Testis & paratestis

• Common precursor of type II germ cell tumors (i.e., seminomas and most postpubertal nonseminomatous germ cell tumors of the testis) (Nat Rev Cancer 2019;19:522)
• Neoplastic gonocyte-like cells with latent totipotent (naive) developmental potential, located in the spermatogonial niche of seminiferous tubules

• Precursor for a subset of adult germ cell tumors (in WHO classification, referred to as germ cell neoplasia in situ [GCNIS] associated)
• Associated with uncorrected cryptorchidism, ambiguous genitalia, infertility and a prior history of contralateral postpubertal germ cell tumor or GCNIS
• Presence in testicle from a patient with extragonadal germ cell tumors may represent a burnt out germ cell tumor
• Difficult to diagnose in infantile / prepubertal testis due to morphologic and immunohistochemical overlap with normal or delayed maturation
• Frequently demonstrate aneuploidy but lack isochromosome 12p seen in invasive adult germ cell tumors

• Germ cell neoplasia in situ (GCNIS) was introduced in the 2016 edition of WHO's Tumors of the Urinary System and Male Genital Organs
• Intratubular germ cell neoplasia (ITGCN) (not recommended / obsolete)
• Intratubular germ cell neoplasia of unclassified type (not recommended / obsolete)
• Carcinoma in situ of the testis (not recommended)

• ICD-O: 9064/2 - intratubular malignant germ cells
• ICD-10: C62 - malignant neoplasm of testis
  • With relevant subcodes (e.g., C62.9 - malignant neoplasm of testis, unspecified whether descended or undescended)
• ICD-11: 2C80.2 & XH8AD3 - germ cell tumor of testis & intratubular malignant germ cells

• Frequent in seminiferous tubules of testicles involved by postpubertal germ cell tumors and sometimes represents the only residual manifestation (e.g., burnt out germ cell tumor) (Cancer 1981;47:2660, APMIS 2003;111:32, Am J Surg Pathol 2007;31:1045, Eur Urol 2007;51:175)

• Thought to arise from incompletely differentiated primordial germ cells, which undergo whole genome duplication events followed by recurrent losses of chromosome arms and whole chromosomes, thus creating an aneuploid state with subsequent additional mutations (e.g., KIT, KRAS) in a subset (Br J Cancer 2001;85:213, Cell Rep 2018;23:3392)
  • KIT mutations that occur early (i.e., after genome duplication) are thought to result in a subset of seminomas with global genomic hypomethylation that do not differentiate to other histologic subtypes
• Believed to represent the universal precursor of type II germ cell tumors, which represent ~95% of germ cell tumors in postpubertal males (e.g., seminoma, embryonal carcinoma, choriocarcinoma, some teratomas and yolk sac tumors)
• Show overexpression of embryonic transcription factors that increase proliferation and suppress apoptosis

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• Microlithiasis detected by ultrasonography in patients undergoing workup for infertility may be associated with a higher risk of GCNIS (especially if bilateral) (J Urol 2004;171:158)
• Testicular biopsies can be offered to patients with microlithiasis and 1 additional risk factor for GCNIS (Andrology 2020;8:1736)

• There are no specific imaging findings (World J Urol 1996;14:S55)

• 30 year old man with infertility and bilateral testicular microlithiasis (Int J Surg Pathol 2008;16:21)
• 33 year old man with progressive painless testicular swelling (Urol Case Rep 2022;42:101997)
• 42 year old man with massive retroperitoneal mass and multifocal right testicular mass (Radiol Case Rep 2022;17:2732)

• Orchiectomy if not already performed or close surveillance with routine monitoring for progression
• Chemotherapy does not reduce the risk of progression
• Low dose radiotherapy may be considered for contralateral GCNIS in patients with localized adult germ cell tumor (Ann Oncol 1998;9:657, BMC Urol 2013;13:71, Oncology 2009;77:33)

• Neoplastic cells located along the basement membrane of seminiferous tubules (spermatogonial niche)
• Cells are large atypical gonocyte-like with abundant clear cytoplasm and large (10 - 11 μm) hyperchromatic nuclei with coarse chromatin, angulated borders and prominent nucleoli; these cells are similar in appearance as seminoma (Histopathology 1978;2:157)
• Affected seminiferous tubules frequently have a thickened basement membrane / peritubular hyalinization and lack spermatogenic maturation
• Can spread in pagetoid fashion into rete testis, along the plane between the rete epithelium and the basement membrane

Contributed by Stephanie Siegmund, M.D., Ph.D., Maria Tretiakova, M.D., Ph.D., Alexander Subtelny, M.D., Ph.D. and Michelle Hirsch, M.D., Ph.D.

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• Alpha inhibin
• SF1
• WT1
• Pancytokeratin (AE1 / AE3)
• CD30
• SOX2 (Hum Pathol 2023;133:32)
• AFP
• Glypican 3 (Am J Surg Pathol 2006;30:1570)

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• Infantile or prepubertal testis with gonocytes with normal or delayed maturation:
  • Normal immature gonocytes are positive for OCT 3/4, KIT and PLAP by IHC but are located basally and centrally
  • Difficult to differentiate from GCNIS in patients < 6 months old (Scand J Urol 2016;50:74, J Urol 2014;191:1084)
• Intratubular seminoma:
  • Large atypical gonocyte-like cells filling the seminiferous tubules without invasion
• Seminoma with microinvasion:
  • Subtle single cells and small clusters of large atypical gonocyte-like cells with foci of microinvasion beyond the basement membrane into testicular parenchyma
  • Immunostains (OCT 3/4, KIT / c-KIT / CD117, D2-40, PLAP) can highlight cells that may be overlooked on H&E

Which of the following tumors of the testicle is associated with the finding shown in the image above?

1. Embryonal carcinoma
2. Juvenile granulosa cell tumor
3. Spermatocytic tumor
4. Teratoma, prepubertal type
5. Yolk sac tumor, prepubertal type

A. Embryonal carcinoma. Germ cell neoplasia in situ (GCNIS) is associated with type II germ cell tumors (e.g., seminoma, embryonal carcinoma) and of the options listed embryonal carcinoma is the only option that fits this designation. Answers B, C, D and E are incorrect because GCNIS is not known to be associated with other testicular neoplasms such as sex cord stromal tumors (e.g., juvenile granulosa cell tumor), spermatocytic tumor or prepubertal germ cell tumors.

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Reference: Germ cell neoplasia in situ

Which of the following histologic features is associated with germ cell neoplasia in situ (GCNIS)?

1. Atypical appearing gonocytes filling seminiferous tubules and extending into stroma as single cells
2. Presence of i(12p)
3. Seminiferous tubules lined with germinal epithelium undergoing maturation from spermatogonia to mature spermatids towards the lumen
4. Sertoli only pattern
5. Thickened seminiferous tubule basement membrane

E. Thickened seminiferous tubule basement membrane. Of the listed features, only a thickened basement membrane is associated with germ cell neoplasia in situ (GCNIS). Answer D is incorrect because a Sertoli only pattern would be found in testicles lacking germ cells and possessing only Sertoli cells (as in some types of infertility). Answers A and C are incorrect because atypical gonocytes invading the interstitium between seminiferous tubules would be diagnostic of invasive disease, while a population of maturing germinal epithelium ranging from spermatogonia to mature spermatids in the lumen of the tubule would be consistent with nonneoplastic, maturing spermatogenesis and unlikely in the context of GCNIS. Answer B is incorrect because the presence of i(12p) indicates molecular progression beyond in situ disease (e.g., seminoma) and is therefore absent in the precursor GCNIS lesion.

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Reference: Germ cell neoplasia in situ