1	Testicular cancer Anita Goossens 24th May 2008
2	Introduction (1) Testicular cancer is the most common solid malignancy in men aged 15 to 35 years. The large majority of primary testicular tumours originate from germ cells (95%) (GCT). More than half of the tumours contain more than one histological tumour type. The survival rates are 95%, if they are adequately treated. The distinction of seminoma from non-seminomatous tumours remains of critical clinical importance.
3	"Introduction (2)" Introduction (2) The tumours of non-germinal origin, while relatively uncommon, are frequent diagnostic problems from as regards classification and prognosis. Sex cord-stromal tumours are much less common (4%), occur over a wider age range and are more often benign. Other elements may be the sources for neoplasm,i.e. the mesothelium that lines the tunica vaginalis (mesothelioma, adenomatoid tumor). The paratesticular area has a rich component of supporting mesenchymal cells as well as embryonic remnants that allow for a truly diverse number of paratesticular tumours.
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5	"Epidemiology (1)" Epidemiology (1) GCT occurs predominantly in the white population, while people from Africa or Asia have a low incidence. There has been a recent increase in the incidence of testicular cancer. An annual increase of 3 - 6% is reported for Caucasian populations. The incidence has doubled in the past 30 years.
6	"Epidemiology (2)" Epidemiology (2) The incidence increases shortly after the onset of puberty and reaches a maximum in men in their late twenties and thirties. The rate of GCT is very low in older men.
7	Treatment and prognosis The mortality has sharply declined. Seminoma is treated by low dose radiation. The critical distinction is the recognition of seminoma.
8	"Etiology" Etiology There are 5 well- established and positive associations with testicular cancer. cryptorchidism a prior GCT a family history of GCT intersex syndromes infertility, subfertility Cryptorchidism is associated with an increased risk of testicular germ cell tumour. Increased risk in the undescended and the contralateral testicle. Patients with Klinefelter’s syndrome have a high risk of mediastinal GCT
9	"General clinical aspects" General clinical aspects A nodule or a painless swelling of one testicle. A metastasis is the presenting symptom in 10%. a mass in the left neck hemoptysis or dyspnea abdominal mass Endocrine symtoms: gynecomastia (5%)
10	"Patterns of spread" Patterns of spread Direct extension The lymphatic vessels from the right testis drain into lymph nodes lateral, anterior and medial to the vena cava. The left testis drains into lymph nodes distal, lateral and anterior to the aorta, above the level of the arteria mesenterica anterior. These drain into the left supraclavicular lymph nodes and the subclavian vein. Hematogenous spread choriocarcinoma: lung, brain seminoma: bone
11	"Adequate fixation is crucial" Adequate fixation is crucial. Cytological features are obscured by poor tissue preservation.
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13	"Gross examination" Gross examination Tumor size Extension into spermatic cord, tunica albuginea The presence of variations in gross appearance (necrosis, hemorhages) Extensive slicing is necessary (1 section for each 1 cm tumour diameter). More slices are necessary if the tumour is heterogenous. Regressive changes!! Germ cell tumours are friable making knife implantation into vascular spaces common. Care during sampling is recommended.
14	Diagnosis (1) Neonate: granulosa cell tumour Infants : teratoma or Yolk sac tumour Adolescence and young adults: non- seminoma 35- 45 years old: seminoma 60 years old: spermatocytic seminoma
15	"Diagnosis (2)" Diagnosis (2) Routine staining is sufficient for the diagnosis in many cases. . IH may help to reach the correct classification (solid or eosinophilic tumours, tumours with a tubular pattern) IH is also useful in evaluating the possibility of germ cell origin for a metastic poorly differentiated carcinoma in a young adult man.
16	Diagnosis (3) Some of the tumour markers are retained despite extensive tumour necrosis (PLAP). Some markers retain their reactivity after chemotherapy (OCT4). Some markers are useful in specific situations (HMB45, CD45).
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22	"IGCNU" IGCNU Testicular germ cell tumours in adults and adolescents are associated with IGCNU. This association is strong and specific. In adults and adolescents, it is practically always present in the tissue surrounding a testicular germ cell tumour. Exception : spermatocytic seminoma In children, rare association with germ cell tumour.
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26	Histology Germ cells with enlarged, hyperchromatic nuclei and clear cytoplasm basally located between the Sertoli cells. Spermatogenesis is absent in the tubule. D2-40, OCT4, PLAP,CD117: +
27	"IGCNU" IGCNU Is identified in 1% of testicular biopsy for infertility. 70% of the patients with IGCNU develop invasive testicular cancer within 7 years of diagnosis. screening of the cryptorchid testis in late adolescence.
28	"Seminoma" Seminoma Seminoma is the most common pure testicular germ cell tumour. It comprises over 60% of neoplasm in cryptorchid testes. It is a component in a many mixed GCT. Average age: 35- 40 years old. relatively uniform cells with abundant clear cytoplasm. well defined cell borders. there is an associated lymfoied infiltrate and frequently a granulomatous response.
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31	Immunohistochemistry PLAP: + (90- 100%), membranous pattern. D2-40: + (95%), membranous pattern. OCT4: + (> 95%), nuclear staining. cKIT: + (> 80%), membranous pattern. Cytokeratin: -/+ CD30: -/+ Inhibin: - Note: PLAP persists in necrotic areas. OCT4 persists after chemotherapy.
32	"Microscopy (1)" Microscopy (1) Variants : Growth pattern : . Indian - files . Pseudoglandular . Cribriform . Tubular . Interstitial . Microcystic
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34	"Microscopy (2)" Microscopy (2) Variants: Cell type : . Plasmacytoid appearance. . Signet-ring cell appearance.
35	Microscopy (3) Variants: Mitotic rate : . High mitotic rate (more than 3/HPF). . Originally defined as an anaplastic seminoma. . The degree of mitotic activity carries no known prognostic significance. . The tumor needs no separate classification.
36	Intertubular (inconspicious, interstitial) seminoma
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42	"Seminoma versus malignant lymphoma" Seminoma versus malignant lymphoma growth pattern presence of IGCNU perform IH
43	"LYMPHOMA" LYMPHOMA Primary lymphoma and plasmacytoma of testis and paratesticular tissues arise in the testis, epididymis or spermatic cord and are neither associated with lymphoma elsewhere nor leucemia. More often a late manifestation of disseminated disease. Most patients are in older age group. In this age group TL is the single most frequent testicular cancer.
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48	"Metastatic disease versus seminoma" Metastatic disease versus seminoma interstitial growth pattern age of the patient extensive vascular invasion absence of IGCNU morphology inconsistent with a primary testicular tumour perform IH
49	"Secondary tumours" Secondary tumours Uncommon Older males It is found at autopsy in patients with disseminated disease or after orchietectomy for prostatic carcinoma. Prostate, lung, colon, kidney, melanoma Single or multiple nodules. The presence of multiple nodules should raise the possibility of metastasis in patients over 50 years of age.
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53	"Granulomatous seminoma" Granulomatous seminoma 50% contain clusters of histiocytes. Well- formed granuloma with Langhans giant cells. The reaction is so extensive as to obscure the neoplastic nature of the process. The diagnosis of a granulomatous orchitis can be made.
54	"Idiopathic granulomatous orchitis" Idiopathic granulomatous orchitis It is the most common non-neoplastic lesion to mimic a malignant neoplasm. It is likely an autoimmune disease. Sudden onset of testicular swelling, associated with pain suggests an inflammatory process.
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56	"Seminoma versus granulomatous orchitis" Seminoma versus granulomatous orchitis Localisation of the infiltrate Presence of IGCNU Perform IH
57	Granulomatous lymphadenitis Granulomatous inflammation can obscure the seminoma cells in needle biopsy specimens of a retroperitoneal mass or lymph node. IH is fundamental in these cases.
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61	"Seminoma with syncytotrofoblastic" Seminoma with syncytotrofoblastic cells (10-20%): These cells appear isolated or as small clusters. They are closely related to blood vessels and foci of hemorrhage. They are not associated with cytotrofoblastic cells. They stain for bHCG. They are associated with a mildly elevated level of hCG (high levels of hCG suggest choriocarcinoma) The prognosis of these tumours is the same as for the classical seminoma.
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64	"Choriocarcinoma" Choriocarcinoma Choriocarcinoma is a malignant neoplasm composed of syncytiotrofoblastic, cytotrofoblastic and intermediate cells. Epidemiology In its pure form, choriocarcinoma is extremely rare (< 1% of GCT). It is admixed with other germ cell elements in 8% of NSGCT
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67	"Immunohistochemistry" Immunohistochemistry Cytokeratines: + HCG: + in syncytiotrofoblast Inhibin: + in syncytiotrofoblast EMA: + PLAP : patchy reactivity Vimentin, OCT4, D2-40: -
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70	"Spermatocytic Seminoma" Spermatocytic Seminoma Definition Composed of germ cells with a prominent variation in size from lymfocyte-like to bizarre giant cells. Uncommon tumor that behaves in an indolent fashion.
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75	Immunohistochemistry The diagnosis is largely based on routine LM. Many of the IH-markers useful in other types of germ cell tumour are generally negative. PLAP, D2-40 and OCT4: - Cytokeratin, CD30, aFP, bHCG : - cKit : + in 40%.
76	"Spermatocytic seminoma versus classic seminoma" Spermatocytic seminoma versus classic seminoma - age of the patient - growth pattern - absence of IGCNU - absence of a lymphocytic/granulomatous reaction - PLAP -, OCT4 -, D2-40: -
77	"General features" General features This tumor usually arises in older men ( mean age at diagnosis: 54 years). It does not arise in cryptorchid testes, extratesticular sites. It does not arise in association with other germ cell tumours. IGCNU is not found in association with spermatocytic seminoma. The biological behaviour is benign except in rare cases with sarcomateus transformation.
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79	"EMBRYONAL CARCINOMA" EMBRYONAL CARCINOMA Definition A tumour composed of undifferentiated cells of epithelial appearance with a variety of growth patterns. (solid, glandular, papillary)
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85	"Seminoma versus embryonal carcinoma" Seminoma versus embryonal carcinoma D2-40: + CD30: -/+ Pancytokeratin: -/+
86	"IH : CD30 : +" IH : CD30 : + it is rarely seen in other germ cell tumors may disappear following chemotherapy. It is a useful marker in separating somatic carcinomas from embryonal carcinoma at metastatic sites (Oct4). PLAP : + (membranous and cytoplasmic positivity, focally and intense) Cytokeratin : + CD117, D2-40: - aFP : + in scattered cells, early differentation into yolk sac tumour The diagnosis of embryonal carcinoma is maintened unless tissue patterns of YST can be identified by LM bHCG : + (syncytiotiofoblastic cells).
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89	"General features" General features It occurs in the pure form and as a tumour component in germ cell tumours of more than one histologic type (it occurs as a component in more than 80% of mixed germ cell tumours). It is not found in infants and children and rare after 50 years of age. The peak incidence is around 30 years of age (10 years before the peak incidence of classical seminoma).
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92	"YOLK SAC TUMOR" YOLK SAC TUMOR (endodermal sinus tumor) Definition A tumour characterized by numerous growth patterns that recapitulate the yolk sac, allantois and extra-embryonic mesenchym. It produces aFP.
93	"General features" General features Infants, young children: 80% of all prepubertal GCT are YST. The children are usually less than 5 years. . It occurs in all races. It occurs invariably in its pure form. . No association with cryptorchidism. It has an excellent prognosis. In adults, it is present as a component in about 40% of mixed GCT. Much more common in caucasians. A pure YST is rare. Age incidence, the clinical signs and symptoms and the pattern of spread is similar to that seen in other NSGCT. Strong correlation between the presence of YST and the serum levels of aFP
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96	Histology Occurrence of intracytoplasmic globules. Presence of band-like extracellular material. Presence of distinct patterns.
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102	"Immunohistochemistry" Immunohistochemistry aFP : +, variable staining Cytokeratine : + PLAP : + (50%) CD30 : -, variable staining OCT4, D2-40 : - Glypican 3: +
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104	"Scar versus regressed tumour" Scar versus regressed tumour A GCT can completely or partially undergo necrosis and regression, leaving a scar. ( choriocarcinoma, embryonal carcinoma, seminoma, mixed GCT). Variants of YST and teratoma show resistance to spontaneous and chemotherapy induced necrosis.
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106	Conclusion The age of the patient. Look for IGCNU: biopsy for infertility at he periphery of an invasive tumor: GCT IGCNU and seminoma are not always “easy” diagnoses. Think about a GCT in a young or middle-aged male with metastatic disease. Exclude metastatic seminoma in an “idiopathic” granulomatous lymphadenitis. YST is the most commonly overlooked component in a mixed GCT.
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