sexes. The lesions are seen more
commonly on the face, upper chest and upper back. The
appearance of lesions around puberty is related to
Figure 26.3 Chronic dermatitis (eczema). The epidermis shows physiologic hormonal variations. The condition affects the
hyperkeratosis, acathosis and broadened papillae and spongiosis of the hair follicle, the opening of which is blocked by keratin
epidermal layers. The dermis shows mild perivascular chronic material resulting in formation of comedones. Comedones may
inflammatory cell infiltrate.
be open having central black appearance due to oxidation of
melanin called black heads, or they may be in closed follicles CHAPTER 26
Histologically, there is dermal oedema and a perivascular referred to as white heads. A closed comedone may get infected
mononuclear infiltrate. There is localised mast cell and result in pustular acne.
degranulation by sensitisation with specific IgE antibodies
but no increase in dermal mast cells (c.f. mastocytosis in Histologically, a comedone consists of keratinised cells,
which there is increase in dermal mast cells). sebum and bacteria. The hair follicle containing a
comedone is surrounded by lymphocytic infiltrate in
3. MILIARIA. Miliaria is a condition in which there is papular acne, and neutrophilic infiltrate in pustular acne. The Skin
cutaneous retention of sweat due to obstruction of sweat Sometimes, the wall of the distended follicle is disrupted
ducts. There are 2 types of miliaria: miliaria crystallina and so that the contents escape into the dermis where they
miliaria rubra. may incite granulomatous reaction.
Miliaria crystallina occurs when there is obstruction of
sweat duct within the stratum corneum. It occurs in areas of III. INFECTIOUS DERMATOSES
the skin exposed to sun or may occur during a febrile illness. Microorganisms such as bacteria, viruses and fungi are
Histologically, there are intracorneal or subcorneal responsible for a large number of dermatoses. Some common
vesicles which are in continuity with underlying sweat examples of each category are described below.
ducts. 1. IMPETIGO. Impetigo is a common superficial bacterial
infection caused by staphylococci and streptococci. The
Miliaria rubra occurs when there is obstruction of sweat condition may occur in children or in adults and more
ducts within the deeper layers of the epidermis. It is seen commonly involves hands and face. The lesions appear as
more often in areas of skin covered by clothes following vesico-pustules which may rupture and are followed by
profuse sweating and the lesions are itchy. characteristic yellowish crusts.

Histologically, there are spongiotic vesicles in the stratum Histologically, the characteristic feature is the subcorneal
malpighii similar to those seen in dermatitis. These pustule which is a collection of neutrophils under the
vesicles are in continuity with a sweat duct. Adjacent stratum corneum. Often, a few acantholytic cells and
dermis usually shows chronic inflammatory infiltrate. gram-positive bacteria are found within the pustule. The
upper dermis contains severe inflammatory reaction
4. PANNICULITIS (ERYTHEMA NODOSUM AND composed of neutrophils and lymphoid cells.
ERYTHEMA INDURATUM). Panniculitis is inflammation
of the subcutaneous fat. Panniculitis may be acute or chronic. 2. VERRUCAE (WARTS). Verrucae or warts are common
Generally, panniculitis appears as nodular lesions, viral lesions of the skin. They are caused by human
predominantly on the lower legs. The following types of papillomaviruses (HPV) that belong to papovavirus group,
panniculitis are described: a type of DNA oncogenic virus (page 224). More than

772 iii) Verruca planatairs or plantar warts occur on the sole of
 TABLE 26.1: Correlation of HPV Types with Disease.
the foot and is caused by HPV-1. They are covered with a
Disease Common Malignant thick callus. They may, therefore, resemble calluses or a
Type Potential
verrucous carcinoma.
1. Common wart 1, 2 41 iv) Epidermodysplasia verruciformis resembles verruca
(verruca vulgaris) plana but differs by having familial occurrence with
2. Palmoplantar wart 1, 2 — autosomal recessive inheritance. The genome of HPV types
3. Flat wart (verruca plana) 3, 10 41 5 and 8 have been found in some of these tumours. Epidermo-
4. Anogenital warts 6, 11 30, 45 dysplasia verruciformis is of special clinical significance as
(condyloma acuminatum) it may undergo malignant change, usually into Bowen’s
5. Bowen's disease 16 31 disease, and occasionally into squamous cell carcinoma.
6. Bowenoid papulosis 16 39, 45 v) Condyloma acuminatum or venereal wart or anogeni-
7. Laryngeal papilloma 6, 11 — tal wart occurs on the penis, on the vulva and around the
8. Conjunctival papilloma 6, 11, 16 16 anus (page 714). They are commonly caused by HPV-6. The
9. Epidermodysplasia 2, 3, 9, 10 5, 8 lesions appear as soft, papillary, cauliflower-like mass that
verruciformis may grow fairly large in size (giant condyloma acuminata).
10. Cervical carcinoma 16, 18 16, 18, 31, 33 In rare cases, transformation into verrucous carcinoma may
occur.
100 HPV types have been identified. But it must be Histologically, prototype of verruca is common viral wart
appreciated that various types of HPVs produce not only having following features (Fig. 26.4):
different morphologic lesions but also have variable i) Papillomatosis (papillary folds).
oncogenic potential as summed up in Table 26.1. Infection ii) Acanthosis (hyperplasia of stratum malpighii
with HPV is acquired by direct contact or by autoinoculation. containing foci of vacuolated cells in the upper stratum
Verrucae may undergo spontaneous regression in a few malpighii.
months to 2 years, or may spread to other sites. Depending iii) Hyperkaratosis with parakeratosis.
upon the clinical appearance and location, they are classified iv) Clumped keratohyaline granules in the granular cells
into different types described below. in the valleys between adjacent papillae.
i) Verruca vulgaris is the most common human wart, v) Elongation of rete ridges with their lower tips bent
commonly caused by HPV-1 and 2. The lesions are often inwards.
SECTION III
multiple, less than 1 cm in size, circumscribed, firm, elevated vi) Virus-infected epidermal cells contain prominent
papules occurring more commonly on the dorsal surfaces of vacuolation (koilocytosis) and keratohyaline granules of
hands and fingers. intracytoplasmic keratin aggregates due to viral
ii) Verruca plana on the other hand, is flat or slightly cytopathic effects. These cells on electron microscopy
elevated wart, common on the face and dorsal surface of reveal numerous intranuclear viral particles.
hands and is usually associated with HPV-10.






Systemic Pathology

























Figure 26.4 Typical appearance of a verruca. The histologic features include papillomatosis, acanthosis, hyperkeratosis with parakeratosis
and elongated rete ridges appearing to point towards the centre. Foci of vacuolated cells (koilocytes) are found in the upper stratum malpighii. Inset
shows koilocytes and virus-infected keratinocytes containing prominent keratohyaline granules.

nerves and the tissues supplied by the nerves. The condition 773
is characterised by sharp burning pain, often dispropor-
tionate to the rash. Herpes simplex, caused by HSV-1, and
another related herpetic infection, herpes genitalis, caused
by HSV-2, are characterised by transmission by direct
physical contact and prolonged latency. The vesicular lesions
are often located on the skin, especially the facial skin around
lips and external nares; other sites are mucosal surfaces and
eyes.

Histologically, the characteristic feature of viral exan-
themata is the formation of intra-epidermal vesicles or
bullae due to cytopathic effects of viruses. In the early
stage, there is proliferation of epidermal cells and
formation of multinucleate giant cells. This is followed
by intracellular oedema and ballooning degeneration that
progresses on to rupture of the cells with eventual
formation of vesicles or bullae.
Figure 26.5 Molluscum contagiosum. The epidermal layers show
numerous molluscum bodies which are intracytoplasmic inclusions. Inset 5. SUPERFICIAL MYCOSES. Superficial fungal infections
shows close-up view of molluscum bodies.
of the skin are localised to stratum corneum (page 183). These
include some of the common dermatophytes such as
3. MOLLUSCUM CONTAGIOSUM. Molluscum conta- Trichophyton rubrum and Pityrosporum. Clinically, these fungal
giosum is a common self-limiting contagious lesion caused infections are labelled according to the region involved. These
by a poxvirus which is a DNA virus. It is more common in are as follows:
children and young adults. Infection is acquired by direct i) Tinea capitis occurring on the scalp, especially in
contact. Clinically, the lesions are often multiple, discrete, children. CHAPTER 26
waxy, papules, about 5 mm in diameter and are seen more ii) Tinea barbae affecting the region of beard in adult males.
frequently on the face and trunk. In a fully-developed lesion,
small amount of paste-like material can be expressed on iii) Tinea corporis involving the body surface at all ages.
pressing. iv) Tinea cruris occurs most frequently in the region of groin
in obese men, especially in hot weather.
Histologically, typical lesion consists of sharply v) Tinea pedis or ‘athlete foot’ is located in the web spaces
circumscribed cup-like epidermal lesion growing down between the toes. The Skin
into the dermis. The proliferating epidermal cells contain vi) Onychomycosis shows disintegration of the nail
the pathognomonic intracytoplasmic eosinophilic substance.
inclusion bodies called molluscum bodies (Fig. 26.5). These vii) Tinea versicolor caused by Malassezia furfur generally
bodies contain numerous viral particles.
affects the upper trunk.
4. VIRAL EXANTHEMATA. Viral exanthemata are a
group of contagious conditions in which the epidermal cells
are destroyed by replicating viruses causing eruption or rash.
There are predominantly two groups of viruses which may
cause exanthem. These are: the poxvirus group (e.g. smallpox
or variola, cowpox or vaccinia), and the herpesvirus group (e.g.
chickenpox or varicella, herpes zoster or shingles, herpes
simplex). Clinically, these conditions have different
presentations but the eruptive lesions may look alike and
are, therefore, considered together.
Variola (smallpox) has been globally eradicated since
1978. The route of infection is via upper respiratory tract or
mouth followed by viraemia and characteristic skin lesions.
Vaccinia (cowpox) is primarily a disease of the teats and
udders of cows but humans are infected by milking the
infected animals. Varicella (chickenpox) and herpes zoster
(shingles) are both caused by a common virus, varicella-
zoster virus. Chickenpox is transmitted by the respiratory
route followed by viraemia and successive crops of lesions.
Herpes zoster is different manifestation of infection with the Figure 26.6 Tinea capitis in the skin. The stratum corneum around
same viral agent after years of latency. It is a disease of the the hair follicle shows presence of numerous arthrospores and hyphae.

774 Histologically, fungal hyphae (or mycelia) and
arthrospores of dermatophytes are present in the stratum
corneum of skin, nails or hair. Hyphae may be septate or
nonseptate. Spores are round to oval bodies which grow
by budding. Special stains can be used to demonstrate
the fungi. These are: periodic acid-Schiff (PAS) reaction
which stains the fungi deep pink to red (Fig. 26.6), and
methenamine silver nitrate method that stains fungi black.

IV.GRANULOMATOUS DISEASES
In many skin diseases, the host may respond by granu-
lomatous inflammation to a variety of microbial agents and
nonmicrobial material. Tuberculosis of the skin is the classical
example in which typical tubercles are formed; other
conditions are leprosy, syphilis, sarcoidosis, deep fungal
infection etc. These conditions have already been discussed
in Chapter 6. Nonmicrobial agents which can incite
granulomatous inflammation are keratin, hair, thorns, talc,
minerals like beryllium, asbestos and tattoo pigment etc.
Important representative examples of granulomatous
inflammation—lupus vulgaris, cutaneous sarcoidosis and
granuloma annulare, are described here. Figure 26.8 Cutaneous sarcoidosis. The dermis shows non-
caseating epithelioid granulomas having Langhans’ giant cells and paucity
1. LUPUS VULGARIS. The lesions of lupus vulgaris, the of lymphocytes, termed as naked granulomas.
prototype of skin tuberculosis, are found most commonly
on the head and neck, especially skin of the nose. They are
yellowish-brown to reddish-brown tiny nodules (apple-jelly are present in very small numbers that are hard to
nodules). demonstrate by acid-fast staining.
Histologically, the nodules consist of well-defined 2. CUTANEOUS SARCOIDOSIS. Sarcoidosis is a systemic
SECTION III
tubercles lying in the upper dermis. They consist of granulomatous disease of unknown etiology (page 164). The
accumulation of epithelioid cells surrounded by lymphoid lesions appear in the lungs, skin, eyes, nose and lymph nodes.
cells. Caseation necrosis may be slight or absent. Cutaneous manifestations appear as presenting feature in
Langhans’ and foreign body type of giant cells are often about a quarter of patients and include erythema nodosum,
present (Fig. 26.7). The condition needs to be distinguished or brown-red jelly-like papules or plaques with central
from sarcoidosis of the skin (vide infra). Tubercle bacilli clearing. When these lesions are seen around nose, eyes and
cheeks they are referred to as lupus perinio.
Microscopically, characteristic feature is the presence of
non-caseating epithelioid cell granulomas having
Langhans’ giant cells but having paucity of lymphocytes,
Systemic Pathology
also called ‘naked granulomas’ (Fig. 26.8). Fibrinoid
necrosis and presence of intracellular inclusions such as
asteroid bodies are some other features which may be seen.

3. GRANULOMA ANNULARE. The lesions of granuloma
annulare are often numerous. Dermal nodules are arranged
in a ring-like fashion, commonly on the hands and feet. The
condition appears to have correlation with diabetes mellitus.

Histologically, the centre of the lesion shows a well
demarcated focus of complete collagen degeneration.
These foci are surrounded by an infiltrate composed
largely of histiocytes and some mononuclear inflam-
matory cells forming a palisade arrangement and are
therefore also referred to as palisading granulomas.

V. CONNECTIVE TISSUE DISEASES

Figure 26.7 Lupus vulgaris. The dermis contains caseating Group of diseases caused by self-antigens or autoimmune
epithelioid cell granulomas having giant cells and lymphocytes. diseases are included under connective tissue diseases. A

list of such diseases along with their etiology and patho- Direct immunofluorescence reveals granular deposits of 775
genesis is given in Chapter 4. Morphology of skin lesions of immunoglobulins, most commonly IgG and IgM, and
two important representative examples—lupus erythematosus components of complement on the basement membrane of
and systemic sclerosis (scleroderma), is given below. Another the affected skin in both DLE and SLE. High serum titres of
connective tissue disease of unknown etiology, lichen antinuclear antibodies and demonstration of LE cells (page
sclerosus et atrophicus, is also considered here. 79) are other notable features, especially in SLE.
1. LUPUS ERYTHEMATOSUS. Two types of lupus 2. SYSTEMIC SCLEROSIS (SCLERODERMA). Two
erythematosus are recognised—a chronic form, discoid lupus types of systemic sclerosis or scleroderma are identified: a
erythematosus (DLE) which is confined to the skin; and a localised form called morphea, and a generalised form called
systemic form, systemic lupus erythematosus (SLE) that has progressive systemic sclerosis. A variant of progressive
widespread visceral vascular lesions. The discoid variety is systemic sclerosis is CREST syndrome. (C = calcinosis,
more common which is generally benign, while systemic R = Raynaud’s phenomenon, E = esophageal dismotility,
form may be fatal, usually from renal involvement. The S = sclerodactyly and T = telangiectasia). Etiology and
diagnosis is made on the basis of clinical, serologic and pathogenesis of these conditions are already described
pathologic changes. The characteristic cutaneous lesions in (page 80). Morphea consists of lesions limited to the skin
DLE consist of well-defined erythematous discoid patches and subcutaneous tissue, while progressive systemic
associated with scaling and atrophy and often limited to the sclerosis consists of extensive involvement of the skin and
face. In contrast, cutaneous lesions in SLE are present only the subcutaneous tissue and has visceral lesions too. The
in a small proportion of cases and consist of erythematous, lesions generally begin in the fingers and distal extremities
slightly oedematous patches which are without significant and then extend proximally to involve the arms, shoulders,
scaling and without atrophy. neck and face.
Histologically, cutaneous lesion in DLE and SLE may not Histologically, there is thickening of the dermal collagen
be distinguishable in all cases. The important features are extending into the subcutaneous tissue. There is
as follows (Fig. 26.9): pronounced chronic inflammatory infiltrate in the affected
i) Hyperkeratosis with keratotic plugging. area. The epidermis is often thin, devoid of rete ridges CHAPTER 26
ii) Thinning and flattening of rete malpighii. and adnexal structures, and there is hyalinised thickening
iii) Hydropic degeneration of basal layer. of the walls of dermal arterioles and capillaries.
iv) Patchy lymphoid infiltrate around cutaneous adnexal Subcutaneous calcification may develop.
structures. 3. LICHEN SCLEROSUS ET ATROPHICUS. This condi-
v) Upper dermis showing oedema, vasodilatation and tion involves genital skin most frequently and is often the
extravasation of red cells. only site of involvement. It occurs in both sexes, more
commonly in women than in men. It is termed kraurosis vulvae The Skin
in women while the counterpart in men is referred to as
balanitis xerotica obliterans. Occasionally, the condition may
coexist with morphea. Clinically, the condition may simulate
malignancy.
Histologically, the characteristic features are as under:
i) Hyperkeratosis with follicular plugging.
ii) Thinning and atrophy of the epidermis.
iii) Hydropic degeneration of the basal layer.
iv) Upper dermis showing oedema and hyaline appear-
ance of collagen.
v) Inflammatory infiltrate in mid-dermis.

VI. NON-INFECTIOUS BULLOUS DERMATOSES
This is a group of skin diseases characterised by bullae and
vesicles. A bulla is a cavity formed in the layers of the skin
and containing blood, plasma, epidermal cells or
inflammatory cells, while a vesicle is a small bulla less than 5
mm in diameter. Blister is the common term used for both
bulla and vesicle. The blister can be located at different sites
such as subcorneal, intra-epidermal (suprabasal or
subcorneal) and subepidermal. These blisters can appear in
Figure 26.9 Discoid lupus erythematosus (DLE). The epidermis is infectious as well as in noninfectious dermatoses. A few
flat and is devoid of rete ridges. There is hyperkeratosis and follicular common examples of noninfectious dermatoses are
plugging. The basal layer shows hydropic degeneration and loss of dermo-
epidermal junction (arrow). The upper dermis is oedematous and shows pemphigus, pemphigoid, dermatitis herpetiformis and
moderate lymphocytic infiltration. erythema multiforme and are illustrated in Fig. 26.10.

776


































Figure 26.10 Location of bullae and vesicles in non-infectious bullous dermatoses. A, Pemphigus vulgaris: The bulla is predominantly suprabasilar
in position and contains acantholytic cells. B, Pemphigus vegetans: An intraepidermal abscess composed of eosinophils is seen. C, Pemphigus
foliaceous: The bulla is superficial in subcorneal position and contains acantholytic cells. D, Pemphigoid: The bulla containing eosinophilis is
subepidermal with regeneration of the epidermis at the periphery. E, Dermatitis herpetiformis: There is a papillary microabscess composed of
neutrophils. F, Erythema Multiforme: The affected area shows necrotic keratinocytes and inflammatory cells.
SECTION III
1. PEMPHIGUS. Pemphigus is an autoimmune bullous Histologically, superficial subcorneal bullae are found
disease of the skin and mucosa which has 4 clinical and which contain acantholytic epidermal cells.
pathologic variants: pemphigus vulgaris, pemphigus
vegetans, pemphigus foliaceous and pemphigus erythe- iv) Pemphigus erythematosus is an early form of pemphigus
matosus. foliaceous. The distribution of clinical lesions is similar to
All forms of pemphigus have acantholysis as common lupus erythematosus involving face.
histologic feature. Sera from these patients contain IgG
antibodies to cement substance of skin and mucosa.
i) Pemphigus vulgaris is the most common type
characterised by the development of flaccid bullae on the
Systemic Pathology
skin and oral mucosa. These bullae break easily leaving
behind denuded surface.
Histologically, the bullae are suprabasal in location so
that the basal layer remains attached to dermis like a row
of tombstones. The bullous cavity contains serum and
acantholytic epidermal cells (Fig. 26.11).
ii) Pemphigus vegetans is an uncommon variant consisting
of early lesions resembling pemphigus vulgaris. But later,
verrucous vegetations are found on the skin and oral mucosa
instead of bullous lesions.
Histologically, there is considerable acanthosis and
papillomatosis. Intraepidermal abscesses composed
almost entirely of eosinophils are diagnostic of pemphigus
vegetans (Fig. 24.4,B).
iii) Pemphigus foliaceous is characterised by quite
superficial bullae which leave shallow zones of erythema and Figure 26.11 Pemphigus vulgaris. An intraepidermal bulla in
crust. suprabasal location containing acantholytic cells (arrow) is seen.

epidermal regeneration from the periphery at the floor of 777
the bulla. The bullous cavity contains fibrin network and
many mononuclear inflammatory cells and many
eosinophils (Fig. 26.12). Dermal changes seen in
inflammatory bullae consist of infiltrate of mononuclear
cells, a few eosinophils and neutrophils.

3. DERMATITIS HERPETIFORMIS. Dermatitis herpeti-
formis is a form of chronic, pruritic, vesicular dermatosis.
The lesions are found more commonly in males in 3rd to 4th
decades of life. The disease has an association with gluten-
sensitive enteropathy (coeliac disease). Both dermatitis
herpetiformis and gluten-sensitive enteropathy respond to
a gluten-free diet. The pathogenesis of the disease is not quite
clear but probably individuals with certain histocompatibility
types develop IgA and IgG antibodies to gliadin which is a
fraction of gluten present in the flour (page 575).

Histologically, the early lesions of dermatitis herpeti-
formis consist of neutrophilic micro-abscesses at the tips
of papillae, producing separation or blister between the
papillary dermis and the epidermis (Fig. 26.13). The older
Figure 26.12 Bullous pemphigoid. The skin shows non-acantholytic blisters contain fair number of eosinophils causing
subepidermal bulla containing microabscess of eosinophils (arrow). confusion with bullous pemphigoid. Direct immuno-
fluorescence shows granular deposits of IgA at the
papillary tips in dermatitis herpetiformis.
Histologically, the picture is identical to that of pemphi- CHAPTER 26
gus foliaceous. 4. ERYTHEMA MULTIFORME. This is an acute, self-
limiting but recurrent dermatosis. The condition occurs due
2. PEMPHIGOID. This is a form of bullous disease affecting to hypersensitivity to certain infections and drugs, and in
skin or the mucous membranes. Three variants have been many cases, it is idiopathic. As the name suggests, the lesions
described—localised form occurring on the lower extremities; are multiform such as macular, papular, vesicular and bullous.
vesicular form consisting of small tense blisters; and vegetating Quite often, the lesions have symmetric involvement of the
form having verrucous vegetations found mainly in the axillae extremities. Stevens-Johnson syndrome is a severe, at times The Skin
and groins. fatal, form of involvement of skin and mucous membranes
of the mouth, conjunctivae, genital and perianal area.
Histologically, the characteristic distinguishing feature Another variant termed toxic epidermal necrolysis consists of
from pemphigus is the subepidermal location of the non- diffuse necrosis of the epidermis and mucosa, exposing the
acantholytic bullae. With passage of time, there is some dermis giving the skin a scalded appearance.



























Figure 26.13 Dermatitis herpetiformis. The tips of dermal papillae Figure 26.14 Erythema multiforme. There is pronounced dermo-
show neutrophilic microabscess (arrow) causing dermo-epidermal epidermal interface dermatitis. There is oedema and necrosis of
separation at tips. kertinocytes at the junction and mild lymphocytic infiltrate.

778































Figure 26.15 Psoriasis. There is regular elongation of the rete ridges with thickening of their lower portion. The papillae are elongated and
oedematous with suprapapillary thinning of epidermis. There is marked parakeratosis with diagnostic Munro microabscesses in the parakeratotic
layer.


Histologically, the changes vary according to the clinical i) Acanthosis with regular downgrowth of rete ridges
multiform stage. to almost the same dermal level with thickening of their
i) Early lesions show oedema and lymphocytic infiltrate lower portion.
at the dermoepidermal junction. The superfical dermis ii) Elongation and oedema of the dermal papillae with
SECTION III
shows perivascular lymphocytic infiltrate. broadening of their tips.
ii) Later stage is associated with migration of lymphocytes iii) Suprapapillary thinning of stratum malpighii.
upwards into the epidermis resulting in epidermal iv) Absence of granular cell layer.
necrosis and blister formation (Fig. 26.14). v) Prominent parakeratosis.
vi) Presence of Munro microabscesses in the parakeratotic
VII. SCALING DERMATOSES horny layer is diagnostic of psoriasis.

The skin surface in some chronic inflammatory dermatoses 2. LICHEN PLANUS. Lichen planus is a chronic dermatosis
is roughened due to excessive and abnormal scale formation characterised clinically by irregular, violaceous, shining, flat-
and desquamation. Common examples of this group are topped, pruritic papules. The lesions are distributed
psoriasis and lichen planus. Hereditary ichthyosis having symmetrically with sites of predilection being flexor surfaces
Systemic Pathology
similar scaly lesions has already been described. of the wrists, forearms, legs and external genitalia. Buccal
1. PSORIASIS. Psoriasis is a chronic inflammatory derma- mucosa is also involved in many cases of lichen planus.
tosis that affects about 2% of the population. It usually Histologically, the characteristic features are as under
appears first between the age of 15 and 30 years. The lesions (Fig. 26.16):
are characterised by brownish-red papules and plaques i) Marked hyperkeratosis.
which are sharply demarcated and are covered with fine, ii) Focal hypergranulosis.
silvery white scales. As the scales are removed by gentle iii) Irregular acanthosis with elongated saw-toothed rete
scrapping, fine bleeding points appear termed Auspitz sign. ridges.
Commonly involved sites are the scalp, upper back, sacral iv) Liquefactive degeneration of the basal layer.
region and extensor surfaces of the extremities, especially v) A band-like dermal infiltrate of mononuclear cells,
the knees and elbows. In about 25% of cases, peculiar pitting sharply demarcated at its lower border and closely
of nails is seen. Psoriatic arthritis resembling rheumatoid hugging the basal layer.
arthritis is produced in about 5% of cases but rheumatoid
factor is absent.
VIII. METABOLIC DISEASES OF SKIN
Histologically, the following features are observed in Skin is involved in a variety of systemic metabolic derange-
fully-developed lesions (Fig. 26.15):
ments. The examples include the following:

779































Figure 26.16 Lichen planus. There is hyperkeratosis, focal hypergranulosis and irregular acanthosis with elongated saw-toothed rete ridges.
The basal layer shows liquefactive degeneration. The upper dermis shows a band-like mononuclear infiltrate with a sharply-demarcated lower
border.


1. Amyloidosis (primary as well as secondary, page 82). Many of these conditions have been discussed elsewhere CHAPTER 26
2. Lipoid proteinosis is rare. in the book; calcinosis cutis is briefly considered below.
3. Porphyria of various types (page 42). CALCINOSIS CUTIS. There are four types of calcification
4. Calcinosis cutis in the skin:
5. Gout due to urate deposits or tophi (page 853). i) Metastatic calcinosis cutis
6. Ochronosis due to alkaptonuria (page 40). ii) Dystrophic calcinosis cutis
7. Mucinosis seen in myxoedema (page 102). iii) Idiopathic calcinosis cutis The Skin
8. Idiopathic haemochromatosis with skin pigmentation iv) Subepidermal calcified nodule
(page 41).
i) Metastatic calcinosis cutis develops due to hypercal-
caemia or hyperphosphataemia as discussed on page 53.
ii) Dystrophic calcinosis cutis results when there is
deposition of calcium salts at damaged tissue.
iii) Idiopathic calcinosis cutis resembles dystrophic type but
is not associated with any underlying disease. A special
manifestation of idiopathic calcinosis cutis is tumoral calcinosis
in which there are large subcutaneous calcified masses, often
accompanied by foreign body giant cell reaction. Calcium
may discharge from the surface of the lesion. Idiopathic
calcinosis of the scrotum consists of multiple asymptomatic
nodules of the scrotal skin (Fig. 26.17).
iv) Subepidermal calcified nodule or cutaneous calculus is a
single raised hard calcified nodule in the upper dermis.

TUMOURS AND TUMOUR-LIKE LESIONS


The skin is the largest organ of the body. Tumours and
tumour-like lesions may arise from different components of
the skin such as surface epidermis, epidermal appendages
and dermal tissues. Each of these tissues may give rise to
benign and malignant tumours as well as tumour-like lesions.
Figure 26.17 Idiopathic calcinosis cutis. The subcutaneous tissue
shows masses or nodules of calcium salt surrounded by foreign body Besides these, there is a group of conditions and lesions which
giant cells. are precancerous. Another group of tumours have their origin

780 from elsewhere in the body but are cellular migrants to the
 TABLE 26.2: Tumours and Tumour-like Lesions of the Skin.
skin. A comprehensive list of tumours and tumour-like
I. EPIDERMAL TUMOURS
lesions of the skin is presented in Table 26.2. It is beyond the
A. Benign tumours scope of this book to describe all these tumours and lesions,
1. Squamous papilloma for which the interested reader may consult specialised work
2. Seborrhoeic keratosis on dermatopathology. Some important and common
3. Fibroepithelial polyps examples of these conditions are considered here.
4. Keratoacanthoma
B. Epithelial cysts I. TUMOURS AND CYSTS OF THE EPIDERMIS
1. Epidermal cyst
2. Pilar (trichilemmal, sebaceous) cyst A. Benign Tumours
3. Dermoid cyst 1. SQUAMOUS PAPILLOMA. Squamous papilloma is a
4. Steatocystoma multiplex
benign epithelial tumour of the skin. Though considered by
C. Pre-malignant lesions many authors to include common viral warts (verrucae) and
1. Solar keratosis (actinic keratosis, senile keratosis) condyloma acuminata, true squamous papillomas differ from
2. Bowen’s disease these viral lesions. If these ‘viral tumours’ are excluded,
3. Xeroderma pigmentosum
4. Erythroplasia of Queyrat squamous papilloma is a rare tumour.
D. Malignant tumours Histologically, squamous papillomas are characterised by
1. Squamous cell carcinoma hyperkeratosis, acanthosis with elongation of rete ridges
2. Basal cell carcinoma (Rodent ulcer) and papillomatosis (Fig. 26.18). The verrucae, in addition
3. Metatypical (Basosquamous) carcinoma
to these features, have foci of vacuolated cells in the
II. ADNEXAL (APPENDAGEAL) TUMOURS acanthotic stratum malpighii, vertical tiers of
A. Tumours of hair follicles parakeratosis between the adjacent papillae and irregular
1. Trichoepithelioma (Brooke’s tumour) clumps of keratohyaline granules in the virus-infected
2. Pilomatricoma (Calcifying epithelioma of Malherbe) granular cells lying in the valleys between the papillae
3. Trichofolliculoma (page 772) .
4. Trichilemmoma
B. Tumours of sebaceous glands 2. SEBORRHEIC KERATOSIS. Seborrheic keratosis is a
SECTION III
1. Naevus sebaceous very common lesion in middle-aged adults. There may be
2. Sebaceous adenoma only one lesion, but more often these are many. The common
3. Sebaceous carcinoma locations are trunk and face. They are sharply-demarcated,
C. Tumours of sweat glands brownish, smooth-surfaced, measuring a few millimeters in
1. Eccrine tumours diameter.
i) Eccrine poroma
ii) Eccrine hidradenoma Histologically, the pathognomonic feature is a sharply-
iii) Eccrine spiradenoma demarcated exophytic tumour overlying a straight line
2. Apocrine tumours from the normal epidermis at one end of the tumour to
i) Papillary hidradenoma
ii) Cylindroma (Turban tumour) the normal epidermis at the other end. The other features
3. Sweat gland carcinoma are papillomatosis, hyperkeratosis and acanthosis as seen
in squamous cell papillomas (Fig. 26.19).
Systemic Pathology
III. MELANOCYTIC TUMOURS
1. Naevocellular naevi 3. FIBROEPITHELIAL POLYPS. Also known by other
2. Malignant melanoma
names such as ‘skin tags’, ‘acrochordons’ and ‘soft fibromas’,
IV. DERMAL TUMOURS these are the most common cutaneous lesions. They are often
1. Dermatofibroma and malignant fibrous histiocytoma multiple, soft, small (a few mm in size), bag-like tumours
2. Dermatofibrosarcoma protuberans commonly seen on the neck, trunk and axillae.
3. Xanthoma
4. Lipoma and liposarcoma Histologically, the tumours are composed of loosely-
5. Leiomyoma and leiomyosarcoma arranged fibrovascular cores with overlying hyperplastic
6. Haemangiomas, lymphangiomas and angiosarcoma epidermis (Fig. 26.20).
(page 411)
7. Glomangioma (page 412)
8. Kaposi’s sarcoma (page 415) B. Epithelial Cysts
V. CELLULAR MIGRANT TUMOURS
Various cysts in the skin may arise from downward growth
1. Mycosis fungoides of the epidermis and the appendages. These cysts often
2. Langerhans’ cell histiocytosis (page 385) contain paste-like pultaceous material containing keratin,
3. Mastocytosis
4. Lymphomas and leukaemias (page 353) sebaceous secretions and lipid-containing debris. Depending
5. Plasmacytoma (page 384) upon the structure of the cyst wall, these cysts are of various
types as under:

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Figure 26.18 Squamous cell papilloma. A, The skin surface shows a papillary growth with a pedicle while the surface is smooth. B, Microscopy
resembles verruca but differs from it by not having vacuolated koilocytic cells in stratum malpighii.


1. EPIDERMAL CYST. These intradermal or subcutaneous Histologically, the cyst wall is composed of palisading
cysts, commonly called sebaceous cysts, are common and squamous epithelial cells. These cells undergo degene-
may occur spontaneously or due to implantation of the ration towards the cyst cavity. Rupture of the cyst wall is
epidermis into the dermis or subcutis (implantation cysts). common and leads to foreign body giant cell inflammatory CHAPTER 26
Most frequent sites are the skin of face, scalp, neck and trunk. reaction. Calcification in the cyst wall is often present.
Histologically, epidermal cysts have a cyst wall composed
of true epidermis with laminated layers of keratin 3. DERMOID CYST. These are subcutaneous cysts often
(Fig. 26.21). Rupture of the cyst may incite foreign body present since birth. Dermoid cysts are more common on the
giant cell inflammatory reaction in the wall. face, along the lines of embryonic closure

2. PILAR (TRICHILEMMAL, SEBACEOUS) CYST. These Histologically, the cyst wall contains epidermis as well The Skin
cysts clinically resemble epidermal cysts but occur more as appendages such as hair follicles, sebaceous glands and
frequently on the scalp and are less common than the sweat glands (Fig. 26.22).
epidermal cysts.





























Figure 26.19 Seborrheic keratosis. The border of the elevated lesion
at the lateral margin is in a straight line from the normal uninvolved Figure 26.20 Fibroepithelial polyp (acrochordon or soft fibroma).
epidermis (arrow). The other features include papillomatosis, hyper- The epidermis is raised as polypoid mass over dense hyalinised fibrous
keratosis and acanthosis. connective tissue in the dermis.

782 in sun-exposed areas of the skin in fair-skinned elderly
people. Similar lesions may be induced by exposure to
ionising radiation, hydrocarbons and arsenicals. The
condition is considered to be a forerunner of invasive
squamous cell and/or basal cell carcinoma. Clinically, the
lesions are tan-brown, erythematous, about 1 cm in diameter
with rough, sandpaper-like surface and are seen more
commonly on the dorsum of the hands and on the balded
portion of the skin.
Histologically, solar keratoses are squamous cell
carcinoma in situ with the following characteristic features:
i) Considerable hyperkeratosis.
ii) Marked acanthosis.
iii) Dyskeratosis and dysplasia of the epidermal cells
showing features such as hyperchromatism, loss of
polarity, pleomorphism and increased number of mitotic
figures.
iv) Non-specific chronic inflammatory cell infiltrate in the
upper dermis encroaching upon the basement membrane
of the epidermis.
2. BOWEN’S DISEASE. Bowen’s disease is also a
Figure 26.21 Epidermal inclusion cyst. The cyst wall is composed carcinoma in situ of the entire epidermis but differs from solar
of all layers of the epidermis and has laminated layers of keratin towards keratosis in having solitary lesion often that may occur on
the lumen of the cyst. sun-exposed as well as sun-unexposed skin. The condition
4. STEATOCYSTOMA MULTIPLEX. This is an inherited may occur anywhere on the skin but is found more often on
autosomal dominant disorder having multiple cystic nodules, the trunk, buttocks and extremities. Clinically, the lesions of
1-3 cm in size. They are more common in the axillae, sternum Bowen’s disease are sharply circumscribed, rounded,
and arms. reddish-brown patches which enlarge slowly.
SECTION III
Histologically, the characteristic features are as under
Histologically, the cyst walls are composed of several (Fig. 26.23):
layers of epithelial cells and contain lobules of sebaceous i) Marked hyperkeratosis.
glands in the cyst wall.

C. Pre-malignant Lesions
1. SOLAR KERATOSIS (ACTINIC KERATOSIS, SENILE
KERATOSIS). Solar (sun-induced) or actinic (induced by a
variety of rays) keratoses are the multiple lesions occurring

Systemic Pathology






















Figure 26.23 Bowen’s disease. The epidermis is thick with loss of
rete ridges but the normal base to surface maturation of epidermal layers
Figure 26.22 Dermoid cyst. In addition to features of epidermal is effaced. Instead, there are bizarre atypical squamous cells but the
cyst, dermoid cyst has adnexal structures in the cyst wall (i.e. hair follicles, border between the epidermis and dermis is intact i.e. the basement
sweat and sebaceous glands). membrane is not breached.

ii) Pronounced parakeratosis. Cancer of scrotal skin in chimney-sweeps was the first 783
iii) Marked epidermal hyperplasia with disappearance of cancer in which an occupational carcinogen (soot) was impli-
dermal papillae. cated. ‘Kangari cancer’ of the skin of inner side of thigh and
iv) Scattered bizarre dyskeratotic cells distributed lower abdomen common in natives of Kashmir is another
throughout the epidermis. example of skin cancer due to chronic irritation (Kangari is
an earthenware pot containing glowing charcoal used by
Bowen’s disease, unlike solar keratosis which invariably Kashmiris close to their abdomen to keep them warm).
leads to invasive cancer, may remain confined to the surface Although squamous carcinomas can occur anywhere on
for many years. the skin, most common locations are the face, pinna of the
3. XERODERMA PIGMENTOSUM. This condition is a ears, back of hands and mucocutaneous junctions such as
hypersensitivity of the skin to sunlight that is determined on the lips, anal canal and glans penis. Cutaneous squamous
by a recessive gene. The disorder may lead to multiple carcinoma arising in a pre-existing inflammatory and
malignancies of the skin such as basal cell carcinoma, degenerative lesion has a higher incidence of developing
squamous cell carcinoma and malignant melanoma. metastases.
Xeroderma pigmentosum has already been described under MORPHOLOGIC FEATURES. Grossly, squamous
genetic dermatoses. carcinoma of the skin and squamous-lined mucosa can
have one of the following two patterns (Fig. 26.24):
D. Malignant Tumours
i) More commonly, an ulcerated growth with elevated and
1. SQUAMOUS CELL CARCINOMA. Squamous cell indurated margin is seen.
carcinoma may arise on any part of the skin and mucous ii) Less often, a raised fungating or polypoid verrucous
membranes lined by squamous epithelium but is more likely lesion without ulceration is found.
to occur on sun-exposed parts in older people. Various Microscopically, squamous cell carcinoma is an invasive
predisposing conditions include the following: carcinoma of the surface epidermis characterised by the
i) Xeroderma pigmentosum following features (Fig. 26.25):
ii) Solar keratosis CHAPTER 26
iii) Chronic inflammatory conditions such as chronic ulcers i) There is irregular downward proliferation of
and draining osteomyelitis epidermal cells into the dermis.
iv) Old burn scars (Marjolin’s ulcers) ii) Depending upon the grade of malignancy, the masses
v) Chemical burns of epidermal cells show atypical features such as variation
vi) Psoriasis in cell size and shape, nuclear hyperchromatism, absence
vii) HIV infection of intercellular bridges, individual cell keratinisation and
viii) Ionising radiation occurrence of atypical mitotic figures. The Skin
ix) Industrial carcinogens (coal tars, oils etc) iii) Better-differentiated squamous carcinomas have
x) In the case of cancer of oral cavity, chewing betel nuts whorled arrangement of malignant squamous cells
and tobacco.





























Figure 26.24 Squamous cell carcinoma. A, Main macroscopic
patterns showing ulcerated and fungating polypoid growth. B, The skin
surface on the sole of the foot shows a fungating and ulcerated growth.
On cutting, the growth is both exophytic and endophytic and is chalky
white in colour.

784
























Figure 26.25 Microscopic features of well-differentiated squamous cell carcinoma. The dermis is invaded by downward proliferating epidermal
masses of cells which show atypical features. A few horn pearls with central laminated keratin are present. There is inflammatory reaction in the
dermis between the masses of tumour cells.

undifferentiated, keratinising, non-keratinising, spindle cell
forming horn pearls. The centres of these horn pearls may
contain laminated, keratin material. type etc.
iv) Higher grades of squamous carcinomas, however, 2. BASAL CELL CARCINOMA (RODENT ULCER).
have fewer or no horn pearls and may instead have highly Typically, the basal cell carcinoma is a locally invasive, slow-
atypical cells. growing tumour of middle-aged that rarely metastasises. It
v) An uncommon variant of squamous carcinoma may occurs exclusively on hairy skin, the most common location
have spindle-shaped tumour cells (spindle cell carcinoma). (90%) being the face, usually above a line from the lobe of
SECTION III
vi) Adenoid changes may be seen in a portion of squa- the ear to the corner of the mouth (Fig. 26.26). Basal cell
mous cell carcinoma (adenoid squamous cell carcinoma). carcinoma is seen more frequently in white-skinned people
vii) Verrucous carcinoma is a low-grade squamous cell and in those who have prolonged exposure to strong sunlight
carcinoma in which the superficial portion of the tumour like in those living in Australia and New Zealand (page 221).
resembles verruca (hyperkeratosis, parakeratosis,
acanthosis and papillomatosis) but differs from it in MORPHOLOGIC FEATURES. Grossly, the most
having downward proliferation into deeper portion of the common pattern is a nodulo-ulcerative basal cell
tumour. carcinoma in which a slow-growing small nodule
undergoes central ulceration with pearly, rolled margins.
viii) All variants of squamous cell carcinoma show inflam-
matory reaction between the collections of tumour cells, The tumour enlarges in size by burrowing and by
while in pseudocarcinomatous hyperplasia there is permea- destroying the tissues locally like a rodent and hence the
Systemic Pathology
tion of the epithelial proliferations by inflammatory cells.

A system of grading of squamous cell carcinoma called
Broders’ grading has been proposed that depends upon the
percentage of anaplastic cells present in a tumour (page 204).
Accordingly, following 4 grades are recognised:
Grade I : Less than 25% anaplastic cells
Grade II : 25-50% anaplastic cells
Grade III : 50-75% anaplastic cells
Grade IV : More than 75% anaplastic cells.
However, it is important to take into account other factors
for grading the tumour such as: the degree of atypicality of
the tumour cells, presence or absence of keratinisation and
the depth of penetration of the lesion. Therefore, based on
combination of these factors, it is customary with pathologists
to label squamous cell carcinomas with descriptive terms Figure 26.26 Common location and macroscopic appearance of
such as: well-differentiated, moderately-differentiated, basal cell carcinoma (rodent ulcer).