The Male Reproductive System And Prostate Pathology Notes

The Male Reproductive System and Prostate

Testis And Epididymis

Normal Structure

• Contents of the scrotal sac include the testicle and epididymis along with the lower end of the spermatic cord and the tunica vaginalis that forms the outer serous investing layer.
• The epididymis is attached to the body of the testis posteriorly. Thus, the testicle and epididymis may be regarded as one organ.
• Structurally, the main components of the testicle are the seminiferous tubules which when uncoiled are of considerable length.

Read And Learn More: Systemic Pathology Notes

Histologically, the seminiferous tubules are formed of a lamellar connective tissue membrane and contain several layers of cells.

In the adult, the cells lining the seminiferous tubules are of 2 types:

1. Spermatogonia or germ cells produce spermatocytes (primary and secondary), spermatids and mature spermatozoa.
2. Sertoli cells secrete AMH (anti-Mullerian hormone) which leads to the regression of Mullerian ducts. After puberty, these cells switch to their role in spermatogenesis for support, protection and nourishment of germ cells).

• • The seminiferous tubules drain into collecting ducts which form the rete testis from where the secretions pass into the vasa efferentia.
  • Vasa efferentia opens at the upper end of the epididymis.
  • The lower end of the epididymis is prolonged into a thick muscular tube, the vas deferens, that transports the secretions into the urethra.
  • The fibrovascular stroma present between the seminiferous tubules contains a varying number of interstitial cells of Leydig.
  • Leydig cells have abundant cytoplasm containing lipid granules and brown lipochrome pigment and some contain elongated Reinke’s crystals.
  • These cells are the main source of testosterone and other androstenedione in males.

Developmental Disorders

Cryptorchidism

• Cryptorchidism or undescended testis is a condition in which the testicle is arrested at some point along its descent. Its incidence is about 0.2% in the adult male population.
• In 70% of cases, the undescended testis lies in the inguinal ring, in 25% in the abdomen and, in the remaining 5%, it may be present at other sites along its descent from intra-abdominal location to the scrotal sac.
• Aetiology Exact aetiology is being increasingly understood and includes the following factors

1. Mechanical factors example short spermatic cord, narrow inguinal canal, and adhesions to the peritoneum.
2. Inguinal hernia A concomitant inguinal hernia is frequently present along with cryptorchidism.
3. Torsion and infarction Rarely, torsion and ischaemic necrosis of undescended testis located in the inguinal canal may occur.
4. Malignancy Cryptorchid testis is at 30-50 times increased risk of developing testicular malignancy, most commonly seminoma and embryonal carcinoma, than a normally descended testis.
5. The risk of malignancy is greater in the intra-abdominal testis than in the testis in the inguinal canal for the simple reason that the neoplastic process in the testis in the scrotal location is detected earlier than in the intra-abdominal site.

Male Infertility

The morphologic pattern of testicular atrophy described above for cryptorchidism can result from various other congenital or acquired causes of male infertility. These causes can be divided into 3 groups: pre-testicular, testicular and post-testicular.

Pre-testicular Causes

1. Hypopituitarism Pre-pubertal or post-pubertal hypopituitarism such as from tumour, trauma, infarction, cyst and genetic deficiency of FSH and LH secretion.
2. Oestrogen excess Endogenous excesses such as from hepatic cirrhosis, adrenal tumour, Sertoli and Leydig cell tumour; or exogenous excess such as in the treatment of carcinoma of the Genetic factors example trisomy 13, maldevelopment of the scrotum or cremaster muscles.
3. Hormonal factors example abnormalities in the hypothalamic-pituitary-testicular axis, deficient production of AMH, or deficient action or production of androgens.

Morphologic Features Cryptorchidism is unilateral in 80% of cases and bilateral in the rest.

Grossly, the cryptorchid testis is small in size, firm and fibrotic.

Histologically, the thickening of seminiferous tubules begins to occur as early as the first year of life.

The changes are as under:

1. Seminiferous tubules There is the progressive loss of germ cell elements so that the tubules may be lined by only spermatogonia and spermatids but foci of spermatogenesis are discernible in 10% of cases.
   • The tubular basement membrane is thickened and the tubular diameter is reduced. Advanced cases show hyalinised tubules with a few Sertoli cells only, surrounded by the prominent basement membrane.
2. Interstitial stroma There is usually an increase in the interstitial fibrovascular stroma and the conspicuous presence of Leydig cells, seen singly or in small clusters.

Clinical Features As such, cryptorchidism is completely asymptomatic and is discovered only on physical examination.

However, if surgical correction by orchiopexy is not undertaken by about 2 years of age, or certainly in the prepubertal period, following significant adverse clinical outcome may result

1. Sterility-infertility Bilateral cryptorchidism is associated with sterility while unilateral disease may result in infertility. prostate.
2. Glucocorticoid excess Endogenous excess may occur in Cushing’s syndrome while exogenous excess may occur in the treatment of ulcerative colitis, bronchial asthma, rheumatoid arthritis etc.
3. Other endocrine disorders Hypothyroidism and diabetes mellitus are associated with hypospermatogenesis.
4. Testicular Causes
   • Agonadism total absence of the testes.
   • Cryptorchidism or undescended testis is described above.
   • Maturation arrest failure of spermatogenesis beyond one of the immature stages.
   • Hypospermatogenesis presence of all the maturation stages of spermatogenesis but in decreased numbers.
   • Sertoli cell-only syndrome in which there is congenital or acquired absence of all germ cells so that the seminiferous tubules are lined by Sertoli cells only.
   • Klinefelter’s syndrome in which there is an XXY intersexuality characterised by primary hypogonadism, azoospermia, gynecomastia, eunuchoid built and subnormal intelligence.
   • Mumps orchitis occurs as a complication of parotitis.
   • Irradiation damage results in permanent germ cell destruction.
5. Post-testicular Causes
   • Congenital block example absence or atresia of vas deferens.
   • Acquired block example due to gonorrhoea and surgical intervention.
   • Impaired sperm motility in the presence of normal sperm counts example immotile cilia syndrome.

Haematocele

Haematocele is a haemorrhage into the sac of the tunica vaginalis. It may result from direct trauma, injury to a vein by the needle, or from haemorrhagic diseases.

• In recent haematocele, the blood coagulates and the wall is coated with ragged deposits of fibrin.
• In long-standing cases, the tunica vaginalis is thickened with dense fibrous tissue coated with brownish material due to old organised haemorrhage and occasionally may get partly calcified.

Testis and Epididymis General Conditions

• Cryptorchidism or undescended testis is a condition in which the testicle is arrested congenitally at some point along its descent.
• Testicular atrophy can also result from various other congenital or acquired causes of testicular, testicular and post-testicular origin and cause male infertility.
• Orchitis, epididymitis and epididymal-orchitis are inflammations of these tissues and may be non-specific, granulomatous (autoimmune) or caseating tuberculous inflammation.
• Elephantiasis is a thickening of the scrotal skin due to a chronic inflammatory response initiated by lymphatic infection with adult filarial worms.
• Torsion of the testicle is a sudden cessation of venous drainage and arterial supply to the testis, following sudden muscular effort or physical trauma.
• Varicocele is the dilatation and tortuosity of the veins of the pampiniform plexus in the spermatic cord.
• Hydrocele and haematocele are abnormal collections of serous fluid or blood respectively in the tunica vaginalis.

Testicular Tumours

• Testicular tumours are the cause of about 1% of all cancer deaths. They are more frequent in the white male population but are less common in Africans and Asians.
• They have a trimodal age distribution peak during infancy, another during late adolescence and early adulthood, and a third peak after 60 years of age.

Classification

The most widely accepted classification is the WHO classification of tumours of the testis (2016) based on histogenesis. This classification is schematically illustrated in. According to this classification, all testicular tumours are divided into the following groups

1. Germ cell tumours (GCTs) derived from germ cell neoplasia in situ (non-invasive, single histologic type or pure forms, non-seminomatous of more than one histologic type)
2. Germ cell tumours unrelated to germ cell neoplasia in situ
3. Sex cord-stromal tumours
4. Combined germ cell-sex cord-stromal tumours
5. Miscellaneous tumours (epithelial type, non-epithelial)
6. Haematolymphoid tumours

• • The vast majority of testicular tumours (95%) arise from germ cells or their precursors in the seminiferous tubules, while less than 5% originate from sex cord-stromal components and other tissue elements of the testis.
  • Since seminoma has a different clinical course and management than the other GCTs, clinically all testicular GCTs are categorised into 2 main groups seminomatous and non-seminomatous. Contrasting features of these two groups of GCTs are given in.

Etiologic Factors

The exact aetiology of testicular germ cell tumours is unknown, but the following factors have been implicated:

• Cryptorchidism The probability of a germ cell tumour developing in an undescended testis is 30-50 times greater than in a normally-descended testis.
  • About 10% of testicular germ cell tumours are associated with cryptorchidism. The high incidence is attributed to a higher temperature to which the undescended testis in the groin or abdomen is exposed.
  • Intra-abdominal testis is at greater risk than the inguinal testis. There is an increased incidence of tumours in the contralateral normally-descended testis.
  • There are no data to confirm or deny whether surgical repositioning or orchiopexy of a cryptorchid testis alters the incidence of testicular tumour.
  • However, surgical correction is still helpful since it is easier to detect the tumour in the scrotal testis than in an abdominal or inguinal testis.
• Other developmental disorders Dysgenetic gonads associated with endocrine abnormalities such as androgen insensitivity syndrome have a higher incidence of development of germ cell tumours.

• Genetic factors play a role in the development of germ cell tumours supported by the observation of high incidence in first-degree family members, twins and white male populations while blacks in Africa have a very low incidence.
  • However, no definite pattern of inheritance has been recognised.
• Other factors A few less common factors include the following:

1. • Orchitis A history of mumps or other forms of orchitis may be given by the patient with a germ cell tumour.
   • Trauma Many patients give a history of trauma prior to the development of the tumour but it is not certain how trauma initiates the neoplastic process. Instead, possibly it brings the patient to the attention of the physician.
   • Carcinogens A number of carcinogens such as the use of certain drugs (for example LSD, hormonal therapy for sterility, copper, zinc etc), exposure to radiation and endocrine abnormalities may play a role in the development of testicular tumours.

Histogenesis

Pathogenesis of testicular tumours remains controversial except that the vast majority of these tumours originate from germ cells. Based on current concepts on the histogenesis of testicular tumours, the following agreements and disagreements have emerged:

• Developmental disorders Disorders such as cryptorchidism, gonadal dysgenesis and androgen insensitivity syndrome are high-risk factors for the development of testicular germ cell tumours. These observations point to a developmental defect in gonadogenesis.
• Germ cell neoplasia in situ (GCNIS) Most of the GCTs develop from an in situ neoplasia termed GCNIS, a term that has replaced the previously used term of CIS/ITGCN (carcinoma in situ/intratubular germ cell neoplasia).
  • Other forms of intratubular neoplasia should be referred to by their differentiated phenotype with the prefix intratubular example intratubular seminoma, intratubular embryonal carcinoma etc.
  • It has also been emphasised to draw a distinction between GCNIS from maturation-delayed germ cells, which are a relatively common feature in the gonads of patients with disorders of sex development.
• Molecular genetic features Testicular GCTs have been found to have several genetic abnormalities suggesting the following molecular pathogenesis of all GCTs:
  • 1. Hyperdiploidy is almost a constant feature of all germ cell tumours of the testis.
    2. Germ cell neoplasia in situ (GCNIS)-derived tumours show amplification of isochrones of the short arm of chromosome 12.
    3. Spermatocytic tumour lacks association with GCNIS and 12p amplification instead it shows a unique amplification of chromosome 9 corresponding to the DMRT1 gene.
    4. Deletion of the long arm of chromosome 12 abbreviated as del(12q), is present.
    5. Telomerase activity is present in all GCTs of the testis.
    6. Other mutations include p53, cyclin E and the FAS gene.
• ‘Three hits’ process Germ cells in seminiferous tubules undergo activation (‘first hit’) before undergoing malignant transformation confined to seminiferous tubules (GCNIS) (‘second hit’) and eventually into an invasive stage by some epigenetic phenomena (‘third hit’).

Clinical Features And Diagnosis

1. The usual presenting clinical symptoms of testicular tumours are gradual gonadal enlargement and a dragging sensation in the testis.
2. Metastatic involvement may produce secondary symptoms such as pain, lymphadenopathy, haemoptysis and urinary obstruction.
3. Spread Since testicular germ cell tumours originate from totipotent germ cells, it is not unusual to find metastases of histologic types different from the primary growth. Testicular tumours may spread by both lymphatic and haematogenous routes:
   • Lymphatic spread occurs in retroperitoneal para-aortic lymph nodes, mediastinal lymph nodes and supraclavicular lymph nodes.
   • Haematogenous spread primarily occurs in the lungs, liver, brain and bones.
4. Tumour Markers Testicular cancers secrete polypeptide hormones and certain enzymes which can be detected in the blood.
5. Three tumour markers widely used in the diagnosis, staging and monitoring the follow-up of patients with testicular tumours are human chorionic gonadotropin (hCG), alpha-foetoprotein (AFP) and lactate dehydrogenase (LDH).
6. In addition, carcinoembryonic antigen (CEA), human placental lactogen (HPL), placental alkaline phosphatase, testosterone, oestrogen and luteinising hormone may also be elevated.
7. HCG is synthesised by placental syncytiotrophoblast such as in various non-seminomatous germ cell tumours of the testis (for example in choriocarcinoma, yolk sac tumour and embryonal carcinoma). However, ectopic hCG production may occur in a variety of non-testicular non-germ cell tumours as well.
8.  AFP is normally synthesised by the foetal liver cells, yolk sac and foetal gut. Its levels are elevated in testicular tumours associated with yolk sac components. However, elevated serum AFP levels are also found in liver cell carcinoma.
9.  LDH This enzyme is normally produced by the muscle (smooth, cardiac, skeletal), liver, kidney and brain. LDH catalyses the lactate-pyruvate conversion. Out of its five isoforms, LDH1 is elevated in testicular cancers, mostly in GCTs.
   • Prognosis AJCC staging is for seminoma only and includes tumour size with the invasion of surrounding anatomical structures and soft tissue, lymphovascular invasion, lymph nodes involvement (including number and size), distant metastasis (non-retroperitoneal nodal, pulmonary or non-pulmonary visceral metastasis) and serum markers (hCG, AFP and LDH).
   • Seminomas are extremely radiosensitive while non-seminomatous germ cell tumours are radio-resistant.
   • In general, seminomas have a better prognosis with a 90% cure rate while the nonseminomatous tumours behave in a more aggressive manner and have a poor prognosis.
10. After these general comments, specific testicular tumours are described below.

Germ Cell Tumours

Germ cell tumours comprise approximately 95% of all testicular tumours and are more frequent before the age of 45 years.

• Post-pubertal testicular germ cell tumours are always malignant. Nearly half of them contain more than one histologic type of GCT.
• Besides their counterparts in the female gonads, germ cell tumours are also found at the extragonadal sites such as the retroperitoneum, mediastinum, base of the brain, coccyx etc.

Germ Cell Neoplasia in Situ

• GCTs may originate via one of two pathways: an intermediate preinvasive stage called GCNIS (example development of seminoma), and directly from germ cells without GCNIS (example origin of spermatocytic tumour).
• GCNIS comprises a small proportion of testicular tumours and arises from blocked foetal germ cell differentiation that persists in the neonatal testis and remains dormant and non-proliferating in the adult testis.
• Some biomarkers are being developed for its detection.

Seminoma

• Seminoma is the most commonest malignant tumour of the testis (~50%) and its corresponding counterpart in the ovary is dysgerminoma.
• Its incidence peaks in the 4th decade of life and is rare before puberty. Undescended testis harbours seminoma more frequently as compared to other germ cell tumours.
• About 10% of pure seminomas are associated with elevated hCG levels in serum while serum PLAP is elevated in 50% patients of with seminoma.

Morphologic Features Grossly, the involved testis is enlarged up to 10 times its normal size but tends to maintain its normal contour since the tumour rarely invades the tunica.

• The larger tumour replaces the entire testis, whereas the smaller tumour appears as a circumscribed mass in the testis. The cut section of the affected testis shows a homogeneous, grey-white lobulated appearance. Necrosis and haemorrhage in the tumour are rare.

Microscopically,

the tumour has the following characteristics:

1. Tumour cells The seminoma cells generally lie in cords, sheets or columns forming lobules. Typically, in a classic seminoma, the tumour cells are fairly uniform in size with clear cytoplasm and well-defined cell borders.

• The cytoplasm contains a variable amount of glycogen that stains positively with the PAS reaction. The nuclei are centrally located, large, hyperchromatic and usually contain 1-2 prominent nucleoli.
• Tumour giant cells may be present. Mitotic figures are infrequent. Syncytiotrophoblastic cells are occasionally present in seminoma, and this may be associated with typically modest elevations in serum beta-hCG levels.

2. Stroma The stroma of seminoma is a delicate fibrous tissue which divides the tumour into lobules. The stroma shows a characteristic lymphocytic infiltration, indicative of the immunologic response of the host to the tumour.

• About 20% of the tumours show granulomatous reactions in the stroma.

• The prognosis of classic seminoma is better than other germ cell tumours. The tumour is highly radiosensitive.
• The natural history of anaplastic seminoma, however, is unclear—perhaps it represents an advanced stage of classic seminoma with more aggressive behaviour.

Spermatocytic Tumour

• In the 2016 WHO classification, spermatocyte tumour has been included under the category of ‘germ cell tumour unrelated to GCNIS’. It is an uncommon tumour having an incidence of about 5% of all germ cell tumours.
• Spermatocytic tumour usually occurs in older patients, generally in 6th decade of life. The tumour is bilateral in 10% of patients.

Morphologic Features Grossly, a spermatocyte tumour is homogeneous, larger, softer and more yellowish and gelatinous than the classic seminoma.

Histologically, the distinctive features are as under:

1. Tumour cells The tumour cells vary considerably in size from lymphocyte-like to huge mononucleate or multinucleate giant cells. The majority of the tumour cells are, however, of intermediate size.
   • The cells have eosinophilic cytoplasm devoid of glycogen. The nuclei of intermediate and large cells have a filamentous pattern. Mitoses are often frequent.
   • Tumour cells are positive for immunohistochemical markers PLAP, c-kit, OCT3/4, and NANOG.
2. Stroma The stroma lacks lymphocytic and granulomatous reactions seen in classic seminoma.
   • The prognosis of spermatocyte tumours is excellent and better than pure seminoma since the tumour is slow-growing and rarely metastasises. The tumour is radiosensitive.

Embryonal Carcinoma

• Pure embryonal carcinoma constitutes ~3% of germ cell tumours but areas of embryonal carcinoma are present in 40% of various other germ cell tumours.
• These tumours are more common in 2nd to 3rd decades of life. About 90% of cases are associated with the elevation of AFP or hCG or both. They are more aggressive than the seminomas.

Morphologic Features Grossly, embryonal carcinoma is usually a small tumour in the testis. It distorts the contour of the testis as it frequently invades the tunica and the epididymis. The cut surface of the tumour is grey-white, and soft with areas of haemorrhages and necrosis.

Microscopically, the following features are seen:

1. The tumour cells are arranged in a variety of patterns glandular, tubular, papillary and solid.
2. The tumour cells are highly anaplastic carcinomatous cells having a large size, indistinct cell borders, amphophilic cytoplasm and prominent hyperchromatic nuclei showing considerable variation in nuclear size.
3. Mitotic figures and tumour giant cells are frequently present. Tumour cells are positive for IHC markers: CD30, OCT3/4, NANOC, and cytokeratin.
4. The stroma is not as distinct as in seminoma and may contain a variable amount of primitive mesenchyme. Haemorrhage and necrosis are common.
5. Embryonal carcinoma is more aggressive and less radiosensitive than seminoma. Chemotherapy is more effective in treating this tumour.

Yolk Sac Tumour

• This characteristic tumour is the most common testicular tumour of infants and young children up to the age of 4 years. In adults, however, yolk sac tumour in pure form is rare but may be present as the major component in 40% of germ cell tumours.
• AFP levels are elevated in 100% of cases of yolk sac tumours. As per the current classification, yolk sac tumour is further divided into two types:

• • Postpubertal-type yolk sac tumour derived from GCNIS (in the non-seminomatous group)
  • Prepubertal-type yolk sac tumour unrelated to GCNIS However, there are very subtle morphologic differences between the two types of yolk sac tumours.

Morphologic Features Grossly, the tumour is generally soft, yellow-white, and mucoid with areas of necrosis and haemorrhages. Microscopically, a yolk sac tumour has the following features.

1. The tumour cells form a variety of patterns loose reticular networks, and papillary, glandular, tubular and solid arrangements.
2. The tumour cells are flattened to cuboid epithelial cells with clear vacuolated cytoplasm.
3. The tumour cells may form distinctive glomeruloid structures and appearance resembling the yolk sac or endodermal sinuses of the rat placenta called Schiller-Duval bodies.
4. IHC markers for tumour cells are AFP and CK7.
5. There may be the presence of both intracellular and extracellular PAS-positive hyaline globules, many of which contain AFP.

Choriocarcinoma

• Among the trophoblastic GCTs, choriocarcinoma is more common and is a highly malignant tumour composed of elements consisting of syncytiotrophoblast and cytotrophoblast.
• However, pure form is extremely rare and occurs more often in combination with other GCTs. The patients are generally in their 2nd decade of life.
• Many times, the primary tumour is indistinct and the patient may manifest initially with symptoms of metastasis. The serum and urinary levels of hCG are greatly elevated in 100% of cases.

Morphologic Features Grossly, the tumour is usually small and may appear as a soft, haemorrhagic and necrotic mass.
Microscopically, the characteristic feature is the identification of intimately related syncytiotrophoblast and cytotrophoblast without the formation of definite placental-type villi.

1. 1. 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.
   2. Cytotrophoblastic cells are polyhedral cells which are more regular and have clear or eosinophilic cytoplasm with hyperchromatic nuclei.

Teratoma

• 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 GCTs.
• However, teratomas are found in combination with other GCTs (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 Grossly, most teratomas are large, grey-white masses enlarging the involved testis. The cut surface shows characteristic variegated appearance grey white solid areas, cystic and honey-combed areas, and foci of cartilage and bone.

Dermoid tumours commonly seen in the ovaries are rare in testicular teratomas.

Microscopically, the traditional classification of testicular teratomas into mature (differentiated), immature, and teratoma with malignant transformation, has been replaced with the 2016 WHO classification scheme.

As per this classification, based on histogenesis and prognosis testicular teratomas are divided into the following three types:

1. Postpubertal teratomas These teratomas are derived from GCNIS and are grouped under non-seminomatous GCTs. These teratomas (earlier termed immature teratomas) are composed of mature-differentiated and incompletely-differentiated and primitive or embryonic tissues.
   • These may include cartilage, mesenchyme, neural tissues, abortive eye, intestinal and respiratory tissue elements etc.
   • It has now been documented that the distinction between mature and immature tissue elements in post-pubertal testicular teratomas carries no prognostic value.
   • They are always malignant and the patient may develop metastasis of teratomatous or nonteratomatous components.
2. Teratoma with somatic malignancy These teratomas too are derived from GCNIS and fall under the category of non-seminomatous GCTs (in the earlier classification called teratomas with malignant transformation).
   • A variety of malignancies have been reported to occur as secondary, somatic-type neoplasms arising from GCTs, and include sarcoma (commonly embryonal rhabdomyosarcoma, more often than leiomyosarcoma or angiosarcoma), PNET, carcinoma, glial and meningeal neoplasms, haematological neoplasms, and nephroblastoma-like (Wilms’) tumour.
3. Prepubertal teratomas Teratomas developing in prepubertal patients are unrelated to GCNIS. In the previous classification, these teratomas were grouped under mature or differentiated testicular teratomas.
   • Prepubertal teratomas have a more organised architecture and lack significant cytological atypia.
   • These tumours largely lack 12p amplification and have not been reported to metastasise. They are further divided into dermoid cysts, epidermoid cysts, and well-differentiated neuroendocrine tumours (NET).

Mixed Germ Cell Tumours

• About 50% of germ cell tumours have more than one of the above histologic types of germ cell elements and are called mixed GCTs.
• The clinical behaviour of these tumours is worsened by the presence of a more aggressive tumour component in a less malignant tumour. Interestingly, metastases of the mixed GCTs may not exactly reproduce the histologic types present in the primary tumour.

The most common combinations of mixed GCTs are as under:

1. 1. Teratoma, embryonal carcinoma, yolk sac tumour
   2. Embryonal carcinoma and teratoma (teratocarcinoma)
   3. Seminoma and embryonal carcinoma

Sex Cord-Stromal Tumours

Tumours arising from specialised gonadal stroma are classified on the basis of histogenesis.

• The primitive mesenchyme which forms the specialised stroma of gonads in either sex gives rise to theca, granulosa and lutein cells in the female, and Sertoli and interstitial Leydig cells in the male.
• Since the cell of origin of primitive mesenchyme is identical, Sertoli and interstitial Leydig cell tumours may also occur in the ovaries (in addition to theca cell, granulosa cell and lutein cell tumours).
• Likewise, the latter three tumours may occur in the testis (in addition to the Sertoli cell and Leydig cell tumours). All these tumours secrete various hormones.
• The biological behaviour of these tumours generally cannot be determined on histological grounds alone but is related to clinical parameters and hormonal elaboration by these tumours.

Leydig Cell Tumour:

• Leydig cell tumours are quite uncommon. They may occur at any age but are more frequent in the age group of 20 to 50 years.
• Characteristically, these cells secrete androgen, or both androgen and oestrogen and rarely corticosteroids. Bilateral tumours may occur typically in congenital adrenogenital syndrome.

Morphologic Features Grossly, the tumour appears as a small, well-demarcated and lobulated nodule. The Cut surface is homogeneously yellowish or brown.

Histologically, the tumour is composed of sheets and cords of normal-looking Leydig cells. These cells contain abundant eosinophilic cytoplasm and Reinke’s crystals and a small central nucleus.

Tumour cells are positive for IHC markers inhibin, calretinin A, and melan A. Majority of Leydig cell tumours are benign while about 10% are malignant which may invade and metastasise.

Sertoli Cell Tumours

• Sertoli cell tumours correspond to arrhenoblastoma of the ovary. They may occur at all ages but are more frequent in infants and children. These tumours may elaborate oestrogen or androgen and may account for gynaecomastia in an adult, or precocious sexual development in a child.

Morphologic Features Grossly, the tumour is fairly large, firm, round, and well-circumscribed. The cut surface of the tumour is yellowish or yellow-grey.

Microscopically, the Sertoli cell tumour is composed of benign Sertoli cells arranged in well-defined tubules. IHC markers for tumour cells are inhibin, calretinin, and cytokeratin.

The majority of Sertoli cell tumours are benign but about 10% may metastasise to regional lymph nodes.

Granulosa Cell Tumour

This is an extremely rare tumour in the testis and resembles morphologically its ovarian counterpart.

Mixed Germ Cell-Sex Cord Stromal Tumours

An example of a combination of both germ cells and sex cord-stromal components is gonadoblastoma.

Gonadoblastoma

• Dysgenetic gonads and undescended testis are predisposed to develop such combined proliferation of germ cells and sex cord-stromal elements.
• The patients are commonly intersexuals, particularly phenotypic females. Most of the gonadoblastomas secrete androgen and therefore produce virilisation in the female phenotype. A few, however, secrete oestrogen.

Morphologic Features Grossly, the tumour is of variable size, yellowish-white and soft.
Microscopically, gonadoblastoma is composed of 2 principal cell types large germ cells resembling seminoma cells, and small cells resembling immature Sertoli, Leydig and granulosa cells.

Call-Exner bodies of a granulosa cell tumour may be present. Prognosis largely depends upon the malignant potential of the type of germ cell components included.

Malignant Lymphoma

Malignant lymphomas comprise 5% of testicular malignancies and are the most common testicular tumour in the elderly. Bilaterality is seen in half the cases. The most common are large cell non-Hodgkin’s lymphoma of B cell type.

Testicular Tumours

• Testicular tumours are divided into several groups germ cell tumours (GCTs), sex cord-stromal tumours, combined, and haematolymphoid tumours.
• GCTs are the largest group (95%)and include 2 subgroups: tumours derived from GCNIS, and tumours unrelated to GCNIS. Clinically, GCTs are divided into seminomatous and non-seminomatous.
• Cryptorchidism and dysgenetic gonads are implicated in the aetiology of testicular tumours. AFP, hCG and LDH are commonly used as serum tumour markers in their diagnosis, staging and monitoring.
• Testicular tumours may spread by the lymphatic and haematogenous routes.
• Seminoma (pure form) is the commonest malignant tumour of the testis. Spermatocytic seminoma is histogenetically distinct from pure seminoma and has a better prognosis.
• Teratomas are composed of tissues derived from three germ cell layers endoderm, mesoderm and ectoderm. They may be post-pubertal teratomas, teratomas with somatic malignancy, and prepubertal teratomas. The first two types are always malignant.
• Other primary germ cell tumours are yolk sac tumours seen in children, embryonal carcinoma in young adults and choriocarcinoma, a highly malignant tumour.
• Leydig cell, Sertoli cell and granular cell tumours are uncommon sex-cord stromal tumours.
• Malignant lymphoma is a tumour of the elderly

Penis

Normal Structure

• The penis is covered by skin, foreskin (prepuce) and stratified squamous mucosa. The structure of the penis consists of 3 masses of erectile tissue two corpora cavernosa, one on each side dorsally, and the corpus spongiosum ventrally through which the urethra passes.
• The expanded free end of the corpus spongiosum forms the glans. Scrotum is covered by the skin which is not different from the skin elsewhere in the body.
• The lumen of the urethra in the sectioned surface of the penis appears as an irregular cleft in the middle of the corpus spongiosum.
• In the prostatic part, it is lined by transitional epithelium, but elsewhere it is lined by columnar epithelium except near its orifice where stratified squamous epithelium lines it.
• Two groups of conditions are discussed here: developmental and inflammatory, and tumours.

Developmental And Inflammatory Disorders

Glans and prepuce are frequently involved in inflammation in a number of specific and nonspecific conditions.

The specific inflammations include various sexually-transmitted diseases such as hard chancre in syphilis, chancroid caused by Haemophilus ducreyi, gonorrhoea caused by gonococci, herpes urogenital, granuloma inguinale (donovanosis), and lymphopathia venereum caused by Chlamydia trachomatis.

Phimosis

• Phimosis is a condition in which the prepuce is too small to permit its normal retraction behind the glans. It may be congenital or acquired.
• Congenital phimosis is a developmental anomaly whereas acquired phimosis may result from inflammation, trauma or oedema leading to the narrowing of the preputial opening.
• In either case, phimosis interferes with cleanliness and predisposes to the development of secondary infection, preputial calculi and squamous cell carcinoma.
• Paraphimosis is a condition in which the phimotic prepuce is forcibly retracted resulting in constriction over the glans penis and subsequent swelling.

Hypospadias And Epispadias

• • Hypospadias is a developmental defect of the urethra in which the urethral meatus fails to reach the end of the penis, but instead, opens on the ventral surface of the penis.
  • A similar developmental defect with a resultant urethral opening on the dorsal surface of the penis is termed epispadias.
  • Hypospadias and epispadias may cause urethral constriction with consequent infection and may also interfere with normal ejaculation and insemination. Both these urethral anomalies are more frequently associated with cryptorchidism.

Balanoposthitis:

• Balanoposthitis is the term used for non-specific inflammation of the inner surface of the prepuce (balanitis) and an adjacent surface of the glans (posthitis).
• It is caused by a variety of microorganisms such as staphylococci, streptococci, coliform bacilli and gonococci. Balanoposthitis usually results from a lack of cleanliness resulting in the accumulation of secretions and smegma.
• It is a common accompaniment of phimosis. The type of inflammation may be acute or chronic, sometimes with ulceration on the mucosal surface of the glans.

Balanitis Xerotica Obliterans:

Balanitis xerotica obliterans is a white atrophic lesion on the glans penis and the prepuce and is a counterpart of the lichen sclerosis et atrophicus in the vulva described.

Penile Tumours

Benign and malignant tumours as well as certain premalignant lesions may occur on the penis.

Benign Tumours

Condyloma Acuminatum

Condyloma acuminatum or anogenital wart is a benign tumour caused by human papillomavirus (HPV) types 6 and 11. The tumour may occur singly, or there may be conglomerated papillomas.

Morphologic Features: The condyloma is commonly located on the coronal sulcus on the penis or the perineal area. Grossly, the tumour consists of solitary or multiple, warty, cauliflower-shaped lesions of variable size with exophytic growth patterns.

Histologically, the lesions are essentially like common warts (verruca vulgaris). The features include the formation of papillary villi composed of connective tissue stroma and covered by squamous epithelium which shows hyperkeratosis, parakeratosis, and hyperplasia of the prickle cell layer.

• Many of the prickle cells show clear vacuolisation of the cytoplasm (koilocytosis) indicative of HPV infection. Giant condyloma shows upward as well as downward growth of the tumour but is otherwise histologically identical to condyloma acuminatum.
• Though histologically benign, clinically the giant condyloma is associated with recurrences and behaves as an intermediate between truly benign condyloma acuminatum and squamous cell carcinoma.

Premalignant Lesions (Carcinoma In Situ)

In the region of external male genitalia, three lesions display cytological changes of malignancy confined to epithelial layers only without evidence of invasion. These conditions are Bowen’s disease, erythroplasia of Queyrat and bowenoid papulosis.

Bowen’s Disease

Bowen’s disease is located on the shaft of the penis and the scrotum besides the sun-exposed areas of the skin.

Grossly, it appears as a solitary, circumscribed plaque lesion with ulceration.

Histologically, the changes are superficial to the dermo-epidermal border. The epithelial cells of the epidermis show hyperplasia, hyperkeratosis, parakeratosis and scattered bizarre dyskeratotic cells.

A fair proportion of cases of Bowen’s disease are associated with internal visceral cancers.

Erythroplasia of Queyrat

The lesions of erythroplasia of Queyrat appear on the penile mucosa.

Grossly, the lesions are pink, shiny and velvety soft.

Histologically, the thickened and acanthotic epidermis shows a variable degree of dysplasia.

Unlike Bowen’s disease, there is no relationship between erythroplasia of Queyrat and internal malignancy.

Bowenoid Papulosis

The lesions of bowenoid papulosis appear on the penile shaft and adjacent genital skin. Grossly, they are solitary or multiple, shiny, red-brown papular lesions.

Histologically, there is orderly maturation of epithelial cells in the hyperplastic epidermis with scattered hyperchromatic nuclei and dysplastic cells.

Malignant Tumours

Squamous Cell Carcinoma

• The incidence of penile carcinoma shows wide variation in different populations. In the United States, the overall incidence of penile cancer is less than 1% of all cancers in males but it is 3-4 times more common in blacks than in whites.
• In some Asian (except Japan), African and Latin American countries, its incidence is 10-20% of all cancers.
• The relationship of penile cancer with HPV has been well supported high-risk HPV types 16 and 18 are strongly implicated and their DNA has been documented in the nuclei of malignant cells.
• Carcinoma of the penis is quite rare in Jews and Muslims who undergo a ritual of circumcision early in life.
• In India, cancer of the penis is rare in Muslims who practice circumcision as a religious rite in infancy, whereas Hindus who are normally not circumcised have a higher incidence.
• Circumcision provides protection against penile cancer due to the prevention of accumulation of smegma which is believed to be carcinogenic. The greatest incidence of penile cancer is between 45 and 60 years.
• 2016 Who Classification While earlier classifications of penile cancer were exclusively based on morphology, the 2016 WHO classification presents a new classification based on distinct clinicopathologic features and the relationship of penile cancer to HPV infection as the etiologic agent.
• Accordingly, squamous cell carcinoma (SCC), the most common penile cancer, is divided into 2 types: HPV-related SCC and non-HPV-related SCC. Both types have further morphologic variants described below.

Morphologic Features Grossly, most squamous cell carcinomas originate in the inner mucosal lining of the glans, coronal sulcus, or foreskin. The tumour may be cauliflowerlike and papillary, or flat and ulcerating.

Histologically, squamous cell carcinoma of both fungating and ulcerating type is generally well differentiated to moderately-differentiated type which resembles in morphology to similar cancer elsewhere in the body.

• • HPV-related SCC is morphologically basaloid and warty; HPV is present in 40-50% of penile carcinomas.
  • Non-HPV-related SCC has various morphologic patterns usual type, pseudohyperplastic type, pseudo glandular type, verrucous type, and papillary SCC.
  • It is yet uncertain whether HPV-related penile SCC has better survival than non-HPV-related penile cancer.
  • The tumour metastasises via lymphatics to regional lymph nodes. Visceral metastases by the haematogenous route are uncommon and occur in advanced cases only.

Diseases of the Penis

• Phimosis in which there is narrowed preputial opening, and hypospadias in which the urethral meatus opens on the ventral surface of the penis, are developmental anomalies.
• Balanoposthitis is inflammation of the inner surface of the prepuce (balanitis) and the adjacent surface of the glans (posthitis).
• Balanitis xerotica obliterans is a white atrophic lesion on the glans penis and the prepuce.
• Penile tumours may be benign (for example condyloma acuminatum), with few premalignant conditions (Bowen’s disease, bowenoid papulosis) and squamous cell carcinoma (SCC). SCC may be HPV-related or non-HPV related.

Prostate

Normal Structure

• The prostate gland in a normal adult weighs approximately 20 gm. It surrounds the commencement of the male urethra and is composed of 5 lobes during embryonic development anterior, middle, posterior and two lateral lobes.
• But at birth, the five lobes fuse to form 3 distinct lobes—two major lateral lobes and a small median lobe.
• Histologically, the prostate is composed of tubular alveoli (acini) embedded in fibromuscular tissue mass.
• The glandular epithelium forms infoldings and consists of 2 layers—a basal layer of low cuboidal cells and an inner layer of mucus-secreting tall columnar cells.
• The alveoli are separated by thick fibromuscular septa containing abundant smooth muscle fibres.
• The prostate has numerous blood vessels and nerves. In addition to nervous control, the prostate is an endocrine-dependent organ. Based on hormonal responsiveness, the prostate is divided into 2 separate parts
  1. The inner periurethral female part is sensitive to oestrogen and androgen.
  2. The outer subcapsular true male part is sensitive to androgen.

• • The prostate is involved in 3 important pathologic processes: prostatitis, nodular hyperplasia and carcinoma.
  • While benign nodular hyperplasia occurs in the periurethral part distorting and compressing the centrally located urethral lumen, the prostatic carcinoma usually arises from the outer subcapsular part in which case it does not compress the urethra.