Textbook of Pathology, 6th Edition

hyperphosphataemia and renal tubular acidosis. Most  TABLE 22.14: Clinical Classification of Hypertension*. 685
commonly, it develops as a complication of severe
Systolic
hypercalcaemia such as due to hyperparathyroidism, Category (mmHg) Diastolic
(mmHg)
hypervitaminosis D, excessive bone destruction in metastatic
malignancy, hyperthyroidism, excessive calcium intake such Normal < 120 and < 80
as in milk-alkali syndrome and sarcoidosis (page 53). Prehypertension 120-139 or 80-89
Clinically, patients of hypercalcaemia and nephrocalcinosis Hypertension
may have renal colic, band keratopathy due to calcium Stege 1 140-159 or 90-99
Stege 2
>160
or >100
deposits in the cornea, visceral metastatic calcification,
polyuria and renal failure. Isolated systolic hypertension >140 and < 90
Malignant hypertension > 200 > 140
MORPHOLOGIC FEATURES. Nephrocalcinosis due to (sudden onset) (sudden onset)
hypercalcaemia characteristically shows deposition of *Chobanian et al, JAMA, 2003.
calcium in the tubular epithelial cells in the basement
membrane, within the mitochondria and in the cytoplasm. diastolic blood pressure above normal levels. Recently,
These concretions may produce secondary tubular atro- criteria for normal blood pressure, prehypertension and
phy, interstitial fibrosis and nonspecific chronic inflamm- hypertension (stage 1 and stage 2) have been laid by the
ation in the interstitium. As the calcification occurs National Institutes of Health (NIH), US (Table 22.14).
intracellularly, radiological evidence is usually not present According to this criteria, normal cut-off values for systolic
until fairly late in the disease. The calcium deposits are and diastolic blood pressure are taken as < 120 and < 80
first visible as small opacities in the renal papillae. mmHg respectively. As per this criteria, arterial or systemic
hypertension in adults is defined clinically as persistently
elevated systolic blood pressure of 140-159 mmHg, or
RENAL VASCULAR DISEASES
diastolic pressure of 90-99 mmHg as stage 1 hypertension,
Renal blood vessels which enormously perfuse the kidney and corresponding values above 160 or above 100 mmHg
are affected secondarily in majority of renal diseases. Renal as stage 2 hypertension. Cases falling between upper normal CHAPTER 22
blood flow is controlled by systemic and local haemo- values for systolic and diastolic blood pressure (i.e. above
dynamic, hormonal and intrinsic intra-renal mechanisms. 120/80 mmHg) and those for stage 1 hypertension (120-
Diseases which disturb these controlling mechanisms give 139/80-89 mmHg) are grouped under prehypertension
rise to primary renal vascular lesions. These diseases are as requiring monitoring anf follow-up. The diastolic pressure
under: is often considered more significant. Since blood pressure
I. Most importantly, hypertensive vascular disease and its varies with many factors such as age of the patient, exercise,
consequent renal manifestations in the form of benign and emotional disturbances like fear and anxiety, it is important
malignant nephrosclerosis. to measure blood pressure at least twice during two
II. Thrombotic microangiopathy. separate examinations under least stressful conditions.
Hypertension is generally classified into 2 types:
III. Renal cortical necrosis.
1. Primary or essential hypertension in which the cause of
IV. Renal infarcts.
increase in blood pressure is unknown. Essential
Renal infarcts are already described in Chapter 5; other hypertension constitutes about 80-95% patients of
conditions are discussed here. hypertension. The Kidney and Lower Urinary Tract
2. Secondary hypertension, in which the increase in blood
HYPERTENSIVE VASCULAR DISEASE
pressure is caused by diseases of the kidneys, endocrines or
An elevated arterial blood pressure is a major health problem, some other organs. Secondary hypertension comprises
particularly in developed countries. A persistent and remaining 5-20% cases of hypertension.
sustained high blood pressure has damaging effects on the According to the clinical course, both essential and
heart (e.g. hypertensive heart disease, Chapter 16), brain (e.g. secondary hypertension may be benign or malignant.
cerebrovascular accident or stroke, Chapter 30) and kidneys Benign hypertension is moderate elevation of blood
(benign and malignant nephrosclerosis). pressure and the rise is slow over the years. About 90-95%
patients of hypertension have benign hypertension.
Definition and Classification
Malignant hypertension is marked and suden increase
Hypertension is a common disease in industrialised count- of blood pressure to 200/140 mmHg or more in a known
ries and accounts for 6% of death worldwide. Epidemiologic case of hypertension or in a previously normotensive
studies have revealed that with elevation in systolic and individual; the patients develop papilloedema, retinal
diastolic blood pressure above normal in adults, there is a haemorrhages and hypertensive encephalopathy. Less than
continuous increased risk of cardiovascular disease, stroke 5% of hypertensive patients develop malignant hypertension
and renal disease—cardiovascular risk doubles with every and life expectancy after diagnosis in these patients is
20 mmHg increase in systolic and 10 mmHg increase in generally less than 2 years if not treated effectively.

686 contributory role of other independent factors like cigarette
 TABLE 22.15: Etiologic Classification of Hypertension.
smoking, elevated serum cholesterol, glucose intolerance and
A. ESSENTIAL HYPERTENSION (90%)
obesity.
1. Genetic factors iv) Other risk factors. Other factors which alter the prognosis
2. Racial and environmental factors in hypertension include: smoking, excess of alcohol intake,
3. Risk factors modifying the course
diabetes mellitus, persistently high diastolic pressure above
B. SECONDARY HYPERTENSION (10%)
normal and evidence of end-organ damage (i.e. heart, eyes,
1. Renal kidney and nervous system).
i) Renovascular
ii) Renal parenchymal diseases The pathogenetic mechanism in essential hypertension is
2. Endocrine explained by many theories. These are as under:
i) Adrenocortical hyperfunction 1. High plasma level of catecholamines.
ii) Hyperparathyroidism 2. Increase in blood volume i.e. arterial overfilling (volume
iii) Oral contraceptives
3. Coarctation of Aorta hypertension) and arteriolar constriction (vasoconstrictor
4. Neurogenic hypertension).
3. Increased cardiac output.
4. Low-renin essential hypertension found in approximately
Etiology and Pathogenesis 20% patients due to altered responsiveness to renin release.
The etiology and pathogenesis of secondary hypertension 5. High renin essential hypertension seen in about 15% cases
that comprises less than 10% cases has been better due to decreased adrenal responsiveness to angiotensin II.
understood, whereas the mechanism of essential SECONDARY HYPERTENSION. Though much less
hypertension that constitutes about 90% of cases remains common than essential hypertension, mechanisms under-
largely obscure. In general, normal blood pressure is lying secondary hypertension with identifiable cause have
regulated by 2 haemodynamic forces—cardiac output and total been studied more extensively. Based on the etiology, these
peripheral vascular resistance. Factors which alter these two are described under four headings: renal hypertension,
factors result in hypertension. The role of kidney in endocrine hypertension, hypertension associated with
hypertension, particularly in secondary hypertension, by coarctation of aorta and neurogenic causes.
elaboration of renin and subsequent formation of angiotensin
II, is well established (renin-angiotensin system). 1. RENAL HYPERTENSION. Hypertension produced by
SECTION III
With this background knowledge, we next turn to the renal diseases is called renal hypertension. Renal
mechanisms involved in the two forms of hypertension hypertension is subdivided into 2 groups:
(Table 22.15). i) Renal vascular hypertension e.g. in occlusion of a major
renal artery, pre-eclampsia, eclampsia, polyarteritis nodosa
ESSENTIAL (PRIMARY) HYPERTENSION. By definition, and fibromuscular dysplasia of renal artery.
the cause of essential hypertension is unknown but a number
of factors are related to its development. These are as under: ii) Renal parenchymal hypertension e.g. in various types of
glomerulonephritis, pyelonephritis, interstitial nephritis,
1. Genetic factors. The role of heredity in the etiology of diabetic nephropathy, amyloidosis, polycystic kidney disease
essential hypertension has long been suspected. The and renin-producing tumours.
evidences in support are the familial aggregation, occurrence In either case, renal hypertension can be produced by
of hypertension in twins, epidemiologic data, experimental one of the following 3 inter-related pathogenetic mechanisms:
animal studies and identification of hypertension
Systemic Pathology
susceptibility gene (angiotensinogen gene). a) Activation of renin-angiotensin system. Renin is a
proteolytic enzyme produced and stored in the granules of
2. Racial and environmental factors. Surveys in the US the juxtaglomerular cells surrounding the afferent arterioles
have revealed higher incidence of essential hypertension in of glomerulus (page 651). The release of renin is stimulated
African Americans than in whites. A number of environ- by renal ischaemia, sympathetic nervous system stimulation,
mental factors have been implicated in the development of depressed sodium concentration, fluid depletion and
hypertension including salt intake, obesity, skilled decreased potassium intake. Released renin is transported
occupation, higher living standards and individuals under through blood stream to the liver where it acts upon substrate
high stress. angiotensinogen, an α -globulin synthesised in the liver, to
2
3. Risk factors modifying the course of essential hyper- form angiotensin I, a decapeptide. Angiotensin I is converted
tension. There is sufficient evidence to show that the course into angiotensin II, an octapeptide, by the action of convertase
of essential hypertension that begins in middle life is in the lungs. Angiotensin II is the most potent naturally-
modified by a number of factors. These are as under: occurring vasoconstrictor substance and its pressor action is
i) Age. Younger the age at which hypertension is first noted mainly attributed to peripheral arteriolar vasoconstriction.
but left untreated, lower the life expectancy. The other main effect of angiotensin II is to stimulate the
ii) Sex. Females with hypertension appear to do better than adrenal cortex to secrete aldosterone that promotes
males. reabsorption of sodium and water.
iii) Atherosclerosis. Accelerated atherosclerosis invariably Thus, the renin-angiotensin system is concerned mainly
accompanies essential hypertension. This could be due to with 3 functions:

2. ENDOCRINE HYPERTENSION. A number of hormonal 687
secretions may produce secondary hypertension. These are:
i) Adrenal gland—e.g. in primary aldosteronism, Cushing’s
syndrome, adrenal virilism and pheochromocytoma.
ii) Parathyroid gland—e.g. hypercalcaemia in hyperpara-
thyroidism.
iii) Oral contraceptives—Oestrogen component in the oral
contraceptives stimulates hepatic synthesis of renin substrate.

3. COARCTATION OF AORTA. Coarctation of the aorta
causes systolic hypertension in the upper part of the body
due to constriction itself (Chapter 15). Diastolic hypertension
results from changes in circulation.
4. NEUROGENIC. Psychogenic, polyneuritis, increased
intracranial pressure and section of spinal cord are all
uncommon causes of secondary hypertension.

EFFECTS OF HYPERTENSION

Systemic hypertension causes major effects in three main
organs—heart and its blood vessels, nervous system, and
kidneys. The renal effects in the form of benign and malignant
nephrosclerosis are discussed below, whereas hypertensive
effects on other organs are described elsewhere in the
respective chapters. An important and early clinical marker
for renal injury from hypertension and risk factor for CHAPTER 22
cardiovascular disease is macroalbuminuria (i.e. albuminuria
> 150 mg/day or random urine albumin/creatinine ratio of
>300 mg/gm creatinine), or microalbuminuria estimated by
radioimmunoassay (i.e. microalbumin 30-300 mg/day or
random urine microalbumin/creatinine ratio of
30-300 mg/gm creatinine).
Figure 22.34 The renin-angiotensin mechanism.
Benign Nephrosclerosis
i) Control of blood pressure by altering plasma concen- Benign nephrosclerosis is the term used to describe the
tration of angiotensin II and aldosterone. kidney of benign phase of hypertension. Mild benign
ii) Regulation of sodium and water content. nephrosclerosis is the most common form of renal disease in
iii) Regulation of potassium balance. persons over 60 years of age but its severity increases in the
The renin-angiotensin mechanism is summarised in presence of hypertension and diabetes mellitus. The Kidney and Lower Urinary Tract
Fig. 22.34.
b) Sodium and water retention. Blood volume and cardiac MORPHOLOGIC FEATURES. Grossly, both the kidneys
output, both of which have a bearing on blood pressure, are are affected equally and are reduced in size and weight,
regulated by blood levels of sodium which is significant for often weighing about 100 gm or less. The capsule is often
maintaining extracellular fluid volume. Blood concentration adherent to the cortical surface. The surface of the kidney
of sodium is regulated by 3 mechanisms: is finely granular and shows V-shaped areas of scarring.*
i) Release of aldosterone from activation of renin-angiotensin The cut surface shows firm kidney and narrowed cortex
system, as already explained. (Fig. 22.35).
ii) Reduction in GFR due to reduced blood flow as occurs in Microscopically, there are primarily diffuse vascular
reduced renal mass or renal artery stenosis. This results in changes which produce parenchymal changes secondarily
proximal tubular reabsorption of sodium.
iii) Release of atriopeptin hormone from atria of the heart in
response to volume expansion. These peptides cause *The various acquired causes of ‘small contracted kidney’ and their
increased GFR and inhibit sodium reabsorption. characteristic gross macroscopic appearance may be recollected here.
These are: 1. Chronic GN (granular appearance); 2. Chronic pyelonephritis
c) Release of vasodepressor material. A number of vaso- (U-shaped scars); and 3. Benign nephrosclerosis (V-shaped scars).
depressor materials and antihypertensives counterbalance Although granular, U- and V-shaped scars correspond to the respective
the vasopressor effect of angiotensin II. These substances macroscopic patterns, acronym to remember is: ‘granular’ for glomerular
scars of chronic GN; ‘U-scars’ for uneven scars of chronic pyelonephritis;
include: prostaglandins (PGE2, PGF2, PGA or medullin) and ‘V-scars’ for vascular scars of benign nephrosclerosis. Less common
released from interstitial cells of the medulla, urinary causes are: amyloidosis of the kidney, myeloma kidney and diabetic
kallikrein-kinin system and platelet-activating factor. nephropathy.

688





















Figure 22.35 Small, contracted kidney in chronic hypertension
(benign nephrosclerosis). The kidney is small and contracted. The capsule
is adherent to the cortex and has granular depressed scars on the surface.




as a result of ischaemia. The histologic changes are, thus, and have finely granular surface. However, the kidneys
described as vascular and parenchymal (Fig. 22.36,A): of a patient who develops malignant hypertension in pure
i) Vascular changes: Changes in blood vessels involve form are enlarged, oedematous and have petechial
arterioles and arteries up to the size of arcuate arteries. haemorrhages on the surface producing so called ‘flea-
There are 2 types of changes in these blood vessels: bitten kidney’.* Cut surface shows red and yellow mottled
a) Hyaline arteriolosclerosis that results in homogeneous appearance (Fig. 22.37).
and eosinophilic thickening of the wall of small blood Microscopically, most commonly the changes are
vessels. superimposed on benign nephrosclerosis. These changes
b) lntimal thickening due to proliferation of smooth muscle are as under (Fig. 22.36,B):
SECTION III
cells in the intima. i) Vascular changes: These are more severe and involve
ii) Parenchymal changes: As a consequence of ischaemia, the arterioles. The two characteristic vascular changes seen
there is variable degree of atrophy of parenchyma. This are as under:
includes: glomerular shrinkage, deposition of collagen in a) Necrotising arteriolitis develops on hyaline arterio-
Bowman’s space, periglomerular fibrosis, tubular atrophy losclerosis. The vessel wall shows fibrinoid necrosis, a few
and fine interstitial fibrosis. acute inflammatory cells and small haemorrhages.
b) Hyperplastic intimal sclerosis or onionskin proliferation is
CLINICAL FEATURES. There is variable elevation of the characterised by concentric laminae of proliferated smooth
blood pressure with headache, dizziness, palpitation and muscle cells, collagen and basement membranes.
nervousness. Eye ground changes may be found but ii) Ischaemic changes: The effects of vascular narrowing
papilloedema is absent. Renal function tests and urine on the parenchyma include tubular loss, fine interstitial
Systemic Pathology
examination are normal in early stage. In long-standing cases, fibrosis and foci of infarction necrosis.
there may be mild proteinuria with some hyaline or granular
casts. Rarely, renal failure and uraemia may occur. CLINICAL FEATURES. The patients of malignant
nephrosclerosis have malignant or accelerated hypertension
Malignant Nephrosclerosis with blood pressure of 200/140 mmHg or higher. Headache,
dizziness and impaired vision are commonly found. The
Malignant nephrosclerosis is the form of renal disease that presence of papilloedema distinguishes malignant from
occurs in malignant or accelerated hypertension. Malignant benign phase of hypertension. The urine frequently shows
nephrosclerosis is uncommon and usually occurs as a haematuria and proteinuria. Renal function tests show
superimposed complication in 5% cases of pre-existing deterioration during the course of the illness. Azotaemia
benign essential hypertension or in those having secondary (high BUN and serum creatinine) and uraemia develop soon
hypertension with identifiable cause such as in chronic renal if malignant hypertension is not treated aggressively.
diseases. However, the pure form of disease also occurs, Approximately 90% of patients die within one year from
particularly at younger age with preponderance in males. causes such as uraemia, congestive heart failure and
cerebrovascular accidents.
MORPHOLOGIC FEATURES. Grossly, the appearance
of the kidney varies. In a case of malignant hypertension
superimposed on pre-existing benign nephrosclerosis, the *Recall the other causes of flea-bitten kidney: acute post-streptococcal GN,
kidneys are small in size, shrunken and reduced in weight rapidly progressive GN, haemolytic-uraemic syndrome, thrombotic
thrombocytopenic purpura and Henoch-Schonlein purpura.

689











































Figure 22.36 Microscopic changes in kidney in hypertension. A, CHAPTER 22
Benign nephrosclerosis. The vascular changes are hyaline
arteriolosclerosis and intimal thickening of small blood vessels in the
glomerular tuft. The parenchymal changes include sclerosed glomeruli,
tubular atrophy and fine interstitial fibrosis. B, Malignant nephrosclerosis.
The vascular changes are necrotising arteriolitis and hyperplastic intimal
sclerosis or onion-skin proliferation. The parenchymal changes are tubular
loss, fine interstitial fibrosis and foci of infarction necrosis.



THROMBOTIC MICROANGIOPATHY The common clinical manifestations include microangio- The Kidney and Lower Urinary Tract
pathic haemolytic anaemia, thrombocytopenia, DIC, and
Thrombotic renal disease encompasses a group of diseases eventually renal failure.
having in common the formation of thrombi composed by
platelets and fibrin in arterioles and glomeruli of the kidney PATHOGENESIS In all such cases, endothelial injury
and culminating clinically in acute renal failure. Causes of appears to be the trigger for vascular changes. The injured
thrombotic microangiopathy of renal microvasculature are endothelial surface causes the following effects:
listed in Table 22.16. Passage of plasma constituents to the subendothelial zone
of microvasculature.
 TABLE 22.16: Causes of Thrombotic Microangiopathy. Promotes thrombosis.
1. Infections MORPHOLOGIC FEATURES. The lesions closely
(E.coli, Shigella, Pseudomonas) resemble those of malignant nephrosclerosis. The features
2. Drugs are as under:
(e.g. mitomycin, cisplatin, cyclosporine)
3. Autoimmune disease Fibrinoid necrosis of arterioles.
(scleroderma, SLE) Thrombi in renal microvasculature.
4. Thrombotic thrombocytopenic purpura Oedema of intima of arterioles.
5. Haemolytic-uraemic syndrome Consolidation, necrosis and congestion of glomeruli.
6. Pregnancy and pre-eclampsia If the renal lesions are massive, the prognosis is generally
7. Malignant hypertension lethal.

690




























Figure 22.37 Malignant nephrosclerosis. The kidney is enlarged in
size and weight. The cortex shows characteristic ‘flea bitten kidney’ due
to tiny petechial haemorrhages on the surface.



RENAL CORTICAL NECROSIS common and important cause of obstructive uropathy,
urolithiasis, is given below.
Renal cortical necrosis is infarction of renal cortex varying
from microscopic foci to a situation where most of the renal NEPHROLITHIASIS
cortex is destroyed. The medulla, the juxtamedullary cortex
SECTION III
and a rim of cortex under the capsule are usually spared. Nephrolithiasis or urolithiasis is formation of urinary calculi
The condition develops most commonly as an obstetrical at any level of the urinary tract. Urinary calculi are worldwide
emergency (e.g. in eclampsia, pre-eclampsia, premature in distribution but are particularly common in some
separation of the placenta). Other causes include septic shock, geographic locations such as in parts of the United States,
poisoning, severe trauma etc. South Africa, India and South-East Asia. It is estimated that
The lesions may be present focally, patchily or diffusely. approximately 2% of the population experiences renal stone
The gross and microscopic characteristics of infarcts of cortex disease at sometime in their life with male-female ratio of
are present. Patients present with sudden oliguria or anuria 2:1. The peak incidence is observed in 2nd to 3rd decades of
and haematuria. If the process has involved renal cortex life. Renal calculi are characterised clinically by colicky pain
extensively, acute renal failure and uraemia develop and
prognosis is grave.   TABLE 22.17: Causes of Obstructive Uropathy.
Systemic Pathology
A. INTRALUMINAL
OBSTRUCTIVE UROPATHY
1. Calculi
Obstruction in the urinary tract is common and important 2. Tumours (e.g. cancer of kidney and bladder)
because it increases the susceptibility to infection and stone 3. Sloughed renal papilla
formation. Obstruction can occur at any age and in either 4. Blood clots
Foreign body
5.
sex. The cause of obstruction may lie at any level of the
urinary tract—renal pelvis, ureters, urinary bladder and B. INTRAMURAL
urethra. The obstruction at any of these anatomic locations 1. Pelvi-ureteric junction (PUJ) obstruction
may be intraluminal, intramural or extramural. Important 2. Vesicoureteric obstruction
Urethral stricture
3.
causes are listed in Table 22.17 and illustrated in Fig. 22.38. 4. Urethral valves
The obstruction may be unilateral or bilateral, partial or 5. Inflammation (e.g. phimosis, cystitis etc)
complete, sudden or insidious. Complete bilateral 6. Neuromuscular dysfunction
obstruction may result in irreversible renal failure, whereas C. EXTRAMURAL
long-standing chronic partial obstruction may cause various 1. Pregnant uterus
functional abnormalities and anatomic changes. There are 2. Retroperitoneal fibrosis
three important anatomic sequelae of obstruction, namely: 3. Tumours (e.g. carcinoma of cervix, rectum, colon, caecum etc)
hydronephrosis, hydroureter and hypertrophy of the bladder. 4. Prostatic enlargement, prostatic carcinoma and prostatitis
Before describing these conditions, an account of the most 5. Trauma

Pathogenesis. The mechanism of calcium stone formation is 691
explained on the basis of imbalance between the degree of
supersaturation of the ions forming the stone and the
concentration of inhibitors in the urine. Most likely site where
the crystals of calcium oxalate and/or calcium phosphate
are precipitated is the tubular lining or around some
fragment of debris in the tubule acting as nidus of the stone.
The stone grows, as more and more crystals are deposited
around the nidus. A number of other predisposing factors
contributing to formation of calcium stones are alkaline
urinary pH, decreased urinary volume and increased
excretion of oxalate and uric acid.
Morphology. Calcium stones are usually small (less than a
centimeter), ovoid, hard, with granular rough surface. They
are dark brown due to old blood pigment deposited in them
as a result of repeated trauma caused to the urinary tract by
these sharp-edged stones.
2. MIXED (STRUVITE) STONES. About 15% of urinary
calculi are made of magnesium-ammonium-calcium
phosphate, often called struvite; hence mixed stones are also
called as ‘struvite stones’ or ‘triple phosphate stones’.
Etiology. Struvite stones are formed as a result of infection
of the urinary tract with urea-splitting organisms that
produce urease such as by species of Proteus, and occasionally
Klebsiella, Pseudomonas and Enterobacter. These are, therefore, CHAPTER 22
also known as infection-induced stones. However, E. coli does
not form urease.
Figure 22.38 Causes of obstructive uropathy. Morphology. Struvite stones are yellow-white or grey. They
tend to be soft and friable and irregular in shape. ‘Staghorn
stone’ which is a large, solitary stone that takes the shape of
(renal colic) as they pass down along the ureter and manifest the renal pelvis where it is often formed is an example of
by haematuria. struvite stone (Fig. 22.39).


Types of Urinary Calculi
There are 4 main types of urinary calculi—calcium
containing, mixed (struvite), uric acid and cystine stones, and
a few rare types (Table 22.18). The Kidney and Lower Urinary Tract
1. CALCIUM STONES. Calcium stones are the most
common comprising about 75% of all urinary calculi. They
may be pure stones of calcium oxalate (50%) or calcium
phosphate (5%), or mixture of calcium oxalate and calcium
phosphate (45%).
Etiology. Etiology of calcium stones is variable.
i) About 50% of patients with calcium stones have idiopathic
hypercalciuria without hypercalcaemia.
ii) Approximately 10% cases are associated with hyper-
calcaemia and hypercalciuria, most commonly due to hyper-
parathyroidism, or a defect in the bowel (i.e. absorptive
hypercalciuria), or in the kidney (i.e. renal hypercalciuria).
iii) About 15% of patients with calcium stones have
hyperuricosuria with a normal blood uric acid level and without
any abnormality of calcium metabolism. Figure 22.39 Staghorn renal stone with chronic pyelonephritis.The
iv) In about 25% of patients with calcium stones, the cause kidney is enlarged and heavy. The capsule is adherent to the cortex and
is unknown as there is no abnormality in urinary excretion has irregular scars on the surface. Sectioned surface shows dilated pelvi-
calyceal system with atrophied and thin peripheral cortex. The pelvis of
of calcium, uric acid or oxalate and is referred to as ‘idiopathic the kidney contains a single, large, sof t yellow white stone t aking the
calcium stone disease’. contour of the pelvi-calyceal system (arrow).

692
  TABLE 22.18: Salient Features of Urinary Calculi.
Type Incidence Etiology Pathogenesis
1. Calcium stones 75% Hypercalciuria with or Supersaturation of ions in urine, alkaline
without hypercalcaemia; pH of urine; low urinary volume, oxaluria
idiopathic and hyperuricosuria
2. Mixed (struvite) 15% Urinary infection with urea- Alkaline urinary pH produced by ammonia
stones splitting organisms like from splitting of urea by bacterially
Proteus produced urease
3. Uric acid 6% Hyperuricosuria with or without Acidic urine (pH below 6) decreases the
stones hyperuricaemia (e.g. in solubility of uric acid in urine and favours
primary and secondary gout) its precipitation
4. Cystine stones 2% Genetically-determined Cystinuria containing least soluble cystine
defect in cystine transport precipitates as cystine crystals
5. Other types < 2% Inherited abnormalities of Xanthinuria
amino acid metabolism


3. URIC ACID STONES. Approximately 6% of urinary outflow of urine (see Fig. 22.38). Hydronephrosis develops if
calculi are made of uric acid. Uric acid calculi are radiolucent one or both the pelviureteric sphincters are incompetent, as
unlike radio-opaque calcium stones. otherwise there will be dilatation and hypertrophy of the
Etiology. Uric acid stones are frequently formed in cases with urinary bladder but no hydronephrosis. Hydroureter nearly
hyperuricaemia and hyperuricosuria such as due to primary always accompanies hydronephrosis. Hydronephrosis may
gout or secondary gout due to myeloproliferative disorders be unilateral or bilateral.
(e.g. in leukaemias), especially those on chemotherapy, and
administration of uricosuric drugs (e.g. salicylates, Unilateral Hydronephrosis
probenacid). Other factors contributing to their formation are This occurs due to some form of ureteral obstruction at the
acidic urinary pH (below 6) and low urinary volume. level of pelviureteric junction (PUJ). The causes are:
Pathogenesis. The solubility of uric acid at pH of 7 is 200 1. Intraluminal e.g. a calculus in the ureter or renal pelvis.
SECTION III
mg/dl while at pH of 5 is 15 mg/dl. Thus, as the urine 2. Intramural e.g. congenital PUJ obstruction, atresia of
becomes more acidic, the solubility of uric acid in urine ureter, inflammatory stricture, trauma, neoplasm of ureter
decreases and precipitation of uric acid crystals increases or bladder.
favouring the formation of uric acid stones. Hyperuricosuria
is the most important factor in the production of uric acid 3. Extramural e.g. obstruction of upper part of the ureter
stones, while hyperuricaemia is found in about half the cases. by inferior renal artery or vein, pressure on ureter from
outside such as carcinoma cervix, prostate, rectum, colon or
Morphology. Uric acid stones are smooth, yellowish-brown, caecum and retroperitoneal fibrosis.
hard and often multiple. On cut section, they show laminated
structure.
Bilateral Hydronephrosis
4. CYSTINE STONES. Cystine stones comprise less than This is generally the result of some form of urethral obstruc-
Systemic Pathology
2% of urinary calculi.
tion but can occur from the various causes listed above if the
Etiology. Cystine stones are associated with cystinuria due lesions involve both sides. Based on this, hydronephrosis may
to a genetically-determined defect in the transport of cystine be of following types:
and other amino acids across the cell membrane of the renal 1. Congenital e.g. atresia of the urethral meatus, congenital
tubules and the small intestinal mucosa.
posterior urethral valve.
Pathogenesis. The resultant excessive excretion of cystine 2. Acquired e.g. bladder tumour involving both ureteric
which is least soluble of the naturally-occurring amino acids orifices, prostatic enlargement, prostatic carcinoma and
leads to formation of crystals and eventually cystine calculi.
prostatitis, bladder neck stenosis, inflammatory or traumatic
Morphology. Cystine stones are small, rounded, smooth and urethral stricture and phimosis.
often multiple. They are yellowish and waxy.
5. OTHER CALCULI. Less than 2% of urinary calculi MORPHOLOGIC FEATURES. The pathologic changes
consist of other rare types such as due to inherited abnor- vary depending upon whether the obstruction is sudden
mality of enzyme metabolism e.g. hereditary xanthinuria and complete, or incomplete and intermittent. The latter
developing xanthine stones. situation is more common.
Grossly, the kidneys may have moderate to marked
HYDRONEPHROSIS enlargement. Initially, there is extrarenal hydronephrosis
characterised by dilatation of renal pelvis medially in the
Hydronephrosis is the term used for dilatation of renal pelvis form of a sac (Fig. 22.40,A). As the obstruction persists,
and calyces due to partial or intermittent obstruction to the

693
 TABLE 22.18: Urinary Calculi (continued)
Morphology


Calcium oxalate stones


Struvite (‘Staghorn’) stone


Uric acid stones




Cystine stones


Figure facing Table 22.18

Figure 22.41 Hydronephrosis with nephrolithiasis. The kidney is
there is progressive dilatation of pelvis and calyces and enlarged and heavy. On cut section, the renal pelvis and calyces are
pressure atrophy of renal parenchyma. Eventually, the dilated and cystic and contain a large stone in the pelvis of the kidney
(arrow). The cystic change is seen to extend into renal p
arenchyma,
dilated pelvi-calyceal system extends deep into the renal compressing the cortex as a thin rim at the periphery . Unlike polycystic
cortex so that a thin rim of renal cortex is stretched over kidney, however, these cysts are communicating with the pelvi-calyceal
the dilated calyces and the external surface assumes system.
lobulated appearance. This advanced stage is called as
intrarenal hydronephrosis (Fig. 22.40,B). An important point TUMOURS OF KIDNEY CHAPTER 22
of distinction between the sectioned surface of advanced
hydronephrosis and polycystic kidney disease (page 657) Both benign and malignant tumours occur in the kidney, the
is the direct continuity of dilated cystic spaces (i.e. dila- latter being more common. These may arise from renal tubules
ted calyces) with the renal pelvis in the former (Fig. 22.41). (adenoma, adenocarcinoma), embryonic tissue (mesoblastic
Microscopically, the wall of hydronephrotic sac is nephroma, Wilms’ tumour), mesenchymal tissue
thickened due to fibrous scarring and chronic inflam- (angiomyolipoma, medullary interstitial tumour) and from
matory cell infiltrate. There is progressive atrophy of the epithelium of the renal pelvis (urothelial carcinoma). Besides
tubules and glomeruli alongwith interstitial fibrosis. Stasis these tumours, the kidney may be the site of the secondary
tumours.
of urine in hydronephrosis causes infection (pyelitis) Table 22.19 provides a list of kidney tumours; the impor-
resulting in filling of the sac with pus, a condition called tant forms of renal neoplasms are described below.
pyonephrosis.
BENIGN TUMOURS
Benign renal tumours are usually small and are often an The Kidney and Lower Urinary Tract
incidental finding at autopsy or nephrectomy.

Cortical Adenoma
Cortical tubular adenomas are more common than other
benign renal neoplasms. They are frequently multiple and
associated with chronic pyelonephritis or benign
nephrosclerosis.

Grossly, these tumours may form tiny nodules up to 3
cm in diameter. They are encapsulated and white or
yellow.
Microscopically, they are composed of tubular cords or
papillary structures projecting into cystic space. The cells
of the adenoma are usually uniform, cuboidal with no
atypicality or mitosis. However, size of the tumour rather
than histologic criteria is considered more significant
parameter to predict the behaviour of the tumour—those
larger than 3 cm in diameter are potentially malignant
Figure 22.40 Hydronephrosis, stages in its evolution. and metastasising.

694 Grossly, it is a solitary, unilateral well demarcated tumour
 TABLE 22.19: Classification of Kidney Tumours.
of varying size. Cut surface shows characteristic
Benign Malignant
multilocular appearance.
A. EPITHELIAL TUMOURS OF RENAL PARENCHYMA Microscopically, the cysts are lined by tubular epithelium
while the stroma between the cysts contains mesenchymal
Adenoma Adenocarcinoma
Oncocytoma (hypernephroma, renal cell tissue with some immature blastemal or abortive tubules.
carcinoma) Some authors consider this entity as fully-differentiated
variant of Wilms’ tumour. However, clinically multicystic
B. EPITHELIAL TUMOURS OF RENAL PELVIS nephroma is always benign compared to Wilms’ tumour.
Transitional cell papilloma Transitional cell carcinoma
Others (squamous cell carcinoma, Medullary interstitial cell tumour is a tiny nodule in the
adenocarcinoma of renal pelvis, medulla composed of fibroblast-like cells in hyalinised
undifferentiated carcinoma of stroma. These tumours used to be called renal fibromas but
renal pelvis) electron microscopy has revealed that the tumour cells are
not fibrocytes but are medullary interstitial cells.
C. EMBRYONAL TUMOURS
Juxtaglomerular tumour or reninoma is a rare tumour
Mesoblastic nephroma Wilms’ tumour (nephroblastoma)
of renal cortex consisting of sheets of epithelioid cells with
Multicystic nephroma
many small blood vessels. The tumour secretes excessive
quantities of renin and, thus, the patients are likely to have
D. NON-EPITHELIAL TUMOURS
hypertension.
Angiomyolipoma Sarcomas (rare)
Medullary interstitial
tumour (fibroma) MALIGNANT TUMOURS
The two most common primary malignant tumours of the
E. MISCELLANEOUS
kidney are adenocarcinoma and Wilms’ tumour. A third
Juxtaglomerular cell malignant renal tumour is urothelial carcinoma occurring more
tumour (Reninoma)
commonly in the renal pelvis is described in the next section
F. METASTATIC TUMOURS along with other tumours of the lower urinary tract.
SECTION III
Adenocarcinoma of Kidney (Synonyms: Renal cell
Oncocytoma carcinoma, Hypernephroma, Grawitz tumour)
Oncocytoma is a benign epithelial tumour arising from Hypernephroma is an old misnomer under the mistaken
collecting ducts. belief that the tumour arises from adrenal rests because of
Grossly, The tumour is encapsulated and has variable size. the resemblance of the tumour cells with clear cells of the
Cut section is homogeneous and has characteristic adrenal cortex. It is now known that the renal cell carcinoma
mahogany-brown or tan colour. (RCC) is an adenocarcinoma arising from tubular epithelium.
This cancer comprises 70 to 80% of all renal cancers and
Microscopically, the tumour cells are plump with occurs most commonly in 50 to 70 years of age with male
abundant, finely granular, acidophilic cytoplasm and preponderance (2:1).
round nuclei. Electron microscopy demonstrates
Systemic Pathology
numerous mitochondria in the cytoplasm. ETIOLOGY AND PATHOGENESIS. Various etiologic
factors implicated in the etiology of RCC are as follows:
Other Benign Tumours 1. Tobacco. Tobacco is the major risk factor for RCC,
Angiomyolipoma is a hamartoma of the kidney that whether chewed or smoked and accounts for 20-30% cases
contains differentiated tissue element derived from blood of RCC. Cigarette smokers have two-fold higher risk of
vessels, smooth muscle and fat. Patients of tuberous sclerosis, developing RCC.
a multisystem disease characterised by skin lesions, CNS and 2. Genetic factors. Heredity and first-degree relatives of
renal involvement, frequently have bilateral angiomyo- RCC are associated with higher risk. Although majority of
lipomas. cases of RCC are sporadic but about 5% cases are inherited.
These cases have following associations:
Mesoblastic nephroma is a congenital benign tumour.
i) von Hippel-Lindau (VHL) disease: It is an autosomal
Grossly, the tumour resembles a uterine leiomyoma in dominant cancer syndrome that includes: haemangio-
having whorled appearance. blastoma of the cerebellum, retinal angiomas, multiple RCC
Microscopically, it shows cellular growth of spindle cells (clear cell type), pheochromocytoma and cysts in different
derived from secondary mesenchyme. organs. Patients of VHL disease have germline mutations of
tumour suppressor VHL gene located on chromosome 3p,
Multicystic nephroma is another uncommon tumour of commonly as homozygous loss of VHL gene. About 35%
early infancy. cases of VHL develop RCC.

  TABLE 22.20: Classification of Renal Cell Carcinoma 695
Type Incidence Genetics Main Histology
1. Clear cell type 70% Sporadic and familial Clear cytoplasm (due to glycogen
(non-papillary) (Homozygous loss of VHL gene located and lipid), well differentiated
on chromosome 3)
2. Papillary type 15% Familial and sporadic Papillary pattern, psammoma bodies
(Familial cases: mutation in MET gene
on chromosome 7; sporadic cases trisomy
of chromosome 7, 16, 17 and loss of Y
chromosome)
3. Granular cell type 8% Sporadic and familial Abundant acidophilic cytoplasm,
marked atypia
4. Chromophobe type 5% Multiple chromosome losses, Mixture of pale clear cells with
hypodiploidy perinuclear halo and granular cells
5. Sarcomatoid type 1.5% — Whorls of atypical anaplastic spindle
cells
6. Collecting duct type 0.5% — Tubular and papillary pattern



ii) Hereditary clear cell RCC: These are cases of clear cell type ischaemic necrosis, cystic change and foci of haemor-
RCC confined to the kidney without other manifestations of rhages. Another significant characteristic is the frequent
VHL but having autosomal dominant inheritance. presence of tumour thrombus in the renal vein which may
iii) Papillary RCC: This form of RCC is characterised by extend into the vena cava (Fig. 22.42).
bilateral and multifocal cancer with papillary growth pattern. CHAPTER 22
Genetic abnormality in these cases lies in MET gene located Histologically, the features of various types of RCC are
on chromosome 7. as under:
iv) Chromophobe RCC: These cases have genetic defects in the 1. Clear cell type RCC (70%): This is the most common
pattern. The clear cytoplasm of tumour cells is due to
form of multiple losses of whole chromosomes i.e. they have removal of glycogen and lipid from the cytoplasm during
extreme degree of hypodiploidy.
processing of tissues. The tumour cells have a variety of
3. Cystic diseases of the kidneys. Both hereditary and patterns: solid, trabecular and tubular, separated by
acquired cystic diseases of the kidney have increased risk of delicate vasculature. Majority of clear cell tumours are well
development of RCC. Patients on longterm dialysis develop differentiated (Fig. 22.43).
acquired cystic disease which may evolve into RCC and 2. Papillary type RCC (15%): The tumour cells are arran-
adenomas. Adult polycystic kidney disease and multicystic ged in papillary pattern over the fibrovascular stalks. The
nephroma is associated with higher occurrence of papillary tumour cells are cuboidal with small round nuclei.
RCC. Psammoma bodies may be seen.
4. Other risk factors. Besides above, following other factors 3. Granular cell type RCC (8%): The tumour cells have The Kidney and Lower Urinary Tract
are associated with higher incidence of RCC: abundant acidophilic cytoplasm. These tumours have
i) Exposure to asbestos, heavy metals and petrochemical more marked nuclear pleomorphism, hyperchromatism
products. and cellular atypia.
ii) In women, obesity and oestrogen therapy. 4. Chromophobe type RCC (5%): This type shows
iii) Analgesic nephropathy. admixture of pale clear cells with perinuclear halo and
v) Tuberous sclerosis. acidophilic granular cells. The cytoplasm of these tumour
cells contains many vesicles.
CLASSIFICATION. Based on cytogenetics of sporadic and
familial tumours, RCC has been reclassified into clear cell, 5. Sarcomatoid type RCC (1.5%): This is the most anaplastic
papillary, granular cell, chromophobe, sarcomatoid and and poorly differentiated form. The tumour is
collecting duct type (Table 22.20). characterised by whorls of atypical spindle tumour cells.
6. Collecting duct type RCC (0.5%): This is a rare type that
MORPHOLOGIC FEATURES. Grossly, RCC commonly occurs in the medulla. It is composed of a single layer of
arises from the poles of the kidney as a solitary and cuboidal tumour cells arranged in tubular and papillary
unilateral tumour, more often in the upper pole. The pattern.
tumour is generally large, golden yellow and circum-
scribed. Papillary tumours have grossly visible papillae CLINICAL FEATURES. Renal cell carcinoma is generally a
and may be multifocal. About 1% RCC are bilateral. Cut slow-growing tumour and the tumour may have been
section of the tumour commonly shows large areas of present for years before it is detected. The classical clinical

696
























Figure 22.42 Renal cell carcinoma. The upper pole of the kidney
shows a large and tan mass while rest of the kidney has reniform contour
.
Sectioned surface shows irregular , circumscribed, yellowish mass with
areas of haemorrhages and necrosis. The residual kidney is compressed
on one side and shows obliterated calyces and renal pelvis.



evidence for diagnosis of renal cell carcinoma is the triad of hypertension (by renin), effects of feminisation or masculinisation
gross haematuria, flank plain and palpable abdominal mass. The (by gonadotropins) and Cushing’s syndrome (by gluco-
most common presenting abnormality is haematuria that corticoids).
occurs in about 60% of cases. By the time the tumour is The prognosis in renal cell carcinoma depends upon the
detected, it has spread to distant sites via haematogenous extent of tumour involvement at the time of diagnosis. The
SECTION III
route to the lungs, brain and bone, and locally to the liver overall 5-year survival rate is about 70%. Presence of
and perirenal lymph nodes. metastases, renal vein invasion and higher nuclear grade of
Systemic symptoms of fatiguability, weight loss, cachexia the tumour are some of the predictors of poor prognosis.
and intermittent fever unassociated with evidence of infection
are found in many cases at presentation. A number of Wilms’ Tumour
paraneoplastic syndromes due to ectopic hormone (Synonym: Nephroblastoma)
production by the renal cell carcinoma have been described. Nephroblastoma or Wilms’ tumour is an embryonic tumour
These include polycythaemia (by erythropoietin), hyper- derived from primitive renal epithelial and mesenchymal
calcaemia (by parathyroid hormone and prostaglandins), components. It is the most common abdominal malignant


Systemic Pathology

























Figure 22.43 Renal cell carcinoma. The tumour shows solid masses and acini of uniform-appearing tumour cells. Clear cells predominate in
the tumour while the stroma is composed of fine and delicate fibrous tissue.

697



















Figure 22.44 Nephroblastoma (W ilms’ tumour). The kidney is
enlarged and has ovoid and nodular appearance. The sectioned surface
shows replacement of almost whole kidney by the tumour leaving a thin
strip of compressed renal tissue at lower end (arrow). Cut section of the
tumour is gray white, fleshy and has small areas of haemorrhages and
necrosis.


tumour of young children, seen most commonly between 1 kidney. It is generally solitary and unilateral but
to 6 years of age with equal sex incidence. 5-10% cases may have bilateral tumour. On cut section,
ETIOLOGY AND PATHOGENESIS. Wilms’ tumour has the tumour shows characteristic variegated appearance—
following etiologic associations: soft, fishflesh-like grey-white to cream-yellow tumour
1. A defect in chromosome 11p13 results in abnormal growth with foci of necrosis and haemorrhages and grossly CHAPTER 22
of metanephric blastema without differentiation into normal identifiable myxomatous or cartilaginous elements
tubules and glomeruli. (Fig. 22.44). Invasion into renal vein is grossly evident in
half the cases.
2. A higher incidence has been seen in monozygotic twins Microscopically, nephroblastoma shows mixture of
and cases with family history.
primitive epithelial and mesenchymal elements. Most of
3. Association of Wilms’ tumour with some other congenital the tumour consists of small, round to spindled,
anomalies has been observed, especially of the genitourinary anaplastic, sarcomatoid tumour cells. In these areas are
tract. present abortive tubules and poorly-formed glomerular
4. A few other malignancies are known to have higher structures (Fig. 22.45). Mesenchymal elements such as
incidence of Wilms’ tumour. These include osteosarcoma, smooth and skeletal muscle, cartilage and bone, fat cells
botyroid sarcoma, retinoblastoma, neuroblastoma etc.
and fibrous tissue, may be seen.
MORPHOLOGIC FEATURES. Grossly, the tumour is CLINICAL FEATURES. The most common presenting
usually quite large, spheroidal, replacing most of the feature is a palpable abdominal mass in a child. Other The Kidney and Lower Urinary Tract




























Figure 22.45 Wilms’ tumour. There is predominance of small round to spindled sarcomatoid tumour cells. A few abortive tubules and poorly-
formed glomerular structures are present in it.

698 common abnormalities are haematuria, pain, fever and mucous glands in the urethral mucosa. The female urethra is
hypertension. The tumour rapidly spreads via blood, shorter and runs from the bladder parallel with the anterior
especially to lungs. wall of the vagina. The mucous membrane in female urethra
The prognosis of the tumour with combination therapy is lined throughout by columnar epithelium except near the
of nephrectomy, post-operative irradiation and chemo- bladder where the epithelium is transitional. The other layers
therapy, has improved considerably and the 5-year survival and mucous glands are similar to those in male urethra.
now is 80-90%.
CONGENITAL ANOMALIES
Secondary Tumours
Leukaemic infiltration of the kidneys is a common finding, Vesicoureteric reflux is the most common anomaly described
particularly in chronic myeloid leukaemia. Kidney is a already on page 682. A few others are considered below.
common site for blood-borne metastases from different DOUBLE URETER. This is a condition in which the entire
primary sites, chiefly from cancers of the lungs, breast and ureter or only the upper part is duplicated. Double ureter is
stomach. invariably associated with a double renal pelvis, one in the
upper part and the other in the lower part of the kidney. If
LOWER URINARY TRACT double ureter affects the entire length, then there are two
separate openings into the bladder on one side but more
commonly they are joined in the intravesical portion and
NORMAL STRUCTURE
open by a single ureteric orifice.
The lower urinary tract consists of ureters, urinary bladder and URETEROCELE. Ureterocele is cystic dilatation of the
urethra.
terminal part of the ureter which lies within the bladder wall.
URETERS are tubular structures, 30 cm in length and half a The cystic dilatation lies beneath the bladder mucosa and
centimeter in diameter, and extend from the renal pelvis can be visualised by cystoscopy.
(pelvi-ureteric junction) to the urinary bladder (vesico- ECTOPIA VESICAE (EXSTROPHY). This is a rare condition
ureteric junction). Normally they enter obliquely into the owing to congenital developmental deficiency of anterior
bladder, so that ureter is compressed during micturition, thus wall of the bladder and is associated with splitting of the
preventing vesico-ureteric reflux. Ureters lie retroperitoneally overlying anterior abdominal wall. This results in exposed
throughout their course.
interior of the bladder. There may be prolapse of the posterior
SECTION III
Histologically, ureter has an outer fibrous investing layer wall of the bladder through the defect in the anterior bladder
which overlies a thick muscular layer and is lined internally and abdominal wall. The condition in males is often
by transitional epithelium or urothelium similar to the lining associated with epispadias in which the urethra opens on the
of the renal pelvis above and bladder below. dorsal aspect of penis. If the defect is not properly repaired,
the exposed bladder mucosa gets infected repeatedly and
URINARY BLADDER lies extraperitoneally and the
peritoneum is reflected on its superior surface. Besides may undergo squamous metaplasia with subsequent
increased tendency to develop carcinoma of the bladder.
superior surface (or dome), the bladder has posterior surface
(or base) and two lateral surfaces. The trigone is at the base of URACHAL ABNORMALITIES. Rarely, there may be
the bladder and continues as blader neck. Normally, the persistence of the urachus in which urine passes from the
capacity of bladder is about 400 to 500 ml without over- bladder to the umbilicus. More often, part of urachus remains
Systemic Pathology
distension. Micturition is partly a reflex and partly a patent which may be the umbilical end, bladder end, or
voluntary act under the control of sympathetic and central portion. Persistence of central portion gives rise to
parasympathetic innervation. urachal cyst lined by transitional or squamous epithelium.
Histologically, the greater part of the bladder wall is made Adenocarcinoma may develop in urachal cyst.
up of muscular layer (detrusor muscle) having 3 coats—
internal, middle and external. The trigone muscle is derived INFLAMMATIONS
from the prolongation of the longitudinal muscle layer of
each ureter. The inner layer of bladder consists of urothelium Urinary tract infection (UTI) is common, especially in females
6-7 layers in thickness. The superficial epithelial layer is made and has been described already along with its morphologic
of larger cells in the form of a row and have abundant consequences (page 681). Inflammation of the tissues of lower
eosinphilic cytoplasm; these cells are called umbrella cells. urinary tract (ureteritis, cystitis and urethritis) are considered
here.
URETHRA runs from the bladder up to the external meatus.
The male urethra consists of 3 parts—prostatic, membranous Ureteritis
and penile. It is lined in the prostatic part by urothelium but
elsewhere by stratified columnar epithelium except near its Infection of the ureter is almost always secondary to pyelitis
orifice where the epithelium is stratified squamous. The above, or cystitis below. Ureteritis is usually mild but
urethral mucosa rests on highly vascular submucosa and repeated and longstanding infection may give rise to chronic
outer layer of striated muscle. There are numerous small ureteritis.

Cystitis get repeated attacks of severe and excruciating pain on 699
distension of the bladder, frequency of micturition and great
Inflammation of the urinary bladder is called cystitis. Primary decrease in bladder capacity. Cystoscopy often reveals a
cystitis is rare since the normal bladder epithelium is quite localised ulcer. The etiology of the condition is unknown but
resistant to infection. Cystitis may occur by spread of it is thought to be neurogenic in origin.
infection from upper urinary tract as seen following renal
tuberculosis, or may spread from the urethra such as in Microscopically, the submucosa and muscle coat show
instrumentation. Cystitis is caused by a variety of bacterial increased fibrosis and chronic inflammatory infiltrate,
and fungal infections as discussed in the etiology of chiefly lymphocytes, plasma cells and eosinophils.
pyelonephritis (page 682). The most common pathogenic
organism in UTI is E. coli, followed in decreasing frequency CYSTITIS CYSTICA. As a result of long-standing chronic
by Enterobacter, Klebsiella, Pseudomonas and Proteus. Infection inflammation, there occurs a downward projection of
with Candida albicans may occur in the bladder in immuno- epithelial nests known as Brunn’s nests from the deeper layer
suppressed patients. Besides bacterial and fungal organisms, of bladder mucosa. These epithelial cells may appear as small
parasitic infestations such as with Schistosoma haematobium cystic inclusions in the bladder wall, or may actually develop
is common in the Middle-East countries, particularly in columnar metaplasia with secretions in the lumen of cysts.
Egypt. Chlamydia and Mycoplasma may occasionally cause MALAKOPLAKIA. This is a rare condition most frequently
cystitis. In addition, radiation, direct exposure to chemical found in the urinary bladder but can occur in the ureters,
irritant, foreign bodies and local trauma may all initiate kidney, testis and prostate, and occasionally in the gut. The
cystitis. etiology of the condition is unknown but probably results from
Cystitis, like UTI, is more common in females than in persistence of chronic inflammation with defective
males because of the shortness of urethra which is liable to phagocytic process by the macrophages. Malakoplakia
faecal contamination and due to mechanical trauma during occurs more frequently in immunosuppressed patients and
sexual intercourse. In males, prostatic obstruction is a recipients of transplants.
frequent cause of cystitis. All forms of cystitis are clinically
characterised by a triad of symptoms—frequency (repeated Grossly, the lesions appear as soft, flat, yellowish, slightly CHAPTER 22
urination), dysuria (painful or burning micturition) and low raised plaques on the bladder mucosa. They may vary
abdominal pain. There may, however, be systemic manifes- from 0.5 to 5 cm in diameter.
tations of bacteraemia such as fever, chills and malaise. Microscopically, the plaques are composed of massive
accumulation of foamy macrophages with occasional
MORPHOLOGIC FEATURES. Cystitis may be acute or multinucleate giant cells and some lymphocytes. These
chronic. macrophages have granular PAS-positive cytoplasm and
some of them contain cytoplasmic laminated concretions
ACUTE CYSTITIS. Grossly, the bladder mucosa is red,
swollen and haemorrhagic. There may be suppurative of calcium phosphate called Michaelis-Gutmann bodies.
exudate or ulcers on the bladder mucosa. These bodies ultrastructurally represent lysosomes filled
Microscopically, this form of cystitis is characterised by with partly digested debris of bacteria phagocytosed by
intense neutrophilic exudate admixed with lymphocytes macrophages which have not been digested fully by them
and macrophages. There is oedema and congestion of due to defective phagocytosis.
mucosa. POLYPOID CYSTITIS. Polypoid cystitis is characterised by The Kidney and Lower Urinary Tract
CHRONIC CYSTITIS. Repeated attacks of acute cystitis papillary projections on the bladder mucosa due to
lead to chronic cystitis. submucosal oedema and can be confused with transitional
Grossly, the mucosal epithelium is thickened, red and cell carcinoma. The condition occurs due to indwelling
granular with formation of polypoid masses. Long- catheters and infection.
standing cases result in thickened bladder wall and
shrunken cavity. Urethritis
Microscopically, there is patchy ulceration of the mucosa
with formation of granulation tissue in the regions of Urethritis may be gonococcal or non-gonococcal.
polypoid masses. Submucosa and muscular coat show Gonococcal (gonorrhoeal) urethritis is an acute
fibrosis and infiltration by chronic inflammatory cells. A suppurative condition caused by gonococci (Neisseria gonorr-
form of chronic cystitis characterised by formation of lym- hoeae). The mucosa and submucosa are eventually converted
phoid follicles in the bladder mucosa is termed cystitis into granulation tissue which becomes fibrosed and scarred
follicularis. resulting in urethral stricture.
Non-gonococcal urethritis is more common and is most
A few other special forms of cystitis having distinct
clinical and morphological appearance are described below. frequently caused by E. coli. The infection of urethra often
accompanies cystitis in females and prostatitis in males.
INTERSTITIAL CYSTITIS (HUNNER’S ULCER). This Urethritis is one of the components in the triad of Reiter’s
variant of cystitis occurs in middle-aged women. The patients syndrome which comprises arthritis, conjunctivitis and

700 urethritis (Chapter 4). The pathologic changes are similar to 3. Dietary factors. Certain carcinogenic metabolites of
inflammation of the lower urinary tract elsewhere but tryptophan are excreted in urine of patients with bladder
strictures are less common than following gonococcal cancer. These metabolites have been shown to induce bladder
infection of the urethra. cancer in experimental animals. The role of artificial
sweeteners like saccharin, coffee or caffeine and chronic
TUMOURS alcoholism in the etiology of bladder cancer in man is
controversial.
Majority of lower urinary tract tumours are epithelial. Both
benign and malignant tumours occur; the latter being more 4. Local lesions. A number of local lesions in the bladder
common. About 90% of malignant tumours of the lower predispose to the development of bladder cancer. These
urinary tract occur in the urinary bladder, 8% in the renal include ectopia vesicae (extrophied bladder), vesical
pelvis and remaining 2% are seen in the urethra or ureters. diverticulum, leukoplakia of the bladder mucosa and urinary
diversion in defunctionalised bladder. All these conditions
TUMOURS OF THE BLADDER are associated with squamous metaplasia and high incidence
of bladder cancer.
Epithelial (Urothelial) Bladder Tumours 5. Smoking. Tobacco smoking is associated with 2 to 3 fold

More than 90% of bladder tumours arise from transitional increased risk of developing bladder cancer, probably due
epithelial (urothelium) lining of the bladder in continuity to increased urinary excretion of carcinogenic substances.
with the epithelial lining of the renal pelvis, ureters, and the 6. Drugs. Immunosuppressive therapy with cyclo-
major part of the urethra. Though many workers consider phosphamide and patients having analgesic-abuse
all transitional cell tumours as transitional cell carcinoma, (phenacetin-) nephropathy have high risk of developing
others distinguish true transitional cell papilloma from grade bladder cancer.
I transitional cell carcinoma. Multicentric nature of urothelial cancer and high rate of
Bladder cancer comprises about 3% of all cancers. Most recurrence has led to the hypothesis that a field effect in the
of the cases appear beyond 5th decade of life with 3-times urothelium is responsible for this form of cancer. This is
higher preponderance in males than females. responsible for polychronotropism in bladder cancer i.e. the
ETIOPATHOGENESIS. Urothelial tumours in the urinary tumour tends to recur with time and develops at new
tract are typically multifocal and the pattern of disease locations within the urinary tract.
becomes apparent over a period of years. A number of Several cytogentic abnormalities have been seen in
SECTION III
environmental and host factors are associated with increased bladder cancer. These include mutations in p53, RB gene and
risk of bladder cancer. These are as under: p21 gene, all of which are associated with higher rate of
recurrences and metastasis.
1. Industrial occupations. Workers in industries that
produce aniline dyes, rubber, plastic, textiles, and cable have MORPHOLOGIC FEATURES. Grossly, urothelial
high incidence of bladder cancer. Bladder cancer may occur tumours may be single or multiple. About 90% of the
in workers in these factories after a prolonged exposure of tumours are papillary (non-invasive or invasive), whereas
about 20 years. The carcinogenic substances responsible for the remaining 10% are flat indurated (non-invasive or
bladder cancer in these cases are the metabolites of β- invasive) (Fig. 22.46). The papillary tumours have free
naphthylamine and benzene. floating fern-like arrangement with a broad or narrow
2. Schistosomiasis. There is increased risk of bladder cancer, pedicle. The non-papillary tumours are bulkier with
Systemic Pathology
particularly squamous cell carcinoma, in patients having ulcerated surface (Fig. 22.47). More common locations for
bilharzial infestation (Schistosoma haematobium) of the either of the two types are the trigone, the region of
bladder. Schistosomiasis is common in Egypt and accounts ureteral orifices and on the lateral walls.
for high incidence of bladder cancer in that country. It is Histologically, urothelial tumours are of 3 cell types—
thought to induce local irritant effect and initiate squamous transitional cell, squamous cell, and glandular
metaplasia followed by squamous cell carcinoma. (Table 22.21).



















Figure 22.46 Gross patterns of epithelial bladder tumours.

carcinomas. Similar foci may be present in the ureters and 701
renal pelvis. The malignant potential of epithelial
hyperplasia and dysplasia is uncertain but carcinoma in
situ is certainly precancerous and is currently included as
grade 0 transitional cell carcinoma. Carcinoma in situ is
characterised by anaplastic malignant cells confined to
layers superficial to basement membrane of the bladder
mucosa. These pathologic changes can be induced in
experimental animals by chemical carcinogens. Therefore,
it is reasonable to assume that these stages are precursors
of invasive bladder cancer.
3. Transitional cell carcinoma (TCC). This is the commo-
nest cancer of the bladder. The widely accepted
classification of Mostofi (1960) adopted by the American
Bladder Tumour Registry divides TCC into 3 grades. The
basis for this grading depends upon 2 features: the degree
of anaplasia and the extent of invasion.
The criteria for anaplasia are: increased cellularity,
nuclear crowding, deranged cellular polarity, failure of
normal orientation from base to the surface, variation in
cell size and shape, variation in nuclear chromatin pattern,
Figure 22.47 Carcinoma urinary bladder . The mucosal surface
shows papillary tumour floating in the lumen (arrow). mitotic figures and giant cells.
The criteria for invasion in papillary as well as non-
papillary tumours are: penetration of the basement
A. TRANSITIONAL CELL TUMOURS. Approximately membrane of bladder mucosa.
90% of all epithelial tumours of the bladder are transitional Based on these salient features, the characteristics of CHAPTER 22
cell tumours. As stated before, transitional cell papilloma three grades of transitional cell carcinoma are as under:
is distinguished by some workers from grade I transitional
cell carcinoma (TCC), whereas others do not consider this Grade I: The tumour cells are clearly transitional type but
as a distinct entity. show increased number of layers of cells (c.f. transitional
cell papilloma). The individual cells are generally regular
1. Transitional cell papilloma. Papillomas may occur but are slightly larger and show mild hyperchromatism.
singly or may be multiple. They are generally small, less Grade II: The tumour cells are still recognisable as of
than 2 cm in diameter, papillary with branching pattern. transitional cell origin and the number of layers of cells is
Each papilla is composed of fibrovascular stromal core increased. The individual tumour cells are less regular,
covered by normal-looking transitional cells having larger in size, and show pronounced nuclear
normal number of layers (upto 6-7) in thickness. The hyperchromatism, mitotic activity and loss of polarity. The
individual cells resemble the normal transitional cells and tumour may or may not be invasive (Fig.22.48).
do not vary in size and shape. Mitoses are absent and basal
polarity is retained. It must be emphasised that the Grade III: This is the anaplastic or undifferentiated grade The Kidney and Lower Urinary Tract
designation transitional cell papilloma is purely a histo- of the tumour which is always invasive extending into
logical diagnosis but does not imply an innocent biologic the bladder wall to variable depth depending upon the
behaviour. In fact, it may recur and behave in a malignant clinical stage (described later). The tumour cells are no
manner. longer recognisable as of transitional origin. The
individual tumour cells show pronounced features of
2. Carcinoma in situ (CIS). Foci of epithelial hyperplasia, anaplasia such as marked pleomorphism, hyperchro-
dysplasia and carcinoma in situ are seen in other parts of matism, total loss of polarity with loosened surface cells
the bladder in non-invasive as well as in invasive exfoliated in the bladder lumen.
There may be foci of squamous or glandular
metaplasia in any grade of the tumour.
  TABLE 22.21: Histologic Classification of Epithelial B. SQUAMOUS CELL CARCINOMA. Squamous cell
(Urothelial) Tumours (Mostofi, 1960).
carcinoma comprises about 5% of the bladder carcinomas.
A. Transitional cell tumours (90%) Unlike TCC which is mostly papillary and non-ulcerating,
1. Transitional cell papilloma most squamous carcinomas of the bladder are sessile,
2. Transitional cell carcinoma (grade I, II and III) nodular, infiltrating and ulcerating. Association of
B. Carcinoma in situ squamous carcinoma and schistosomiasis has already
C. Squamous cell carcinoma (5%) been highlighted. The carcinoma may be well-
D. Adenocarcinoma (Rare) differentiated with keratin pearl formation, or may be
E. Mixed carcinoma (5%) anaplastic.

702
























Figure 22.48 Transitional cell carcinoma, grade II. There is increase in the number of layers of epithelium. The cells are still recognisable as
of transitional origin and show features of anaplasia.


C. ADENOCARCINOMA. Adenocarcinoma of the myosarcoma. It is morphologically characterised by
bladder is rare. Adenocarcinoma has association with masses of embryonic mesenchyme consisting of masses
exostrophy of the bladder with glandular metaplasia, or of highly pleomorphic stellate cells in myxomatous
may arise from urachal rests, periurethral and background. Similar tumours occur in the female genital
periprostatic glands, or from cystitis cystica. The tumour tract (Chapter 24).
is characterised by glandular and tubular pattern with or
without mucus production. TUMOURS OF RENAL PELVIS AND URETERS
Almost all the tumours of the renal pelvis and ureters are of
SECTION III
STAGING OF BLADDER CANCER. The clinical behaviour epithelial origin. They are of the same types as are seen in
and prognosis of bladder cancer can be assessed by the the urinary bladder. However, tumours in the ureters are
following simple staging system: quite rare.
Stage 0: Carcinoma confined to the mucosa.
TUMOURS OF URETHRA
Stage A: Carcinoma invades the lamina propria but not the
muscularis. Tumours of the urethra are rare except for the urethral
Stage B1: Carcinoma invades the superficial muscle layer. caruncle which is a tumour-like lesion.
Stage B2: Carcinoma invades the deep muscle layer. URETHRAL CARUNCLE. Urethral caruncle is not
Stage C: Carcinoma invades the perivesical tissues. uncommon. It is an inflammatory lesion present on external
urethral meatus in elderly females.
Systemic Pathology
Stage D1: Carcinoma shows regional metastases.
Stage D2: Carcinoma shows distant metastases. Grossly, the caruncle appears as a solitary, 1 to 2 cm in
diameter, pink or red mass, protruding from urethral
Non-epithelial Bladder Tumours meatus. It is quite friable and ulcerated.
Microscopically, the mass may be covered by squamous
These may be benign or malignant.
or transitional epithelium or there may be ulcerated
BENIGN. The most common benign mesenchymal tumour surface. The underlying tissues show proliferating blood
of the bladder is leiomyoma. Other less common examples vessels, fibroblastic connective tissue and intense acute
are neurofibroma, haemangioma and granular cell and chronic inflammatory infiltrate. Thus, the histologic
myoblastoma. appearance closely resembles a pyogenic granuloma.
MALIGNANT. Rhabdomyosarcoma is the most frequent
malignant mesenchymal tumour. It exists in 2 forms: URETHRAL CARCINOMA. Carcinoma of the urethra is
Adult form occurring in adults over 40 years of age and uncommon. In most cases it occurs in the distal urethra near
resembles the rhabdomyosarcoma of skeletal muscle. the external meatus and thus is commonly squamous cell
Childhood form occurring in infancy and childhood and carcinoma. Less often, there may be transitional cell
appears as large polypoid, soft, fleshy, grapelike mass carcinoma or adenocarcinoma arising from periurethral
and is also called sarcoma botryoides or embryonal rhabdo- glands.

❑

703

The Male Reproductive System
Chapter 23
Chapter 23
and Prostate







TESTIS AND EPIDIDYMIS at other sites along its descent from intra-abdominal location
to the scrotal sac.
NORMAL STRUCTURE ETIOLOGY. The exact etiology is not known in majority of
cases. However, a few apparent causes associated with
Contents of the scrotal sac include the testicle and epididymis
along with lower end of the spermatic cord and the tunica cryptorchidism are as under:
vaginalis that forms the outer serous investing layer. The 1. Mechanical factors e.g. short spermatic cord, narrow
epididymis is attached to body of the testis posteriorly. Thus, inguinal canal, adhesions to the peritoneum.
the testicle and epididymis may be regarded as one organ. 2. Genetic factors e.g. trisomy 13, maldevelopment of the
Structurally, the main components of the testicle are the scrotum or cremaster muscles.
seminiferous tubules which when uncoiled are of 3. Hormonal factors e.g. deficient androgenic secretions.
considerable length.
Histologically, the seminiferous tubules are formed of a MORPHOLOGIC FEATURES. Cryptorchidism is unila-
lamellar connective tissue membrane and contain several teral in 80% cases and bilateral in the rest.
layers of cells (Fig. 23.1,A). In the adult, the cells lining the Grossly, the cryptorchid testis is small in size, firm and
seminiferous tubules are of 2 types: fibrotic. CHAPTER 23
1. Spermatogonia or germ cells which produce spermatocytes Histologically, contrary to previous beliefs, the changes
(primary and secondary), spermatids and mature of atrophy begin to appear by about 2 years of age. These
spermatozoa. changes are as under (Fig. 23.1,B):
2. Sertoli cells which are larger and act as supportive cells 1. Seminiferous tubules: There is progressive loss of germ
to germ cells, produce mainly androgen (testosterone) and cell elements so that the tubules may be lined by only
little oestrogen. spermatogonia and spermatids but foci of
The seminiferous tubules drain into collecting ducts spermatogenesis are discernible in 10% of cases. The
which form the rete testis from where the secretions pass tubular basement membrane is thickened. Advanced
into the vasa efferentia. Vasa efferentia opens at the upper cases show hyalinised tubules with a few Sertoli cells only,
end of the epididymis. The lower end of the epididymis is surrounded by prominent basement membrane.
prolonged into a thick muscular tube, the vas deferens, that 2. Interstitial stroma: There is usually increase in the
transports the secretions into the urethra. interstitial fibrovascular stroma and conspicuous presence
The fibrovascular stroma present between the of Leydig cells, seen singly or in small clusters.
seminiferous tubules contains varying number of interstitial
cells of Leydig. Leydig cells have abundant cytoplasm CLINICAL FEATURES. As such, cryptorchidism is comp- The Male Reproductive System and Prostate
containing lipid granules and elongated Reinke’s crystals. letely asymptomatic and is discovered only on physical
These cells are the main source of testosterone and other examination. However, if surgical correction by orchiopexy
androgenic hormones in males. Thus, Sertoli and Leydig cells is not undertaken by about 2 years of age, or certainly in the
are hormone-producing cells homologous to their ovarian prepubertal period, significant adverse clinical outcome may
counterparts (granulosa-theca cells) and are termed specialised result as under:
stromal cells of the gonads. 1. Sterility-infertility. Bilateral cryptorchidism is associa-
Thus, the main functions of the testis are to produce ted with sterility while unilateral disease may result in
sperms and testosterone. infertility.
2. Inguinal hernia. A concomitant inguinal hernia is
CONGENITAL ANOMALIES frequently present along with cryptorchidism.
3. Malignancy. Cryptorchid testis is at 30-50 times increa-
Cryptorchidism
sed risk of developing testicular malignancy, most commonly
Cryptorchidism or undescended testis is a condition in which seminoma and embryonal carcinoma, than a normally
the testicle is arrested at some point along its descent. Its descended testis. The risk of malignancy is greater in intra-
incidence is about 0.2% in adult male population. In 70% of abdominal testis than in testis in the inguinal canal for the
cases, the undescended testis lies in the inguinal ring, in 25% simple reason that the neoplastic process in the testis in
in the abdomen and, in the remaining 5%, it may be present scrotal location is detected early than intra-abdominal site.

704









































SECTION III





Figure 23.1 Microscopic appearance of normal testis (A) contrasted
with that of cryptorchid testis (B).




Male Infertility B. TESTICULAR CAUSES:
The morphologic pattern of testicular atrophy described 1. Agonadism i.e. total absence of the testes.
Systemic Pathology
above for cryptorchidism can result from various other 2. Cryptorchidism or undescended testis described above.
causes of male infertility. These causes can be divided into 3 3. Maturation arrest i.e. failure of spermatogenesis beyond
groups: pre-testicular, testicular and post-testicular. one of the immature stages.
A. PRE-TESTICULAR CAUSES: 4. Hypospermatogenesis i.e. presence of all the maturation
stages of spermatogenesis but in decreased number.
1. Hypopituitarism. Pre-pubertal or post-pubertal hypo-
pituitarism such as from tumour, trauma, infarction, cyst and 5. Sertoli cell-only syndrome. Congenital or acquired
genetic deficiency of FSH and LH secretion. absence of all germ cells so that the seminiferous tubules are
lined by Sertoli cells only.
2. Oestrogen excess. Endogenous excess such as from hepatic 6. Klinefelter’s syndrome. An XXY intersexuality charac-
cirrhosis, adrenal tumour, Sertoli and Leydig cell tumour; terised by primary hypogonadism, azoospermia, gynaeco-
or exogenous excess such as in the treatment of carcinoma of mastia, eunuchoid built and subnormal intelligence.
the prostate. 7. Mumps orchitis occurring as a complication of parotitis
3. Glucocorticoid excess. Endogenous excess may occur in (Chapter 19).
Cushing’s syndrome while exogenous excess may occur in
the treatment of ulcerative colitis, bronchial asthma, 8. Irradiation damage resulting in permanent germ cell
rheumatoid arthritis etc. destruction.
4. Other endocrine disorders. Hypothyroidism and C. POST-TESTICULAR CAUSES:
diabetes mellitus are associated with hypospermatogenesis. 1. Congenital block e.g. absence or atresia of vas deferens.

2. Acquired block e.g. due to gonorrhoea and surgical Tuberculous Epididymo-orchitis 705
intervention. Tuberculosis invariably begins in the epididymis and
3. Impaired sperm motility in the presence of normal sperm spreads to involve the testis. Tuberculous epididymo-orchitis
counts e.g. immotile cilia syndrome (Chapter 17). is generally secondary tuberculosis from elsewhere in the
body. It may occur either by direct spread from genitourinary
INFLAMMATIONS tuberculosis such as tuberculous seminal vesiculitis,
Inflammation of the testis is termed as orchitis and of prostatitis and renal tuberculosis, or may reach by
epididymis is called as epididymitis; the latter being more haematogenous spread of infection such as from tuberculosis
common. A combination epididymo-orchitis may also occur. of the lungs. Primary genital tuberculosis may occur rarely.
A few important types are described below.
MORPHOLOGIC FEATURES. Grossly, discrete,
Non-specific Epididymitis and Orchitis yellowish, caseous necrotic areas are seen.
Microscopically, numerous tubercles which may coalesce
Non-specific epididymitis and orchitis, or their combination, to form large caseous mass are seen. Characteristics of
may be acute or chronic. The common routes of spread of typical tubercles such as epithelioid cells, peripheral
infection are via the vas deferens, or via lymphatic and mantle of lymphocytes, occasional multinucleate giant
haematogenous routes. Most frequently, the infection is cells and central areas of caseation necrosis are seen
caused by urethritis, cystitis, prostatitis and seminal (Fig. 23.2). Numerous acid-fast bacilli can be
vesiculitis. Other causes are mumps, smallpox, dengue fever, demonstrated by Ziehl-Neelsen staining. The lesions
influenza, pneumonia and filariasis. The common infecting produce extensive destruction of the epididymis and may
organisms in sexually-active men under 35 years of age are form chronic discharging sinuses on the scrotal skin. In
Neisseria gonorrhoeae and Chlamydia trachomatis, whereas in late stage, the lesions heal by fibrous scarring and may
older individuals the common organisms are urinary tract undergo calcification.
pathogens like Escherichia coli and Pseudomonas.
Spermatic Granuloma
MORPHOLOGIC FEATURES. Grossly, in acute stage the CHAPTER 23
testicle is firm, tense, swollen and congested. There may Spermatic granuloma is the term used for development of
be multiple abscesses, especially in gonorrhoeal infection. inflammatory lesions due to invasion of spermatozoa into
In chronic cases, there is usually variable degree of the stroma. Spermatic granuloma may develop due to
atrophy and fibrosis. trauma, inflammation and loss of ligature following
Histologically, acute orchitis and epididymitis are charac- vasectomy.
terised by congestion, oedema and diffuse infiltration by
neutrophils, lymphocytes, plasma cells and macrophages MORPHOLOGIC FEATURES. Grossly, the sperm granu-
or formation of neutrophilic abscesses. Acute loma is a small nodule, 3 mm to 3 cm in diameter, firm,
inflammation may resolve, or may progress to chronic white to yellowish-brown.
form. In chronic epididymo-orchitis, there is focal or
diffuse chronic inflammation, disappearance of
seminiferous tubules, fibrous scarring and destruction of
interstitial Leydig cells. Such cases usually result in
permanent sterility.

Granulomatous (Autoimmune) Orchitis The Male Reproductive System and Prostate
Non-tuberculous granulomatous orchitis is a peculiar type
of unilateral, painless testicular enlargement in middle-aged
men that may resemble a testicular tumour clinically. The
exact etiology and pathogenesis of the condition are not
known though an autoimmune basis is suspected.

MORPHOLOGIC FEATURES. Grossly, the affected testis
is enlarged with thickened tunica. Cut section of the
testicle is greyish-white to tan-brown.
Histologically, there are circumscribed non-caseating
granulomas lying within the seminiferous tubules. These
granulomas are composed of epithelioid cells, lympho-
cytes, plasma cells, some neutrophils and multinucleate
giant cells. The origin of the epithelioid cells is from Sertoli
cells lining the tubules. The tubules show peritubular Figure 23.2 Tuberculous epididymo-orchitis. The interstitium
fibrosis which merges into the interstitial tissue that is contains several epithelioid cell granulomas with central areas of
infiltrated by lymphocytes and plasma cells. caseation necrosis. These granulomas are surrounded by Langhans’
giant cells and mantle of lymphocytes.

706 Histologically, it consists of a granuloma composed of
histiocytes, epithelioid cells, lymphocytes and some
neutrophils. Characteristically, the centre of spermatic
granuloma contains spermatozoa and necrotic debris. The
late lesions have fibroblastic proliferation at the periphery
and hyalinisation.


Elephantiasis
Elephantiasis is enormous thickening of the scrotal skin
resembling the elephant’s hide and results in enlargement
of the scrotum. The condition results from filariasis in which
the adult worm lives in the lymphatics, while the larvae
travel in the blood. The most important variety of filaria is
Wuchereria bancrofti. The condition is common in all tropical
countries. The vector is generally the Culex mosquito. The
patients may remain asymptomatic or may manifest with
fever, local pain, swelling, rash, tender lymphadenopathy
and blood eosinophilia. An asthma-like respiratory comp- Figure 23.3 Haematocele testis. Sectioned surface of the sac shows
thick wall coated internally by brownish, tan and necrotic material which
laint may develop in some cases. is organised blood clot (arrow).
MORPHOLOGIC FEATURES. Grossly, the affected leg
and scrotum are enormously thickened with enlargement the left side as the loaded rectum presses the left vein.
of regional lymph nodes. The affected area of skin may Besides, the left spermatic vein enters the renal vein at right
show dilated dermal lymphatics and varicosities. angles while the right spermatic vein enters the vena cava
Histologically, the changes begin with lymphatic obliquely.
obstruction by the adult worms. The worm in alive, dead Secondary form occurs due to pressure on the spermatic
or calcified form may be found in the dilated lymphatics vein by enlarged liver, spleen or kidney. It is commoner in
or in the lymph nodes. Dead or calcified worm in middle-aged people.
SECTION III
lymphatics is usually followed by lymphangitis with
intense infiltration by eosinophils. Sometimes, Hydrocele
granulomatous reaction may be evident. In advanced
cases, chronic lymphoedema with tough subcutaneous A hydrocele is abnormal collection of serous fluid in the
fibrosis and epidermal hyperkeratosis develops which is tunica vaginalis. It may be acute or chronic, congenital or
termed elephantiasis. acquired. The usual causes are trauma, systemic oedema
such as in cardiac failure and renal disease, and as a
MISCELLANEOUS LESIONS complication of gonorrhoea, syphilis and tuberculosis.
The hydrocele fluid is generally clear and straw-coloured
Torsion of Testis but may be slightly turbid or haemorrhagic. The hydrocele
sac may have single loculus or may have multiple loculi. The
Torsion of the testicle may occur either in a fully-descended wall of the hydrocele sac is composed of fibrous tissue
Systemic Pathology
testis or in an undescended testis. The latter is more common infiltrated with lymphocytes and plasma cells.
and more severe. It results from sudden cessation of venous
drainage and arterial supply to the testis, usually following Haematocele
sudden muscular effort or physical trauma. Torsion is
common in boys and young men. Haematocele is haemorrhage into the sac of the tunica
vaginalis. It may result from direct trauma, from injury to a
MORPHOLOGIC FEATURES. The pathologic changes vein by the needle, or from haemorrhagic diseases.
vary depending upon the duration and severity of In recent haematocele, the blood coagulates and the wall
vascular occlusion. There may be coagulative necrosis of is coated with ragged deposits of fibrin. In long-standing
the testis and epididymis, or there may be haemorrhagic cases, the tunica vaginalis is thickened with dense fibrous
infarction. The inflammatory reaction is generally not so tissue and occasionally may get partly calcified (Fig. 23.3).
pronounced.
TESTICULAR TUMOURS
Varicocele
Testicular tumours are the cause of about 1% of all cancer
Varicocele is the dilatation, elongation and tortuosity of the deaths. They are more frequent in white male population
veins of the pampiniform plexus in the spermatic cord. It is but are less common in Africans and Asians. They have
of 2 types: primary (idiopathic) and secondary. trimodal age distribution—a peak during infancy, another
Primary or idiopathic form is more frequent and is during late adolescence and early adulthood, and a third
common in young unmarried men. It is nearly always on peak after 60 years of age.

germ cell tumours are associated with cryptorchidism. The 707
 TABLE 23.1: Classification of Testicular Tumours.
high incidence is attributed to higher temperature to which
I. GERM CELL TUMOURS the undescended testis in the groin or abdomen is exposed.
1. Seminoma Intra-abdominal testis is at greater risk than the inguinal
2. Spermatocytic seminoma testis. There is increased incidence of tumour in the contra-
3. Embryonal carcinoma lateral normally-descended testis. There are no data to
4. Yolk sac tumour (Syn. endodermal sinus tumour, orchio- confirm or deny whether surgical repositioning or
blastoma, infantile type embryonal carcinoma) orchiopexy of a cryptorchid testis alters the incidence of
5. Polyembryoma testicular tumour. However, surgical correction is still helpful
6. Choriocarcinoma since it is easier to detect the tumour in scrotal testis than in
7. Teratomas an abdominal or inguinal testis.
(i) Mature
(ii) Immature 2. Other developmental disorders. Dysgenetic gonads
(iii) With malignant transformation associated with endocrine abnormalities such as androgen
8. Mixed germ cell tumours insensitivity syndrome have higher incidence of
II. SEX CORD-STROMAL TUMOURS development of germ cell tumours.
1. Leydig cell tumour 3. Genetic factors. Genetic factors play a role in the develop-
2. Sertoli cell tumour (Androblastoma) ment of germ cell tumours supported by the observation of
3. Granulosa cell tumour high incidence in first-degree family members, twins and in
4. Mixed forms white male populations while blacks in Africa have a very
III. COMBINED GERM CELL-SEX CORD-STROMAL TUMOURS low incidence. However, no definite pattern of inheritance
Gonadoblastoma has been recognised.
IV. OTHER TUMOURS 4. Other factors. A few less common factors include the
1. Malignant lymphoma (5%) following:
2. Rare tumours i) Orchitis. A history of mumps or other forms of orchitis
may be given by the patient with germ cell tumour. CHAPTER 23
ii) Trauma. Many patients give a history of trauma prior to
CLASSIFICATION the development of the tumour but it is not certain how
trauma initiates the neoplastic process. Instead, possibly it
The most widely accepted classification is the histogenetic brings the patient to attention of the physician.
classification proposed by the World Health Organisation iii) Carcinogens. A number of carcinogens such as use of
(Table 23.1). Based on this, all testicular tumours are divided certain drugs (e.g. LSD, hormonal therapy for sterility,
into 3 groups: germ cell tumours, sex cord-stromal tumours and copper, zinc etc), exposure to radiation and endocrine abnor-
mixed forms. Vast majority of the testicular tumours (95%) malities may play a role in the development of testicular
arise from germ cells or their precursors in the seminiferous tumours.
tubules, while less than 5% originate from sex cord-stromal
components of the testis. From clinical point of view, germ HISTOGENESIS
cell tumours of the testis are categorised into 2 main groups—
seminomatous and non-seminomatous which need to be Pathogenesis of testicular tumours remains controversial
distinguished (Table 23.2). except that vast majority of these tumours originate from
germ cells. Based on current concepts on histogenesis of
ETIOLOGIC FACTORS testicular tumours, following agreements and disagreements The Male Reproductive System and Prostate
have emerged (Fig. 23.4):
Exact etiology of testicular germ cell tumours is unknown,
but the following factors have been implicated: 1. Developmental disorders. Disorders such as cryptor-
chidism, gonadal dysgenesis and androgen insensitivity
1. Cryptorchidism. The probability of a germ cell tumour syndrome are high risk factors for development of testicular
developing in an undescended testis is 30-50 times greater germ cell tumours. These observations point to develop-
than in a normally-descended testis. About 10% of testicular mental defect in gonadogenesis.

  TABLE 23.2: Distinguishing Features of Seminomatous (SGCT) and Non-seminomatous (NSGCT) Germ Cell Tumours of Testis.
Feature SGCT NSGCT
1. Primary tumour Larger, confined to testis for sufficient time; Smaller, at times indistinct;
testicular contour retained testicular contour may be distorted
2. Metastasis Generally to regional lymph nodes Haematogenous spread early
3. Response to radiation Radiosensitive Radioresistant
4. Serum markers hCG; generally low levels hCG, AFP, or both; high levels
5. Prognosis Better Poor

708









































SECTION III
Figure 23.4 Schematic diagram showing histogenesis of testicular tumours.


2. Molecular genetic features. Testicular germ cell tumours 4. ‘Three hit’ process. Germ cells in seminiferous tubules
have been found to have several genetic abnormalities undergo activation (‘first hit’) before undergoing malignant
suggesting a common molecular pathogenesis of all germ transformation confined to seminiferous tubules (CIS)
cell tumours: (‘second hit’) and eventually into invasive stage by some
i) Hyperdiploidy is almost a constant feature of all germ cell epigenetic phenomena (‘third hit’). Though this sequential
tumours of the testis. tumorigenesis explains the development of seminomatous
ii) In more than 90% of testicular germ cell tumours tumours, it is yet not clear whether non-seminomatous germ
Systemic Pathology
irrespective of histologic type (as also ovarian germ cell cell tumours develop directly or through intermediate stage.
tumours), an isochromosome of short arm of chromosome
12, abbreviated as i(12p), is found. CLINICAL FEATURES AND DIAGNOSIS
iii) Similarly, deletion of long arm of chromosome 12
abbreviated as del(12q), is present. The usual presenting clinical symptoms of testicular tumours
iv) Telomerase activity is present in all germ cell tumours of are gradual gonadal enlargement and a dragging sensation
the testis. in the testis. Metastatic involvement may produce secondary
v) Other mutations include p53, cyclin E and FAS gene. symptoms such as pain, lymphadenopathy, haemoptysis and
urinary obstruction.
3. CIS/ITGCN. A preinvasive stage of carcinoma in situ
(CIS) termed intratubular germ cell neoplasia (ITGCN) generally SPREAD. Since testicular germ cell tumours originate from
precedes the development of most of the invasive testicular totipotent germ cells, it is not unusual to find metastases of
germ cell tumours in adults. CIS originates from spermato- histologic types different from the primary growth. Testicular
genic elements. Areas of CIS are found in seminiferous tumours may spread by both lymphatic and haematogenous
tubules adjacent to most seminomas, embryonal carcinomas routes:
and other mixed germ cell tumours. However, CIS is not Lymphatic spread occurs to retroperitoneal para-aortic
found in seminiferous tubules adjoining yolk sac carcinoma lymph nodes, mediastinal lymph nodes and supraclavicular
of childhood, benign teratoma in children and adolescents, lymph nodes.
and spermatocytic seminoma indicating their different patho- Haematogenous spread primarily occurs to the lungs, liver,
genetic mechanisms. brain and bones.

TUMOUR MARKERS. Germ cell tumours of the testis 45 years. Testicular germ cell tumours are almost always 709
secrete polypeptide hormones and certain enzymes which malignant. Nearly half of them contain more than one
can be detected in the blood. Two tumour markers widely histologic type. Germ cell tumours are also found at the
used in the diagnosis, staging and monitoring the follow-up extragonadal sites such as the retroperitoneum and media-
of patients with testicular tumours are: human chorionic stinum, besides their counterparts in the female gonads (page
gonadotropin (hCG) and alpha-foetoprotein (AFP). In 745).
addition, carcinoembryonic antigen (CEA), human placental
lactogen (HPL), placental alkaline phosphatase, testosterone, Intratubular Germ Cell Neoplasia
oestrogen and luteinising hormone may also be elevated. The term intratubular germ cell neoplasia (ITGCN) is used
hCG is synthesised by placental syncytio-trophoblast to describe the preinvasive stage of germ cell tumours,
such as in various non-seminomatous germ cell tumours of notably intratubular seminoma and intratubular embryonal
the testis (e.g. in choriocarcinoma, yolk sac tumour and carcinoma. Others have used carcinoma in situ (CIS) stage
embryonal carcinoma). However, ectopic hCG production of germ cell tumours as synonymous term.
may occur in a variety of non-testicular non-germ cell
tumours as well. Histologically, the malignant atypical tumour cells are
AFP is normally synthesised by the foetal liver cells, yolk restricted to the seminiferous tubules without evident
sac and foetal gut. Its levels are elevated in testicular tumours invasion into the interstitium.
associated with yolk sac components. However, elevated
serum AFP levels are also found in liver cell carcinoma. Classic Seminoma

PROGNOSIS. For selecting post-orchiectomy treatment Seminoma is the commonest malignant tumour of the testis
(radiation, surgery, chemotherapy or all the three) and for and corresponds to dysgerminoma in the female (page 747).
monitoring prognosis, 3 clinical stages are defined: It constitutes about 45% of all germ cell tumours, and in
Stage I: tumour confined to the testis. another 15% comprises the major component of mixed germ
Stage II: distant spread confined to retroperitoneal lymph cell tumour. Seminoma is divided into 2 main categories:
nodes below the diaphragm. classic and spermatocytic. Classic seminoma comprises about CHAPTER 23
Stage III: distant metastases beyond the retroperitoneal 93% of all seminomas and has a peak incidence in the 4th
lymph nodes. decade of life and is rare before puberty. Undescended testis
Seminomas tend to remain localised to the testis (stage harbours seminoma more frequently as compared to other
I) while non-seminomatous germ cell tumours more often germ cell tumours. About 10% pure seminomas are
present with advanced clinical disease (stage II and III). associated with elevated hCG levels in serum.
Seminomas are extremely radiosensitive while non-
seminomatous germ cell tumours are radio-resistant. In MORPHOLOGIC FEATURES. Grossly, the involved
general, seminomas have a better prognosis with 90% cure testis is enlarged up to 10 times its normal size but tends
rate while the non-seminomatous tumours behave in a more to maintain its normal contour since the tumour rarely
aggressive manner and have poor prognosis. invades the tunica. The larger tumour replaces the entire
After these general comments, specific testicular tumours testis, whereas the smaller tumour appears as
are as described below. circumscribed mass in the testis. Cut section of the affected
testis shows homogeneous, grey-white lobulated
appearance (Fig. 23.5). Necrosis and haemorrhage in the
GERM CELL TUMOURS
tumour are rare.
Germ cell tumours comprise approximately 95% of all Microscopically, the tumour has the following charac- The Male Reproductive System and Prostate
testicular tumours and are more frequent before the age of teristics (Fig. 23.6):




















Figure 23.5 Seminoma testis. The testis is enlarged but without
distorting its contour. Sectioned surface shows replacement of the entire
testis by lobulated, homogeneous, grey-white mass.

710
























Figure 23.6 Seminoma testis. Microscopy of the tumour shows lobules of monomorphic seminoma cells separated by delicate fibrous stroma
containing lymphocytic infiltration.



1. Tumour cells. The seminoma cells generally lie in cords, Histologically, the distinctive features are as under:
sheets or columns forming lobules. Typically, in a classic 1. Tumour cells. The tumour cells vary considerably in
seminoma, the tumour cells are fairly uniform in size with size from lymphocyte-like to huge mononucleate or
clear cytoplasm and well-defined cell borders. The cyto- multinucleate giant cells. Majority of the tumour cells are,
plasm contains variable amount of glycogen that stains however, of intermediate size. The cells have eosinophilic
positively with PAS reaction. The nuclei are centrally cytoplasm devoid of glycogen. The nuclei of intermediate
located, large, hyperchromatic and usually contain 1-2 and large cells have filamentous pattern. Mitoses are often
prominent nucleoli. Tumour giant cells may be present. frequent.
SECTION III
Mitotic figures are infrequent. However, about 10% of 2. Stroma. The stroma lacks lymphocytic and granulo-
seminomas have increased mitotic activity and have matous reaction seen in classic seminoma.
aggressive behaviour and are categorised as anaplastic
seminomas. The prognosis of spermatocytic seminoma is excellent
2. Stroma. The stroma of seminoma is delicate fibrous compared and better than classic seminoma since the tumour
tissue which divides the tumour into lobules. The stroma is slow-growing and rarely metastasises. The tumour is
shows a characteristic lymphocytic infiltration, indicative radiosensitive.
of immunologic response of the host to the tumour. About
20% of the tumours show granulomatous reaction in the Embryonal Carcinoma
stroma.
Pure embryonal carcinoma constitutes 30% of germ cell
Systemic Pathology
The prognosis of classic seminoma is better than other tumours but areas of embryonal carcinoma are present in
germ cell tumours. The tumour is highly radiosensitive. 40% of germ cell tumours. These tumours are more common
Natural history of anaplastic seminoma, however, is in 2nd to 3rd decades of life. About 90% cases are associated
unclear—perhaps it represents an advanced stage of classic with elevation of AFP or hCG or both. They are more
seminoma with a more aggressive behaviour. aggressive than the seminomas.

Spermatocytic Seminoma MORPHOLOGIC FEATURES. Grossly, embryonal carci-
noma is usually a small tumour in the testis. It distorts
Spermatocytic seminoma is both clinically and
morphologically a distinctive tumour from classic seminoma the contour of the testis as it frequently invades the tunica
and is, therefore, classified separately in the WHO and the epididymis. Cut surface of the tumour is grey-
classification. It is an uncommon tumour having an incidence white, soft with areas of haemorrhages and necrosis.
of about 5% of all germ cell tumours. Spermatocytic Microscopically, the following features are seen:
seminoma usually occurs in older patients, generally in 6th 1. The tumour cells are arranged in a variety of patterns—
decade of life. The tumour is bilateral in 10% of patients. glandular, tubular, papillary and solid.
2. The tumour cells are highly anaplastic carcinomatous
MORPHOLOGIC FEATURES. Grossly, spermatocytic cells having large size, indistinct cell borders, amphophilic
seminoma is homogeneous, larger, softer and more cytoplasm and prominent hyperchromatic nuclei showing
yellowish and gelatinous than the classic seminoma. considerable variation in nuclear size. Mitotic figures and

tumour giant cells are frequently present. Haemorrhage 4. There may be presence of both intracellular and 711
and necrosis are common. extracellular PAS-positive hyaline globules, many of which
3. The stroma is not as distinct as in seminoma and may contain AFP.
contain variable amount of primitive mesenchyme.
Polyembryoma
Embryonal carcinoma is more aggressive and less
radiosensitive than seminoma. Chemotherapy is more Polyembryoma is defined as a tumour composed predo-
effective in treating this tumour. minantly of embryoid bodies. Embryoid bodies are structures
containing a disc and cavities surrounded by loose
Yolk Sac Tumour mesenchyme simulating an embryo of about 2 weeks’
(Synonyms: Endodermal Sinus Tumour, gestation. Polyembryoma is extremely rare but embryoid
Orchioblastoma, Infantile Embryonal Carcinoma) bodies may be present with embryonal carcinoma and
teratoma.
This characteristic tumour is the most common testicular
tumour of infants and young children upto the age of 4 years. Choriocarcinoma
In adults, however, yolk sac tumour in pure form is rare but
may be present as the major component in 40% of germ cell Pure choriocarcinoma is a highly malignant tumour compo-
tumours. AFP levels are elevated in 100% cases of yolk sac sed of elements consisting of syncytiotrophoblast and
tumours. cytotrophoblast.
However, pure form is extremely rare and occurs more
MORPHOLOGIC FEATURES. Grossly, the tumour is often in combination with other germ cell tumours. The
generally soft, yellow-white, mucoid with areas of necrosis patients are generally in their 2nd decade of life. The primary
and haemorrhages. tumour is usually small and the patient may manifest initially
Microscopically, yolk sac tumour has the following with symptoms of metastasis. The serum and urinary levels
features (Fig. 23.7): of hCG are greatly elevated in 100% cases.
1. The tumour cells form a variety of patterns—loose MORPHOLOGIC FEATURES. Grossly, the tumour is CHAPTER 23
reticular network, papillary, tubular and solid arrange- usually small and may appear as a soft, haemorrhagic and
ment. necrotic mass.
2. The tumour cells are flattened to cuboid epithelial cells Microscopically, the characteristic feature is the
with clear vacuolated cytoplasm. identification of intimately related syncytiotrophoblast
3. The tumour cells may form distinctive perivascular and cytotrophoblast without formation of definite
structures resembling the yolk sac or endodermal sinuses placental-type villi.
of the rat placenta called Schiller-Duval bodies.
Syncytiotrophoblastic cells are large with many irregular
and bizarre nuclei and abundant eosinophilic vacuolated
cytoplasm which stains positively for hCG. These cells
often surround masses of cytotrophoblastic cells.
Cytotrophoblastic cells are polyhedral cells which are
more regular and have clear or eosinophilic cytoplasm
with hyperchromatic nuclei.

Teratoma The Male Reproductive System and Prostate
Teratomas are complex tumours composed of tissues derived
from more than one of the three germ cell layers—endoderm,
mesoderm and ectoderm. Testicular teratomas are more
common in infants and children and constitute about 40%
of testicular tumours in infants, whereas in adults they
comprise 5% of all germ cell tumours. However, teratomas
are found in combination with other germ cell tumours (most
commonly with embryonal carcinoma) in about 45% of
mixed germ cell tumours. About half the teratomas have
elevated hCG or AFP levels or both.

MORPHOLOGIC FEATURES. Testicular teratomas are
classified into 3 types:
1. Mature (differentiated) teratoma
Figure 23.7 Yolk sac tumour testis. The tumour has microcystic
pattern and has highly anaplastic tumour cells. Several characteristic 2. Immature teratoma
Schiller-Duval bodies are present. Inset shows intra- and extracellular 3. Teratoma with malignant transformation.
hyaline globules.

712






























Figure 23.8 Immature teratoma testis. The testis is enlarged and nodular distorting the testicular contour. Sectioned surface shows replacement
of the entire testis by variegated mass having grey-white solid areas, cystic areas, honey-combed areas and foci of cartilage and bone.

Grossly, most teratomas are large, grey-white masses infants and children and has favourable prognosis.
enlarging the involved testis. Cut surface shows However, similar mature and benign-appearing tumour
characteristic variegated appearance—grey-white solid in adults is invariably associated with small hidden foci
areas, cystic and honey-combed areas, and foci of cartilage of immature elements so that their clinical course in adults
and bone (Fig. 23.8). Dermoid tumours commonly seen is unpredictable. It is believed that all testicular teratomas
SECTION III
in the ovaries are rare in testicular teratomas. in the adults are malignant.
Microscopically, the three categories of teratomas show As mentioned above, dermoid cysts similar to those
different appearances: of the ovary are rare in the testis.
1. Mature (differentiated) teratoma. Mature teratoma is 2. Immature teratoma. Immature teratoma is composed
composed of disorderly mixture of a variety of well- of incompletely differentiated and primitive or embryonic
differentiated structures such as cartilage, smooth muscle, tissues along with some mature elements (Fig. 23.9).
intestinal and respiratory epithelium, mucus glands, cysts Primitive or embryonic tissue commonly present are
lined by squamous and transitional epithelium, neural poorly-formed cartilage, mesenchyme, neural tissues,
tissue, fat and bone. This type of mature or differentiated abortive eye, intestinal and respiratory tissue elements etc.
teratoma is the most common, seen more frequently in Mitoses are usually frequent.
Systemic Pathology


























Figure 23.9 Immature teratoma testis. Microscopy shows a variety of incompletely differentiated tissue elements.

3. Teratoma with malignant transformation. This is an Sertoli Cell Tumours (Androblastoma) 713
extremely rare form of teratoma in which one or more of Sertoli cell tumours correspond to arrhenoblastoma of the
the tissue elements show malignant transformation. Such ovary. They may occur at all ages but are more frequent in
malignant change resembles morphologically with typical infants and children. These tumours may elaborate oestrogen
malignancies in other organs and tissues and commonly or androgen and may account for gynaecomastia in an adult,
includes rhabdomyosarcoma, squamous cell carcinoma or precocious sexual development in a child.
and adenocarcinoma.
MORPHOLOGIC FEATURES. Grossly, the tumour is
Mixed Germ Cell Tumours fairly large, firm, round, and well circumscribed. Cut
About 60% of germ cell tumours have more than one of the surface of the tumour is yellowish or yellow-grey.
above histologic types (except spermatocytic seminoma) and Microscopically, Sertoli cell tumour is composed of
are called mixed germ cell tumours. The clinical behaviour benign Sertoli cells arranged in well-defined tubules.
of these tumours is worsened by inclusion of more aggressive
tumour component in a less malignant tumour. Interestingly, Majority of Sertoli cell tumours are benign but about 10%
metastases of the mixed germ cell tumours may not exactly may metastasise to regional lymph nodes.
reproduce the histologic types present in the primary
tumour. Granulosa Cell Tumour
The most common combinations of mixed germ cell This is an extremely rare tumour in the testis and resembles
tumours are as under: morphologically with its ovarian counterpart (Chapter 24).
1. Teratoma, embryonal carcinoma, yolk sac tumour and
syncytiotrophoblast. MIXED GERM CELL-SEX CORD STROMAL TUMOURS
2. Embryonal carcinoma and teratoma (teratocarcinoma).
3. Seminoma and embryonal carcinoma. An example of combination of both germ cells and sex cord
stromal components is gonadoblastoma.
SEX CORD-STROMAL TUMOURS
Gonadoblastoma CHAPTER 23
Tumours arising from specialised gonadal stroma are classi-
fied on the basis of histogenesis. The primitive mesenchyme Dysgenetic gonads and undescended testis are predisposed
which forms the specialised stroma of gonads in either sex to develop such combined proliferations of germ cells and
gives rise to theca, granulosa and lutein cells in the female, sex cord-stromal elements. The patients are commonly
and Sertoli and interstitial Leydig cells in the male. Since the intersexuals, particularly phenotypic females. Most of the
cell of origin of primitive mesenchyme is identical, Sertoli gonadoblastomas secrete androgen and therefore produce
and interstitial Leydig cell tumours may occur in the ovaries virilisation in female phenotype. A few, however, secrete
(in addition to theca cell, granulosa cell and lutein cell oestrogen.
tumours). Likewise, the latter three tumours may occur in
the testis (in addition to Sertoli cell and Leydig cell tumours). MORPHOLOGIC FEATURES. Grossly, the tumour is of
All these tumours secrete various hormones. The biologic variable size, yellowish-white and soft.
behaviour of these tumours generally cannot be determined Microscopically, gonadoblastoma is composed of 2
on histological grounds alone but is related to clinical principal cell types—large germ cells resembling
parameters and hormonal elaboration by these tumours. seminoma cells, and small cells resembling immature
Sertoli, Leydig and granulosa cells. Call-Exner bodies of
Leydig (Interstitial) Cell Tumour a granulosa cell tumour may be present. The Male Reproductive System and Prostate
Leydig cell tumours are quite uncommon. They may occur Prognosis largely depends upon the malignant potential
at any age but are more frequent in the age group of 20 to 50 of the type of germ cell components included.
years. Characteristically, these cells secrete androgen, or both
androgen and oestrogen, and rarely corticosteroids. Bilateral OTHER TUMOURS
tumours may occur typically in congenital adrenogenital
syndrome. Malignant Lymphoma
MORPHOLOGIC FEATURES. Grossly, the tumour Malignant lymphomas comprises 5% of testicular malignan-
appears as a small, well-demarcated and lobulated cies and is the most common testicular tumour in the elderly.
nodule. Cut surface is homogeneously yellowish or Bilaterality is seen in half the cases. Most common are large
brown. cell non-Hodgkin’s lymphoma of B cell type.
Histologically, the tumour is composed of sheets and
cords of normal-looking Leydig cells. These cells contain Rare Tumours
abundant eosinophilic cytoplasm and Reinke’s crystals
and a small central nucleus. In addition to the testicular tumours described above, some
other uncommon tumours in this location include: plasma-
Most of Leydig cell tumours are benign. Only about 10% cytoma, leukaemic infiltration, carcinoid tumour,
may invade and metastasise. haemangioma, primary sarcomas and metastatic tumours.

714 usually results from lack of cleanliness resulting in
PENIS
accumulation of secretions and smegma. It is a common
NORMAL STRUCTURE accompaniment of phimosis. The type of inflammation may
be acute or chronic, sometimes with ulceration on the
The penis is covered by skin, foreskin (prepuce) and strati- mucosal surface of the glans.
fied squamous mucosa. The structure of penis consists of 3
masses of erectile tissue— two corpora cavernosa, one on Balanitis Xerotica Obliterans
each side dorsally, and the corpus spongiosum ventrally Balanitis xerotica obliterans is a white atrophic lesion on the
through which the urethra passes. The expanded free end of glans penis and the prepuce and is a counterpart of the lichen
the corpus spongiosum forms the glans. sclerosus et atrophicus in the vulva described on page 721.
The lumen of the urethra in sectioned surface of the penis
appears as an irregular cleft in the middle of the corpus TUMOURS
spongiosum. In the prostatic part, it is lined by transitional
epithelium, but elsewhere it is lined by columnar epithelium Benign and malignant tumours as well as certain premalig-
except near its orifice where stratified squamous epithelium nant lesions may occur on the penis. These are discussed
lines it. below:

CONGENITAL ANOMALIES BENIGN TUMOURS

Phimosis Condyloma Acuminatum
Phimosis is a condition in which the prepuce is too small to Condyloma acuminatum or anogenital wart is a benign
permit its normal retraction behind the glans. It may be tumour caused by human papilloma virus (HPV) types 6
congenital or acquired. Congenital phimosis is a developmental and 11. The tumour may occur singly, or there may be
anomaly whereas acquired phimosis may result from conglomerated papillomas. A more extensive, solitary,
inflammation, trauma or oedema leading to narrowing of exophytic and cauliflower-like warty mass is termed giant
preputial opening. In either case, phimosis interferes with condyloma or Buschke-Löwenstein tumour or verrucous
cleanliness and predisposes to the development of secondary carcinoma.
infection, preputial calculi and squamous cell carcinoma. MORPHOLOGIC FEATURES. The condyloma is
Paraphimosis is a condition in which the phimotic pre- commonly located on the coronal sulcus on the penis or
SECTION III
puce is forcibly retracted resulting in constriction over the the perineal area.
glans penis and subsequent swelling. Grossly, the tumour consists of solitary or multiple, warty,
cauliflower-shaped lesions of variable size with exophytic
Hypospadias and Epispadias growth pattern.

Hypospadias is a developmental defect of the urethra in which Histologically, the lesions are essentially like common
the urethral meatus fails to reach the end of the penis, but warts (verruca vulgaris). The features include formation
instead, opens on the ventral surface of the penis. Similar of papillary villi composed of connective tissue stroma
developmental defect with resultant urethral opening on the and covered by squamous epithelium which shows
dorsal surface of the penis is termed epispadias. Hypospadias hyperkeratosis, parakeratosis, and hyperplasia of prickle
and epispadias may cause urethral constriction with cell layer. Many of the prickle cells show clear
Systemic Pathology
consequent infection and may also interfere with normal vacuolisation of the cytoplasm (koilocytosis) indicative of
ejaculation and insemination. Both these urethral anomalies HPV infection.
are more frequently associated with cryptorchidism.
Giant condyloma shows upward as well as downward
growth of the tumour but is otherwise histologically identi-
INFLAMMATIONS
cal to condyloma acuminatum. Though histologically benign,
Glans and prepuce are frequently involved in inflammation clinically the giant condyloma is associated with recurrences
in a number of specific and non-specific conditions. The and behaves as intermediate between truly benign
specific inflammations include various sexually-transmitted condyloma acuminatum and squamous cell carcinoma.
diseases such as hard chancre in syphilis, chancroid caused
by Haemophilus ducreyi, gonorrhoea caused by gonococci, PREMALIGNANT LESIONS (CARCINOMA IN SITU)
herpes progenitalis, granuloma inguinale (donovanosis), and In the region of external male genitalia, three lesions display
lymphopathia venereum caused by Chlamydia trachomatis.
cytological changes of malignancy confined to epithelial
layers only without evidence of invasion. These conditions
Balanoposthitis
are: Bowen’s disease, erythroplasia of Queyrat and bowenoid
Balanoposthitis is the term used for non-specific inflam- papulosis.
mation of the inner surface of the prepuce (balanitis) and
adjacent surface of the glans (posthitis). It is caused by a Bowen’s Disease
variety of microorganisms such as staphylococci, Bowen’s disease is located on the shaft of the penis and the
streptococci, coliform bacilli and gonococci. Balanoposthitis scrotum besides the sun-exposed areas of the skin (page 782).

715



















Figure 23.10 Carcinoma of the penis. Diagrammatic representation of flat-ulcerating (A) and cauliflower papillary (B) patterns of growth at
common locations. C, Amputated specimen of the penis shows a cauliflower growth on the coronal sulcus (arrow). The surface of the growth is
ulcerated and is chalky-white in appearance.




Grossly, it appears as a solitary, circumscribed plaque Bowenoid Papulosis
lesion with ulceration. The lesions of bowenoid papulosis appear on the penile shaft
Histologically, the changes are superficial to the dermo- and adjacent genital skin.
epidermal border. The epithelial cells of the epidermis
show hyperplasia, hyperkeratosis, parakeratosis and Grossly, they are solitary or multiple, shiny, red-brown
scattered bizarre dyskeratotic cells. papular lesions.
Histologically, there is orderly maturation of epithelial
A fair proportion of cases of Bowen’s disease are cells in hyperplastic epidermis with scattered hyper- CHAPTER 23
associated with internal visceral cancers. chromatic nuclei and dysplastic cells.

Erythroplasia of Queyrat
MALIGNANT TUMOURS
The lesions of erythroplasia of Queyrat appear on the penile
mucosa. Squamous Cell Carcinoma

Grossly, the lesions are pink, shiny and velvety soft. The incidence of penile carcinoma shows wide variation in
Histologically, the thickened and acanthotic epidermis different populations. In the United States, the overall
shows variable degree of dysplasia. incidence of penile cancer is less than 1% of all cancers in
Unlike Bowen’s disease, there is no relationship males but it is 3-4 times more common in blacks than in
between erythroplasia of Queyrat and internal whites. In some Asian, African and Latin American countries,
malignancy. its incidence is about 10% of all cancers. Relationship of
penile cancer with HPV has been well supported; high-risk The Male Reproductive System and Prostate





























Figure 23.11 Squamous cell carcinoma penis. Microscopy shows whorls of malignant squamous cells with central keratin pearls.

716 HPV types 16 and 18 are strongly implicated and their DNA The prostate has numerous blood vessels and nerves. In
has been documented in the nuclei of malignant cells. addition to nervous control, the prostate is an endocrine-
Carcinoma of the penis is quite rare in Jews and Muslims dependent organ. Based on hormonal responsiveness, the
who undergo a ritual of circumcision early in life. In India, prostate is divided into 2 separate parts:
cancer of the penis is rare in Muslims who practice circum- the inner periurethral female part which is sensitive to
cision as a religious rite in infancy, whereas Hindus who do oestrogen and androgen; and
not normally circumcise have higher incidence. Circumcision outer subcapsular true male part which is sensitive to
provides protection against penile cancer due to prevention androgen.
of accumulation of smegma which is believed to be Prostate is involved in 3 important pathologic processes:
carcinogenic. The greatest incidence of penile cancer is prostatitis, nodular hyperplasia and carcinoma. While benign
between 45 and 60 years. nodular hyperplasia occurs in the periurethral part distorting
and compressing the centrally located urethral lumen, the
MORPHOLOGIC FEATURES. Grossly, the tumour is
located, in decreasing frequency, on frenum, prepuce, prostatic carcinoma usually arises from the outer subcapsular
glans and coronal sulcus. The tumour may be cauliflower- part in which case it does not compress the urethra
like and papillary, or flat and ulcerating (Fig. 23.10). (Figs. 23.12, B, C).
Histologically, squamous cell carcinoma of both
fungating and ulcerating type is generally well differen- PROSTATITIS
tiated to moderately-differentiated type which resembles Inflammation of the prostate i.e. prostatitis, may be acute,
in morphology to similar cancer elsewhere in the body chronic and granulomatous types.
(Fig. 23.11).
Acute Prostatitis
The tumour metastasises via lymphatics to regional
lymph nodes. Visceral metastases by haematogenous route Acute focal or diffuse suppurative inflammation of the
are uncommon and occur in advanced cases only. prostate is not uncommon. It occurs most commonly due to
ascent of bacteria from the urethra, less often by descent from
PROSTATE the upper urinary tract or bladder, and occasionally by
lymphogenous or haematogenous spread from a distant
NORMAL STRUCTURE focus of infection. The infection may occur spontaneously
or may be a complication of urethral manipulation such as
SECTION III
The prostate gland in the normal adult weighs approximately by catheterisation, cystoscopy, urethral dilatation and
20 gm. It surrounds the commencement of the male urethra surgical procedures on the prostate. The common pathogens
and is composed of 5 lobes during embryonic development— are those which cause UTI, most frequently E. coli, and others
anterior, middle, posterior and two lateral lobes. But at birth, such as Klebsiella, Proteus, Pseudomonas, Enterobacter, gono-
the five lobes fuse to form 3 distinct lobes—two major lateral cocci, staphylococci and streptococci. The diagnosis is made
lobes and a small median lobe (Fig. 23.12,A). by culture of urine specimen.
Histologically, the prostate is composed of tubular alveoli
(acini) embedded in fibromuscular tissue mass. The MORPHOLOGIC FEATURES. Grossly, the prostate is
glandular epithelium forms infoldings and consists of 2 enlarged, swollen and tense. Cut section shows multiple
layers—a basal layer of low cuboidal cells and an inner layer abscesses and foci of necrosis.
of mucus-secreting tall columnar cells. The alveoli are Histologically, the prostatic acini are dilated and filled
Systemic Pathology
separated by thick fibromuscular septa containing abundant with neutrophilic exudate. There may be diffuse acute
smooth muscle fibres.






















Figure 23.12 Normal prostate, benign nodular hyperplasia and prostatic carcinoma. The nodule in case of benign nodular hyperplasia (B) is
located in the inner periurethral part and compresses the prostatic urethra while prostatic carcinoma (C) generally arises in the peripheral glands
and, thus, does not compress the urethra.

inflammatory infiltrate. Oedema, hyperaemia and foci of of 50 years and its incidence approaches 75-80% in men above 717
necrosis frequently accompany acute inflammatory 80 years. However, symptomatic BEP producing urinary tract
involvement. obstruction and requiring surgical treatment occurs in 5-10%
of cases only.
Chronic Prostatitis ETIOLOGY. The cause of BEP has not been fully established.
Chronic prostatitis is more common and foci of chronic However, a few etiologic factors such as endocrinologic, racial,
inflammation are frequently present in the prostate of men inflammation and arteriosclerosis have been implicated but
above 40 years of age. Chronic prostatitis is usually endocrine basis for hyperplasia has been more fully
asymptomatic but may cause allergic reactions, iritis, neuritis investigated and considered a strong possibility in its genesis.
or arthritis. It has been found that both sexes elaborate androgen and
oestrogen, though the level of androgen is high in males and
Chronic prostatitis is of 2 types—bacterial and abacterial. that of oestrogen is high in females. With advancing age,
Chronic bacterial prostatitis is caused in much the same there is decline in the level of androgen and a corresponding
way and by the same organisms as the acute prostatitis. It is rise of oestrogen in the males. The periurethral inner prostate
generally a consequence of recurrent UTI. Diagnosis is made which is primarily involved in BEP is responsive to the rising
by detection of more than 10-12 leucocytes per high power level of oestrogen, whereas the outer prostate which is mainly
field in expressed prostatic secretions, and by positive culture involved in the carcinoma is responsive to androgen. A
of urine specimen and prostatic secretions. This condition is plausible hypothesis suggested is that there is synergistic
more difficult to treat since antibiotics penetrate the prostate stimulation of the prostate by both hormones—the oestrogen
poorly. acting to sensitise the prostatic tissue to the growth
Chronic abacterial prostatitis is more common. There is promoting effect of dihydroxy-testosterone derived from
no history of recurrent UTI and culture of urine and prostatic plasma testosterone.
secretions is always negative, though leucocytosis is
demonstrable in prostatic secretions. The pathogens MORPHOLOGIC FEATURES. Grossly, the enlarged pro-
implicated are Chlamydia trachomatis and Ureaplasma state is nodular, smooth and firm and weighs 2-4 times CHAPTER 23
urealyticum. its normal weight i.e. may weigh up to 40-80 gm. The
appearance on cut section varies depending upon whether
MORPHOLOGIC FEATURES. Pathologic changes in the hyperplasia is predominantly of the glandular or
both bacterial and abacterial prostatitis are similar. fibromuscular tissue (Fig. 23.13). In primarily glandular BEP
Grossly, the prostate may be enlarged, fibrosed and the tissue is yellow-pink, soft, honey-combed, and milky
shrunken. fluid exudes, whereas in mainly fibromuscular BEP the cut
Histologically, the diagnosis of chronic prostatitis is made surface is firm, homogeneous and does not exude milky
by foci of lymphocytes, plasma cells, macrophages and fluid. The hyperplastic nodule forms a mass mainly in
neutrophils within the prostatic substance. Corpora the inner periurethral prostatic gland so that the
amylacea, prostatic calculi and foci of squamous surrounding prostatic tissue forms a false capsule which
metaplasia in the prostatic acini may accompany enables the surgeon to enucleate the nodular masses. The
inflammatory changes. Seminal vesicles are invariably
involved.

Granulomatous Prostatitis
Granulomatous prostatitis is a variety of chronic prostatitis, The Male Reproductive System and Prostate
probably caused by leakage of prostatic secretions into the
tissue, or could be of autoimmune origin.

MORPHOLOGIC FEATURES. Grossly, the gland is firm
to hard, giving the clinical impression of prostatic
carcinoma on rectal examination.
Histologically, the inflammatory reaction consists of
macrophages, lymphocytes, plasma cells and some
multinucleate giant cells. The condition may be confused
with tuberculous prostatitis.

NODULAR HYPERPLASIA
Non-neoplastic tumour-like enlargement of the prostate,
commonly termed benign nodular hyperplasia (BNH) or
benign enlargement of prostate (BEP), is a very common Figure 23.13 Nodular enlargement of the prostate. Sectioned
condition in men and considered by some as normal ageing surface of enlarged prostate shows soft to firm, grey-white, nodularity
process. It becomes increasingly more frequent above the age with microcystic areas.

718
























Figure 23.14 Nodular hyperplasia of the prostate. There is hyperplasia of fibromuscular elements. There are areas of intra-acinar papillary
infoldings (convolutions) lined by two layers of epithelium with basal polarity of nuclei.



left-over peripheral prostatic tissue may sometimes and detected as microscopic foci in a prostate removed for
undergo recurrent nodular enlargement or may develop BEP or found incidentally at autopsy. Thus, it is common to
carcinoma later. classify carcinoma of the prostate into the following 4 types:
Histologically, in every case, there is hyperplasia of all 1. Latent carcinoma. This is found unexpectedly as a small
three tissue elements in varying proportions—glandular, focus of carcinoma in the prostate during autopsy studies in
fibrous and muscular (Fig. 23.14): men dying of other causes. Its incidence in autopsies has been
Glandular hyperplasia predominates in most cases and variously reported as 25-35%.
is identified by exaggerated intra-acinar papillary 2. Incidental carcinoma. About 15-20% of prostatectomies
SECTION III
infoldings with delicate fibrovascular cores. The lining done for BEP reveal incidental carcinoma of the prostate.
epithelium is two-layered: the inner tall columnar mucus- 3. Occult carcinoma. This is the type in which the patient
secreting with poorly-defined borders, and the outer has no symptoms of prostatic carcinoma but shows evidence
cuboidal to flattened epithelium with basal nuclei. of metastases on clinical examination and investigations.
Fibromuscular hyperplasia when present as dominant 4. Clinical carcinoma. Clinical prostatic carcinoma is the
component appears as aggregates of spindle cells forming type detected by rectal examination and other investigations
an appearance akin to fibromyoma of the uterus. and confirmed by pathologic examination of biopsy of the
In addition to glandular and/or fibromuscular prostate.
hyperplasia, other histologic features frequently found
include foci of lymphocytic aggregates, small areas of ETIOLOGY. The cause of prostatic cancer remains obscure.
Systemic Pathology
infarction, corpora amylacea and foci of squamous However, a few factors have been suspected. These are as
metaplasia. under:
1. Endocrinologic factors. Androgens are considered
CLINICAL FEATURES. Clinically, the symptomatic cases essential for development and maintenance of prostatic
develop symptoms due to complications such as urethral epithelium. But how androgens are responsible for causing
obstruction and secondary effects on the bladder (e.g. malignant transformation is not yet clear. However, the
hypertrophy, cystitis), ureter (e.g. hydroureter) and kidneys etiologic role of androgens is supported by the following
(e.g. hydronephrosis). The presenting features include indirect evidences:
frequency, nocturia, difficulty in micturition, pain, i) Orchiectomy causes arrest of metastatic prostatic cancer
haematuria and sometimes, the patients present with acute disease (testis being the main source of testosterone).
retention of urine requiring immediate catheterisation. ii) Administration of oestrogen causes regression of pros-
tatic carcinoma.
CARCINOMA OF PROSTATE iii) Cancer of the prostate is extremely rare in eunuchs and
Cancer of the prostate is the second most common form of in patients with Klinefelter’s syndrome.
cancer in males, followed in frequency by lung cancer. It is a iv) Cancer of the prostate begins at the stage of life when
disease of men above the age of 50 years and its prevalence androgen levels are high. However, the cancer may remain
increases with increasing age so that more than 50% of men latent with decline in androgen level with advancing age.
80 years old have asymptomatic (latent) carcinoma of the 2. Racial and geographic influences. There are some racial
prostate. Many a times, carcinoma of the prostate is small and geographic differences in the incidence of prostatic

719
























Figure 23.15 Carcinoma of the prostate. The field shows microacini of small malignant cells infiltrating the prostatic stroma. Inset in the
photomicrograph shows perineural invasion by prostatic adenocarcinoma.



cancer. It is uncommon in Japanese and Chinese, while the prostate is firm and fibrous. Cut section is homogeneous
prevalence is high in Americans. African Americans have a and contains irregular yellowish areas.
markedly higher incidence as compared to whites which may Microscopically, 4 histologic types are described—
be related to genetic variation in androgen receptor gene. adenocarcinoma, transitional cell carcinoma, squamous
3. Environmental influences. Some common environ- cell carcinoma and undifferentiated carcinoma. However, CHAPTER 23
mental factors and carcinogens have been identified with adenocarcinoma is the most common type found in 96% of
high risk to development of prostatic cancer. These include cases and is the one generally referred to as carcinoma of
high dietary fat, and exposure to polycyclic aromatic the prostate. The other three histologic types are rare and
hydrocarbons. Flavonoids, antioxidants and selenium may resemble in morphology with similar malignant tumours
reduce the risk. elsewhere in the body.
4. Nodular hyperplasia. Though nodular prostatic The histologic characteristics of adenocarcinoma of the
hyperplasia has been suggested by some as precursor for prostate are as under (Fig. 23.15):
development of prostatic cancer, it is considered unlikely. 1. Architectural disturbance. In contrast to convoluted
Most prostatic cancers develop in the periphery of the gland appearance of the glands seen in normal and hyperplastic
while BEP occurs in the periurethral part of the gland. Any prostate, there is loss of intra-acinar papillary
concomitant occurrence of the two diseases may be convolutions. The groups of acini are either closely packed
considered as aging process. Approximately 15-20% of in back-to-back arrangement without intervening stroma
nodular hyperplastic prostates harbour carcinoma. or are haphazardly distributed.
5. Heredity. The possibility of genetic basis of prostatic 2. Stroma. Normally, fibromuscular sling surrounds the
cancer has been suggested by the observations of familial acini, whereas malignant acini have little or no stroma The Male Reproductive System and Prostate
clustering and 2-fold higher frequency in first-degree between them. The tumour cells may penetrate and
relatives. Prostatic cancer susceptibility gene has been replace the fibromuscular stroma.
identified in familial cases. 3. Gland pattern. Most frequently, the glands in well-
HISTOGENESIS. Histogenesis of prostatic adenocarcinoma differentiated prostatic adenocarcinoma are small or
has been documented as a mutistep process arising from medium-sized, lined by a single layer of cuboidal or low
premalignant stage of prostatic intraepithelial neoplasia (PIN). columnar cells. Moderately-differentiated tumours have
PIN refers to multiple foci of cytologically atypical luminal cribriform or fenestrated glandular appearance. Poorly-
cells overlying diminished number of basal cells in prostatic differentiated tumours have little or no glandular arrange-
ducts and is a forerunner of invasive prostatic carcinoma. ment but instead show solid or trabecular pattern.
Based on cytologic atypia, PIN may be low grade to high 4. Tumour cells. In many cases, the individual tumour
grade. PIN of high-grade progresses to prostatic adeno- cells in prostatic carcinoma do not show usual
carcinoma. morphologic features of malignancy. The tumour cells
may be clear, dark and eosinophilic cells. Clear cells have
MORPHOLOGIC FEATURES. Grossly, the prostate may foamy cytoplasm, dark cells have homogeneous basophilic
be enlarged, normal in size or smaller than normal. In 95% cytoplasm, and eosinophilic cells have granular cytoplasm.
of cases, prostatic carcinoma is located in the peripheral The cells may show varying degree of anaplasia and
zone, especially in the posterior lobe. The malignant nuclear atypia but is generally slight.

720 5. Invasion. One of the important diagnostic features of (WHO) histologic grading categorising prostate cancer into
malignancy in prostate is the early and frequent grade I (well-differentiated), grade II (moderately
occurrence of invasion of intra-prostatic perineural spaces. differentiated) and grade III (poorly differentiated) has
Lymphatic and vascular invasion may be present but are largely been replaced with Gleason’s microscopic grading
difficult to detect. system which is based on two features:
i) Degree of glandular differentiation.
SPREAD. The tumour spreads within the gland by direct ii) Growth pattern of the tumour in relation to the stroma.
extension, and to distant sites by metastases. These features are assessed by low-power examination
of the prostatic tissue. For clinical staging of prostate cancer,
Direct spread. Direct extension of the tumour occurs into TNM system is considered international standard.
the prostatic capsule and beyond. In late stage, the tumour
may extend into the bladder neck, seminal vesicles, trigone The diagnosis of prostatic carcinoma is made by
and ureteral openings. cytologic, biochemical, radiologic, ultrasonographic and
pathologic methods. However, definite diagnosis is
Metastases. Distant spread occurs by both lymphatic and established by histopathologic examination of transrectal
haematogenous routes. The rich lymphatic network ultrasound (TRUS)- guided core needle biopsy.
surrounding the prostate is the main mode of spread to the Two serum tumour markers employed commonly for
sacral, iliac and para-aortic lymph nodes. The earliest diagnosis and monitoring the prognosis of prostatic
metastasis occur to the obturator lymph node. Haemato- carcinoma are as under:
genous spread leads most often to characteristic osteoblastic
osseous metastases, especially to pelvis, and lumbar spine; Prostatic acid phosphatase (PAP) is secreted by prostatic
other sites of metastases are lungs, kidneys, breast and brain. epithelium. Elevation of serum level of PAP is found in cases
The route of blood-borne metastases may be retrograde of prostatic cancer which have extended beyond the capsule
spread by prostatic venous plexus or via systemic circulation. or have metastasised. PAP can also be demonstrated in the
normal prostatic tissues.
CLINICAL FEATURES. By the time symptoms appear, the Prostate-specific antigen (PSA) can be detected by
carcinoma of prostate is usually palpable on rectal immunohistochemical method in the malignant prostatic
examination as a hard and nodular gland fixed to the epithelium as well as estimated in the serum. A reading
surrounding tissues. In such symptomatic cases, clinical between 4 and 10 (normal 0-4 ng/ml) is highly suspicious
features are: urinary obstruction with dysuria, frequency, (10% risk) but value above 10 is diagnostic of prostatic carci-
SECTION III
retention of urine, haematuria, and in 10% of cases pain in noma. PSA assay is useful in deciding whether the metastasis
the back due to skeletal metastases. originated from the prostate or not. PSA assay is also helpful
Clinical staging of carcinoma prostate takes into account in distinguishing high-grade prostatic cancer from urothelial
the following: carcinoma, colonic carcinoma, lymphoma and prostatitis.
The tumour found incidentally or a clinically unsuspected PSA level is generally higher in low-grade tumours than in
cancer in prostate removed for benign disorder (Stage A). high-grade tumours.
Treatment of prostatic carcinoma consists of surgery,
The tumour palpable by rectal digital examination but radiotherapy and hormonal therapy. The hormonal depen-
confined to the prostate (Stage B). dence of prostate cancer consists of depriving the tumour
The tumour has extended locally beyond the prostate into cells of growth-promoting influence of testosterone. This can
the surrounding tissues (Stage C). be achieved by bilateral orchiectomy followed by
Systemic Pathology
The tumour is associated with distant metastases administration of oestrogen. Surgical approaches for prostate
(Stage D). cancer include transurethral resection (TUR), radical
Clinical staging has good correlation with histologic prostatectomy and transurethral US-guided laser-induced
grading and, thus, has a prognostic significance. Mostofi’s prostatectomy (TULIP).

❑

721


Chapter 24 The Female Genital Tract
Chapter 24








VULVA duct to a flattened lining because of increased intracystic
pressure. The cyst wall may show chronic inflammatory
NORMAL STRUCTURE infiltrate and a few mucus-secreting acini.

The vulva consists of structures of ectodermal origin—labia
majora, labia minora, mons pubis, clitoris, vestibule, hymen, NON-NEOPLASTIC EPITHELIAL DISORDERS
Bartholin’s glands and minor vestibular glands. The mons The older nomenclature vulvar dystrophy has been replaced
pubis and labia majora are covered externally by skin with by more descriptive and clinically relevant term, non-
hair follicles, sebaceous glands and sweat glands including neoplastic epithelial disorders of vulval skin and mucosa of
apocrine glands. The inner surface of labia majora, labia vulva. The term is applied to chronic lesions of the vulva
minora and vestibule are covered by stratified squamous characterised clinically by white, plaque-like, pruritic
epithelium. The clitoris is made up of vascular erectile tissue. mucosal thickenings and pathologically by disorders of
Bartholin’s or vulvovaginal glands are located one on each epithelial growth. Clinicians often use the term ‘leukoplakia’
side of the mass of tissue forming labia majora. The glands for such white lesions. But white lesions may represent other
are racemose type and their secretions are released during depigmented conditions as well such as vitiligo, inflam-
sexual excitement. matory dermatoses, carcinoma in situ, Paget’s disease, or
Since vulva is of ectodermal origin, the common inflam- even invasive carcinoma, and thus use of the term CHAPTER 24
matory conditions affecting it are similar to those found on leukoplakia by pathologists is not recommneded.
the skin generally. A few specific conditions such as Currently, non-neoplastic epithelial disorders of the skin
Bartholin’s cyst and abscess, vulvar dystrophy and certain of vulva includes following 2 lesions:
tumours are described below. 1. Lichen sclerosus (older term: atrophic dystrophy).
2. Squamous hyperplasia (older term: hyperplastic
BARTHOLIN’S CYST AND ABSCESS dystrophy).
The two types of lesions may coexist in the same patient.
Inflammation of Bartholin’s vulvovaginal glands (Bartholin’s
adenitis) may occur due to bacterial infection, notably Lichen Sclerosus
gonorrhoeal infection. Infection may be acute or chronic. The Female Genital Tract
Acute Bartholin’s adenitis occurs from obstruction and Lichen sclerosus may occur anywhere in the skin (Chapter
dilatation of the duct by infection resulting in formation of a 26) but is more common and more extensive in the vulva in
Bartholin’s abscess. The condition presents with intense pain, post-menopausal women. The lesions appear as multiple,
swelling and fluctuant mass which can be incised and small, coalescent, yellowish-blue macules or papules which
drained. produce thin and shiny parchment-like skin. The lesions may
extend from vulva onto the perianal and perineal area.
Microscopic examination shows the usual appearance of Clinically, the patient, usually a post-menopausal woman,
acute suppurative inflammation with neutrophilic infil- complains of intense pruritus which may produce excoriation
tration, hyperaemia, oedema and epithelial degeneration. of the affected skin. Eventually, there is progressive shrinkage
and atrophy resulting in narrowing of the introitus, clinically
Chronic Bartholin’s adenitis results from a less virulent referred to as kraurosis vulvae.
infection so that the process is slow and prolonged. Alter-
natively, the chronic process evolves from repeated attacks MORPHOLOGIC FEATURES. Microscopically, the
of less severe acute inflammation which may be short of following characteristics are seen (Fig. 24.1,A):
abscess formation and resolves incompletely. In either case, 1. Hyperkeratosis of the surface layer.
the chronic inflammatory process terminates into fluid-filled 2. Thinning of the epidermis with disappearance of rete
Bartholin’s cyst. The resulting cyst may be quite large, ridges.
3-5 cm in diameter and readily palpable in the perineum, 3. Amorphous homogeneous degenerative change in the
but may remain asymptomatic for years. dermal collagen.
4. Chronic inflammatory infiltrate in the mid-dermis.
Histologic examination shows variable lining of the cyst
varying from the transitional epithelium of the normal Lichen sclerosus is not a premalignant lesion and responds
favourably to topical treatment with androgens.

722 Histologically, they are covered by an orderly stratified
squamous epithelium. The stroma consists of loose fibrous
and myxomatous connective tissue with some adipose
tissue and blood vessels.

Papillary Hidradenoma (Hidradenoma Papilliferum)
This is a benign tumour arising from apocrine sweat glands
of the vulva. Most commonly, it is located in the labia or in
the perianal region as a small sharply circumscribed nodule.

Histologically, the tumour lies in the dermis under a
normal epidermis. The tumour consists of papillary
structures composed of fibrovascular stalk and is covered
by double layer of epithelial cells—a layer of flattened
myoepithelial cells and an overlying layer of columnar
cells.

Condyloma Acuminatum

Condyloma acuminata or anogenital warts are benign
Figure 24.1 Non-neoplastic epithelial disorders of vulval skin.
papillary lesions of squamous epithelium which can be
transmitted venereally to male sex partner. They may be
Squamous Hyperplasia solitary but more frequently are multiple forming soft warty
masses. The common locations are the anus, perineum,
Squamous hyperplasia is characterised by white, thickened vaginal wall, vulva and vagina. They are induced by human
vulvar lesions which are usually itchy. The cause is unknown papilloma virus (HPV), particularly types 6 and 11.
but symptomatic relief results from use of topical treatment
with corticosteroids. Histologically, they are identical to their counterparts on
male external genitalia (Chapter 23). The features consist
MORPHOLOGIC FEATURES. The histologic charac-
SECTION III
teristics are as under (Fig. 24.1,B): of a tree-like proliferation of stratified squamous
1. Hyperkeratosis. epithelium, showing marked acanthosis, hyperkeratosis,
2. Hyperplasia of squamous epithelium with elongation parakeratosis, papillomatosis and perinuclear
of rete ridges. vacuolisation of epithelium called koilocytosis, indicative
3. Increased mitotic activity of squamous layers but of HPV infection. The papillary projections consist of fibro-
cytologically no atypia. vascular stoma.
4. Chronic inflammatory infiltrate in the underlying Condylomas are benign lesions and regress sponta-
dermis. neously except in immunosuppressed individuals.

A small proportion of cases of hyperplastic dystrophy
(1-4%) may show cytologic atypia and produce vulvar dys- Extra-Mammary Paget’s Disease
Systemic Pathology
plasia which may progress to vulvar carcinoma in situ and Paget’s disease of the vulva is a rare condition which has
invasive carcinoma. skin manifestations like those of Paget’s disease of the nipple
(Chapter 25). The affected skin, most often on the labia
VULVAL TUMOURS
majora, appears as map-like, red, scaly, elevated and
Vulva is the site of a variety of benign and malignant neo- indurated area.
plasms which are in common with skin neoplasms elsewhere
in the body. These include papillomas, fibromas, neuro- Histologically, extra-mammary Paget’s disease is
fibromas, angiomas, lipomas, sweat gland tumours, identified by the presence of large, pale, carcinoma cells
squamous cell carcinoma, verrucous carcinoma, malignant lying singly or in small clusters within the epidermis and
melanoma and mesenchymal sarcomas. However, a few adnexal structures. These cells characteristically have halo
tumours peculiar to the vulva such as stromal polyps, which stains positively with PAS, alcian blue and
papillary hidradenoma, condyloma acuminatum, extra- mucicarmine and are thus believed to be of apocrine
mammary Paget’s disease, vulval carcinoma and intra- epithelial origin.
epithelial neoplasia are discussed below.
Unlike Paget’s disease of the breast in which case there
is always an underlying ductal carcinoma, extra-mammary
Stromal Polyps
Paget’s disease is confined to the epidermis in most cases
Stromal (fibroepithelial) polyps or acrochordons may form and only a small proportion of cases have an underlying
in the vulva or vagina. There may be single or multiple adenocarcinoma. Prognosis is good if there is no invasion
polypoid masses. but occasional cases progress into invasive carcinoma.

the stage (Fig. 24.2). HPV-positive tumours are more often 723
poorly-differentiated squamous cell carcinoma while
HPV-negative are well-differentiated keratinising type.
Verrucous carcinoma is a rare variant which is a fungating
tumour but is locally malignant.
Clinical staging for vulval carcinoma based on tumour size
(< or > 2 cm) and extent of spread has been described by
International Federation of Gynaecology and Obstetrics
(FIGO staging, Table 24.1).

VAGINA
NORMAL STRUCTURE

The vagina consists of a collapsed cylinder extending
between vestibule externally and the cervix internally.

Figure 24.2 Vulval intraepithelial neoplasia (VIN) lesion (Bowen’s Histologically, the vaginal wall consists of 3 layers: an outer
disease). There is hyperkeratosis, parakeratosis, acanthosis, koilocytosis fibrous, a middle muscular and an inner epithelial. The
and presence of atypical anaplastic cells throughout the entire thickness muscular coat has a double layer of smooth muscle. The
of the epithelium. Photomicrograph on right under higher magnification
shows mitotic figures in the layers of squamous epithelium. epithelial layer consists of stratified squamous epithelium
which undergoes cytologic changes under hormonal stimuli.
Vulval Intraepithelial Neoplasia and Oestrogen increases its thickness such as during reproductive
Invasive Carcinoma years, whereas the epithelium is thin in childhood, and
atrophic after menopause when oestrogen stimulation is
Vulval intraepithelial neoplasia (VIN) and invasive minimal.
squamous cell carcinoma are morphologically similar to Primary diseases of the vagina are uncommon. The only CHAPTER 24
those in the cervix and vagina. The etiologic role of certain important clinicopathologic conditions which require to be
viruses in carcinogenesis, particularly high-risk HPV types described here are vaginitis and certain tumours.
16 and 18, in these sites is well documented. Mention has
already been made about the preceding stage of vulval VAGINITIS AND VULVOVAGINITIS
epithelial disorders, particularly squamous hyperplasia, in
the development of these lesions. Vulval carcinoma Since vulva and vagina are anatomically close to each other,
constitutes 3% of all female genital tract cancers. The usual often inflammation of one affects the other location. Certain
age for development of cancer or VIN is the 4th to 6th decade. other infections are quite common in the vulva and vagina
as follows:
Grossly, VIN and vulval carcinoma in early stage is a Bacterial e.g. streptococci, staphylococci, Escherichia coli,
‘white’ lesion (leukoplakia) while later the area develops Haemophilus vaginalis. The Female Genital Tract
an exophytic or endophytic (ulcerative) growth pattern.
The traditional VIN lesion, described as Bowen’s disease Fungal e.g. Candida albicans.
of the vulva, is generally a slightly elevated velvety plaque Protozoal e.g. Trichomonas vaginalis.
lesion. Viral e.g. Herpes simplex.
Microscopically, these lesions are squamous cell type with The most common causes of vaginitis are Candida
varying anaplasia and depth of invasion depending upon (moniliasis) and Trichomonas (trichomoniasis). The hyphae
of Candida can be seen in the vaginal smears. Similarly, the
protozoa, Trichomonas, can be identified in smears (Chapter
 TABLE 24.1: FIGO Staging of Carcinoma of the Vulva. 11). These infections are particularly common in pregnant
and diabetic women and may involve both vulva and vagina.
Stage 0 Carcinoma in situ. However, the adult vaginal mucosa is relatively resistant to
Stage I Tumour confined to the vulva and/or perineum; 2 cm gonococcal infection because of its histology.
or less in diameter.
Stage II Tumour confined to the vulva and/or perineum; more
than 2 cm in diameter. TUMOURS AND TUMOUR-LIKE CONDITIONS
Stage III Tumour of any size with
(1) adjacent spread to the lower urethra and/ or Vaginal cysts such as Gartner’s duct (Wolffian) cyst lined by
vagina, or the anus, and/or glandular epithelium and vaginal inclusion cyst arising from
(2) unilateral regional lymph node metastasis. inclusion of vaginal epithelium are more common benign
Stage IVA Tumour invades any of the following—upper urethra, vaginal tumours and tumour-like conditions. Other
bladder mucosa, rectal mucosa, pelvic bone, and/or uncommon benign tumours are papillomas, fibromas,
bilateral regional node metastasis. lipomas, angiomas and leiomyomas and resemble their
Stage IVB Any distant metastasis including pelvic lymph nodes. counterparts elsewhere in the body. Primary malignancies

724 of the vagina are rare and include carcinoma (squamous cell The tumour invades extensively in the pelvis and
carcinoma and adenocarcinoma) and embryonal metastasises to regional lymph nodes and distant sites such
rhabdomyosarcoma (sarcoma botyroides). as to lungs and liver. Radical surgery combined with
chemotherapy offers some benefit.
Carcinoma of Vagina
Primary carcinoma of the vagina is an uncommon tumour. CERVIX
Squamous cell dysplasia or vaginal intraepithelial neoplasia NORMAL STRUCTURE
occur less frequently as compared to the cervix or vulva and
can be detected by Pap smears as discussed in Chapter 11. The cervix consists of an internal os communicating with the
Invasive carcinoma of the vagina includes two main types: endometrial cavity above, and an external os opening into
1. Squamous cell carcinoma of vagina constitutes less than the vagina below. Ectocervix (exocervix) or portio vaginalis is
2% of all gynaecologic malignancies and is similar in the part of the cervix exposed to the vagina and is lined by
morphology as elsewhere in the female genital tract. The role stratified squamous epithelium, whereas the endocervix is
of HPV types 16 and 18 in its etiology and the possibility of continuous with the endocervical canal and is lined by a
an extension from cervical carcinoma to the vagina have been single layer of tall columnar mucus-secreting epithelium. The
emphasised. endocervical mucosa is thrown into folds resulting in
formation of clefts and tunnels, commonly referred to as
2. Adenocarcinoma of the vagina is much less than cervical glands that secrete mucus. The junction of the
squamous cell carcinoma of the vagina. It may be endo- ectocervix and endocervix—junctional mucosa, consists of
metrioid or mucinous type. The significance of association gradual transition between squamous and columnar
of diethylstilbestrol administered during pregnancy to the epithelia (squamo-columnar junction) and is clinically and
mother with development of adenocarcinoma of the vagina pathologically significant landmark. The cervical mucosa
in the daughter has been discussed in Chapter 8. undergoes changes under the influence of hormones and
Clinical staging of carcinoma of vagina proposed by FIGO during pregnancy. The cervical mucus varies during the men-
is given in Table 24.2.
strual cycle, being viscus after menses, but under the
influence of oestrogen becomes thin which on drying forms
Embryonal Rhabdomyosarcoma fern-like pattern on glass slide.
(Sarcoma Botyroides)
Lesions of the cervix are rather common. Of great signifi-
This is an unusual and rare malignant tumour occurring in cance are cervicitis, certain benign tumours, dysplasia,
SECTION III
infants and children under 5 years of age. The common carcinoma in situ and invasive carcinoma.
location is anterior vaginal wall. Similar tumours may occur
in the urinary bladder (Chapter 22), head and neck region CERVICITIS
(Chapter 18) (orbit, nasopharynx, middle ear, oral cavity) and Some degree of cervical inflammation is present in virtually
biliary tract.
all multiparous women and some nulliparous women. The
normal intact ectocervical stratified epithelium is usually
MORPHOLOGIC FEATURES. Grossly, the tumour is more resistant to infection whereas the endocervical
characterised by bulky and polypoid grape-like mass columnar epithelium bears the brunt of the initial
(botyroides = grape) that fills and projects out of the vagina.
inflammation.
Histologically, the features are as under: Cervicitis may be specific or nonspecific, acute or chronic.
Systemic Pathology
1. Groups of round to fusiform tumour cells are Specific cervicitis may be caused by tuberculosis, syphilis,
characteristically lying underneath the vaginal epithelium, granuloma inguinale, lymphogranuloma venereum,
called cambium layer of tumour cells. chlamydia and chancroid. Nonspecific cervicitis is more
2. The central core of polypoid masses is composed of frequent and is generally divided into acute and chronic
loose and myxoid stroma with many inflammatory cells. forms, the latter being quite common.
ACUTE CERVICITIS. Acute cervicitis is usually associated
with puerperium or gonococcal infection. Other causes are
  TABLE 24.2: FIGO Clinical Staging of Carcinoma of the Vagina. primary chancre and infection with herpes simplex.
Stage 0 Carcinoma in situ.
Stage I Carcinoma is limited to the vaginal wall. Grossly, the cervix shows everted endocervical mucosa
Stage II Carcinoma has involved the subvaginal tissue but which is red and oedematous.
has not extended to the pelvic wall. Histologically, there is infiltration of the subepithelial and
Stage III Carcinoma has extended to the pelvic wall periglandular tissue with neutrophils, and there is oedema
Stage IV Carcinoma has extended beyond the true pelvis or and congestion. The mucosa may be ulcerated and
has clinically involved the mucosa of the bladder or haemorrhagic.
rectum.
Stage IVA Spread of the growth to adjacent organs and/ or direct CHRONIC CERVICITIS. Chronic nonspecific cervicitis is
extension beyond the true pelvis. encountered quite frequently and is the common cause of
Stage IVB Spread to distant organs.
leukorrhoea. The most common organisms responsible for

chronic cervicitis are the normal mixed vaginal flora that 725
includes streptococci, enterococci (e.g. E. coli) and
staphylococci. Other infecting organisms include gonococci,
Trichomonas vaginalis, Candida albicans and herpes simplex.
Factors predisposing to chronic cervicitis are sexual
intercourse, trauma of childbirth, instrumentation and excess
or deficiency of oestrogen.
Grossly, there is eversion of ectocervix with hyperaemia,
oedema and granular surface. Nabothian (retention) cysts
may be grossly visible from the surface as pearly grey
vesicles.
Histologically, chronic cervicitis is characterised by
extensive subepithelial inflammatory infiltrate of
lymphocytes, plasma cells, large mononuclear cells and a
few neutrophils. There may be formation of lymphoid
follicles termed follicular cervicitis. The surface epithelium
may be normal, or may show squamous metaplasia. The
squamous epithelium of the ectocervix in cases of uterine
prolapse may develop surface keratinisation and
hyperkeratosis, so called epidermidisation. Areas of Figure 24.3 Endocervical polyp. The surface is covered by
squamous metaplasia and hyperkeratosis may be endocervical mucosa with squamous metaplasia. The stromal core is
mistaken on cursory microscopic look for a well- composed of dense fibrous tissue which shows nonspecific inflammation.
differentiated squamous carcinoma.

TUMOURS endocervical glands without intervening stroma. The
condition is caused by progestrin stimulation such as during CHAPTER 24
Both benign and malignant tumours are common in the pregnancy, postpartum period and in women taking oral
cervix. In addition, cervix is the site of ‘shades of grey’ lesions contraceptives. Morphologically, condition may be mistaken
that include cervical dysplasia and carcinoma in situ (cervical for well-differentiated adenocarcinoma.
intraepithelial neoplasia, CIN), currently termed squamous
intraepithelial lesions (SIL). Benign tumours of the cervix Squamous Intraepithelial Lesion (SIL)
consist most commonly of cervical polyps. Uncommon (Cervical Intraepithelial Neoplasia, CIN)
benign cervical tumours are leiomyomas, papillomas and
condyloma acuminatum which resemble in morphology with TERMINOLOGY. Presently, the terms dysplasia, CIN,
similar tumours elsewhere in the genital tract. The most carcinoma in situ, and SIL are used synonymously as follows:
common malignant tumour is squamous carcinoma of the DYSPLASIA. The term ‘dysplasia’ (meaning ‘bad moul-
cervix. ding’) has been commonly used for atypical cytologic The Female Genital Tract
changes in the layers of squamous epithelium, the changes
Cervical Polyps
being progressive (Chapter 3). Depending upon the thickness
Cervical polyps are localised benign proliferations of of squamous epithelium involved by atypical cells, dysplasia
endocervical mucosa though they may protrude through the is conventionally graded as mild, moderate and severe. Carci-
external os. They are found in 2-5% of adult women and noma in situ is the full-thickness involvement by atypical
produce irregular vaginal spotting. cells, or in other words carcinoma confined to layers above
the basement membrane. At times, severe dysplasia may not
MORPHOLOGIC FEATURES. Grossly, cervical polyp is be clearly demarcated from carcinoma in situ. It is well
a small (up to 5 cm in size), bright red, fragile growth accepted that invasive cervical cancer evolves through
which is frequently pedunculated but may be sessile.
Microscopically, most cervical polyps are endocervical progressive stages of dysplasia and carcinoma in situ.
polyps and are covered with endocervical epithelium CIN. An alternative classification is to group various grades
which may show squamous metaplasia. Less frequently, of dysplasia and carcinoma in situ together into cervical
the covering is by squamous epithelium of the portio intraepithelial neoplasia (CIN) which is similarly graded
vaginalis. The stroma of the polyp is composed of loose from grade I to III. According to this concept, the criteria are
and oedematous fibrous tissue with variable degree of as under:
inflammatory infiltrate and contains dilated mucus- CIN-1 represents less than one-third involvement of the
secreting endocervical glands (Fig. 24.3). thickness of epithelium (mild dysplasia).
CIN-2 is one-third to two-third involvement (moderate
Microglandular Hyperplasia dysplasia).
Microglandular hyperplasia is a benign condition of the CIN-3 is full-thickness involvement or equivalent to
cervix in which there is closely packed proliferation of carcinoma in situ (severe dysplasia and carcinoma in situ).

726
  TABLE 24.3: Classification of Cervical Intraepithelial Neoplasia/Squamous Intraepithelial Lesion (CIN/SIL).
Bethesda System HPV Types Morphology CIN Dysplasia
L-SIL 6, 11 Koilocytic atypia, flat condyloma CIN-1 Mild
H-SIL 16, 18 Progressive cellular atypia, loss of maturation CIN-2, CIN-3 Moderate, severe,
carcinoma in situ
(L-SIL = Low-grade squamous intraepithelial lesions; H-SIL = High-grade squamous intraepithelial lesion; CIN= Cervical intraepithelial neoplasia)

SIL. Currently, the National Cancer Institute (NCI) of the women, cigarette smoking women, users of oral
US has proposed the Bethesda System (TBS) for reporting contraceptives, HIV infection and immunosuppression,
cervical and vaginal cytopathology. According to the while a low incidence is noted in virgins and nuns.
Bethesda system, based on cytomorphologic features and 2. Virologic studies. Human papilloma virus (HPV)
HPV types implicated in their etiology, the three grades of infection is strongly implicated in the etiology of cervical
CIN are readjusted into two grades of squamous cancer. By recombinant DNA hybridisation techniques,
intraepithelial lesions (SIL)— low-grade SIL (L-SIL) and high- following observations have been documented:
grade SIL (H-SIL) as under: High-risk type HPV, most commonly of types 16 and 18
L-SIL corresponds to CIN-1 and is a flat condyloma, (in 70% cases), and less often types 31, 33, 52 and 58, are
having koilocytic atypia, usually related to HPV 6 and 11 present in 70-100% cases of cervical cancer.
infection (i.e. includes mild dysplasia and HPV infection). Low-risk type HPV types 6 and 11 are found most
H-SIL corresponds to CIN-2 and 3 and has abnormal frequently in condylomas.
pleomorphic atypical squamous cells. HPV 16 and 18 are Mixed high and low risk types of HPV may be found in
implicated in the etiology of H-SIL (i.e. includes moderate dysplasias.
dysplasia, severe dysplasia, and carcinoma in situ). Besides HPV, a few other viruses may adversely affect
A comparison of these classifications is shown in the prognosis but do not have etiologic relationship are HIV,
Table 24.3. HTLV-1 and EBV infection.
Progressive grades of dysplsia/CIN/SIL is a classical
example of progression of malignancy through stepwise
epithelial changes and that it can be detected early by simple
Papanicolaou cytologic test (‘Pap smear’) (Chapter 11). The
SECTION III
use of Pap smear followed by colposcopy and biopsy
confirms the diagnosis which has helped greatly in instituting
early effective therapy and thus has reduced the incidence
of cervical cancer in the West.
CIN or SIL can develop at any age though it is rare before
puberty. Low-grade reversible changes arise in young
women between 25 and 30 years old, whereas progressive
higher grades of epithelial changes develop a decade later.
Hence, the desirability of periodic Pap smears on all women
after they become sexually active.
Systemic Pathology
ETIOPATHOGENESIS. The biology of CIN/SIL and its
relationship to invasive carcinoma of the cervix is well
understood by epidemiologic, virologic, molecular,
immunologic and ultrastructural studies (Fig. 24.4):
1. Epidemiologic studies. Based on epidemiology of large
population of women with cervical cancer, several risk factors
have been identified which include the following 4 most
important factors:
i) Women having early age of sexual activity.
ii) Women having multiple sexual partners.
iii) Women with persistent HPV infection with high-risk types
of oncogenic virus.
iv) Potential role of high risk male sexual partner such as
promiscuous male having previous multiple sexual partners,
having history of penile condyloma, or male who had
previous spouse with cervical cancer.
In addition to the above factors, other epidemiologic
observations reveal high incidence of cervical cancer in lower Figure 24.4 Role of human papillomavirus (HPV) in the patho-
socioeconomic strata, in multiparous women, promiscuous genesis of cervical neoplasia.

727
















































Figure 24.5 Cervical intraepithelial neoplasia (CIN) and squamous intraepithelial lesions (SIL). A, Schematic representation of histologic CHAPTER 24
changes (lower part of figure). The grades of CIN-1 or mild dysplasia (L-SIL), CIN-2 (moderate dysplasia) and CIN-3 (severe dysplasia and
carcinoma in situ) (together grouped as H-SIL) show progressive increase in the number of abnormal cells parallel to the increasing severity of
grades. B, Exfoliative cytologic studies in various grades of cellular changes (upper part of figure). The Female Genital Tract

3. Molecular studies. Immunohistochemical, cytogenetic 5. Ultrastructural studies. The changes observed on ultra-
and molecular studies have shown that low-risk HPV types structural studies of cells in CIN/SIL reveal increased mito-
do not integrate in the host cell genome, while high-risk HPV chondria and free ribosomes, and depletion of normally
types are integrated into the nucleus of cervical epithelial accumulated glycogen in the surface cells. The latter change
cells. Upon integration, protein product of HPV-16 and 18, forms the basis of Schiller’s test in which the suspected cervix
E7 and E6 proteins respectively, inactivate tumour suppres- is painted with solution of iodine and potassium iodide. The
sor genes, p53 and RB-1 gene, thus permitting uncontrolled cancerous focus, if present, fails to stain because of lack of
cellular proliferation. It has been possible to document that glycogen in the surface cells.
morphologic abnormalities in cervical lesions have good
correlation with underlying cellular events by use of MORPHOLOGIC FEATURES. Grossly, no specific
techniques such as proliferation cell nuclear antigen picture is associated with cellular atypia found in
(PCNA), p16, p53 and p63 expression, and nucleolar organizer dysplasias or carcinoma in situ except that the changes
region (AgNOR). However, all women who harbour HPV begin at the squamocolumnar junction or transitional
infection with high-risk type do not develop invasive cancer zone. The diagnosis can be suspected clinically on the basis
of the cervix. Women who have persistence of this infection of Schiller’s test done on bedside.
or those who have another cofactor such as cigarette smoking Histologically, distinction between various grades of CIN
or immunodeficiency, are at greater risk to develop is quite subjective, but, in general dysplastic cells are
progression of lesions. distributed in the layers of squamous epithelium for
4. Immunologic studies. Circulating tumour specific anti- varying thickness, and accordingly graded as mild,
gens and antibodies are detected in patients of cervical cancer. moderate and severe dysplasia, and carcinoma in situ
Antibodies to virus specific antigens are identified on tumour (Fig. 24.5,A).
cells and in sera of such patients.

728 In mild dysplasia (CIN-1), the abnormal cells extend up worldwide cervical cancer remains third most common
to one-third thickness from the basal to the surface layer; cancer in women, next to breast and lung cancer. Although
In moderate dysplasia (CIN-2) up to two-thirds; accurate statistics are not available from India, but it is
In severe dysplasia (CIN-3), these cells extend from 75- perhaps the leading cause of death in women. In the Pap
90% thickness of epithelium; and screening programme, patients having abnormal Pap smear
In carcinoma in situ (included in CIN-3), the entire are appropriately followed up and, therefore, it requires
thickness from the basement membrane to the surface understanding of the Bethesda system by the clinician as
shows dysplastic cells. regards value and limitations of cytology reports prepared
The atypical cells migrate to the surface layers from by the cytologist/cytotechnician.
where they are shed off (exfoliated) into vaginal secre- Cervical screening recommendations include annual
tions in Pap smear. The individual dysplastic or abnor- cervical smear in all sexually active women having any risk
mal cells in these grades of atypia show various cytologic factors listed above. However, if three consecutive Pap
changes such as: crowding of cells, pleomorphism, high smears are negative in ‘high-risk women’ or satisfactory in
nucleocytoplasmic ratio, coarse and irregular nuclear ‘low risk women’, frequency of Pap screening is reduced.
chromatin, numerous mitoses and scattered dyskaryotic There is no upper age limit for cervical screening.
cells. The broad principles of the Bethesda system of cytologic
evaluation are as under:
The diagnosis of dysplasia and carcinoma in situ or CIN/ Pap smears are evaluated as regards adequacy of specimen
SIL is best made by exfoliative cytologic studies discussed in i.e. satisfactory for evaluation, satisfactory but limited, or
Chapter 11. The degree of atypicality in the exfoliated surface unsatisfactory for evaluation giving reason.
epithelial cells can be objectively graded on the basis of 3 General diagnosis is given in the form of normal or
principal features (Fig. 24.5,B): abnormal smear.
1. More severe nuclear dyskaryotic changes such as Descriptive diagnosis is given in abnormal smears that
increased hyperchromasia and nuclear membrane folding. includes: benign cellular changes, reactive cellular changes,
2. Decreased cytoplasmic maturation i.e. less cytoplasm as and abnormalities of epithelial cells.
the surface cells show less maturation. Cellular abnormalities include: ASCUS (atypical
3. In lower grades of dysplasia (CIN-1/L-SIL) predomi- squamous cells of undetermined significance), L-SIL
nantly superficial and intermediate cells are shed off whereas (mentioning HPV infection and CIN-1 present or not), H-SIL
in severe dysplasia and in carcinoma in situ (CIN-3/H-SIL) (stating CIN-2 or CIN-3) and squamous cell carcinoma.
SECTION III
the desquamated cells are mainly small, dark basal cells. The
lesions of SIL in cytology have histologic correlation with Invasive Cervical Cancer
colposcopy-directed cervical biopsy in 70-90% cases Invasive cervical cancer in about 80% of cases is epidermoid
(Fig. 24.6).
(squamous cell) carcinoma. The incidence of invasive
CERVICAL SCREENING AND THE BETHESDA carcinoma of the cervix has shown a declining trend in
SYSTEM. With introduction of effective Pap screening developed countries in the last half of the century due to
programme in the Western countries, incidence of invasive increased use of Pap smear technique for early detection and
cervical cancer has declined greatly. However, still diagnosis but the incidence remains high in developing


Systemic Pathology
























Figure 24.6 Squamous intraepithelial lesions (SIL). A, L-SIL. The smear shows koilocytes having abundant vacuolated cytoplasm and nuclear
enlargement (arrow). B, H-SIL. The squamous cells have scanty cytoplasm and markedly hyperchromatic nuclei having irregular nuclear outlines.
The background shows numerous PMNs.

729























Figure 24.7 Invasive carcinoma of the cervix common gross appear-
ance is of a fungating or exophytic, cauliflower-like tumour. Gross
photograph on right shows replacement of the cervix by irregular grey-
white friable growth (arrow) extending into cervical canal as well as distally
into attached vaginal cuff.



countries with low living standards. The risk factors and nodes. Distant metastases occur in the lungs, liver, bone
etiologic factors are the same as for CIN discussed above. marrow and kidneys.
The peak incidence of invasive cervical cancer is in 4th to Histologically, the following patterns are seen: CHAPTER 24
6th decades of life.
1. Epidermoid (Squamous cell) carcinoma. This type
MORPHOLOGIC FEATURES. Grossly, invasive cervical comprises vast majority of invasive cervical carcinomas
carcinoma may present 3 types of patterns: fungating, (about 70%).
ulcerating and infiltrating. The fungating or exophytic The most common pattern (70%) is moderately-
pattern appearing as cauliflower-like growth infiltrating differentiated non-keratinising large cell type and has
the adjacent vaginal wall is the most common type better prognosis (Fig. 24.8).
(Fig. 24.7). Characteristically, cervical carcinoma arises Next in frequency (25%) is well-differentiated kerati-
from the squamocolumnar junction. The advanced stage nising epidermoid carcinoma.
of the disease is characterised by widespread destruction Small cell undifferentiated carcinoma (neuroendocrine
and infiltration into adjacent structures including the or oat cell carcinoma) is less common (5%) and has a poor The Female Genital Tract
urinary bladder, rectum, vagina and regional lymph prognosis.




























Figure 24.8 Invasive cancer cervix. Common histologic type is epidermoid (squamous cell) carcinoma showing the pattern of a moderately-
differentiated non-keratinising large cell carcinoma.

730 pathologic entities are discussed below, but first, the cyclic
 TABLE 24.4: FIGO Clinical Staging of Carcinoma of the Cervix
Uteri. changes in normal menstrual cycle are briefly reviewed.
Stage 0 Carcinoma in situ NORMAL CYCLIC CHANGES
Stage I Carcinoma strictly confined to the cervix
IA Preclinical carcinomas diagnosed only by microscopy The normal endometrial cycle begins with proliferative phase
Maximum size 5 mm deep and 7 mm across lasting for about 14 days under the influence of oestrogen,
measured from the base of epithelium. followed by ovulation on or around 14th day, and consequent
IA1 Stromal invasion of less than 3 mm in depth and secretory phase under the influence of progesterone. The
7 mm in horizontal axis (minimally invasive).
IA2 Stromal invasion of 3 to 5 mm depth and horizontal cycle ends with endometrial shedding and the next cycle
7 mm or less (microinvasive). begins anew.
IB Clinical lesion confined to the cervix or preclinical The histologic changes in different phases of the
lesions greater than stage IA. menstrual cycle vary.
IB1 Clinical lesions no greater than 4 cm in size.
IB2 Clinical lesions greater than 4 cm in size. Histologically, the endometrium has different appearance
Stage II Carcinoma extends beyond the cervix but has not in different phases of the menstrual cycle. Essentially, the
extended to the pelvic wall. Involvement of the vagina endometrium consists of 3 structures: the endometrial
limited to upper two-thirds. lining epithelium, endometrial glands and stroma.
IIA No obvious parametrial involvement.
IIB Obvious parametrial involvement. Epithelial lining undergoes increase in its thickness
Stage III The carcinoma has extended to the pelvic wall. The from cuboidal to tall columnar appearance at ovulation
tumour invades the lower third of vagina. and subsequently regresses.
IIIA No extension to the pelvic wall. Endometrial glands with their lining provide most of
IIIB Extension to the pelvic wall and/or hydronephrosis the information on phase of the menstrual cycle. In the
or nonfunctioning kidney. immediate postmenstrual period, the glands are straight
Stage IV The carcinoma has extended beyond the true pelvis and tubular, having columnar lining with basal nuclei.
or has clinically involved the mucosa of the bladder
or rectum. This phase is under the predominant influence of
IVA Spread of the growth to adjacent organs. oestrogen and lasts for about 14 days and is called
IVB Spread to distant organs. proliferative phase. The evidence of ovulation is taken from
the appearance of convolutions in the glands and sub-
SECTION III
nuclear vacuolation in the cells indicative of secretions.
2. Adenocarcinoma. Adenocarcinomas comprise about The secretory changes remain prominent for the next 7
20-25% of cases. These may be well-differentiated mucus- days after ovulation for implantation of the ovum if it has
secreting adenocarcinoma, or clear cell type containing been fertilised. Otherwise, the secretory activity wanes
glycogen but no mucin. during the following 7 days with increased luminal
3. Others. The remaining 5% cases are a variety of other secretions and a frayed and ragged luminal border of the
patterns such as adenosquamous carcinoma, verrucous cells lining the glands. This phase is under the
carcinoma and undifferentiated carcinoma. predominant influence of progesterone and is called
secretory phase. Eventually, the endometrium is sloughed
CLINICAL STAGING. Classification of cervical cancer away at menstruation followed by beginning of the fresh
described by the Cancer Committee of the International cycle (Fig. 24.9).
Federation of Gynaecology and Obstetrics (FIGO Endometrial stroma in the pre-ovulatory phase or
Systemic Pathology
classification) is widely adopted by the clinicians and proliferative phase is generally dense and compact,
pathologists and is given in Table 24.4.
composed of oval to spindled cells. In the post-ovulatory
phase or secretory phase, the stroma is loose and
MYOMETRIUM AND ENDOMETRIUM oedematous, composed of large, pale and polyhedral cells.
The true decidual reaction of the stroma occurs if the
NORMAL STRUCTURE
pregnancy has taken place. However, decidual reaction
The myometrium is the thick muscular wall of the uterus may be suggested in the absence of pregnancy due to
which is covered internally by uterine mucosa called the extreme response to progesterone. Thus, it may be
endometrium. The endometrium extends above the level of impossible to distinguish an advanced progestational
the internal os where it joins the endocervical epithelium. endometrium from early pregnancy except for the
The myometrium is capable of marked alterations in its size, presence of trophoblastic tissue.
capacity and contractility during pregnancy and labour. The
endometrium responds in a cyclic fashion to the ovarian EFFECTS OF HORMONES
hormones with resultant monthly menstruation and has
remarkable regenerative capacity. In addition to the changes that take place during the normal
The lesions pertaining to the corpus uteri and the menstrual cycle, the endometrium undergoes morphologic
endometrium are numerous and constitute vast majority of changes when hormonal preparations are administered, or
gynaecologic conditions. However, some of the important during pregnancy and menopause.

731






























Figure 24.9 Sequential physiologic patterns of endometrium.


Oestrogen and Progesterone as it is generally called, is thin and atrophic with inactive
glands and fibrous stroma. However, some of the glands
Oestrogen produces the characteristic changes of may show cystic dilatation. Sometimes, retrogressive CHAPTER 24
proliferative phase at the time of menopause and in young hyperplasia is seen which is characterised by Swiss-cheese
women with anovulatory cycles as occurs in Stein-Leventhal pattern of glands resembling endometrial hyperplasia but
syndrome. The therapeutic addition of progesterone composed of inactive retrogressive lining epithelium. There
produces secretory pattern in an oestrogen-primed is intermingling of cystic and dilated glands with small and
endometrium. Oestrogen-progesterone combination atrophic glands. Postmenopausal endometrium may show
hormonal therapy is employed for control of conception. actual active hyperplasia under the stimulatory influence
The sequential type of oestrogen-progesterone oral of post-menopausal oestrogen originating from the ovary
contraceptives act by producing prolonged oestrogenic or adrenal gland.
effect past the time of ovulation and implantation so that
the secretion is delayed until about 25th day, followed by
progestational effect and shedding. Repeated cyclic DYSFUNCTIONAL UTERINE BLEEDING (DUB) The Female Genital Tract
administration with combination therapy such as after long-
term use of oral contraceptives produces inactive-looking, Dysfunctional uterine bleeding (DUB) may be defined as
small and atrophic endometrial glands, and compact excessive bleeding occurring during or between menstrual
decidua-like stroma. periods without a causative uterine lesion such as tumour,
polyp, infection, hyperplasia, trauma, blood dyscrasia or
Pregnancy pregnancy. DUB occurs most commonly in association with
anovulatory cycles which are most frequent at the two
The implantation of a fertilised ovum results in interruption extremes of menstrual life i.e. either when the ovarian
of the endometrial cycle. The endometrial glands are enlarged function is just beginning (menarche) or when it is waning
with abundant glandular secretions and the stromal cells off (menopause). Anovulation is the result of prolonged and
become more plump, polygonal with increased cytoplasm excessive oestrogenic stimulation without the development
termed decidual reaction. About 25% cases of uterine or of progestational phase. The causes for anovulation at diffe-
extrauterine pregnancy show hyperactive secretory state rent ages are as follows:
called Arias-Stella reaction. It is characterised by 1. In pre-puberty: precocious puberty of hypothalamic,
hyperchromatic, atypical, tall cells lining the glands and the pituitary or ovarian origin.
glandular epithelium may show multilayering and budding 2. In adolescence: anovulatory cycles at the onset of
which may be mistaken for an adenocarcinoma. menstruation.
3. In reproductive age: complications of pregnancy, endo-
Menopause
metrial hyperplasia, carcinoma, polyps, leiomyomas and
The onset of menopause is heralded with hormonal adenomyosis.
transition and consequent varying morphologic changes in 4. At premenopause: anovulatory cycles, irregular shedding,
the endometrium. Most commonly, the senile endometrium, endometrial hyperplasia, carcinoma and polyps.

732 5. At perimenopause: endometrial hyperplasia, carcinoma,
polyps and senile atrophy.
It has been observed that women who ovulate may also
occasionally have anovulatory cycles. In addition to
anovulatory cycles, DUB may occur in inadequate luteal phase
that manifests clinically as infertility (ovulatory dysfunctional
bleeding). In such cases, the premenstrual endometrial biopsy
shows histologic lag of more than 2 days.
ENDOMETRITIS AND MYOMETRITIS
Inflammatory involvement of the endometrium and
myometrium are uncommon clinical problems; myometritis
is seen less frequently than endometritis and occurs in
continuation with endometrial infections. Endometritis and
myometritis may be acute or chronic.
Acute form generally results from 3 types of causes—
puerperal (following full-term delivery, abortion and
retained products of conception), intrauterine contraceptive
device (IUCD), and extension of gonorrheal infection from
the cervix and vagina.
Chronic form is more common and occurs by the same
causes which result in acute phase. In addition, tuberculous Figure 24.11 Adenomyosis. The endometrial glands are present
endometritis is an example of specific chronic inflammation, deep inside the myometrium (arrow).
uncommon in the Western countries but not so uncommon
in developing countries. Its incidence in India is reported to ADENOMYOSIS
be approximately in 5% of women.
Adenomyosis is defined as abnormal distribution of histo-
MORPHOLOGIC FEATURES. In acute endometritis and logically benign endometrial tissue within the myometrium
myometritis, there is progressive infiltration of the endo- alongwith myometrial hypertrophy. The term adenomyoma
metrium, myometrium and parametrium by polymorphs is used for actually circumscribed mass made up of
SECTION III
and marked oedema. Chronic nonspecific endometritis and endometrium and smooth muscle tissue. Adenomyosis is
myometritis are characterised by infiltration of plasma cells found in 15-20% of all hysterectomies. Pathogenesis of the
alongwith lymphocytes and macrophages. Tuberculous condition remains unexplained. The possible underlying
endometritis is almost always associated with tuberculous cause of the invasiveness and increased proliferation of the
salpingitis and shows small non-caseating granulomas endometrium into the myometrium appears to be either a
(Fig. 24.10). metaplasia or oestrogenic stimulation due to endocrine
dysfunction of the ovary. Clinically, the patients of adeno-
myosis generally complain of menorrhagia, colicky
dysmenorrhoea and menstrual pain in the sacral or
sacrococcygeal regions.
Systemic Pathology
MORPHOLOGIC FEATURES. Grossly, the uterus may
be slightly or markedly enlarged. On cut section, there is
diffuse thickness of the uterine wall with presence of
coarsely trabecular, ill-defined areas of haemorrhages.
Microscopically, the diagnosis is based on the finding of
normal, benign endometrial islands composed of glands
as well as stroma deep within the muscular layer. The
minimum distance between the endometrial islands
within the myometrium and the basal endometrium
should be one low-power microscopic field (2-3 mm) for
making the diagnosis (Fig. 24.11). Associated muscle
hypertrophy is generally present.

ENDOMETRIOSIS
Endometriosis refers to the presence of endometrial glands
and stroma in abnormal locations outside the uterus.
Figure 24.10 Tuberculous endometritis. The stroma has caseating Endometriosis and adenomyosis are closely interlinked, so
epithelioid cell granulomas having Langhans’ giant cells and peripheral much so that some gynaecologists have termed adenomyosis
layer of lymphocytes.

as endometriosis interna and the other category termed as common site of endometriosis and shows numerous cysts 733
endometriosis externa for similar appearance at the extrauterine varying in diameter from 0.1 to 2.5 cm. Ovarian
sites. However, the two differ as regards age, fertility and involvement is often bilateral. Larger cysts, 3-5 cm in
histogenesis and thus endometriosis should be regarded as diameter, filled with old dark brown blood form ‘chocolate
a distinct clinicopathologic entity. cysts’ of the ovary.
The chief locations where the abnormal endometrial Histologically, the diagnosis is simple and rests on ident-
development may occur are as follows (in descending order ification of foci of endometrial glands and stroma, old or
of frequency): ovaries, uterine ligaments, rectovaginal new haemorrhages, haemosiderin-laden macrophages
septum, pelvic peritoneum, laparotomy scars, and and surrounding zone of inflammation and fibrosis
infrequently in the umbilicus, vagina, vulva, appendix and (Fig. 24.12).
hernial sacs.
The histogenesis of endometriosis has been a debatable
matter for years. Currently, however, the following 3 theories ENDOMETRIAL HYPERPLASIAS
of its histogenesis are described: Endometrial hyperplasia is a condition characterised by
1. Transplantation or regurgitation theory is based on the proliferative patterns of glandular and stromal tissues and
assumption that ectopic endometrial tissue is transplanted commonly associated with prolonged, profuse and irregular
from the uterus to an abnormal location by way of fallopian uterine bleeding in a menopausal or postmenopausal
tubes due to regurgitation of menstrual blood. woman. It may be emphasised here that the syndrome of
2. Metaplastic theory suggests that ectopic endometrium DUB with which endometrial hyperplasia is commonly
develops in situ from local tissues by metaplasia of the associated is a clinical entity, while hyperplasia is a
coelomic epithelium. pathologic term. Hyperplasia results from prolonged
3. Vascular or lymphatic dissemination explains the develop- oestrogenic stimulation unopposed with any progestational
ment of endometrial tissue at extrapelvic sites by these routes. activity. Such conditions include Stein-Leventhal syndrome,
Endometriosis is characteristically a disease of functioning granulosa-theca cell tumours, adrenocortical
reproductive years of life. Clinical signs and symptoms hyperfunction and prolonged administration of oestrogen.
include intrapelvic bleeding from implants, severe Endometrial hyperplasia is clinically significant due to the CHAPTER 24
dysmenorrhoea, pelvic pain, dyspareunia and infertility. presence of cytologic atypia which is closely linked to endo-
metrial carcinoma.
MORPHOLOGIC FEATURES. Grossly, the appearance The following classification of endometrial hyperplasias
of endometriosis varies widely depending upon the is widely employed by most gynaecologic pathologists:
location and extent of the disease. Typically, the foci of 1. Simple hyperplasia without atypia (Cystic glandular
endometriosis appear as blue or brownish-black hyperplasia).
underneath the surface of the sites mentioned. Often, these 2. Complex hyperplasia without atypia (Complex non-
foci are surrounded by fibrous tissue resulting in atypical hyperplasia).
adherence to adjacent structures. The ovary is the most 3. Complex hyperplasia with atypia (Complex atypical
hyperplasia). The Female Genital Tract

SIMPLE HYPERPLASIA WITHOUT ATYPIA (CYSTIC
GLANDULAR HYPERPLASIA). Commonly termed
cystic glandular hyperplasia (CGH), this form of
endometrial hyperplasia is characterised by the presence
of varying-sized glands, many of which are large and
cystically dilated and are lined by atrophic epithelium.
Mitoses are scanty and there is no atypia. The stroma
between the glands is sparsely cellular and oedematous
(Fig. 24.13,A).
There is minimal risk (1%) of adenocarcinoma developing
in cystic hyperplasia.
COMPLEX HYPERPLASIA WITHOUT ATYPIA
(COMPLEX NON-ATYPICAL HYPERPLASIA). This
type of hyperplasia shows distinct proliferative pattern.
The glands are increased in number, exhibit variation in
size and are irregular in shape. The glands are lined by
multiple layers of tall columnar epithelial cells with large
nuclei which have not lost basal polarity and there is no
significant atypia. The glandular epithelium at places is
Figure 24.12 Endometriosis in abdominal scar following caesarean thrown into papillary infolds or out-pouchings into
section in the past. Dense fibrocollagenic tissue contains endometrial
glands, stroma and evidence of preceding old haemorrhage. adjacent stroma i.e. there is crowding and complexity of

734









































SECTION III














Systemic Pathology





Figure 24.13 Three forms of endometrial hyperplasias.


glands without cytologic atypia. The stroma is generally hyperplasia by the presence of ‘atypical cells’ in the
dense, cellular and compact (Fig. 24.13,B). hyperplastic epithelium. The extent of cytologic atypia
may be mild, moderate or severe. The cytologic features
The malignant potential of complex hyperplasia in the present in these cells include loss of polarity, large size,
absence of cytologic atypia is 3%. irregular and hyperchromatic nuclei, prominent
nucleoli, and altered nucleocytoplasmic ratio
COMPLEX HYPERPLASIA WITH ATYPIA (COMP-
LEX ATYPICAL HYPERPLASIA). Some authors have (Fig. 24.13,C).
suggested the terms such as endometrial intraepithelial Complex atypical hyperplasia is a precancerous condition
neoplasia (EIN) or carcinoma in situ for this form of and its malignant transformation is related to the degree of
endometrial hyperplasia. Complex hyperplasia with cytologic atypia. About 20-25% cases of untreated atypical
atypia is distinguished from complex non-atypical hyperplasia progress to carcinoma.