Neoplastic Conditions

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Testicular neoplasms represent less than 1% of all malignancies in males although their incidence is rising. They are highly curable even if advanced; 95% are germ cell tumours and 5% sex cord-stromal tumours. The rest are rare but include mixed tumours not specific to the testis and metastases. Predisposing factors include cryptorchidism, genetic, testicular dysgenesis, Li-Fraumeni syndrome, prior testicular germ cell tumour or intratubular germ cell neoplasia.

Germ cell tumours: the British and American histological classifications of teratoma differ but the terminology can be correlated (Table 32.1). For management and prognostic purposes the most important distinction is between seminomatous and non-seminomatous tumours. Pathological staging has minor clinical significance as therapy is largely dependent on clinical

Table 32.1. Malignant teratoma classification

British (BTTP)

American/WHO

Teratoma Differentiated (TD)

Mature Teratoma

Immature Teratoma

Malignant Teratoma Intermediate (MTI)

Teratoma with embryonal carcinoma and/or yolk sac tumour

Malignant Teratoma Undifferentiated (MTU)

Embryonal carcinoma

Malignant Teratoma Trophoblastic (MTT)

Choriocarcinoma (only element)

staging (TNM and the modified Royal Marsden systems) based on imaging techniques (for abdominal/pulmonary/cerebral metastases) and levels of serum tumour markers.

Intratubular germ cell neoplasia (ITGCN): in situ stage of germ cell neoplasia seen in 90-100% of testes adjacent to germ cell tumours. There is an association with infertility (0.4-1.0%), cryptorchidism (2-8% of patients) and in the contralateral testis in patients with prior testicular tumour (5%). Fifty per cent progress to germ cell tumour in five years. Histology shows large seminoma-like cells present along a thickened/hyalinised tubular basement membrane. Spermatogenesis is usually absent. There is positive staining with PLAP (97% of cases) and PAS without diastase (glycogen). It can be treated with low-dose radiation but watchful waiting (clinical, ultrasound examination and serum markers) is advocated by some.

Seminoma: represents 30-50% of testicular germ cell tumours with a mean age at diagnosis of 40 years. Forty per cent have increased serum PLAP and 70% of patients have stage I disease. Metastases are to lymph nodes or bone. The presence of elevated serum HCG does not change the classification and has no clinical significance. However, elevated AFP indicates a non-semi-nomatous germ cell component (or liver disease), even if not seen histologically. The gross appearance is that of a bulky, homogeneous, pale tumour with lobulated and bulging cut surface. Histology consists of sheets of relatively uniform large, polyhedral, glycogenated tumour cells and delicate fibrous septa with T lymphocytes and plasma cells. Granulomatous inflammation, trophoblastic giant cells and Pagetoid spread to the rete are seen in a minority of cases. There is positive staining with PLAP (almost all), PAS and vimentin. Cytokeratins may be weak/focal and the tumour cells are negative for AFP, HCG (syncytiotrophoblastic giant cells are positive), CD30 and EMA.

Treatment consists of orchidectomy and or radiotherapy (very radiosensitive). Cis-platinum-based chemotherapy is used for bulky retroperitoneal disease or supradiaphragmatic involvement. Prognosis is excellent with a 95% cure rate for stage I (testis confined) or II (infradi-aphragmatic nodes) disease. Adverse prognostic factors include tumour > 6 cm, age > 35 years and lymphovascular invasion.

Spermatocytic seminoma: One to two per cent of germ cell tumours with a mean age of 55 years. Regarded as benign but occasionally associated with sarcoma (rhabdomyosarcoma), they are pale with a soft, friable cut surface and 10% are bilateral. Microscopy reveals three types of cells; small (lymphocyte size), medium cells and large (giant) cells and mitoses. They are distinguished from seminoma by the absence of stroma, lymphocytes, glycogen, granulomas and ITGCN. They are positive for CAM5.2 (40%) and negative for PLAP, HCG, AFP and EMA.

Non-seminomatous germ cell tumours (NSGCT): in general more aggressive and metastasise earlier than seminomas. The metastases may not resemble the primary tumour and are radiore-sistant. Eighty per cent have elevated AFP or HCG at diagnosis. The prognosis is good with 95% cure rate if there is no lymph node or metastatic involvement but ranges from 40 to 95% with metastases. There is a poor prognosis if extensive pulmonary disease is present. Traditionally, the treatment for stage I non-seminomatous germ cell tumours has been orchidectomy followed by retroperitoneal lymph node dissection to eradicate the disease while confined to the local lymph nodes. It is now believed, however, that most patients with such tumours do not benefit from this dissection, a procedure which is not without complications. More recently, stage I non-seminomatous germ cell tumours have been managed by surveillance (regular serum tumour markers and CT scanning). Stage I tumour with lymphovascular invasion and more advanced disease are best treated with chemotherapy. If the concentrations of tumour markers fall after chemotherapy and residual retroperitoneal masses are seen on CT then lymph node dissection is appropriate as 20% of such nodes will harbour residual tumour. When the tumour markers do not fall to normal concentrations after chemotherapy, opinion on treatment is divided between lymph node dissection and further chemotherapy.

Teratoma: represent five per cent of germ cell tumours and contain cellular components derived from two or three germ layers. It is the second most common testicular tumour after yolk sac in children (age < 3), is not associated with intratubular germ cell neoplasia and almost never metastasises. In adults there is a presumption of malignant behaviour regardless of tumour differentiation. Grossly large (5-10 cm), multinodular and heterogeneous (solid, cartilaginous, cystic). Histologically mature teratomas contain differentiated tissues including cartilage, nerve and various epithelia, whereas immature teratomas have foci resembling embryonic or fetal structures including primitive neuroectoderm, poorly formed cartilage, neuroblasts, loose mesenchyme and primitive glandular structures (amount important). Occasional cases undergo malignant transformation with focal malignancy such as squamous cell carcinoma, adenocarcinoma or sarcoma (adults).

Mixed germ cell tumours: mixed forms are common, accounting for one third of germ cell tumours and 70% of non-seminomatous tumours of the testes. Common combinations include embryonal and teratoma; embryonal and seminoma; embryonal, yolk sac tumour and teratoma. Clinical presentation and management are the same as non-seminomatous germ cell tumour and the prognosis is usually that of the worst component.

Embryonal carcinoma: pure tumours represent 2% of germ cell tumours, but 85% of NSGCTs have an embryonal carcinoma component. Histologically solid, alveolar, tubular or papillary patterns of large, epithelioid, anaplastic cells. There is positive staining with HCG or AFP in mixed tumours, cytokeratin, CD30, PLAP and negative staining with EMA.

Yolk sac tumour: considered a unilaterally developed teratoma mimicking embryonal yolk sac tissue. It is the most common testicular tumour age three or less and often pure with a good prognosis (80%+ are stage I). In adults it is usually part of a mixed tumour and has the prognosis of embryonal carcinoma. Most patients have elevated serum AFP. Microscopy varies greatly but includes papillary Schiller Duval bodies, PAS-positive hyaline globules, solid and microcystic patterns.

Choriocarcinoma: Between 0.3% and 1% of germ cell tumours are pure choriocarcinoma, but mixed tumours are more common. It may present initially with early haematogenous metastases (liver, lung, mediastinum, retroperitoneum) and a normal testis or small tumour, but with increased serum HCG. It is usually fatal if pure. Histologically there is haemorrhage and necrosis with a biphasic arrangement of cytotrophoblast and syncytiotrophoblast cells. There is positive staining with HCG, HPL and EMA (syncytiotrophoblast, not cytotrophoblast), cytokeratin, PLAP (50%) and CEA (25%).

Sex cord-stromal tumours: Four per cent of testicular neoplasms and containing epithelial elements of sex cord origin (Sertoli and granulosa cells) admixed with mesenchymal components (Leydig and theca-lutein cells) in varying combinations and degrees of differentiation. Almost all are immunoreactive for inhibin.

Leydig (interstitial) cell tumours: Between 1 and 3% of testicular tumours (age 20-60) with 3% bilateral. They secrete sex hormones and symptoms include gynaecomastia with virilism, precocious puberty and a testicular mass. In adults 10% have malignant behaviour with metastases to lymph nodes, lung and liver. Features suggesting malignancy include large size (> 5 cm), necrosis, vascular invasion, nuclear atypia, numerous and atypical mitoses, infiltrative margins, older patients, aneuploidy and higher MIB-1 activity. Mean survival when malignant is four years. Grossly they are solid brown tumours and 10% have extratesticular extension. Histology reveals sheets of large, round/polygonal cells with eosinophilic cytoplasm and round central nuclei. Reinke crystals are present in 25% of cases. Treatment includes orchidectomy and/or lymph node dissection if malignant.

Granulosa cell tumour: resembles analogous ovarian tumour. The adult form is rare with an age range 20-53 years, usually non-functional and rarely associated with gynaecomastia. It is usually benign but metastases occur in 10% (associated with size > 7 cm, haemorrhage, necrosis, lymphovascular invasion). The juvenile form is the most common neonatal testicular tumour with an average age of onset less than one month or even congenital. There is an association with trisomy 12 and sex chromosome mosaicism if abnormal external genitalia. There is no association with endocrine manifestations. It has a benign behaviour following orchidectomy.

Sertoli cell tumours: one third present with gynaecomastia without virilism and 10% are malignant (to local lymph nodes), indicators being nuclear pleomorphism, size > 5 cm, mitoses, necrosis and lymphovascular invasion. Grossly firm, small, well-circumscribed yellow-white nodules. Histology shows trabeculae lined by Sertoli-like cells. They show positive staining for vimentin, cytokeratin AE1/AE3, and inhibin (variable) but are PLAP negative. Treatment is orchidectomy (radiation and chemotherapy have little effect). Mixed germ cell-sex cord stromal tumours (gonadoblastoma) Other tumours not specific to testis: Leukaemia: testis may be first site of relapse, e.g., ALL in children.

Lymphoma: Fifty per cent of testicular neoplasms in men age 60+, 20% bilateral, often representing spread from systemic disease. Granulocytic sarcoma: 20-35% patients involved.

Carcinoid: presumed to be a monodermal teratoma, although 20% have other teratomatous elements. It is rare and 10% have clinical carcinoid syndrome. Metastases to testes: rarely the first clinical sign of disease. Lung, prostate and skin (Merkel cell tumours, melanoma) are the usual primary sites. Immunohistochemistry may help in distinguishing the primary site.

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