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Home , Brenner tumour, Granulosa cell tumour, Leydig cell tumour, Lipochrome, Seminoma, Sertoli cell tumour

Non-germ cell tumours of the testis Testis: non-germ cell tumours

. Sex cord-stromal tumours Dr Jonathan H Shanks . Haemolymphoid . Other neoplasms The Christie NHS . Tumour-like conditions Foundation Trust, Manchester, UK . Metastases

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Testis: sex cord-stromal tumours

. tumour . tumour, NOS . Sclerosing . Large cell calcifying Sertoli cell tumour . , adult-type . Juvenile granulosa cell tumour . . . Sertoli-Leydig cell tumours (exceptionally rare in testis) . Sex cord-stromal tumour, unclassified . Mixed germ cell-sex cord stromal tumour - gonadoblastoma - unclassified (some may be sex cord stromal tumours with entrapped germ cells – see Ulbright et al., 2000) - collision tumour

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Differential diagnosis of Leydig cell TTAGS tumour

. Testicular tumour of adrenogenital syndrome (TTAGS) . Multifocal/bilateral lesions (especially in a child/young adult) . Seen in patients with congenital adrenal . Leydig cell hyperplasia (<5mm) . 21 hydroxylase deficience most common . Large cell calcifying Sertoli cell tumour . Elevated serum ACTH . Sertoli cell tumour . (rare cases with cytoplasmic clearing) . Benign lesion treated with steroids; partial orchidectomy reserved for steroid unresponsive cases . Mixed sex cord stromal tumours . Sex cord stromal tumour unclassified . Fibrous bands; pigment ++; nuclear pleomorphism but no mitosis . e.g.

The Christie NHS Foundation Trust The Christie NHS Foundation Trust of testicular Histopathological and immunophenotypic features of testicular tumour of adrenogenital Leydig cell tumour syndrome Wang Z et al. 2011;58:1013-18 McCluggage et al Amin, Young, Scully . 20 cases . 12 cases . TTAGS did not contain Reinke’s crystals, had . Inhibin (15/16) . Inhibin (12/12) thicker fibrous bands and were often bilateral . CAM 5.2 (7/16) . CAM 5.2 (5/12) . All 6 TTAGS tested were diffusely and strongly dot-like in 20% . Vimentin (14/16) positive for CD56 (Leydig cell tumours were . Vimentin (11/12) . S100 protein (10/16) negative or showed focal weak +ve) . S100 protein (2/12) . Androgen receptor was positive in Leydig cell . Desmin (2/16) . EMA (0/12) tumour in 6/7 cases but negative in all TTAGS

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Non-progressive vs. malignant Kim I, Young RH, Scully RE (1985) Leydig cell tumours (1) . 40 cases Leydig cell tumour Non-progressive Malignant . Follow-up available for 30 cases . Mean age 41 years . Mean age 67 . *Smaller size (<5cm) . *Larger size (>5cm) . 5 were malignant mean 2.7cm mean 6.9cm . Size (all cases) 0.5 - 10cm, mean 3cm . *Absence of infiltrative . *Infiltrative margin . 2/40 arose in cryptorchid testis margin . *Absent lymphovascular . *Lymphovascular . Mean age 46.5 years (range 2-90 yrs) invasion invasion present

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Non-progressive vs. malignant *Histological criteria of Kim, Young and Scully Leydig cell tumours (2) associated with malignancy Non-progressive Malignant . Size >5cm . * absent . *Necrosis present . Infiltrative margins . *MF<3/10HPF . *MF>3/10HPF . Lymphovascular invasion . Minimal cytological atypia . Marked cytological atypia . Mitoses >3/10HPF . [Most had high MIB-1 index . [All had low MIB-1 index (0- 20-50%] . Necrosis 2%)] . [Aneuploid by ] . [Most were diploid by flow . [p53 over expression] cytometry] All 5 of their malignant cases satisfied 4 or more criteria . [All p53 negative] In series of McCluggage et al. 2 malignant cases satisfied 5 criteria and 2 satisfied 3 criteria

The Christie NHS Foundation Trust The Christie NHS Foundation Trust 32 Leydig cell tumours (Cheville and Sebo, Metastatic Leydig cell tumour (based on 26 1998) cases) Non- Malignant . Sites in descending order of frequency - regional lymph nodes, lung, liver, bone, kidney, other Progressive . Metastases present at diagnosis in 22% malignant cases Infiltrative 0% 67% . Metastases within 1 year of diagnosis 19% margin* . >1 year from diagnosis in 59% (up to 10 years from Necrosis* 4% 83% diagnosis) MF>5/10HPF* 12% 100% . Median survival 2 years for patients with metastasis Cytological 19% 100% atypia >3-4* Vasc Inv* 8% 50%

Size>5cm 12%The Christie 17% NHS Foundation Trust The Christie NHS Foundation Trust

Variant appearances in testicular Leydig cell tumour Typical profile of Leydig cell tumour . Nested pattern . Pseudoglandular pattern Positive Negative . Trabecular pattern . Inhibin . OCT3/4 . Cord-like pattern . Melan A . Chromogranin . Spindle cell/sarcomatoid areas . PLAP . Small cells . Steroidogenic factor-1 . S100 . Microcystic areas resembling yolk sac tumour (SF-1) . EMA . Stromal hyalinisation, myxoid change or oedema . Calretinin . SALL-4 . Stromal calcification/ossification [exceptional cases] . CAM 5.2 (dot-like), or -ve . Cytoplasmic clearing due to lipid (can mimic seminoma focally) . Synaptophysin (-/+) . Adipose

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Leydig cell tumors of the testis with unusual

features Ulbright et al. AM J Surg Pathol 2002;26:1424-33

. 19 cases . 12 had adipose differentiation (3 of these showed psammomatous calcification with ossification in 2) Sarcomatoid Leydig cell tumour of . 8 had spindle cell growth (spindle cell morphology per se was not associated with a malignant course, testis Richmond I et al. Histopathology 1995;27:578-80 only adverse if pleomorphic spindle cell areas present) . Presence of typical Leydig cell areas distinguishes Leydig cell tumour with spindle/sarcomatoid areas from sex cord-stromal tumour, unclassified (which does not contain typical Leydig cell areas)

The Christie NHS Foundation Trust The Christie NHS Foundation Trust Immunohistochemistry of Sertoli cell tumour, NOS

. Variable from case to case, some similarity to Leydig cell tumour but less often inhibin positive and more often cytokeratin positive Sertoli cell tumour, NOS . May be negative for multiple markers for sex cord stromal tumour in some cases

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Features described/variant features in testicular Sertoli cell tumour, NOS

. Solid/hollow tubules/trabeculae/cords . Diffuse/solid pattern (sheets of Sertoli cells – can be confused with seminoma) NB Rare have a tubular growth pattern which can mimic Sertoli cell tumour . Cystic pattern (can mimic yolk sac tumour) . Retiform areas . Palisading, simulating Verocay bodies Sclerosing Sertoli cell . Grooved nuclei (occasional cases) . Cytoplasmic vacuolation (due to lipid) tumour . Cytoplasmic eosinophilia . Prominent stromal sclerosis/hyalinisation . Stromal calcification in rare cases . Ectatic blood vessels

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Clinical History

. 10 year old boy . Presented with precocious and breast enlargement Large cell calcifying Sertoli cell tumour . 6 months later complained of testicular pain and found to have bilateral irregular enlarged testes . Bilateral testicular biopsies performed

The Christie NHS Foundation Trust The Christie NHS Foundation Trust Follow-up Clinical and molecular genetics of Carney complex Sandrini F and Stratakis C, Mol Genet Metab 2003;78:83-92; Rothenbuhler and Stratakis C Best Prac Res Clin Endocrinol Metab . Treated with aromatase inhibitors and 2010;24:389-99

cyproterone acetate . Lentigines, cardiac , endocrine abnormalities, . 2 years after presentation had bilateral schwannomas. Autosomal dominant inheritance. . Significant clinical heterogeneity breast reductions for gynaecomastia . Mapped to 2p16 and 17q22-24 . Gene for protein kinase A type I-a regulatory subunit . Remains well on endocrine follow-up (PPRKAR1A) mapped to 17q . However, found to have a mutation within . Gene shows mutations in almost half of Carney’s complex patients the regulatory unit of protein kinase A – . Carney’s complex is the first human linked to confirming Carney’s complex mutations in one of the subunits of the PKA enzyme, a critical component of numerous cellular signalling systems

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Differential diagnosis of large cell Features favouring large cell calcifying calcifying Sertoli cell tumour Sertoli cell tumour in differential diagnosis with Leydig cell tumour . Leydig cell tumour . Bilateral/multifocal distribution . Sertoli cell tumour, NOS . Associated syndromes . [Metastatic carcinoma] . Strong cytokeratin and/or S100 positivity . [Metastatic melanoma] . Presence of neutrophils in many cases of large cell calcifying Sertoli cell tumour

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Large cell calcifying Sertoli cell tumour

. Carney’s syndrome . Peutz-Jegher’s syndrome

[Tumours are often bilateral and usually benign in these conditions, though extremely rare malignancy has been recorded; malignancy is less rare (approx 20% cases) in unilateral solitary tumours] Granulosa cell tumour

Patients with Peutz-Jegher’s syndrome may instead have intratubular large cell - adult-type hyalinising Sertoli cell neoplasia of the testis see Ulbright et al. Am J Surg Pathol - juvenile 2007:31:827-35 [always benign]

The Christie NHS Foundation Trust The Christie NHS Foundation Trust Architectural features which may be encountered in adult granulosa .Fibroma cell tumour .Brenner tumour .Sertoli-Leydig cell tumours (exceptionally . Solid rare in testis) . Microcystic .Unclassified . Microfollicular .Mixed germ cell-sex cord stromal . Gyriform tumour . Insular .gonadoblastoma . Trabecular .unclassified (some may be sex cord stromal tumours with entrapped . Spindle cell germ cells – see Ulbright et al., 2000) .collision tumour The Christie NHS Foundation Trust The Christie NHS Foundation Trust

Differential diagnosis

. Sertoli cell tumour . Sclerosing Sertoli cell tumour Sex cord-stromal tumour, . Granulosa cell tumour . (primary/metastatic) unclassified . ‘Testicular gonadal stromal tumour’/fibroma . Metastatic carcinoma . Metastatic melanoma . Leydig cell tumour (sarcomatoid)

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Sex cord-stromal tumour, Gonadoblastoma unclassified . Young patients (<20 yrs) . Occurs in patient with abnormal dysgenetic gonads . Unclassified sex cord-stromal tumours of testis are rare . XY gonadal dysgenesis or X0-XY mosaicism . There is often a prominent spindle cell component . 80% phenotypically female; 20% phenotypically male with partial or incomplete differentiation towards . Invasive germ cell tumour, usually seminoma may Sertoli cell and/or granulosa cell components develop . Areas of classical Leydig cell tumour are not usually . Bilateral gonadectomy recommended a feature . Sertoli cell tumour, NOS and granulosa cell tumour are the major differential diagnoses . Ongoing studies with better delineation of the spectrum of such tumours is required

The Christie NHS Foundation Trust The Christie NHS Foundation Trust Sex cord-stromal tumours of testis: summary of typical immunophenotype Prognosis (sex cord stromal tumours, testis) . The immunophenotype of sex cord-stromal tumours of testis is quite variable . 10% Leydig cell and 10% Sertoli cell tumours . Leydig cell tumours and large cell calcifying Sertoli cell tumours have malignant behaviour according to are consistently positive for inhibin, Sertoli cell tumour and unclassified sex cord stromal tumour less consistently positive literature, though this is historical data and . A variety of other markers, including steroidogenic factor-1 (SF- tumours often present when much smaller today, 1), melan-A (MART-1), S100, calretinin, and sometimes alpha- so incidence of malignancy very likely to be SMA, can be expressed in sex cord-stromal tumours, though HMB45 is consistently negative. lower now . EMA is usually negative. . ? 20% of sex cord-stromal tumour unclassified . Cytokeratins are frequently expressed in Sertoli cell tumour, have malignant behaviour in adults NOS and in some unclassified sex cord-stromal tumours; they also expressed, though less frequently in some Leydig cell (contemporary cases likely to be <20%); tumours. malignant behaviour less common in children, and especially rare <10 years age

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Adverse histological prognostic features for sex-cord Tumour-like conditions stromal tumours of testis . Sertoli cell nodules (‘Pick’s adenoma’) . Testicular ‘tumour’ of adrenogenital syndrome (TTAGS) . Large size (>50mm) [bilateral/multifocal involvement; history; look for large cells with . Infiltrative margins abundant lipochrome pigment; abundant dense . Lymphovascular invasion septa] . Tumour necrosis . Leydig cell hyperplasia . Mitotic index >3/10HPF (Leydig cell tumours) >5/10HPF . Inflammatory myofibroblastic tumour (Sertoli cell tumours) . Sperm . Adrenal rests [behaviour can be difficult to predict and no feature is absolute. . Splenic-gonadal fusion Cheville et al., 1998 found neither MIB-1 index nor ploidy added to . Sclerosing lipogranuloma prognostication ] . Malakoplakia . Granulomatous orchitis

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Haemolymphoid neoplasms Other neoplasms

. Malignant lymphoma . Sarcoma commonest is primary testicular diffuse . Carcinoid tumour large B cell lymphoma which often . Benign tumours involves unusual sites (e.g. CNS, skin, lung) . Plasmacytoma (primary or secondary to myeloma) . Leukaemia (common sanctuary site)

The Christie NHS Foundation Trust The Christie NHS Foundation Trust Reports of unusual spindle cell Testicular sarcoma ‘testicular gonadal stromal tumours’

. Pure, primary (various subtypes) . Evans and Glick 1977 “Unusual gonadal stromal . Arising from: tumour” . Greco et al., 1984 “Testicular stromal tumor with spermatocytic seminoma myofilaments” Leydig cell tumour . Meittinen et al., 1986 “Testicular stromal tumour with . Metastatic epithelial differentiation” . Nistal et al, 1996 “Fusocellular gonadal stromal [ are more common in the paratestis/spermatic tumour of the testis with epithelial and myoid cord e.g. [the most frequent in adults], differentiation (myofibroblastoma)” which may be dedifferentiated; ; . Weidner 1991 “Myoid gonadal stromal tumours with in children/adolescents] epithelial differentiation (testicular myoepithelioma?)”

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Testicular carcinoid tumour

. Primary - pure - component of . Metastatic Metastases

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Paratesticular tumours

. Adenomatoid tumour . Rhabdomyosarcoma (children/adolescents) . Malignant of tunica vaginalis . Liposarcoma of spermatic cord (sclerosing variant of well differentiated liposarcoma more common than at other sites; dedifferentiated elements can also cause of the rete testis diagnostic difficulty) Skailes GE et al. Histopathology 1998;10:401-3 . Leiomyosarcoma . Mullerian epithelial tumours (serous, endometrioid, mucinous, clear cell, Brenner tumour) . Rete testis adenoma; adenocarcinoma . Cystadenoma of the epididymis (clear cell type, associated with VHL syndrome)

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. Absence of primary tumour elsewhere . Tumour centred on testicular hilum . Transition from non-neoplastic rete . Incompatible with other testicular/paratesticular tumour . Papillary serous adenocarcinoma and malignant mesothelioma excluded by immunohistochemistry

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