Testis & paratestis

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Testis & paratestis

Authors: Andres Acosta, M.D., Turki Al-Hussain, M.D., William Anderson, M.D., Manju Aron, M.D., Ritu Bhalla, M.D., Melanie Bourgeau, M.D., Zhengshan Chen, M.D., Ph.D., Maurizio Colecchia, M.D., Kristine M. Cornejo, M.D., J. Cody Craig, M.D. , Christopher Dall, M.D., Michelle R. Downes, M.D. , Sara Moscovita Falzarano, M.D., Ph.D., Sarah Findeis, M.D., Jerad M. Gardner, M.D., Sarwat I. Gilani, M.B.B.S., Jennifer B. Gordetsky, M.D., Priyanka Gupta, M.B.B.S., D.N.B., Rui Henrique, M.D., Ph.D., He Huang, M.D., Ph.D., Kenneth A. Iczkowski, M.D., Rafael E. Jimenez, M.D., M.H.A., Andre Kajdacsy-Balla, M.D., Ph.D., Oleksandr Kravtsov, M.D., Anastasia Lendel, B.A., João Lobo, M.D., Virgilia Macias, M.D., Andres Matoso, M.D., Vikas Mehta, M.D., Hector Mesa, M.D., Ph.D., Brandon Douglas Metcalf, M.D., Vaishali Pansare, M.D., Anil Parwani, M.D., Ph.D., M.B.A., Ashley Patton, D.O., Ph.D., Giacomo Maria Pini, M.D., Swapnil U. Rane, M.D., Julia Rivera, M.D., Francesca Sanguedolce, M.D., Ph.D., Mit D. Shah, B.S., Stephanie Siegmund, M.D., Ph.D., Nadarra L. Stokes, M.D., Lauren N. Stuart, M.D., M.B.A., Burak Tekin, M.D., Alyssa Thompson, B.S., Jason Tretter, Veronica Ulici, M.D., Ph.D., Aida Valencia, M.D., Gang Wang, M.D., Ph.D. , Sean R. Williamson, M.D., Patricija Zot, M.D., Debra L. Zynger, M.D.

Resident / Fellow Advisory Board: Alcino Pires Gama, M.D.

Editorial Board Members: Bonnie Choy, M.D., Maria Tretiakova, M.D., Ph.D., Debra L. Zynger, M.D.

Deputy Editor-in-Chief: Maria Tretiakova, M.D., Ph.D.

Editor-in-Chief: Debra L. Zynger, M.D.

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Related chapters: Penis & scrotum, Prostate gland & seminal vesicles

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Adenocarcinoma Adenocarcinoma of epididymis Adenomatoid tumor Adrenal cortical rests Adult granulosa cell tumor Anatomy & histology Atrophy Biopsy Brenner tumor Choriocarcinoma Cryptorchidism Cystic trophoblastic tumor Cysts Disorders of sexual differentiation Embryonal carcinoma Epidermoid cyst Epididymitis Epithelioid trophoblastic tumor Fibroma thecoma group Fibrous pseudotumor Germ cell neoplasia in situ Gonadoblastoma Gonadoblastoma Granulomatous lesions of testis and paratestis Grossing and features to report Hernia sac with mesothelial entrapment Hydrocele Infertility Inflammatory pseudotumor Intratubular large cell hyalinizing Sertoli cell neoplasia (ITLCHSCN) Juvenile granulosa cell tumor Large cell calcifying Sertoli cell tumor Leiomyosarcoma Leydig cell tumor Liposarcoma Liposarcoma Melanotic neuroectodermal tumor Mesothelioma Metastases Mixed and other sex cord stromal tumors Mucinous borderline tumor Mucinous cystadenocarcinoma Myoid gonadal stromal tumor Papillary cystadenoma Placental site trophoblastic tumor Polyembryoma Polyorchidism Proliferative funiculitis Proliferative funiculitis Regressed germ cell tumor Rete testis adenomatous hyperplasia Seminoma Serous borderline tumor Serous cystadenocarcinoma Sertoli cell nodule Sertoli cell only Sertoli cell tumor Sex cord stromal tumors-general Smooth muscle hyperplasia Spermatocele Spermatocytic tumor Splenogonadal fusion Staging Teratoma Teratoma with somatic type malignancy Teratoma-dermoid cyst Teratoma-neuroendocrine tumor Testicular adrenal rest tumor / tumor of adrenogenital syndrome Testicular regression syndrome / anorchia Torsion Varicocele Vasculitis Vasitis nodosa Well differentiated papillary mesothelial tumor WHO classification Yolk sac tumor

Adenocarcinoma

Table of Contents

Definition / general

Rare malignant neoplasm originating from the epithelium of rete testis and associated with an aggressive clinical behavior
Given its rarity, varied histologic presentations and nonspecific immunoprofile, primary adenocarcinoma of collecting ducts and rete testis is a diagnosis of exclusion

Essential features

Primary adenocarcinoma of collecting ducts and rete testis is a rare aggressive neoplasm originating from the epithelium of rete testis
Diagnosis of exclusion, with the differential diagnosis including mesothelioma, metastatic adenocarcinoma and germ cell tumors, among other entities
On histopathologic examination, a mixture of different architectural patterns is commonly seen, such as complex tubulopapillary, glandular, solid and cribriform
Cytokeratin 7, cytokeratin AE1 / AE3 and epithelial membrane antigen are positive in the majority of the cases, whereas CD30, inhibin, OCT 3/4 and SALL4 are negative

Terminology

Not used anymore: papillary adenocarcinoma of the rete testis, carcinoma of the rete testis

ICD coding

ICD-O: 8140/3 - adenocarcinoma, NOS
ICD-11:
- 2C84 - malignant neoplasms of other specified male genital organs
- XH74S1 - adenocarcinoma, NOS

Epidemiology

Extremely rare, with fewer than 100 cases reported in the literature
More common in elderly Caucasian males (mean age of 54 years); however, anecdotal reports in young adults (Am J Surg Pathol 2021;45:1720)

Sites

Primary involvement of the testicular hilum
Secondary involvement of adjacent anatomic structures by direct extension
Some studies documented a slight right side predominance (Am J Surg Pathol 2021;45:1720, Urology 1995;46:468)
Satellite nodules on the spermatic cord are seen in a subset of patients (Mod Pathol 2005;18:S131)

Pathophysiology

Anecdotal cases with a history of adenomatous hyperplasia of the rete testis and subsequent development of adenocarcinoma, as well as cases with coexistent adenomatous hyperplasia and adenocarcinoma, have been reported (J Urol 1997;158:1525, Diagn Pathol 2013;8:105)
However, more studies are needed to definitively establish a stepwise progression from normal rete testis to adenomatous hyperplasia and subsequent occurrence of primary adenocarcinoma

Etiology

Adenocarcinoma of the rete testis has been reported in mice with in utero exposure to diethylstilbestrol; however, no such association has been described in humans (Cancer Res 1985;45:5145, Am J Surg Pathol 2019;43:670)
Prior trauma, chronic epididymitis, cryptorchidism or inguinal hernia have been documented; however, a definitive etiologic association has not been established (Am J Surg Pathol 2021;45:1720, J Urol 2003;170:1304)
Hydrocele was described in ~33% of cases, with many patients presenting with a working diagnosis of hydrocele and undergoing ipsilateral hydrocelectomy (Urology 1995;46:468, Mod Pathol 2005;18:S131, Am J Surg Pathol 2019;43:670)

Clinical features

Nonspecific clinical presentation
Majority of patients present with a scrotal mass, accompanied by pain in ~20% of the cases (Am J Surg Pathol 2019;43:670)
Occasionally detected incidentally, following trauma (Histopathology 2022;81:77)
Initial signs of presentation can be due to tumor metastases (e.g., groin mass, lumbar pain) (Urology 1995;46:468)

Diagnosis

Testicular, paratesticular and metastatic tumors need to be ruled out before arriving at a diagnosis of primary rete testis adenocarcinoma; as such, it represents a diagnosis of exclusion
Currently accepted diagnostic criteria for primary adenocarcinoma of the rete testis have been revised from Nochomovitz and Orenstein and include the following:
- Testicular hilar localization
- Absence of morphologically similar extrascrotal tumor as a possible primary site
- Morphology incompatible with other types of testicular or paratesticular neoplasms
- Supportive immunohistochemical findings and immunohistochemical exclusion of other entities, especially mesothelioma and papillary serous carcinoma (Am J Surg Pathol 2021;45:1720, Mod Pathol 2005;18:S131, Am J Surg Pathol 1984;8:625)
Demonstration of transition from normal to neoplastic rete epithelium is a desirable criterion but frequently not identifiable since the normal anatomy tends to be obliterated by the neoplastic process (Am J Surg Pathol 2021;45:1720)
Application of these strict criteria led to exclusion or reclassification of many cases that were initially reported as primary rete testis adenocarcinoma in the literature (Am J Surg Pathol 2019;43:670)

Laboratory

Alkaline phosphatase (ALP), alpha fetoprotein (AFP), CA-125, CA 19-9, carcinoembryonic antigen (CEA), β human chorionic gonadotropin, (βhCG) levels are generally normal
Anecdotal reports of elevated CA 19-9 and CEA (Urology 1995;46:468, Int Cancer Conf J 2017;6:84, Int Cancer Conf J 2020;9:240)

Radiology description

Rationale for imaging is threefold:
- Exclusion of an extrascrotal tumor as a possible primary site
- Visualization of the scrotal tumor
- Staging
Ultrasound may show an ill defined, hypoechoic, heterogeneous mass and increased vascularization (Urol Case Rep 2017;16:72, Oncol Lett 2014;7:455)
Intrascrotal calcification may be present on radiographs (Urology 1995;46:468)
Potentially improved utility of CT / PET compared to conventional CT in detecting metastases (Urology 2011;77:334)

Prognostic factors

Predictors associated with a favorable outcome:
- Tumor size Urology 1995;46:468)
- Tumors confined to the testis (Urology 1995;46:468, Am J Surg Pathol 2019;43:670)

Case reports

44 year old man with left scrotal swelling (Int Cancer Conf J 2020;9:240)
59 year old man with swelling of the left scrotum (Int Cancer Conf J 2017;6:84)
66 year old man with a left sided painful testicular mass (Urol Case Rep 2017;16:72)

Treatment

Treatment options for primary rete testis adenocarcinoma are not standardized
Treatment consists of radical orchiectomy with or without retroperitoneal lymph node dissection, in combination with adjuvant chemotherapy or radiotherapy
Resistance to conventional chemotherapy regimens is a frequent problem (Histopathology 2022;81:77)

Gross description

Epicenter of the mass at the testicular hilum, with variable involvement of the testicular parenchyma, spermatic cord or overlying skin by way of direct extension
Ill defined, firm tumors ranging from 2 - 13 cm in greatest dimension
Cut surface tan, yellow or white; solid to cystic, with focally hemorrhagic areas
References: Am J Surg Pathol 2019;43:670, Am J Surg Pathol 2021;45:1720

Gross images

Images hosted on other servers:

Mass in testicular hilum

Solid mass with cystic areas

Microscopic (histologic) description

Invasive growth pattern with extensive intrarete proliferation and extension beyond the rete testis
Architecture: a mixture of architectural patterns among different cases and within the same case, including but not limited to (Am J Surg Pathol 2021;45:1720, Am J Surg Pathol 2019;43:670):
- Complex tubulopapillary
- Glandular
- Solid
- Cribriform
- Glomeruloid
- Retiform
- Sertoliform
- Kaposiform
- Micropapillary
- Nested
Cytomorphology (Histopathology 2022;81:77):
- Epithelioid or biphasic (epithelioid and sarcomatoid) (J Nat Sci Biol Med 2015;6:211)
- Cuboidal to columnar cells with marked nuclear atypia, pleomorphism and prominent nucleoli
- High mitotic activity, with atypical mitoses
- Cytoplasm varies from pale to eosinophilic
- Desmoplastic stroma is a common finding
- Psammomatous calcifications and tumor necrosis may be observed (Urology 1995;46:468)
Areas of gradual transition from normal rete testis lining to dysplastic and malignant epithelium, if present, lend support to a primary rete testis origin

Microscopic (histologic) images

Contributed by Rafael E. Jimenez, M.D.

Areas of central necrosis

Complex architecture

Transition of epithelium

Complex tubuloglandular pattern

Cribriform pattern

High grade cytomorphology

Increased mitotic activity

Positive stains

CK7, CK AE1 / AE3, epithelial membrane antigen (EMA) and vimentin positive in > 80% of cases
CD10 (Mod Pathol 2005;18:S131, Indian J Pathol Microbiol 2015;58:232)
BerEP4, CK5/6, MOC31 and PAX8 positive in > 50% of cases (Am J Surg Pathol 2021;45:1720, Diagn Pathol 2013;8:105, Am J Surg Pathol 2019;43:670, Histopathology 2022;81:77)
Calretinin and WT1 variably positive (J Cutan Pathol 2006;33:181)
- In a series of 5 cases, calretinin was positive in 2 cases (40%) (Am J Surg Pathol 2019;43:670)
- In a recent series, nuclear WT1 was positive in 7/9 and 6/7 cases tested (78 - 86%) (Am J Surg Pathol 2021;45:1720, Histopathology 2022;81:77)

Negative stains

CD30, inhibin, NKX3.1, OCT 3/4, PSA, PSAP and SALL4 consistently negative (Am J Surg Pathol 2021;45:1720, Am J Surg Pathol 2019;43:670, Histopathology 2022;81:77)
CK20 rarely positive (Urol Case Rep 2017;16:72, Int J Urol 2006;13:1532)

Electron microscopy description

Glandular spaces with amorphous, electron dense material
Luminal spaces lined by epithelial cells with ovoid nuclei exhibiting smooth contours, dispersed heterochromatin and prominent nucleoli
Nuclear indentations were described (Am J Surg Pathol 1988;12:492, Indian J Cancer 2002;39:106)
Lipid droplets and bundles of intermediate cytoplasmic filaments in a subset of neoplastic cells (J Cutan Pathol 2006;33:181, Indian J Cancer 2002;39:106, Cancer 1989;64:770)

Molecular / cytogenetics description

Acosta et al. described genomic alterations in a series of 8 cases using massively parallel DNA sequencing (Histopathology 2022;81:77)
Pathogenic variants were noted in 6 cases:
- 3 cases harbored CDKN2A variants
- Authors also described variants in AKT1, RB1, NF2, SETD2 and TP53 genes

Sample pathology report

Testicle, left, orchiectomy:
- Adenocarcinoma, involving the rete testis, most consistent with a primary rete testis adenocarcinoma, 2.5 cm (see comment)
- Surgical margins negative for carcinoma
- Comment: The sections show a high grade cellular proliferation with an invasive growth pattern, centered in and around the rete testis. A mixture of architectural patterns is noted, including complex tubulopapillary, glandular, cribriform and solid areas. Focally, a transition between the surface epithelium of the rete testis and the invasive component is appreciable. The cytomorphology is notable for cuboidal to columnar cells with marked nuclear atypia, pleomorphism and prominent nucleoli. Immunohistochemically, the tumor cells are reactive for BerEP4, CK7 and EMA and negative for CDX2, inhibin, NKX3.1, OCT 3/4, PSA and TTF1. These findings argue against a germ cell tumor or mesothelioma and favor a primary tumor over a metastatic process. Based on this constellation of findings, the most likely possibility is that this is a primary rete testis adenocarcinoma; however, a metastatic process cannot be completely ruled out and thus another primary process should be clinically excluded.

Differential diagnosis

Transition between normal and neoplastic rete testis epithelium, if present, favors a diagnosis of primary rete testis adenocarcinoma over the following entities in the differential diagnosis:
- Mesothelioma:
  - Significant overlap in histopathologic findings
  - Multifocal enveloping of the tunica vaginalis; this is in contrast to the rete testis centered, usually solitary tumor in primary rete testis adenocarcinoma
  - Generally less prominent nuclear atypia
  - Positive immunostaining for calretinin and WT1 combined with negative staining for CEA and BerEP4 favors a diagnosis of mesothelioma, although primary rete testis adenocarcinomas show immunoreactivity for calretinin and WT1 in a subset of cases (see Positive stains above) (Mod Pathol 2005;18:S131)
- Metastatic adenocarcinoma:
  - Should be excluded before a diagnosis of primary rete testis adenocarcinoma is rendered
  - More frequently shows bilateral or multifocal involvement
  - Classically exhibits an interstitial growth pattern, as opposed to originating from the rete testis (Mod Pathol 2005;18:S131)
- Germ cell tumors:
  - Generally younger patient population and associated with increased serum markers
  - OCT 3/4 and SALL4 positive (Am J Surg Pathol 2019;43:670)
- Epididymal carcinoma:
  - More likely to show cuboidal cells having clear to eosinophilic cytoplasm in a tubular pattern
  - May not be possible to distinguish in advanced tumors where anatomic landmarks have been obliterated (Am J Surg Pathol 1997;21:1474)
- Malignant Sertoli cell tumor:
  - Originates from the testicular parenchyma (Mod Pathol 2005;18:S131)
  - Inhibin positive (Am J Surg Pathol 2019;43:670)
- Ovarian type epithelial tumors of the paratesticular region

Additional references

WHO Classification of Tumours Editorial Board: Urinary and Male Genital Tumours, 5th Edition, 2022

Board review style question #1

A 68 year old man presents with a 4.7 cm nodule centered around the testicular hilum, with invasion into the testicular parenchyma. Cut surface is heterogeneous, with solid, cystic and hemorrhagic areas. Histologic examination reveals a mixture of architectural patterns, including glandular, cribriform and solid areas. The cells exhibit nuclear pleomorphism, prominent nucleoli and high mitotic activity (see figures above). Clinicoradiologic examination fails to identify any extrascrotal tumors. Based on the constellation of findings, the man is diagnosed with primary adenocarcinoma of rete testis. Regarding this entity, which of the following statements is true?

CK7, CK AE1 / AE3 and EMA are positive in the majority of the cases
It frequently shows immunoreactivity for CD30, OCT 3/4 and SALL4
Many patients are asymptomatic and these tumors are usually detected incidentally on imaging studies
These tumors typically follow an indolent course, without metastases
This entity is typically associated with increased levels of alpha fetoprotein and βhCG

Board review style answer #1

A. CK7, CK AE1 / AE3 and EMA are positive in the majority of the cases

Comment Here

Reference: Adenocarcinoma of collecting ducts and rete testis

Adenocarcinoma of epididymis

Table of Contents

Definition / general

Adenocarcinoma arising de novo in epididymis

Terminology

Also called papillary adenocarcinoma, cystadenocarcinoma, papillary cystadenocarcinoma

Epidemiology

Extremely rare
Age range: 27 - 82 years, mean age: 67 years

Sites

Tumors are centered on epididymis; may be confined to epididymis or may infiltrate adjacent tissue

Pathophysiology

Believed to arise from metaplastic epididymal epithelium

Clinical features

Usually presents as palpable scrotal mass with / without pain and hydrocele

Diagnosis

Confirmation and differentiation from other malignancies in this region is possible only on histology

Laboratory

No specific laboratory features
Negative serum markers for sex cord and germ cell tumors

Prognostic factors

Due to rarity of tumor, prognostic features are unknown
A large proportion of tumors reported in literature metastasize at presentation or later

Case reports

27 year old man with papillary cystadenocarcinoma of epididymis (Zhonghua Yi Xue Za Zhi (Taipei) 1990;45:139)
35 year old man with radiotherapy treatment for epididymal adenocarcinoma (Onkologie 2012;35:43)
62 year old man (Urology 1998;52:904)
82 year old man with papillary adenocarcinoma of epididymis (Acta Pathol Jpn 1993;43:440)
Papillary cystadenocarcinoma of epididymis presenting with scrotal mass (J Urol 1992;147:162)
Carcinoma of epididymis (Indian J Cancer 1973;10:475)
Adenocarcinoma of the epididymis - 4 cases (Am J Surg Pathol 1997;21:1474)
Primary adenocarcinoma of epididymis (Int Urol Nephrol 2004;36:77)

Treatment

High inguinal orchidectomy with retroperitoneal lymph node dissection
Adjuvant chemotherapy or radiation therapy

Gross description

1 - 7 cm
Infiltrative tumor either confined to epididymis or infiltrating adjacent soft tissue
Tan to grey white cut surface with frequent foci of hemorrhage and necrosis

Microscopic (histologic) description

Tubular, tubulopapillary, papillary and cystic growth patterns, which often occur in combinations and varying degrees of complexity
Also an undifferentiated sheet like pattern
Tumor cells are cuboidal to columnar, predominantly clear, rich in glycogen
Often infiltrates into epididymal smooth muscle or adjacent soft tissue
Necrosis is usually present
Psammoma bodies are rare

Microscopic (histologic) images

Images hosted on other servers:

Adenocarcinoma of rete testis

Positive stains

AE1 / AE3, EMA

Negative stains

PSA, S100, CEA, BerEp4, LeuM1, B72.3, AFP

Differential diagnosis

Other primary tumors of epididymis and paratesticular region
- Adenomatoid tumor
  - Usually lack clear cells
  - Tubules lined by low cuboidal to flat cells which may be vacuolated but are not watery clear as seen in primary epididymal adenocarcinoma
  - Low grade nuclear features
  - Mesothelial origin
  - IHC for mesothelial markers usually positive
- Carcinoma of rete testis
  - Centered on testicular hilum, associated with transition to normal rete testis
  - Elongated tubular pattern, unlike the round tubular pattern of epididymal adenocarcinomas
- Mesothelioma
  - No clear cells
  - Calretinin, HBME1, WT1, mesothelin positive
- Serous cystadenoma of epididymis
  - Lack of invasive features
  - Low grade cellular features
  - Associated with von Hippel-Lindau syndrome
- Serous papillary carcinoma: infiltrates as single isolated papillae, no tubules
Metastatic prostatic carcinoma: PSA+
Metastatic GI adenocarcinoma: CEA+, CK20+; variable mucin

Adenomatoid tumor

Table of Contents

Definition / general

Benign tumor of mesothelial origin
Accounts for about a third of all tumors of paratesticular area and 60% of benign tumors of paratesticular area (Mostofi: Tumors of the Male Genital System, 1st Edition, 1973)

Essential features

Most common benign paratesticular tumor
Usually based in the epididymis and well circumscribed
Expresses markers typical of mesothelial origin

ICD coding

ICD-10: D29.30 - benign neoplasm of unspecified epididymis

Epidemiology

Third - fifth decade (Eble: Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs, 1st Edition, 2004)

Sites

Testicular adnexa

Pathophysiology

Not known

Etiology

Not known

Clinical features

Most patients present with a mass; rarely present with pain due to associated torsion (Am J Surg Pathol 2004;28:77)

Diagnosis

Primarily made histologically

Laboratory

Testicular tumor markers: normal

Radiology description

Circumscribed, solid paratesticular mass
Unable to distinguish benign versus malignant on sonography (Radiology 1997;204:43)
Tumors of the tunica may be indistinguishable from a germ cell tumor by imaging

Radiology images

Images hosted on other servers:

Coronal MR

Ultrasound

Prognostic factors

Benign neoplasm

Case reports

12 year old boy with adenomatoid tumor from tunica albuginea (Case Rep Urol 2015;2015:935193)
32 year old man with infarcted adenomatoid tumor (Case Rep Urol 2013;2013:937689)
39 year old man with a painful, slowly enlarging left testicular mass (Case of the Month #491)
53 year old man with bilateral seminomas and adenomatoid tumor (Indian J Pathol Microbiol 2017;60:415)
55 year old man with distant history of epididymal adenomatoid tumor with paratesticular mesothelioma arising at previous tumor site (Int J Surg Case Rep 2013;4:460)
57 year old man with leiomyoadenomatoid tumor (Curr Urol 2014;7:195)

Treatment

Surgical excision
Intraoperative frozen section may be helpful to indicate testis sparing surgery

Gross description

Typically paratesticular well circumscribed, white-tan firm nodule
Almost always unilateral and solitary
Generally firmer than seminoma (Mod Pathol 2005;18 Suppl 2:S131)
Mostly less than 2 cm, rarely up to 5 cm (Eble: Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs, 1st Edition, 2004)
Most commonly occurs at lower or upper pole of the epididymis
Less common sites include tunica albuginea and spermatic cord (Mostofi: Tumors of the Male Genital System, 1st Edition, 1973)

Gross images

Contributed by Debra L. Zynger, M.D.

Paratesticular tumor

Images hosted on other servers:

Well circumscribed tumor

Frozen section description

May be confused for malignant mesothelioma on biopsy; gross correlation often needed
Can have atrophic testes with fibrous stromal proliferation (Urology 2004;63:779)

Frozen section images

Contributed by Debra L. Zynger, M.D.

Distorted, compressed tubules

Spindle cell appearance

Microscopic (histologic) description

Tubules, cords or small nests
Composed of or lined with cuboidal cells
Moderate to abundant eosinophilic cytoplasm with single to multiple vacuoles
Signet ring cell morphology and lipoblast-like morphologies very common (Mod Pathol 2009;22:1228)
Other patterns: adenoid, angiomatoid, cystic, glandular, oncocytic, solid, tubular (Mod Pathol 2009;22:1228)
Thin bridging strands crossing glandular / tubular spaces (Mod Pathol 2009;22:1228)
Peripheral lymphoid aggregates (Mod Pathol 2009;22:1228)
Infiltrative growth common (Mod Pathol 2009;22:1228)
Can become infarcted (Am J Surg Pathol 2004;28:77)

Microscopic (histologic) images

Contributed by Sarah Findeis, M.D., Stephanie J. Conrad, M.D., Ming Zhou, M.D.,
the Genitourinary Pathology Society (GUPS) and @katcollmd on Twitter

Interface with testis

Cords and trabeculae pattern

Eosinophilic cells

Calretinin

CK AE1/3

Circumscribed tumor

Dilated cystic spaces

Vacuolated and attenuated epithelium

Bland nuclei

Calretinin

Adenomatoid tumor

Virtual slides

Images hosted on other servers:

Adenomatoid tumor

Cytology description

Epithelioid, monolayered sheets or clusters of cells with eccentric, vesicular round to ovoid nuclei, granular chromatin and pale / vacuolated cytoplasm (J Cytol 2009;26:30, J Cytol 2013;30:65)
Can have a background of naked nuclei as well as stromal cells (Acta Cytol 1989;33:6)

Cytology images

Images hosted on other servers:

Moderate cellularity

Monolayered sheets of cells

Positive stains

Negative stains

MOC31 / BerEP4, CEA, B72.3, LEA.135, LeuM1, Factor VIII, CD34 (Histopathology 2000;36:109)
SALL4 (Am J Surg Pathol 2009;33:1065)
34betaE12 weak expression in 25% (Histopathology 2000;36:109)
Thrombomodulin EXCEPT (Histopathology 2000;36:109)
- Membranous staining for acinar adenomatoid tumor
- Scanty pale foci of cytoplasmic staining for solid adenomatoid tumors
HBME1 and OC 125 EXCEPT (Histopathology 2000;36:109)
- Membranous staining of HBME1 and OC 125 for acinar adenomatoid tumors
- Intracytoplasmic staining with discrete granular clump for solid adenomatoid tumors
p53 (Histopathology 2000;36:109)

Electron microscopy description

Rich in cytoplasmic organelles and has superficial desmosomes with microvilli (Cancer 1972;30:244)

Molecular / cytogenetics description

TRAF7 somatic missense mutations (Mod Pathol 2018;31:660)

Sample pathology report

Testicle and spermatic cord, right, radical orchiectomy:
- Paratesticular adenomatoid tumor, 1.5 cm
- Margins widely free of tumor (> 5.0 cm)
- Unremarkable background testis, epididymis and spermatic cord
- Comment: The tumor is positive for AE1/3, WT1 and calretinin and is negative for SALL4 and inhibin.

Differential diagnosis

Malignant mesothelioma:
- BAP1 loss (Appl Immunohistochem Mol Morphol 2020;28:67)
- HBME1+ (Histopathology 2000;36:109)
- Grossly larger and more infiltrative
Metastatic adenocarcinoma:
- Positive for carcinoma markers
- Desmoplasia
- Both will stain with mucin but weaker for adenomatoid tumor and only in a minority of cases (Cancer 1974;34:306)
Sertoli cell tumor:
- Inhibin A+ (Hum Pathol 2000;31:1055)
Leydig cell tumor:
- Inhibin A+ (Hum Pathol 2000;31:1055)
Vascular neoplasms (especially epithelioid hemangioma):
- Lining cells more plump and nuclei with irregular cleaved contours
Yolk sac tumor:
- SALL4+, glypican 3+, AFP+
- Has more primitive nuclear features
- Rarely paratestis primary
Leiomyoma:
- More cellular spindle cell proliferation
- Lacks tubular or glandular structures
- Cytokeratin- or focal, desmin+
- Liposarcoma:
  - Cells with true adipocytic features
  - Lipoblast may be present
  - Negative for cytokeratin

Additional references

Ulbright: Tumors of the testis, Adnexa, Spermatic Cord, and Scrotum, 1sh Edition, 1999

Board review style question #1

Exclusively identified within men
Malignant transformation occurs in 50% of cases
Most common in the sixth to seventh decade
Rarely identified within the testicular parenchyma

Board review style answer #1

D. These tumors are rarely identified within the testicular parenchyma. This is an adenomatoid tumor. They can be identified within both sexes. It occurs in the paratesticular region most commonly in the third to fourth decade. The tumor rarely involves the testicular parenchyma. If there is only intraparenchymal involvement, other primary parenchymal lesions need to be ruled out, such as a sex cord stromal tumors or germ cell tumors.

Comment Here

Reference: Adenomatoid tumor

Board review style question #2

Calretinin +, EMA +, BAP 1+
CK AE1/3 -, CD31 +, CD15 +
OCT3/4 +, CEA+, S100+
Vimentin -, CD99 +, calretinin -

Board review style answer #2

A. Calretinin +, EMA +, BAP 1+. This is an adenomatoid tumor, which is of mesothelial origin as the staining pattern suggests. The patient presentation of a small painless mass in a patient in the third - fourth decade is typical. Adenomatoid tumors rarely involve the testicular parenchyma and are the most common paratesticular tumor. Microscopic infiltration may be misinterpreted as invasion but may occur and the tumor still has a benign course.

Comment Here

Reference: Adenomatoid tumor

Board review style question #3

AFP
B72.3
Calretinin
CD34
Inhibin

Board review style answer #3

C. Calretinin

Comment Here

Reference: Adenomatoid tumor 🧬

Adrenal cortical rests

Table of Contents

Definition / general | Gross description | Microscopic (histologic) description | Microscopic (histologic) images

Definition / general

Occur in 4 - 15% of testis, paratesticular tissue, spermatic cord or epididymis
For additional information, refer to ectopic adrenal tissue

Gross description

Small, round, yellow nodule

Microscopic (histologic) description

Circumscribed nodule of adrenal cortical tissue without medullary tissue

Microscopic (histologic) images

Contributed by Yuto Yamazaki, M.D., Ph.D., Hironobu Sasano, M.D., Ph.D., Debra L. Zynger, M.D. and Sean R. Williamson, M.D.

Spermatic cord adrenal rest and SF1

Radical orchiectomies / spermatic cords with adrenal rests

Spermatic cord adrenal rests

Paratesticular adrenal cortical rest

Adult granulosa cell tumor

Table of Contents

Definition / general

Sex cord stromal tumor resembling granulosa cells of the Graafian follicles of the ovary

Essential features

Rare, low grade, indolent sex cord stromal tumor; 10% have malignant potential
Most common architectural patterns are diffuse / solid, insular and spindled; pathognomonic Call-Exner bodies, which are a part of the microfollicular pattern, are less common
Morphologically, the tumor cells characteristically display uniformly round to ovoid nuclei with conspicuous, longitudinal nuclear grooves
FOXL2 gene mutations occur in a minor subset of cases, which is substantially less frequent than in its ovarian counterpart

ICD coding

ICD-O: 8620/1 - Granulosa cell, adult type
ICD-O: 8620/3 - Granulosa cell, malignant
ICD-10: D40.1 - Neoplasm of uncertain behavior of unspecified testis
ICD-10: C62.9 - Malignant neoplasm of testis, unspecified whether descended or undescended

Epidemiology

Rare (< 0.5% of all sex cord stromal tumors)
Mean age: 40 years (range: 14 - 87 years) (Am J Surg Pathol 2014;38:1242)

Sites

Testicular parenchyma

Pathophysiology

Derived from granulosa cells in which FOXL2, a granulosa cell expressed gene, plays a role in regulating cell fate
Missense mutation (402C → G, C134W) causes a negative effect by dysregulating gene expression, leading to increased cell proliferation and reducing apoptosis (Oncol Lett 2020;20:293)

Etiology

Unknown

Clinical features

Unilateral testicular mass or swelling
Typically no endocrine related symptoms (i.e. gynecomastia, decreased libido) (Am J Surg Pathol 2014;38:1242)
- Reported in up to 20% of cases (Mod Pathol 2005;18:S81, J Cancer Res Clin Oncol 2020;146:2829)

Diagnosis

Imaging studies (e.g. ultrasound) may identify a testicular mass
Definitive diagnosis is made by histopathologic examination only

Laboratory

No elevated serum makers (Am J Surg Pathol 2014;38:1242)

Radiology description

Nonspecific findings but typically shows a well demarcated, hypoechoic mass with hyperechoic foci and calcification (Radiol Case Rep 2015;3:188)

Radiology images

Images hosted on other servers:

Hypoechoic lesion

Hypoechoic lesion /
increased vascularity

Increased vascularity

Prognostic factors

Most are benign; 10% have malignant potential (J Cancer Res Clin Oncol 2020;146:2829)
Pathologic features most commonly associated with more aggressive behavior include (Am J Surg Pathol 2014;38:1242):
- Lymphovascular invasion
- Infiltrative borders / extratesticular involvement
- Size > 4 cm
Other pathologic features reported to be associated with malignant potential include (J Cancer Res Clin Oncol 2020;146:2829, Hum Pathol 1993;24:1120, Hum Pathol 2008;39:701, Arch Pathol Lab Med 2011;135:143):
- Moderate or marked nuclear atypia
- Presence of necrosis
- > 5 mitotic figures per 10 high power fields
- Association with gynecomastia

Case reports

22 year old man with unspecific scrotal discomfort (Case Rep Urol 2019;2019:7156154)
43 year old man with left testicular swelling (Int Braz J Urol 2015;41:1226)
65 year old man with hepatic metastasis (Indian J Pathol Microbiol 2020;63:470)

Treatment

Radical orchiectomy
Testis sparing surgery / wedge excision for smaller, benign tumors (Am J Surg Pathol 2014;38:1242, J Cancer Res Clin Oncol 2020;146:2829)
Retroperitoneal lymph node dissection and platinum based chemotherapy (e.g. bleomycin, etoposide, cisplatin) for metastatic disease (J Cancer Res Clin Oncol 2020;146:2829)
Rare reports of treatment with tyrosine kinase inhibitors, such as pazopanib with partial response (Oncology (Williston Park) 2009;23:792)

Gross description

Mean size: 2.8 cm (0.5 - 6.0 cm) (Am J Surg Pathol 2014;38:1242)
Well circumscribed, predominantly solid; occasionally solid and cystic
Lobulated, yellow-tan or tan-white cut surface
Infiltrative borders / extratesticular involvement, hemorrhage and necrosis are rarely seen and often associated with more aggressive behavior

Gross images

Contributed by Kristine M. Cornejo, M.D.

Tan-yellow solid mass

Lobulated tan-yellow mass

Microscopic (histologic) description

Low power: typically displays a nodular / lobulated appearance
High power: tumor cells contain uniformly round to ovoid nuclei with conspicuous longitudinal nuclear grooves, indistinct cell borders, variable amounts of eosinophilic cytoplasm
Most common patterns: diffuse / solid, insular and spindled (Am J Surg Pathol 2014;38:1242)
- Diffuse / solid: sheets of round cells
- Insular: nests of tumor cells surrounded by stroma
- Spindled: sheets of fusiform cells
- Cords / trabecular: regularly to irregularly arranged thin cords or thick columns of tumor cells
- Water silk / gyriform: interweaving cords and undulating columns of cells
- Microfollicular: numerous small spaces with hyalinized basement membrane material or eosinophilic fluid (Call-Exner bodies)
- Herringbone / fascicular: spindled cells with fibrocollagenous stroma
- Pseudopapillary: tumor cells surrounding fibrovascular cores
- Palisading: tumor cells arranged parallel to each other, resembling a fence
- Luteinized: more abundant clear to eosinophilic cytoplasm with rounded nuclei
Admixed with varying amounts of fibrocollagenous or edematous stroma
Mitotic count: mean 4.9/10 high power fields (0 - 18/10 high power fields); suggests the presence of mitoses are not of prognostic significance (Am J Surg Pathol 2014;38:1242)
May contain hemorrhage or hemosiderin deposition
Rarely displays necrosis and lymphovascular invasion; features of aggressive behavior
Tumor often infiltrates between seminiferous tubules and may involve rete testis and tunica albuginea
- Rarely involves paratesticular or extratesticular tissue

Microscopic (histologic) images

Contributed by Kristine M. Cornejo, M.D.

Nodular appearance

Nuclear grooves

Diffuse pattern

Spindled pattern

Corded pattern

Gyriform / watered silk pattern

Microfollicular pattern (Call-Exner Bodies)

Microfollicular pattern (Call-Exner bodies)

Insular pattern

Palisading pattern

Pseudopapillary pattern

Herringbone / fascicular pattern

Luteinized cells

Inhibin A stain

Positive stains

Inhibin A: best marker of sex cord stromal tumors (Am J Surg Pathol 2014;38:e50)
Vimentin, calretinin, CD99
SMA (70%), S100 (60%) (Am J Surg Pathol 2014;38:1242)
FOXL2 positive in sex cord stromal tumors, such as adult granulosa cell tumor, juvenile granulosa cell tumor, Sertoli cell tumor and thecoma fibroma; positivity does not correlate to mutation status (Appl Immunohistochem Mol Morphol 2011;19:347, Am J Surg Pathol 2011;35:484)

Negative stains

EMA, HMB45, desmin (Am J Surg Pathol 2014;38:1242)
OCT 3/4, SALL4 (markers of germ cell tumors) (Am J Surg Pathol 2014;38:e50)
Beta catenin (no nuclear staining) (Am J Surg Pathol 2015;39:1390)
Variable for cytokeratin / low weight cytokeratin (45% positive, paranuclear and dot-like pattern), melanA (25% positive) (Am J Surg Pathol 2014;38:1242)

Molecular / cytogenetics description

FOXL2 C134W (c.402C > G) gene mutation in a minor subset of cases (up to 40%; 2 of 5 tumors) (Arch Pathol Lab Med 2012;136:825)
- Less frequently identified in comparison to its ovarian counterpart (Appl Immunohistochem Mol Morphol 2011;19:347)

Sample pathology report

Left testis, radical orchiectomy:
- Adult granulosa cell tumor (3.0 cm), confined to the testis (see comment)
- Comment: The tumor is small, well circumscribed and lacks features associated with a more aggressive behavior, such as significant cytologic atypia, conspicuous mitoses, presence of lymphovascular invasion or necrosis.

Differential diagnosis

Juvenile granulosa cell tumor:
- Typically occurs in the first 6 months of life; rare after 1 year of age
- Associated with ambiguous external genitalia and karyotypes
- Most common patterns are solid and follicular, in which the follicles are irregular in size and shape lined by granulosa cells with an outer thecal layer; contains mucinous material that is not found in adult granulosa cell tumor and the follicles tend to be more uniform
- Usually lacks Call-Exner bodies and nuclear grooves
Leydig cell tumor:
- Presents at a similar age (mean: 46.5 years)
- Similarly presents with sheets or lobular aggregates of cells with abundant eosinophilic cytoplasm arranged with variable amounts of fibrous stroma
- Cells may be vacuolated and contain Reinke crystals, which are not seen in adult granulosa cell tumors
Sertoli cell tumor:
- Presents at a similar age (mean: 45 years)
- Displays a variety of patterns, such as trabecular, corded and diffuse, in addition to varying amounts of well formed tubules; the latter is typically not seen in adult granulosa cell tumors and lacks the typical microfollicular pattern or Call-Exner bodies
- Composed of tumor cells with abundant pale to lightly eosinophilic cytoplasm, which may display nuclear grooves
- Positive for nuclear beta catenin (Am J Surg Pathol 2015;39:1390)
Fibrothecoma:
- Presents at a similar age (mean: 44 years)
- Composed of ovoid or spindled cells in varying amounts of collagenous stroma
- Lacks varied architectural patterns and nuclear grooves
- Inhibin A positive (patchy to diffuse pattern) (Am J Surg Pathol 2013;37:1208)
Sex cord stromal tumor, unclassified:
- Tumors that have features of indeterminate differentiation; lack findings characteristic of adult granulosa cell tumors or other sex cord stromal tumors
Sex cord stromal tumor, mixed:
- Tumors that contain characteristics of 2 or more tumor subtypes

Additional references

Case Rep Pathol 2013;2013:932086, Case Rep Urol 2016;2016:9016728, Diagn Pathol 2014;9:107, Arch Pathol Lab Med 2000;124:1525, Tunis Med 2016;94:897, Diagnostic Histopathology 2019;25:398 Moch: WHO Classification of Tumours of the Urinary System and Male Genital Organs, 4th Edition, 2016

Board review style question #1

A 47 year old man presented with a right testicular swelling. Histologic examination revealed the tumor shown above. This tumor typically shows which of the following immunoprofiles?

OCT4+ / SALL4+ / inhibin A- / FOX2L-
OCT4- / SALL4+ / inhibin A+ / FOX2L-
OCT4- / SALL4- / inhibin A+ / FOX2L+
OCT4- / SALL4- / inhibin A- / FOX2L-

Board review style answer #1

C. OCT4- / SALL4- / inhibin A+ / FOX2L+. Histology shows Call-Exner bodies, which are pathognomonic for adult granulosa cell tumor. Adult granulosa cell tumor expresses general sex cord stromal tumor immunohistochemical markers, such as inhibin A. FOX2L has also been found to be a marker of sex cord stromal tumors and does not necessarily correlate with a FOX2L gene mutation, which has been identified in a small subset of testicular adult granulosa cell tumors. OCT4 and SALL4 are markers of germ cell tumors.

Comment Here

Reference: Adult granulosa cell

Anatomy & histology

Table of Contents

Definition / general

Birth to age 4 (static phase): seminiferous tubules filled with small cuboidal cells with no definite lumen present, Leydig cells usually not visible
Age 4 - 10 (growth phase): tubules, tubular lumina and cells enlarge; tubules become tortuous
Age 10 to puberty (maturation phase): tubular cells have mitoses; Leydig cells prominent; spermatocyte differentiation visible
Adult (postpuberty): each testis weights 15 - 19g, measures 5 × 3 cm; takes 70 days for cells to mature from spermatogonium to primary spermatocyte to secondary spermatocyte to spermatid to spermatozoa; maturation is orderly along length of tubule but often not present in biopsy cross section
Normal spermatogenesis:
- Not every tubule has complete spermatogenesis
- Number of late spermatids correlates best with sperm counts
- Some patients have normal sperm counts but low motility or duct obstruction
Testes is paired organ suspended in scrotum by spermatic cord
Each testis is attached to an epididymis, which connects rete testis to vas deferens
Testis is composed of convoluted seminiferous tubules in a stroma with Leydig cells
Three layers: outer serosa (tunica vaginalis, extension of peritoneal cavity) with mesothelial cells; tunica albuginea (tough fibrous septa that extends into testis and separates it into 250 lobules of 1 - 4 seminiferous tubules), inner tunica vasculosa
Seminiferous tubules converge into rete testis at hilum, anastomose into efferent tubules that penetrate tunica albuginea to form head of epididymis

Terminology

Efferent ducts: see micro images below
Epididymis:
- Connects efferent ductules to vas deferens
- Has head, body and tail
- Composed of columnar cells (tall, ciliated with PAS+ nuclear inclusions), clear cells and basal contractile cells (actin positive)
- May have "monster" cells similar to seminal vesicle (no significance, Am J Surg Pathol 1981;5:483)
- Tubules have thick muscular coat
- References: Am J Surg Pathol 2003;27:469
- Nonpathologic morphologic variations:
  - Intranuclear eosinophilic inclusions: 72%, usually older patients
  - Lipofuscin pigment: 33% usually in efferent ducts and associated with obstructive changes
  - Cribriform hyperplasia: 42% usually NOT in normal testis
  - Paneth cell-like metaplasia: 8% with hyalin-like globules that are positive for PAS with and without diastase digestion, associated with obstructive changes
  - Nuclear atypia: 14% similar to that in seminal vesicles, associated with older age
  - Note: rarely present within hernia sacs (Am J Surg Pathol 1999;23:880)
  - References: Am J Surg Pathol 1998;22:990
Interstitium: contains Leydig cells and stromal elements (collagen and myoid cells that surround seminiferous tubules)
Leydig cells:
- Single (20 microns) or in clusters between seminiferous tubules, produce testosterone in response to luteinizing hormone (LH)
- Often associated with nerve fibers and blood vessels
- Have abundant pink cytoplasm with lipid, lipochrome pigment, Reinke crystalloids (hexagonal prisms by EM), round nuclei with distinct nucleoli
- Fewer Leydig cells in elderly
Mediastinum: posterior testicular capsule with vasculature, nerves, mediastinum of rete testis (where tubules converge)
Rete testis:
- At testicular hilum
- Complex tubular architecture may resemble teratoma
- Connects testicular tubules to 12 - 15 ciliated efferent ducts, which merge into a single duct, the epididymis at its head
- Rete lined by flattened to columnar epithelium with numerous microvilli
- Efferent duct lumina are narrower than epididymis, lined by ciliated columnar cells with microvilli
Seminiferous tubules:
- 150 - 250 microns in diameter, the average total length in each testes is 540 m (range 299 - 981 m)
- Lined by multilayered epithelium with most mature cells towards lumina
- Have basal lamina, outer myoid cells (positive for desmin, muscle specific actin, vimentin) and collagen
- Contain Sertoli cells, spermatogonia (types A and B), primary spermatocytes, secondary spermatocytes, spermatids and spermatozoa
- All except spermatozoa are held together by a narrow cytoplasmic bridge
- Immature tubules are positive for alpha inhibin
Sertoli cells:
- Columnar, on basement membrane, surround germ cell elements with cytoplasmic extensions, form blood - testis barrier
- 7% of tubular cells
- May contain Charcot-Bottcher crystalloids (bundles of microfilaments)
- Have irregular, highly folded nuclei with prominent nucleoli
- Produce anti-Müllerian hormone, which causes regression of Müllerian duct structures in utero
- After birth, secrete androgen binding protein and are responsive to FSH
- Also produce inhibin
Vas deferens:
- Also called ductus deferens
- 30 - 40 cm long tubular structure from tail of epididymis to prostatic urethra at level of verumontanum; distal vas deferens joins seminal vesicle to form ejaculatory duct
- Rarely present within hernia sacs (Am J Surg Pathol 1999;23:880)
- Should see complete transection in vasectomy specimens
- References: Am J Surg Pathol 2003;27:469

Vestigial remnants:

Appendix epididymis: remnant of mesonephric duct
Appendix testis (hydatid of Morgagni):
- Remnant of Müllerian duct; attached to tunica albuginea at upper testicular pole; present in 90% of males
- May undergo hemorrhagic infarction from twisting on its pedicle
- Gross: round / oval, 1 - 10 mm, pedunculated
- Micro: columnar epithelium with vascular fibrous core with smooth muscle cells; may have glandular-like structures due to surface invaginations
Paradidymis (organ of Giraldes): remnant of mesonephric tubules
Vas aberrans (organ of Haller): remnant of mesonephric tubules

Embryology

Presence of Y chromosome (possibly sex determining region Y) determines formation of testis
Germ cells migrate to genital ridge, tubules formed by day 45; Wolffian ducts (form epididymis, vas deferens, seminal vesicles and ejaculatory ducts) develop by day 25, Müllerian ducts (form uterus and upper vagina) by day 43
If no Y, gonad becomes an ovary; if Y present becomes a testis
If Y present, Sertoli cells develop from genital ridge and secrete anti-Müllerian hormone / Müllerian inhibiting factor (AMH) by day 62, causing ipsilateral regression of Müllerian duct by day 75 - 80; lack of Sertoli cells means no AMH, no regression and presence of uterus and upper vagina
If Y present, Leydig cells arise by day 64 and produce testosterone, which causes development of Wolffian duct structures (epididymis, vas deferens, seminal vesicles and ejaculatory ducts) if functional androgen receptors are also present
If no testosterone is produced, Wolffian duct structures degenerate
Exogenous androgens or their production by maternal tumor or congenital adrenal hyperplasia cause development of Wolffian duct system regardless of presence of Y chromosome
Development of external genitalia requires testosterone plus androgen receptors plus 5 alpha reductase, which converts testosterone to dihydrotestosterone (DHT), which causes development of external genitalia between days 120 - 140, including elongation of phallus
If ovaries or no gonads present, internal ducts are female
If DHT not present, external genitalia is female

Diagrams / tables

Images hosted on other servers:

Scrotum

Transverse section

Right testis

Vertical section

Transverse section

Section of genital cord

Spermatic cord

Subcutaneous inguinal ring

Cremaster

Spermatic veins

Section of epididymis of guinea pig

Fundus of bladder

Gross images

Contributed by @Andrew_Fltv on Twitter

Testis anatomy

Images hosted on other servers:

Normal testis

Microscopic (histologic) description

Spermatic cord:
- Ciliated, pseudostratified epithelium with prominent nuclear inclusions resting on basal cell layer
- Markedly thickened muscle coat of 3 layers (inner longitudinal, outer longitudinal, middle circular layer)
- May contain psammoma bodies

Microscopic (histologic) images

Contributed by Asmaa Gaber Abdou, M.D. and @Andrew_Fltv on Twitter

Testis histology

Images hosted on other servers:

Normal testis

Efferent ducts

Leydig cells

Seminiferous tubules

Various images of epididymis

Various images of spermatic cord

Positive stains

Epididymis and spermatic cord: CD10

Electron microscopy description

Spermatogenesis: EM may show round headed sperm or immotile cilia syndrome

Atrophy

Table of Contents

Definition / general

Testicular atrophy is a nonneoplastic process characterized by the disappearance of tubular or germinal epithelium and replacement with variable degrees of fibrosis
Atrophy can present in the setting of testicular regression syndrome, postvasectomy, vascular accidents, testicular torsion, cryptorchidism, infectious process, external insults, iatrogenic and other settings

Essential features

Etiology of testicular atrophy is varied; it can be seen in a variety of clinical pathologic settings
Microscopic features include small tubules with few or no viable germ cells and a relative predominance of Leydig cells
Potential risk for germ cell neoplasia in testicular regression syndrome with retained viable germ cells

Terminology

Testicular atrophy
Testicular regression syndrome
- Atrophy or disappearance of initially normal testis in fetal life
- Presence of spermatic cord is evidence of testis in early intrauterine life (J Clin Res Pediatr Endocrinol 2012;4:116)
Bilateral anorchia (BMJ Case Rep 2018;2018:bcr2018225530)
Vanishing testes (Front Pediatr 2022;10:834083)
Postvasectomy atrophy
End stage testis

ICD coding

ICD-10: N50.0 - atrophy of testis
ICD-11: GB03 - atrophy of testis

Epidemiology

Newborn / children for testicular regression syndrome
Any age for other etiologies

Sites

Testicle parenchyma

Pathophysiology

In testicular regression syndrome, absence of a testis in an otherwise normal 46,XY male is usually unilateral and is assumed to be a consequence of intrauterine or perinatal torsion or infarction (J Clin Res Pediatr Endocrinol 2012;4:116)
Hypothalamic - pituitary - gonadal axis dysregulation, leading to reduced steroidogenesis and spermatogenesis (Reprod Sci 2021;28:2735)
Compromised vascular supply after a vascular accident or testicular torsion, leading to atrophy

Etiology

Vascular accident, testicular torsion, thrombosis (Best Pract Res Clin Endocrinol Metab 2022;36:101619)
Trauma
Cryptorchidism
Genetic abnormalities, such as microdeletion of Y chromosome, persistence of Müllerian duct structures (J Clin Res Pediatr Endocrinol 2012;4:116)
Filariasis and other infectious etiologies (J Endourol Case Rep 2019;5:113)
AIDS (Am J Clin Pathol 1990;93:196)
Chemotherapy and radiation
Vasectomy, outflow obstruction
Hormonal imbalances (e.g., persistent FSH stimulation, elevated serum estrogen)
Sequela of COVID-19 infection (Reprod Sci 2021;28:2735)

Clinical features

Unilateral or bilateral nonpalpable testis
Normal external genitalia
Infertility
Presence of micropenis in a subset of patients with testicular regression syndrome (J Clin Res Pediatr Endocrinol 2012;4:116)
Variable degrees of sexual ambiguity in familial cases of testicular regression syndrome

Diagnosis

Measurement of gonadotropin and testosterone levels, human chorionic gonadotropin stimulation test, measurement of anti-Müllerian hormone, inhibin B levels, INSL3 levels and karyotype analysis
Scrotal and abdominal ultrasound
Laparoscopic exploration to visualize blind ending spermatic vessels within the retroperitoneum, or visualization of spermatic vessels and vas deferens exiting a closed internal inguinal ring (J Clin Res Pediatr Endocrinol 2012;4:116)

Laboratory

In bilateral testicular regression syndrome, testosterone, inhibin B and INSL3 are undetectable, gonadotropins are elevated and karyotype is 46,XY (Best Pract Res Clin Endocrinol Metab 2022;36:101619)
Hypothalamic - pituitary - gonadal axis dysregulation causes impaired LH:FSH ratio and decreased testosterone
Lower sperm concentration, lower total sperm count and motility
Azoospermia

Radiology description

Absence or decreased size of testicle in scrotum

Prognostic factors

Potential risk for germ cell neoplasia in testicular regression syndrome with retained viable germ cells

Case reports

Newborn boy with bilateral testicular torsion, resulting in testicular atrophy (Acta Medica (Hradec Kralove) 2017;60:120)
30 year old man with bilateral leiomyomas of the tunica albuginea, causing testicular atrophy (Int J Clin Exp Pathol 2015;8:9703)
40 year old man with filariasis (J Endourol Case Rep 2019;5:113)
42 year old man with bilateral anorchia (BMJ Case Rep 2018;2018:bcr2018225530)

Treatment

Surgical removal of the testicular remnant may or may not be necessary (Front Pediatr 2022;10:834083)
Procedure for removal of outflow obstruction, if fertility is desired
Hormonal supplementation in cases of hypothalamic - pituitary - gonadal axis dysregulation
Treatment of underlying infection

Gross description

Spermatic cord with a small mass of firm, fibrotic tissue at one end as well as elements of the vas deferens, spermatic artery and venous plexuses (J Clin Res Pediatr Endocrinol 2012;4:116)
Small, fibrotic testis

Gross images

Contributed by @Andrew_Fltv on Twitter

Testicular atrophy

Images hosted on other servers:

Comparison to normal testis

Microscopic (histologic) description

Fibrovascular nodule with hemosiderin laden macrophages and dystrophic calcifications
Rare presence of seminiferous tubules (6.3% of cases) and viable germ cells (2.1% of cases) in testicular remnants in testicular regression syndrome (Front Pediatr 2022;10:834083)
Small tubules, thick basement membrane and few or no germ cells in postvasectomy specimens
Sclerotic tubules
Interstitial fibrosis
Increased Leydig cells

Microscopic (histologic) images

Contributed by Patricija Zot, M.D., Rafael E. Jimenez, M.D., @ThatGlassTho on Twitter and @Andrew_Fltv on Twitter

Seminiferous tubules replaced by collagen deposition

Retained germ cells

Atrophy

Testicular atrophy

Positive stains

Inhibin and SF1 may highlight residual Sertoli and Leydig cells
CD117 may highlight residual germ cells

Negative stains

SALL4, OCT 3/4, PLAP, D2-40

Molecular / cytogenetics description

DHX37 pathogenic variants are a new cause of an autosomal dominant form of 46,XY disorders of sex development, including gonadal dysgenesis and testicular regression syndrome (Genet Med 2020;22:150)
Heterozygous partial loss of function mutations in SF1 may be associated with bilateral anorchia (vanishing testis syndrome) and micropenis in humans (Hum Reprod 2007;22:3255)

Sample pathology report

Left testicle, orchiectomy:
- Testicular parenchyma with seminiferous tubule fibrosis

Differential diagnosis

Regressed germ cell tumor:
- Discrete scar; not a diffuse process
- Germ cell neoplasia frequently present in the background (positive for SALL4, OCT 3/4, CD117, PLAP, D2-40)
- Abnormal serum tumor markers
- May present with metastatic disease
Leydig cell tumor:
- Unifocal
- Well circumscribed mass
- May have infiltrative borders in malignant variant
- Reinke crystals may be present

Board review style question #1

A 35 year old man presents for evaluation of infertility. After several laboratory and radiologic tests, a biopsy of a testicle was performed. The biopsy is shown in the image above. Presence or absence of which of the following would support a diagnosis of testicular atrophy?

Absence of germ cell neoplasia in situ
A nodule composed of cells containing Reinke crystals
Presence of isochromosome 12p
Presence of necrosis

Board review style answer #1

A. Absence of germ cell neoplasia in situ

Comment Here

Reference: Testicular atrophy

Board review style question #2

Parents of a 6 month old baby boy bring the child in for evaluation due to a concern for a nonpalpable testicle. On physical exam, there is only one testicle that has descended and is palpable in the scrotum. Imaging studies show no evidence of the second testicle in the abdomen or any other location; however, spermatic cord with a small nodule is present. The nodule is biopsied and shows benign fibrovascular tissue with no evidence of germ cells. What is the most likely diagnosis?

Cryptorchidism
Regressed mixed germ cell tumor
Teratoma
Testicular regression syndrome

Board review style answer #2

D. Testicular regression syndrome

Comment Here

Reference: Testicular atrophy

Biopsy

Table of Contents

Definition / general | Biopsy Results for Azoospermia (No Sperm Present, No Endocrine Abnormalities) | Biopsy Results for No Sperm Count Due to Endocrine Abnormalities (Testicular Failure) | Biopsy Results for Oligospermia | Fine Needle Aspiration (FNA)

Definition / general

Biopsy indicated for azoospermia (no sperm present) without endocrine abnormalities, since biopsies may show focal spermatogenesis
Most biopsies have 3 - 5 lobules plus septa of tunica albuginea
Usually see many spermatozoa, "perfect" tubules mixed with occasional tubules with scattered "disorganized" spermatogenesis
In young men, ratio of germ cells to Sertoli cells is usually 13:1
Multinucleated giant stromal cells are associated with testicular atrophy due to estrogens
Hyalinized tubules with elastic fibers indicate hyalinization developed postpuberty
Zenker's and Bouin's fixative are preferred, as formalin introduces significant artifact

Biopsy Results for Azoospermia (No Sperm Present, No Endocrine Abnormalities)

Germ cell aplasia / Sertoli cell only syndrome (29%): tubular basement membrane thickening, no germ cells, usually normal number of Leydig cells
Spermatocytic arrest (26%): usually early arrest at primary spermatocyte level (no spermatids, no spermatozoa), normal Leydig cells; may be late arrest (no spermatozoa only)
Generalized fibrosis (18%)
Normal (27%): usually associated with bilateral obstruction as seen in Young syndrome (also chronic sinopulmonary infections) or testicular blockage (50% of tubules lack lumina; disorderly maturation of germ cells); surgery (epididymovasotomy, vasovasotomy) is often successful

Azoospermia due to known obstruction:

Severity related to cause / span of obstruction, usually reduction in spermatids only due to increased hydrostatic pressure (47%)
Also can be normal testes (28%), reduction of primary spermatocytes and spermatids (9%), reduction in all germ cell types (13%) or hyalinization (2% [Am J Surg Pathol 1999;23:1546])

Biopsy Results for No Sperm Count Due to Endocrine Abnormalities (Testicular Failure)

Hypogonadotrophic eunuchoidism (60%): low FSH and LH levels; small infantile tubules with few or no Leydig cells, scattered spermatogonia and Sertoli cells
Klinefelter syndrome (30%): XXY karyotype, tubular fibrosis, prominent basement membrane thickening and Leydig cell hyperplasia; associated with increased incidence of breast carcinoma, possibly Leydig cell tumors, extragonadal (mainly mediastinal) germ cell tumors
Testicular aplasia (10%): absence of testicular tissue, high urinary LH and FSH

Biopsy Results for Oligospermia

Incomplete spermatocytic arrest: some tubules normal, some with arrest
Regional or incomplete fibrosis
Spermatogenic hypoplasia: tubules with reduced number of germ cells that are also disordered
Tubular hyalinization: includes Kleinfelter syndrome (small diameter tubules with thickened basement membrane and increased Leydig cells)
Mixed atrophy: synchronous occurrence of seminiferous tubules with germ cells and tubules with Sertoli cells only
Normal spermatogenesis: associated with duct obstruction

Sloughing and disorganization: lumina contain desquamated immature cells, disordered spermatogenesis (nonspecific, can be seen in hypoplasia, duct obstruction or mechanical damage / artifact to specimen)
Other causes of oligospermia: varicocele, cystic fibrosis causing obstruction in epididymis and vas deferens

Fine Needle Aspiration (FNA)

Used to differentiate normal testis, hypospermatogenesis, early and late maturation arrest, Sertoli cell only patterns
Minimally invasive, may replace testis biopsy
2 - 11 aspiration sites, 10 - 30 needle excursions / site; adequate if 100 clusters of 20 or more testis cells
May be more representative than biopsy since more sampling
Interpretation should focus on relative abundance of germ cells (primary spermatocytes, spermatids, mature sperm with tail) and Sertoli (support) cells
Frequency of clinical diagnoses: idiopathic nonobstructive (50%), varicocele (18%), genetic (8%), cryptorchidism (8%), cancer (8%), obstruction (7%), Kartageners syndrome (1%)
Hypospermatogenesis: presence but paucity of all germ cell types
Sertoli cell only: no primary spermatocytes, no spermatids, no spermatozoa
Early maturation arrest: primary spermatocytes but no spermatids, no spermatozoa
Late maturation arrest: all cells but spermatozoa
Note: FNA cannot assess basement membrane, which is important for neoplasm and CIS diagnoses
References: Am J Surg Pathol 2001;25:71

Brenner tumor

Table of Contents

Definition / general

Extremely rare tumor of testis and paratesticular regions composed of transitional type epithelium; usually occurs in ovary
Also called transitional cell tumor

Epidemiology

Age range 37 - 70 years (mean 57.7)

Pathophysiology

Etiology unknown; may originate from Walthard rests within tunica vaginalis or transitional epithelial nests located in testicular / paratesticular locations

Clinical features

Testicular mass, testicular pain
Must rule out metastatic urothelial carcinoma

Radiology description

Ultrasound remains imaging modality of choice for evaluation of scrotal masses

Prognostic factors

Almost always benign (Am J Clin Pathol 1986;86:146); one malignant case reported (Arch Pathol Lab Med 1991;115:524)

Case reports

37 year old man with mixed Brenner and adenomatoid tumor (Cancer 1979;43:539)
41 year old man (Cancer 1970;26:853)
61 year old man (Cancer 1968;21:722)
62 year old man with malignant Brenner tumor of testis and epididymis (Arch Pathol Lab Med 1991;115:524)

Treatment

Orchiectomy

Gross description

Solid and cystic masses, 1 to 5 cm

Microscopic (histologic) description

Nests of transitional cells (solid or cystic) with fibrous or cellular spindle cell stroma
Nests show mostly a pavement type arrangement with some focal columnar type cell appearance
Nuclei are round to oval, some with nucleoli and longitudinal nuclear grooves
Focal mucinous differentiation has been reported

Positive stains

CK7: cytoplasmic staining
Uroplakin III: cytoplasmic and membrane staining
WT1: focal; nuclear staining

Negative stains

CK20, p16, RB, p53

Electron microscopy description

Cells with complex interdigitations interlocking their plasma membranes, which are otherwise joined by tight desmosomes
Small intercellular spaces containing elongated projections of cytoplasm
Cytoplasm contains microfilaments, poorly preserved mitochondria and ribosomes
Deep nuclear clefts (Cancer 1979;43:539)

Differential diagnosis

Additional references

Obstet Gynecol 1977;50:120, Am J Surg Pathol 2009;33:556, Arch Gynecol Obstet 2012;285:1699, Hum Pathol 2011;42:918

Choriocarcinoma

Table of Contents

Definition / general

Choriocarcinoma is a malignant nonseminomatous germ cell tumor (GCT) composed of trophoblastic cells with associated hemorrhage

Essential features

Tumor that arises from trophoblastic tissue and consists of syncytiotrophoblasts, cytotrophoblasts and intermediate trophoblasts with associated hemorrhage
Increased serum beta hCG
Early hematogenous metastasis
Mixed germ cell tumor with choriocarcinoma component has better outcome than pure choriocarcinoma

Terminology

Nonseminomatous germ cell tumor (NSGCT)
Trophoblastic malignant teratoma, chorionepithelioma (not recommended)

ICD coding

ICD-O:
- 9100/3 - choriocarcinoma, NOS
- 9101/3 - choriocarcinoma combined with other germ cell elements
ICD-10:
- C62.90 - malignant neoplasm of unspecified testis, unspecified whether descended or undescended
ICD-11:
- 2C80.2 - germ cell tumor of testis
- XH3WM1 - choriocarcinoma combined with other germ cell elements
- XH8PK7 - choriocarcinoma, NOS

Epidemiology

Testicular GCT are the most common solid tumors in young men (Expert Rev Anticancer Ther 2020;20:75)
95% of testicular tumors are GCT
Testicular GCT with choriocarcinoma affects men aged 20 - 39, with a median age of 29 (Am J Surg Pathol 2014;38:111)
7 - 8% of testicular GCT have choriocarcinoma as a component, usually admixed with other GCT types (J Urol 2014;192:934)
0.9% of testicular mixed GCT have choriocarcinoma as a main component (Am J Surg Pathol 2014;38:111)
0.2 - 0.6% of testicular GCT are pure choriocarcinoma (J Urol 2014;192:934, Am J Surg Pathol 2014;38:111)

Sites

Testicular parenchyma
Metastases to lung, brain, liver, retroperitoneum, gastrointestinal tract, lymph node, bone (Int J Health Sci (Qassim) 2017;11:81, World Neurosurg 2017;106:536, Cureus 2018;10:e3083, J Pak Med Assoc 2013;63:1544, Curr Oncol Rep 2015;17:2)

Pathophysiology

Unknown

Etiology

No specific known cause
Precursor lesion: germ cell neoplasia in situ (GCNIS)
Testicular GCT risk factors include cryptorchidism and a personal or family history of testicular cancer (Am Fam Physician 2018;97:261)
Testicular GCT are likely the result of genetic and environmental factors during fetal development and subsequent changes in premalignant germ cells following puberty (Expert Rev Anticancer Ther 2020;20:75)

Clinical features

Presentation with elevated serum beta hCG, scrotal mass with or without pain, possible hyperthyroidism and gynecomastia (Curr Oncol Rep 2015;17:2, Am Fam Physician 2018;97:261)
Can present with hemoptysis, seizures, confusion (Radiol Case Rep 2021;16:923, Curr Oncol Rep 2015;17:2)
Patients with pure or predominant choriocarcinoma have distant metastasis at presentation (100% in 1 study), usually to the lungs (67%), liver (60%) and less frequently brain (20%) (Am J Surg Pathol 2014;38:111)
Cases with minimal choriocarcinoma component (≤ 5%) have regional lymph node metastases in 10% and distant metastases in 7% at presentation (Am J Surg Pathol 2018;42:1113)
Choriocarcinoma syndrome is a rare, life threatening complication in patients with substantially increased serum beta hCG (usually > 50,000 IU/L) due to high choriocarcinoma tumor burden at metastatic sites, often following chemotherapy induction, yielding fatal bleeding and pulmonary hemorrhage leading to acute respiratory failure (Cureus 2021;13:e14286)

Diagnosis

Initial scrotal ultrasonography followed by orchiectomy histopathology (Am Fam Physician 2018;97:261)
CT, MRI, Xray for staging

Laboratory

Higher levels of serum beta hCG indicate heavier choriocarcinoma burden at presentation (Case Rep Oncol Med 2019;2019:4092941):
- Pure choriocarcinoma: 65,000 - 899,000 IU/L (Am J Surg Pathol 2014;38:111)
- Predominant choriocarcinoma: 55,000 - 666,000 IU/L (Am J Surg Pathol 2014;38:111)
- Pure or predominant choriocarcinoma: median 199,000 IU/L (Am J Surg Pathol 2014;38:111)
- Minimal choriocarcinoma component (≤ 5%): 0.1 - 60,715 IU/L (median 485 IU/L) (Am J Surg Pathol 2018;42:1113)
Serum beta hCG in circulation reflects residual tumor (Curr Oncol Rep 2015;17:2)

Radiology description

Ultrasonography of testicle can reach 100% sensitivity in combination with physical exam for testicular tumors (AJR Am J Roentgenol 2013;200:1215)
Choriocarcinoma appears as hypoechoic lesion on ultrasound (Radiol Case Rep 2021;16:923)
CT, MRI, Xray to identify metastasis and for staging
Metastatic choriocarcinoma forms hemorrhagic masses and in lungs has cannonball appearance on Xray and CT (Radiol Case Rep 2021;16:923)

Radiology images

Images hosted on other servers:

CT with testicular mass

Testis ultrasound with calcification

Chest Xray with nodules

Chest Xray in choriocarcinoma syndrome

Chest CT with cannonball metastasis

MRI of brain

Abdominal CT with retroperitoneal mass

Abdomen CT with liver metastasis

Prognostic factors

Patients with beta hCG > 50,000 IU/L have a 5 year survival of 48% (Int J Health Sci (Qassim) 2017;11:81)
Pure or predominant choriocarcinoma has a median survival of 13 months (Lancet 2006;367:754)
79% of patients with pure or predominant choriocarcinoma (> 50%) treated with orchiectomy and chemotherapy died within 3 years (Am J Surg Pathol 1993;17:1075)
Minimal choriocarcinoma component (≤ 5%) does not seem to negatively impact prognosis (Am J Surg Pathol 2014;38:111)

Case reports

17 year old boy with thyroid storm (Eur J Case Rep Intern Med 2020;7:001754)
18 year old man with metastases to skin, lungs, retroperitoneum (Medicine (Baltimore) 2018;97:e10736)
28 year old man with choriocarcinoma syndrome (Cureus 2021;13:e18681)
30 year old man with upper gastrointestinal bleed (Cureus 2019;11:e5243)
37 year old man with metastases to skin, brain, gastrointestinal tract (Cureus 2018;10:e3083)

Treatment

Unlike other testicular GCT, chemotherapy may be indicated prior to a tissue diagnosis in patients with radiologic findings and a serum hCG > 50,000 mIU/mL (Curr Oncol Rep 2015;17:2)
Orchiectomy is primary treatment for nonmetastatic tumors
Retroperitoneal lymph node dissection or chemotherapy for pT2 or higher
Chemotherapy for pN2 - 3
Treatment regimens:
- Bleomycin, etoposide, cisplatin (BEP) (Curr Oncol Rep 2015;17:2, World Neurosurg 2017;106:536)
- Bleomycin might be held until after induction therapy to avoid pulmonary fibrosis (Front Endocrinol (Lausanne) 2019;10:218)
- 4 cycles with hCG monitoring is often needed (Curr Oncol Rep 2015;17:2)
- Delay can be fatal (Curr Oncol Rep 2015;17:2)
Goal of treatment is tumor marker normalization

Gross description

Central hemorrhage and necrosis, surrounded by viable tumor
Tumor size has a wide range:
- Pure or predominant choriocarcinoma: 1.5 - 10 cm, median 7 cm (Am J Surg Pathol 2014;38:111)
- Minimal choriocarcinoma component (≤ 5%): 1.1 - 8.0 cm, median 4.5 cm (Am J Surg Pathol 2018;42:1113)

Gross images

Contributed by Debra L. Zynger, M.D. and Andres Matoso, M.D.

Mixed GCT with predominately choriocarcinoma

Mixed GCT with predominate choriocarcinoma

Mixed GCT with minor component of choriocarcinoma

Mixed GCT with minor component of choriocarcinoma

Large hemorrhagic tumor

Frozen section description

Intraoperative definitive diagnosis of the type of testicular GCT is not needed because it does not impact intraoperative management
Determination of benign versus malignant testicular tumor for small masses via frozen section is highly accurate (Eur Urol 2003;44:458)

Microscopic (histologic) description

Solid nests and sheets of syncytial cells (syncytiotrophoblasts) and mononucleated trophoblasts (cytotrophoblasts and intermediate trophoblasts)
Syncytiotrophoblasts:
- Large cells
- Abundant, dense, eosinophilic cytoplasm
- Indistinct cell border
- Multinucleated
- Pleomorphic, hyperchromatic nuclei which can have a degenerated, smudged appearance
- Grow over mononucleated cells and can form a thin compressed rim or a thicker cap
Mononucleated trophoblasts (cytotrophoblasts and intermediate trophoblasts):
- Medium sized cells
- Pale, eosinophilic cytoplasm
- Distinct cell border
- Mitotically active
Hemorrhage, cyst formation and necrosis are common (Am J Surg Pathol 2014;38:111)
Lymphovascular invasion is often present in tumors with pure or predominant choriocarcinoma (Am J Surg Pathol 2014;38:111)
Germ cell neoplasia in situ may be present
Remaining nonneoplastic testicular parenchyma may show findings seen in other germ cell tumors, including atrophy, maturation arrest, Leydig cell hyperplasia, microlithiasis, angiopathy, Sertoli cell only tubules and Sertoli cell nodules (Am J Surg Pathol 2006;30:1260)

Microscopic (histologic) images

Contributed by Debra L. Zynger, M.D.

2 cell types

Hemorrhage

Syncytiotrophoblasts

Syncytiotrophoblast rim

Mononucleated trophoblasts

Choriocarcinoma with IHC

Beta hCG

Inhibin

CK7

GATA3

OCT 3/4

Cytology description

Dual cell population composed of mononucleated trophoblasts and syncytiotrophoblasts (Ann Saudi Med 1997;17:432)
Mononucleated trophoblasts:
- Intermediate size, round
- Single round nuclei, coarse chromatin and visible single nucleoli
- Clear to slightly basophilic cytoplasm with few small vacuoles (Ann Saudi Med 1997;17:432)
Syncytiotrophoblasts:
- Large cells
- Multiple, pleomorphic nuclei
- Abundant cytoplasm with variable numbers of small vacuoles (Ann Saudi Med 1997;17:432)
Background of necrosis and hemorrhage which may limit cellularity of specimen (Ann Saudi Med 1997;17:432)

Positive stains

AE1 / AE3
hCG: 96% (caveat that tumors containing choriocarcinoma can have expression that diffuses into all GCT types, requiring careful interpretation and use of more specific markers) (Hum Pathol 2019;84:254)
GATA3: 100% (syncytiotrophoblasts, mononucleated trophoblasts) (Hum Pathol 2016;48:18)
Glypican 3: 30 - 100% (strong in syncytiotrophoblasts, mononucleated trophoblasts) (Am J Surg Pathol 2020;44:e66, Am J Surg Pathol 2006;30:1570, Mod Pathol 2020;33:2354, Urol Ann 2022;14:21)
Syncytiotrophoblasts:
- CK7: 100% (Hum Pathol 2019;84:254)
- Inhibin: 89% (Hum Pathol 2019;84:254)
- HPL: 100% (Am J Surg Pathol 2014;38:111)
Mononucleated trophoblasts:
- SALL4: 100%, but variable percentage of cells (Am J Surg Pathol 2009;33:1065)
- p63 (cytotrophoblasts): 85 - 100% (Hum Pathol 2019;84:254, Am J Surg Pathol 2014;38:111)

Negative stains

OCT 3/4: 0% (Am J Surg Pathol 2020;44:e66, Urol Ann 2022;14:21)
CD30: 0% (Urol Ann 2022;14:21)
CD117 / KIT: 0% (Urol Ann 2022;14:21)
HNF-1B: 13% (Mod Pathol 2020;33:2354)
CDX2: 25% (Hum Pathol 2016;48:18)
AFP: 25% (Mod Pathol 2020;33:2354)

Molecular / cytogenetics description

12p abnormalities are found in testicular GCT (Am J Surg Pathol 2020;44:e66, Genes Chromosomes Cancer 1990;1:289)

Sample pathology report

Right testis, radical orchiectomy:
- Mixed germ cell tumor, teratoma (35%), seminoma (20%), embryonal carcinoma (20%), yolk sac tumor (20%) and choriocarcinoma (5%) types (see synoptic report)

Differential diagnosis

Embryonal carcinoma:
- Sheet-like, glandular and papillary growth
- Can have scattered, rare syncytiotrophoblasts
- Darker cytoplasm, lacks prominent cell membranes throughout
- Positive OCT 3/4, CD30; negative CK7, inhibin, beta hCG
Seminoma:
- Patients tend to be 10 years older at diagnosis (Andrology 2015;3:4)
- Expansile nodules separated by fibrous bands containing lymphocytes
- Monotonous, smaller cells with distinct cell borders throughout
- Can have scattered, occasional clusters of syncytiotrophoblasts
- Usually lacks hemorrhage and necrosis (Am J Surg Pathol 2014;38:111)
- Positive OCT 3/4, CD117 / KIT, D2-40 / podoplanin; negative CK7, inhibin, beta hCG
Squamous cell carcinoma somatic malignancy arising from teratoma:
- Lacks 2 different cell types
- Distinct cell membranes throughout
- Can have keratin formation
- Diffuse positive p63, CK5; negative inhibin, beta hCG
Nonchoriocarcinomatous trophoblastic tumors (cystic trophoblastic tumor, epithelioid trophoblastic tumor, placental site trophoblastic tumor):
- Very rare
- Usually seen posttreatment, particularly in metastatic sites
- Only mild serum beta hCG elevation (unless choriocarcinoma elsewhere)
- Lacks 2 different cell types
Carcinoma of nongerm cell origin, especially squamous cell carcinoma:
- No history of germ cell tumor, no elevation of serum beta hCG
- Lacks 2 different cell types
- Lack 12p abnormalities
- Negative beta hCG, SALL4

Board review style question #1

Which testicular germ cell tumor component is classically associated with hemorrhage?

Choriocarcinoma
Embryonal carcinoma
Seminoma
Teratoma
Yolk sac tumor

Board review style answer #1

A. Choriocarcinoma

Comment Here

Reference: Choriocarcinoma

Board review style question #2

Which testicular germ cell tumor component is shown in the image?

Choriocarcinoma
Embryonal carcinoma
Seminoma
Teratoma
Yolk sac tumor

Board review style answer #2

A. Choriocarcinoma

Comment Here

Reference: Choriocarcinoma

Cryptorchidism

Table of Contents

Definition / general

Absence of one or both testes in the scrotum
Most common congenital abnormality of the genitourinary tract (Transl Pediatr 2016;5:233)
Associated with infertility and subfertility, testicular germ cell tumor, testicular torsion and inguinal hernia

Essential features

Absence of one or both testes in the scrotum most commonly due to failure of descent into the scrotum during fetal development
Increased risk of reduced fertility and testicular germ cell tumor

Terminology

Cryptorchidism: absence of one or both testes in the scrotum
Anorchia or vanishing testis syndrome: absence of one or both testes
Orchiopexy or orchidopexy: procedure that tethers the testicle into the scrotum
Ectopic testis: testis is situated away from normal path of descent; differs from undescended testicle

ICD coding

ICD-10:
- Q53.1 - undescended testicle, unilateral
- Q53.2 - undescended testicle, bilateral
- Q53.9 - undescended testicle, unspecified

Epidemiology

1 - 4% in full term newborns of normal weight; decreases to 1% by the first year (Transl Pediatr 2016;5:233, Int J Urol 2021;28:882)
Incidence varies by region with increased rates in United Kingdom, Denmark and Lithuania (Hum Reprod Update 2008;14:49)

Sites

Undescended testicle may be located in the abdomen or inguinoscrotal region

Pathophysiology

Testicular descent from initial position on abdominal wall is divided into 2 stages with abnormalities of migration thought to be associated with undescended testicle (Endocr Rev 2008;29:560)
- Transabdominal descent: the gubernaculum, a caudal ligament connecting the testicle to the internal ring, holds testicle near internal ring as abdominal cavity develops; insulin-like factor 3 (INSL3) and anti-Müllerian hormone dependent
- Inguinoscrotal descent: the gubernaculum shortens, pulling testicle through inguinal canal to position within scrotum; androgen dependent
May be a component of testicular dysgenesis syndrome, which includes increased levels of testicular malignancy, poor semen quality and hypospadias

Etiology

Numerous genes implicated; lack of a clear association in human studies suggests multifactorial causes
More common in preterm (30%) and low birth weight infants (Transl Pediatr 2016;5:233, J Urol 1999;161:1606)
Concordance in sibling studies (Fertil Steril 2010;93:124)
Associated with and increased risk in certain chromosomal abnormalities and genetic syndromes, such as Klinefelter and Prader-Willi syndrome (Lancet 2004;364:273)
Environmental factors likely play a role: diethylstilbestrol and pesticide exposure have been associated with increased rates; maternal and paternal smoking may increase risk (Mol Cell Endocrinol 2012;355:208, Pediatr Int 2020;62:1256, Med Sci Monit 2005;11:CR274)

Clinical features

80% of undescended testicles palpated within inguinal canal or high scrotal area
20% of undescended testicles not palpated
- 50% lie in abdomen, 50% are atrophic (Am Fam Physician 2000;62:2047)
Associated with increased risk of testicular germ cell tumor
- Increasing risk of malignancy with delayed treatment (J Urol 2009;181:452)
- Relative risk of malignancy is 2 - 8x; higher risks associated with delayed repair, bilateral cryptorchidism, additional endocrinopathies, abnormal karyotype and intra-abdominal testes
- Seminoma is most common malignancy

Diagnosis

Laparoscopy is gold standard in diagnosing a nonpalpable testis
- Ultrasound and other radiologic imaging are not sensitive in diagnosing a nonpalpable testis (Pediatrics 2011;127:119, Pediatrics 2013;131:e1908)
Must exclude retractile testis, a testis that has descended into the scrotum but has been pulled superiorly by cremaster muscle
In bilateral cryptorchidism, must exclude congenital adrenal hyperplasia and persistent Müllerian duct syndrome

Laboratory

In cases of bilateral undescended testicles, hormonal studies (LH, FSH, Müllerian inhibiting substance [MIS] and testosterone) may support diagnosis of gonadal dysgenesis with abnormal hCG stimulation test (Am Fam Physician 2000;62:2037)

Radiology description

Diagnostic imaging is not recommended in most cases (J Pediatr Surg 2011;46:2406)

Prognostic factors

Delayed repair reduces fertility, which is worse with bilateral cryptorchidism
Relative risk for testicular germ cell tumor is 2.2x with prepubertal repair versus 5.4x with postpubertal repair (N Engl J Med 2007;356:1835)

Case reports

1 year old boy with swelling of abdominal wall (Am J Case Rep 2020;21:e927495)
1 year old boy with persistent Müllerian duct syndrome and transverse testicular ectopia (BMJ Case Rep 2018;2018:bcr2017223994)
46 year old man with yolk sac tumor in cryptorchid testis (BMJ Case Rep 2019;12:e229541)

Treatment

Orchiopexy may be performed at 6 - 18 months as it is unlikely that testicle will spontaneously descend after this time (J Pediatr Urol 2021;17:239)
American Urological Association does not recommend hormonal therapy (hCG) to promote the descent of the undescended testicle due to low response rates (AUA: Evaluation and Treatment of Cryptorchidism [Accessed 19 November 2021])

Clinical images

Images hosted on other servers:

Intra-abdominal mass

Abdominal testis

Mass with right gonadal vein

Scrotum with cryptorchidism

Abdominal wall ectopic testis

Gross description

Smaller and atrophic compared to descended testis

Gross images

Contributed by Debra L. Zynger, M.D.

Cryptorchid testicle

Microscopic (histologic) description

Histopathologic differences become much more pronounced after 2 years of life and are increased with delayed orchiopexy (J Urol 2009;182:704)
Peritubular fibrosis
Seminiferous tubule atrophy
Decreased / absent spermatogenesis
Sertoli cells may demonstrate granular cell change with eosinophilic granular cytoplasmic lysosomes
Sertoli cell only seminiferous tubules: tubules with only bland, monotonous pale cells with granular cytoplasm attached to the basement membrane; absent germ cells and no spermatogenesis
Sertoli cell nodule: nodules composed of immature elongated Sertoli cells (Pick adenoma) may be present; can have central microliths
Increased microliths within seminiferous tubules
Retained Leydig cells give appearance of hyperplasia
Evaluate for germ cell neoplasia in situ (GCNIS): large, pleomorphic, basally located cells within the seminiferous tubules may be present; use immunostains for confirmation

Microscopic (histologic) images

Contributed by Debra L. Zynger, M.D.

Sertoli cell only tubules

Absent spermatogenesis

Peritubular fibrosis

Sertoli cell nodule

Retained Leydig cells

Granular cell change within Sertoli cells

Microliths

Cytology description

Not used to evaluate a cryptorchid testis

Positive stains

Germ cell neoplasia in situ (GCNIS) is positive for CD117 (KIT), PLAP, D2-40 and OCT 3/4 but these stains may be falsely positive in boys < 2 years old with cryptorchidism (J Urol 2014;191:1084)

Sample pathology report

Ectopic testis, removal:
- Seminiferous tubules with Sertoli only tubules, peritubular fibrosis, no spermatogenesis and microliths consistent with cryptorchid testis

Differential diagnosis

Germ cell neoplasia in situ (GCNIS):
- Atypical cells with large nuclei located next to the basement membrane of the seminiferous tubules
- Cytoplasmic clearing around nuclei
- Heterogeneity of cells within seminiferous tubules
- Positive for CD117, PLAP, D2-40, OCT 3/4 (but can be falsely positive in boys < 2 years old with cryptorchidism)

Board review style question #1

A 24 year old man with a history of untreated cryptorchidism presents with a painful abdominal mass. Pathology is most likely to be consistent with which of the following?

Dermoid cyst
Germ cell neoplasia in situ
Mixed germ cell tumor
Seminoma
Sertoli cell tumor

Board review style answer #1

D. Seminoma is the most common malignancy in the setting of cryptorchidism.

Comment Here

Reference: Cryptorchidism

Board review style question #2

What histological changes are most likely to be observed in a nonneoplastic cryptorchid testis?

Atrophic seminiferous tubules, peritubular fibrosis and nodules of cells containing dark nucleoli and eosinophilic granular cytoplasm
Bland appearing cysts lined with cuboidal epithelium and ciliated cells
Cysts lined by squamous cells filled with keratin
Glycogen rich cells with large, irregular nuclei arranged in sheets
Rod-like cytoplasmic inclusions with a diffuse growth pattern and rare mitotic cells

Board review style answer #2

A. Atrophic seminiferous tubules, peritubular fibrosis and nodules of cells containing dark nucleoli and eosinophilic granular cytoplasm are findings consistent with an undescended testicle. B is incorrect because these might be the findings associated with benign glands, such as those seen in endometriosis or endosalpingiosis. C is incorrect because this histology may be associated with teratoma. D is incorrect because these might be the findings of a seminoma, which are more common in undescended testicles. E is incorrect because Leydig cell tumors often contain Reinke crystals, described in this answer choice.

Comment Here

Reference: Cryptorchidism

Cystic trophoblastic tumor

Table of Contents

Definition / general

Distinctive cystic trophoblastic lesion arising after spontaneous or chemotherapy induced regression of choriocarcinoma
Described predominantly in postchemotherapy retroperitoneal lymph node dissections of patients with testicular germ cell tumors
Has also been described to involve extragonadal sites in both treated and untreated testes of patients with mixed germ cell tumors

Essential features

Cystic proliferation of trophoblasts in postchemotherapy resections from patients with metastatic, nonseminomatous germ cell tumors of the testis
Not aggressive, with behavior that is similar to postchemotherapy residual teratoma

Terminology

Cystic trophoblastic tumor (CTT)
Previously known as choriocarcinoma-like lesion (CCLL) with 2 subtypes: teratomatous CCLL and cystic atypical choriocarcinoma (Am J Surg Pathol 1988;12:531)

ICD coding

ICD-10: C63.9 - malignant neoplasm of male genital organ, unspecified
ICD-11: 2C80.Y - other specified malignant neoplasms of testis

Epidemiology

Patient age can range from 15 to 43 years (Am J Surg Pathol 2004;28:1212, Am J Surg Pathol 2017;41:788)

Sites

Primarily postchemotherapy retroperitoneal lymph nodes with mixed germ cell tumors
Treated or untreated testes with mixed germ cell tumors
Extragonadal sites (e.g., central nervous system) secondary to treated or untreated testicular mixed germ cell tumors

Etiology

May arise from regressing choriocarcinoma as the more aggressive cells are eliminated by chemotherapy or spontaneous regression, leading to the persistence of a slow growing, less aggressive component of intermediate type trophoblasts that develops into cystic trophoblastic tumor (Am J Surg Pathol 2017;41:788)
Cystic trophoblastic tumor may also represent an intermediate stage in the maturation of choriocarcinoma to teratoma (Am J Surg Pathol 2004;28:1212)
Recent research shows that the levels of miR-371a-3p are negligible in CTT; these findings are similar to those found in postpubertal type teratoma and to the metastatic mature teratoma masses; hence, it supports the hypothesis that CTT represents an advanced maturation step toward teratoma (Histopathology 2023;83:151)

Clinical features

Most commonly seen in patients with testicular germ cell tumors after cisplatin based chemotherapy
Can occur as part of primary testicular mixed germ cell tumors and are occasionally seen in visceral and nonregional lymph node germ cell tumor metastases (Am J Surg Pathol 2017;41:788)
Less commonly, these tumors have been described in germ cell tumor patients without chemotherapy (Virchows Arch 2023;482:581)

Diagnosis

Histologic examination of involved tissue

Laboratory

Normal to mildly elevated levels of the beta subunit of human chorionic gonadotropin (βhCG)

Radiology description

Enlarged retroperitoneal lymph nodes

Prognostic factors

Prognosis of CTT in retroperitoneal lymph node dissection specimens is similar to that of teratoma and complete surgical resection without additional therapy is therefore recommended (Am J Surg Pathol 2017;41:788)

Case reports

12 year old boy with cystic trophoblastic tumor in a primary central nervous system postchemotherapy germ cell tumor (Int J Surg Pathol 2020;28:925)
22 year old man with mixed germ cell tumor composed of postpubertal teratoma, embryonal carcinoma and cystic trophoblastic tumor (Cesk Patol 2022;67:212)
31 year old man with metastatic cystic trophoblastic tumor without prior chemotherapy (Urol Case Rep 2017;13:154)

Treatment

Requires no further treatment, however, these patients should be carefully monitored on follow up

Gross description

CTT is admixed commonly with teratoma and less commonly with other germ cell tumors and it occurs in small proportions; for these reasons, characteristic gross features cannot be ascribed to it

Microscopic (histologic) description

Cysts lined by squamoid appearing, predominantly mononucleated intermediate trophoblasts
Cyst may vary in size and shape and often appears collapsed among other germ cell tumor components
Cells display smudged nuclei with abundant eosinophilic cytoplasm, suggesting a degenerative phenotype
Cytoplasmic lacunae (vacuoles) may be present
Small solid clusters of cells and single cells may be seen adjacent to the larger cysts
Cyst may contain eosinophilic secretion or fibrinoid material
Cytoplasmic lacunae may coalesce to create variably sized spaces
Mitoses are rarely seen
Reference: Am J Surg Pathol 2004;28:1212, Am J Surg Pathol 2017;41:788

Microscopic (histologic) images

Contributed by Vikas Mehta, M.D.

Cyst, fibrinoid material

Intermediate type trophoblasts

Intermediate trophoblasts, smudged chromatin

Solid nest, fibrinoid material

βhCG positivity

Positive stains

GATA3 diffusely positive
- GATA3 has been reported to be negative on rare occasions (Int J Surg Pathol 2020;28:925)
Inhibin, p63 and hCG are variably positive (Am J Surg Pathol 2017;41:788)

Negative stains

Sample pathology report

Retroperitoneal lymph node, lymph node dissection:
- Metastatic teratoma in a background of extensive fibrosis and necrosis; microscopic foci of cystic trophoblastic tumor

Differential diagnosis

Choriocarcinoma:
- Distinctly biphasic, hemorrhagic and pleomorphic; displays brisk mitotic activity
- βhCG levels are expected to be highly elevated
Teratoma:
- Demonstrates varying degrees of atypia
- Any type of tissue may be present, such as gastrointestinal glands, respiratory epithelium, cartilage, squamous epithelium with keratinization, primitive undifferentiated spindle cells or neuroepithelium
Somatic malignancy, such as squamous cell carcinoma:
- Hypercellular variants with foci of solid areas can mimic CTT

Additional references

World J Urol 1994;12:200

Board review style question #1

Which of the following is a feature consistent with cystic trophoblastic tumor?

Biphasic pattern of admixed cytotrophoblasts and syncytiotrophoblasts
Infiltrative growth pattern
Normal to mildly elevated serum levels of βhCG
Variable SALL4 expression in mononuclear cells

Board review style answer #1

C. Normal to mildly elevated serum levels of βhCG is consistent with cystic trophoblastic tumors. Other features are characteristic of choriocarcinoma in which βhCG levels are expected to be highly elevated. Answer A is incorrect because choriocarcinoma is biphasic, hemorrhagic and pleomorphic and it displays brisk mitotic activity. Answer B is incorrect because choriocarcinoma exhibits an infiltrative and destructive pattern. Answer D is incorrect because SALL4 positivity is seen in cytotrophoblasts in choriocarcinoma.

Comment Here

Reference: Cystic trophoblastic tumor

Board review style question #2

Which of the following statements is true for cystic trophoblastic tumors (CTTs)?

CTTs after chemotherapy show a high frequency of progressive disease and warrant additional chemotherapy
CTTs are identified exclusively in the setting of postchemotherapy retroperitoneal lymph node dissections of patients with testicular germ cell tumors
CTTs lack keratohyaline granules and central keratin and often have intracytoplasmic lacunae
CTTs show goblet cells, ciliated cells and other specialized epithelial types

Board review style answer #2

C. CTTs lack keratohyaline granules and central keratin and often have intracytoplasmic lacunae. Answer A is incorrect because the prognosis of CTT is similar to teratoma and requires no further treatment but a close follow up. Answer B is incorrect because CTT was first described in retroperitoneal lymph node dissections after chemotherapy; however, it is now known that these tumors can occur as part of primary testicular mixed germ cell tumors and they are occasionally seen in visceral and nonregional lymph node germ cell tumor metastases. Less commonly, these tumors have been described in germ cell tumor patients without chemotherapy. Answer D is incorrect because cysts are lined by squamoid appearing cells with smudged irregular nuclei, abundant eosinophilic cytoplasm with intracytoplasmic lacunae and associated fibrinoid material.

Comment Here

Reference: Cystic trophoblastic tumor

Cysts

Table of Contents

Definition / general

Benign, cystic lesions that may be confused with testicular tumors
Does not include cystic neoplasms (e.g., epidermoid cyst, dermoid cyst [teratoma], papillary cystadenoma of the epididymis)

Essential features

Mesothelial cysts and hydrocele constitute benign true cysts and fluid collections arising from the mesothelial lining of the visceral and parietal tunica vaginalis and are more common in children
Cysts and cystic dilatations of the epididymis and rete testis (or more rarely, the seminiferous tubule) arise from the tubal epithelium, frequently secondary to obstruction and are more common in adults
Frequently characterized by simple unilocular or multilocular cystic structures and an absence of complex growth / solid areas

Terminology

Includes true cysts and fluid collections (celes) of the spermatic cord and paratesticular structures
2 main types
- Extratesticular (arises from the mesothelial lining [tunica vaginalis] and does not communicate with tubular system)
  - Hydrocele
    - Encysted presentation does not communicate with peritoneal cavity
    - Funicular presentation does communicate with peritoneal cavity
  - Mesothelial cyst (also termed spermatic cord cyst)
- Testicular (arises from the epithelial lining of the rete testis, efferent ducts and epididymis)
  - Epididymal cysts and cystic dilatation (tubular ectasia) of epididymis and rete testis are associated and likely exist on a continuum
  - Epididymal cysts > 2 cm within the vaginal cavity are termed spermatocele
  - Cystic dysplasia of rete testis is distinctive congenital malformation

ICD coding

ICD-10:
- N50.3 - cyst of epididymis
- N50.89 - other specified disorders of the male genital organs
- N50.81 - testicular pain
  - N50.811 - right testicular pain
  - N50.812 - left testicular pain
  - N50.819 - testicular pain, unspecified
- N50.82 - scrotal pain
- N50.9 - disorder of male genital organs, unspecified

Epidemiology

Hydrocele is one of the most common causes of painless scrotal swelling in infants (up to 10%); generally regresses spontaneously by 1 - 2 years old and rarely persists into adulthood
Mesothelial cysts are most common in men > 40 years old
Cysts and cystic dilatation of epididymis and rete testis constitute the most common paratesticular cystic lesions, frequently in men > 55 years old and seen in up to 30% of asymptomatic patients at ultrasound (AJR Am J Roentgenol 1984;143:161)
Cystic dysplasia of rete testis is rare, generally unilateral and most often seen in children (mean presentation of 5 years old), in association with urinary tract malformations (Front Pediatr 2022;10:898038)

Sites

Spermatic cord, testicular adnexa

Etiology

Hydrocele
- Congenital form occurs due to patent processus vaginalis or abnormal closure of processus; most regress by adulthood
- May be associated with trauma, testicular torsion, tumors, chronic inflammation (e.g., in setting of bacterial epidiymoorchitis, filarial disease) or congenital lymphatic malformations
Mesothelial cyst
- Mesothelial rests trapped during embryonic development (J Urol 1975;114:730)
Cysts (and cystic dilatation) of epididymis and rete testis
- Acquired condition frequently associated with or resulting from mechanical compression of epididymis or spermatic cord by surgical changes (e.g., vasectomy), trauma, neoplastic or infectious process, dialysis (rete testis cystic dilation) or hormonally induced atrophy of epididymis (e.g., secondary to cirrhosis) (Hum Pathol 1996;27:336, Am J Surg Pathol 1996;20:1231, J Ultrasound 2011;14:208)
- Rare intraparenchymal cystic dilatation of seminiferous tubules may result from focal malformation or inflammation
- Epididymal cysts associated with in utero exposure to diethylstilbestrol
Cystic dysplasia of rete testis
- Congenital malformation of rete testis, frequently associated with ipsilateral urogenital malformations (e.g., renal agenesis, multicystic dysplasia of the kidney)
- Thought to arise due to disorders of communication between mesonephric duct and germinal epithelium during development (Front Pediatr 2022;10:898038)

Clinical features

Painful or painless cystic swelling of the scrotum
May be incidentally identified

Diagnosis

Transillumination
Ultrasonography (Doppler ultrasonography is important in a setting of painful swelling to rule out testicular torsion)

Radiology description

Varies by entity
Most frequently characterized by simple uninoculated or multiloculated fluid filled cystic structures
Complex loculations or areas of solid growth should raise concern for alternative etiology

Radiology images

Images hosted on other servers:

Cyst of testis (focal dilatation of seminiferous tubule)

Cystic dilatation (tubular ectasia) of rete testis

Epididymis cyst

Cystic dilatation (tubular ectasia) of epididymis

Mesothelial cyst in tunica albuginea

Hydrocele

Chronic hydrocele with multiloculated appearance

Spermatic cord cyst

Case reports

4 day old boy with bilateral scrotal masses (Asian J Surg 2023;46:2546)
18 month old boy with painless unilateral scrotal swelling and spontaneous regression (J Ultrasound 2021;24:81)
2 year old with persistent unilateral scrotal mass (Int J Surg Case Rep 2023;107:108374)
9 year old boy with multicystic unilateral testicular lesion and ipsilateral renal agenesis (Front Pediatr 2022;10:898038)
32 year old man with progressive bilateral painless scrotal swelling (Indian J Urol 2010;26:593)
64 year old man with unilateral painless testicular enlargement (Ann R Coll Surg Engl 2008;90:W1)

Gross description

Hydrocele
- Fluid filled cyst caused by accumulation of clear serous fluid between the visceral and parietal tunica vaginalis
- Cyst fluid is generally clear but may be complicated by hemorrhage or infection
- May appear multiloculated in the setting of chronic inflammation and progressive fibrosis resulting in internal septa (J Ultrasound 2011;14:208)
Mesothelial cyst
- Simple or multilocular cystic dilation within the tunica vaginalis or tunica albuginea
- Clear to bloody serous cyst fluid
Epididymal cyst (spermatocele) and simple cyst of rete testis
- Epididymal cyst fluid contains abundant spermatozoa
- Epididymal cysts > 2 cm present clinically as spermatocele
- Rete testis cysts are typically unilocular and limited to hilum but may bulge into testis; a multilocular form is associated with epididymal cysts

Gross images

AFIP images

Cyst of tunica albuginea

Images hosted on other servers:

Encysted hydrocele

Multiple paratesticular, unilocular, thin walled cysts

Microscopic (histologic) description

Hydrocele and mesothelial cysts
- Single layer of cuboidal or flattened mesothelial cells
- Prominent atypia, squamous metaplasia or inflammation may be present (Mod Pathol 2005;18:S131)
Cysts and cystic dilatation of epididymis and rete testis
- Simple cyst or multicystic distension of the rete testis or epididymis
- Single layer of normal tubal epithelium (cuboidal to flattened ciliated epithelial cells)
- Lumen filled with spermatozoa
- Chronic inflammation may be present
- May show columnar cell change, fibrosis, giant cell reaction
Cystic dysplasia of rete testis
- Multicystic lesion located in the mediastinum testis
- Irregular cystic spaces lined by a single layer of cuboidal epithelium (Front Pediatr 2022;10:898038)

Microscopic (histologic) images

Contributed by Stephanie Siegmund, M.D., Ph.D. and AFIP

Mesothelium lined cystic cavity

Mesothelial lining of hydrocele

Cystic dilatation of epididymis

Spermatocele

Ruptured spermatocele

Cyst of tunica albuginea

Sample pathology report

Right testes:
- Mesothelium lined cyst (3.0 cm), consistent with hydrocele sac

Spermatocele sac:
- Ciliated columnar / cuboidal cell lined cyst with aggregates of spermatozoa, consistent with spermatocele

Differential diagnosis

Ovarian epithelial type tumors:
- Believed to arise from Müllerian duct remnants or secondary to Müllerian metaplasia of mesothelium
- Entire spectrum of serous or mucinous cystadenomas, borderline tumors and carcinomas can be seen, with serous borderline tumors most frequent (Diagn Pathol 2015;10:118)
- Histologically and immunophenotypically identical to ovarian counterparts
- Can be distinguished by their complex papillary structures and expression of PAX8, WT1, variable ER and PR, EMA and CA-125
Cystadenoma of rete testis:
- Irregular proliferation of cystic structures lined by cytologically bland low cuboidal epithelium and separated by fibrous septa (AJR Am J Roentgenol 2007;189:W67)
- Can be distinguished grossly from rete testis cysts and cystic dilatation by admixed irregular cystic and solid areas and histologically by areas of complex growth (e.g., sertoliform cystadenoma), budding and tufting
Papillary cystadenoma of epididymis:
- Associated with von Hippel-Lindau syndrome
- Dilated ducts lined by a single or double layer of cuboidal to low columnar epididymis epithelium, characterized by cilia and secretory droplets / variable cytoplasmic vacuolization; rarely, mucinous features may be present mimicking intestinal type goblet cells
- Can be distinguished from rete testis cysts and cystic dilatation by presence of papillae
Teratoma, prepubertal type:
- Epidermoid cysts are unilocular and can be distinguished grossly and histologically by their simple stratified squamous epithelium lining (lacking skin appendages) and keratinaceous contents
- Dermoid cysts can be distinguished grossly and histologically by the complex structure frequently containing multiple somatic tissue elements (e.g., bone, hair)
Cysts of appendix epididymis and appendix testis:
- These 2 embryonic remnants may become enlarged and cystically dilated by serous fluid, thus mimicking other testicular cysts (Surg Radiol Anat 2005;27:557)

Board review style question #1

A 67 year old patient with a history of cirrhosis presents with painless scrotal swelling. An orchiectomy reveals the paratesticular lesion pictured above. What is the most likely diagnosis?

Cystic dilatation of epididymis
Hydrocele
Mesothelial cyst
Spermatocele
Teratoma

Board review style answer #1

A. Cystic dilation of epididymis. The image shows a cystically dilated epididymis with proteinaceous luminal accumulation in a cystic space lined by tubal epithelium. Answer E is incorrect because the structure is consistent with normal histology in this location rather than teratomatous elements and teratoma would be less common in an elderly patient with a history of hormonal abnormality (i.e., cirrhosis). Answers C and B are incorrect because a mesothelial cyst or hydrocele would be lined by mesothelium. Answer D is incorrect because while spermatocele is also an epididymal structure lined by tubal epithelium, there is no evidence of spermatozoa in this image.

Comment Here

Reference: Cysts

Board review style question #2

Which of the following clinical scenarios is most likely to be associated with cystic dysplasia of the rete testis?

4 day old neonate with persistent bilateral scrotal swelling
5 year old boy with a complex solid and cystic scrotal mass
6 year old boy with right renal agenesis and unilateral scrotal swelling
34 year old man with 2 months of painful unilateral scrotal mass and recent diagnosis of tuberculosis
67 year old man with metastatic castration resistant prostatic adenocarcinoma

Board review style answer #2

C. 6 year old boy with right renal agenesis and unilateral scrotal swelling. Cystic dysplasia of the rete testis is most commonly seen in children (median age is 5 years old) and is frequently associated with ipsilateral urogenital malformations, such as renal agenesis. Answer A is incorrect because by contrast, unilateral or bilateral neonatal scrotal swelling is most commonly due to persistent patency of the processus vaginalis with spontaneous resolution by 1 - 2 years of age. Answers E and D are incorrect because scrotal swelling in adults is more frequently due to cysts or cystic dilatation of the epididymis or rete testis secondary to obstruction in the setting of hormonal changes, neoplastic processes, surgery or infection. Answer B is incorrect because the presence of a complex scrotal mass rather than uniloculated or multiloculated fluid filled mass raises the possibility of prepubertal teratoma.

Comment Here

Reference: Cysts

Disorders of sexual differentiation

Table of Contents

Androgen insensitivity

Definition / general

Either XY or XXY
Called testicular feminization if complete
Most frequent cause of male pseudohermaphroditism
Lack of androgen receptor due to mutations in gene on X chromosome

Clinical features

Phenotypic female, tall with well formed breasts, absent / scanty pubic and axillary hair, shallow vagina and lack of upper vagina because anti-Müllerian hormone (AMH) causes Müllerian duct regression
Patients also have bilateral cryptorchidism with intraabdominal, inguinal or labial testes; usually no Wolffian or Müllerian derivatives
Recommend gonadectomy by puberty since associated with germ cell tumors (30% by age 50)

Case reports

15 year old girl with complete androgen insensitivity with Sertoli cell tumor and intratubular germ cell neoplasia in separate gonads (J Pediatr Endocrinol Metab 2012;25:547)
16 year old girl with complete androgen insensitivity syndrome associated with bilateral Sertoli cell adenomas and paratesticular leiomyomas (J Pediatr Urol 2013;9:e31)
Young woman with associated seminoma (Mod Pathol 1993;6:89)

Gross description

Tanish brown testes with multiple white nodules of Sertoli cells and Wolffian / Müllerian duct cysts at lateral pole of testis

Microscopic (histologic) description

Small seminiferous tubules without lumina composed of Sertoli cells only, usually immature, with sparse spermatogonia, marked Leydig cell hyperplasia (often without Reinke crystals), ovarian type stroma; nodules are probably hamartomas of Sertoli cells

Gonadal dysgenesis-mixed

Definition / general

Testis plus contralateral streak gonad, testis and contralateral gonadal agenesis, hypoplastic gonads with tubules in one gonad or streak gonad with
Müllerian structures present since no / minimal AMH produced
Usually bilateral fallopian tubes
Usually incomplete masculinization of external genitalia, poor development of ipsilateral Wolffian duct structures
External genitalia are male, female or ambiguous (ambiguous in most patients, two - thirds raised as female)
Phenotypic females may develop signs of virilization at puberty
Karyotypes: 45 X0 / 46 XY, 46 XY most common
Associated with low immunoglobulin levels, aberrant bony development of inner ear structures, cardiovascular and renal anomalies

Treatment

Early bilateral gonadectomy advocated if Y chromosome material is present to prevent gonadoblastoma (one - third) or other germ cell tumors; also to prevent virilization if patient is raised as female (Arch Pathol Lab Med 1990;114:679)

Microscopic (histologic) description

Tubules with mild hypospermatogenesis to total sclerosis (Mod Pathol 2002;15:1013, Hum Pathol 1982;13:700)
Streak gonad has ovarian stroma without primordial ovarian follicles
Streak ovary has primitive sex cord-like structures within ovarian type stroma, variable germ cell components, resembles either gonadoblastoma, granulosa cell or Sertoli cell tumors

Differential diagnosis

True hermaphroditism:
- Histology is important in distinguishing, clinical features are not

Gonadal dysgenesis-pure

Definition / general

Also called Swyer syndrome
Female phenotype and female genital appearance, normal Müllerian structures
Bilateral streak gonads, so no hormonal or reproductive potential
46 XY but no testicular tissue; no evidence of Turner syndrome
Early bilateral gonadectomy is recommended due to high incidence of gonadoblastoma and dysgerminoma (J Pediatr Urol 2011;7:72)

Case reports

21 year old woman with dysgerminoma and streak gonad (Diagn Pathol 2011;6:84)

Gross images

Images hosted on other servers:

Woman with dysgerminoma and streak gonad

Microscopic (histologic) images

Images hosted on other servers:

Dysgerminoma

Streak gonad

Klinefelter syndrome

Definition / general

47XXY, reduced body and pubic hair, gynecomastia in 40 - 80%, high FSH, variable LH
Increased risk of breast cancer and extragonadal germ cell tumor

Gross description

Small, firm testes

Microscopic (histologic) description

Reduced number of intratubular germ cells, some tubules are Sertoli cell only
Also tubular sclerosis, Leydig cell nodules (appear hyperplastic due to tubular atrophy), focal spermatogenesis rarely seen

Electron microscopy description

No annulate lamellae in Sertoli cells; microcrystal formation but no Reinke crystals in Leydig cells (Arch Pathol Lab Med 1982;106:228)

Male pseudohermaphroditism

Definition / general

XY, testes present, phenotype ambiguous or female

Congenital adrenal hyperplasia

Autosomal recessive, due to various enzymatic defects that cause different patterns of synthesis of glucocortical, mineralocorticoid and sex hormone synthesis
Genetic males have cryptorchidism, viable Wolffian duct structures, female or ambiguous genitalia, no Müllerian duct structures
Testes resemble cryptorchid testes
May have bilateral Leydig cell hyperplasia with deficiencies of 21-hydroxylase, 11β hydroxylase, 17α hydroxylase, 3β hydroxysteroid dehydrogenase
Treat with corticosteroids or surgical excision of testes

Dysgenetic male pseudohermaphroditism

Bilateral dysgenetic testis, Müllerian structures, cryptorchidism, inadequate virilization
May be XO / XY mosaics
Infertile, no spermatogenesis
30% incidence of testicular tumors (J Urol 1978;119:525)

Persistent Müllerian duct

Definition / general

Rare form of male pseudohermaphroditism, Müllerian duct structures persist due to lack of AMH effect due to either mutation in AMH gene on chromosome 19p13.3 or abnormality of receptor gene on chromosome 12q13
X linked or autosomal recessive
Phenotypic male, normal external genitalia, unilateral or bilateral cryptorchidism, may have empty hemiscrotum, normal Wolffian duct derivatives; however also have Müllerian duct derivatives (uterus and usually 2 fallopian tubes) within an inguinal hernia
2 forms:
- Unilateral cryptorchidism and contralateral hernia
- Bilateral cryptorchidism, uterus in pelvis, both testes embedded in broad ligament
15% risk of germ cell tumors, including intratubular germ cell neoplasia

Case reports

67 year old man with clear cell adenocarcinoma in uterus (Am J Surg Pathol 2002;26:1231)
Choriocarcinoma with teratoma arising from intra-abdominal testis (Lancet Oncol 2004;5:51)

Differential diagnosis

Mixed gonadal dysgenesis:
- No persistent Müllerian duct structures

True hermaphroditism

Definition / general

Unequivocal ovarian and testicular tissue in same patient, occuring as either bilateral or unilateral ovatestes or as a testis opposite an ovary, regardless of karyotype
Ovary is usually normal; testis usually lacks spermatogonia
No streak gonads present; usually no associated gonadoblastomas
Usually no other developmental malformations and patients may have normal sexual and reproductive functions

Treatment

After assigning gender, remove inappropriate gonad and biopsy remaining tissue

Microscopic (histologic) description

Ovarian compartment has numerous primordial follicles with primary oocytes and a few primary or antral follicles (Mod Pathol 2002;15:1013)

Differential diagnosis

Mixed gonadal dysgenesis:
- Histology is important in distinguishing these diagnoses, clinical features are not

Embryonal carcinoma

Table of Contents

Definition / general

Pluripotent and malignant germ cell tumor (GCT) resembling undifferentiated stem cells during embryonic development

Essential features

Pleomorphic, high grade appearing type of GCT
Usually occurs mixed in combination with other types of testicular GCT
Predominance in a mixed GCT is associated with a higher risk of metastases and relapse (BJU Int 2020;125:355, BMC Cancer 2020;20:728)
Positive: OCT 3/4, CD30; negative / weak: D2-40, CD117, glypican 3

ICD coding

ICD-O: 9070/3 - embryonal carcinoma, NOS

Epidemiology

Testicular GCT is more common in Caucasian men than African American men (Arch Pathol Lab Med 2007;131:1267)
Global incidence rates for testicular GCT are highest in Northern Europe and lowest in Northern and sub-Saharan African countries (Cancer Epidemiol Biomarkers Prev 2010;19:1151)
Global incidence of testicular GCT is increasing but mortality rate is decreasing due to advances in treatment (Med Clin North Am 2018;102:251)
Nonseminomas account for 44% of testicular GCTs (Cancer Epidemiol Biomarkers Prev 2010;19:1151, Int Rev Cell Mol Biol 2009;278:277, Acta Radiol Oncol 1984;23:239)
Embryonal carcinoma is the most frequent tumor component of testicular mixed GCT, present in ~80 - 90% of cases (Cancer Epidemiol Biomarkers Prev 2010;19:1151, Int Rev Cell Mol Biol 2009;278:277, Acta Radiol Oncol 1984;23:239, Mod Pathol 2021;34:834, Hum Pathol 2018;82:113)
Pure embryonal carcinoma (Arch Pathol Lab Med 2007;131:1267, Hum Pathol 2018;82:113, Cell Rep 2018;23:3392, Am J Surg Pathol 2014;38:689):
- Up to 16% of testicular GCT cases (Am J Surg Pathol 2014;38:689)
- Second most common type of testicular pure GCT
- Average age of presentation 25 - 35 years old, ~10 years younger than seminoma
- Rare in children and after 50 years of age

Sites

Testis
Anterior mediastinum
Retroperitoneum

Pathophysiology

Gain of pluripotency is likely due to polygenic factors
Chromosome 12 aberrations have been implicated in testicular GCT, 80% of which are isochromosome 12 formation (Expert Rev Anticancer Ther 2020;20:75)
Pluripotency may also be due to transcription factor OCT 3/4 and SOX2 overexpression (Expert Rev Anticancer Ther 2020;20:75)
Low to intermediate amount of DNA methylation (Front Oncol 2018;8:571)

Etiology

Multi hit hypothesis: likely multifactorial, resulting from both genetic and environmental factors (Expert Rev Anticancer Ther 2020;20:75)
Risk factors include cryptorchidism and a personal or family history of testicular GCT
Believed to arise through abnormal differentiation beginning in fetal life (Expert Rev Anticancer Ther 2020;20:75)
Undergoes malignant transformation during puberty due to hormonal influence (Expert Rev Anticancer Ther 2020;20:75)
Precursor lesion is germ cell neoplasia in situ (GCNIS)

Clinical features

Typically presents with a unilateral, painless testicular mass (Med Clin North Am 2018;102:251)
Dull aching sensation in lower abdomen or scrotal area can also be present
Acute pain is less common
Initial presentation may be due to metastatic symptoms, including lower back pain, dyspnea or hemoptysis (Med Clin North Am 2018;102:251)
Initial metastasis to retroperitoneal lymph nodes
Can present with infertility (Statpearls: Nonseminomatous Testicular Tumors [Accessed 19 January 2022])

Diagnosis

Ultrasound
Serum tumor markers
CT imaging with contrast of chest, abdomen and pelvis to evaluate for metastasis
Radical inguinal orchiectomy with histopathologic evaluation is necessary for definitive diagnosis

Laboratory

Serum tumor markers should not be used as a screening tool
Elevated serum human chorionic gonadotropin (hCG), alpha fetoprotein (AFP) and lactate dehydrogenase (LDH) may be present (J Clin Oncol 2010;28:3388)
Current guidelines recommend measuring hCG, AFP and LDH before and after initial treatment (J Clin Oncol 2010;28:3388)
Serum tumor markers can be used to monitor for recurrence

Radiology description

Heterogenous and hypoechoic appearance on ultrasound; microlithiasis may be present (J Clin Ultrasound 2010;38:21)
Testicular non(pure)seminomatous GCTs appear heterogenous on MRI, with enhancement in areas of necrosis and hemorrhage (AJR Am J Roentgenol 2007;189:W331)
CT imaging is recommended to identify presence of metastases
Lymph node metastases from testicular nonseminomatous GCTs appear heterogenous or cystic on CT imaging (Radiol Clin North Am 2012;50:1111)

Radiology images

Images hosted on other servers:

Calcified mass

Prognostic factors

With surveillance, survival rate for nonseminomatous GCTs is 98.6% (Crit Rev Oncol Hematol 2007;64:182)
More aggressive disease course with embryonal carcinoma predominance in mixed GCT (World J Urol 2017;35:1103, J Urol 2009;181:2097)
Most important pathologic prognostic indicator in the testis is presence of lymphovascular invasion (BJU Int 2020;125:355)
Tumor size > 4 cm is more often associated with lymphovascular invasion (Am J Clin Pathol 2016;145:341)
Presence of discontinuous involvement of spermatic cord is predictive of advanced disease (Mod Pathol 2021 Sep 9 [Epub ahead of print])
More likely to relapse if patient is older at presentation (Urol Oncol 2013;31:499)
Higher likelihood of metastases and lymphovascular invasion with micropapillary growth pattern (Int J Surg Pathol 2013;21:599)
For patients presenting with metastatic diseases treated with orchiectomy, chemotherapy and lymph node dissection, pure embryonal carcinoma had lower relapse and lower mortality rates than mixed GCTs (Urology 2018;114:133)

Case reports

24 year old man with endobronchial metastases (Respirol Case Rep 2020;8:e0064)
24 year old man with calcified solitary testicular mass on ultrasound (BMJ Case Rep 2017;2017:bcr2017220081)
28 year old man with extensive metastasis to the gastrointestinal system and inferior vena cava thrombosis (Indian J Pathol Microbiol 2019;62:350)
34 year old man with urethral metastasis (Urol Case Rep 2021;36:101572)
36 year old man with an intra-abdominal embryonal carcinoma in an undescended testicle (Med Pharm Rep 2020;93:213)

Treatment

Initial management is radical inguinal orchiectomy
No further treatment necessary in 75% of clinical stage I nonseminomatous GCT (Ann Oncol 2010;21:1296)
If pT2 or higher, retroperitoneal lymph node dissection or chemotherapy
If pN2 - 3, chemotherapy
Resistant to radiation therapy (Arch Pathol Lab Med 2012;136:435)

Clinical images

Images hosted on other servers:

Cryptorchid testis with embryonal carcinoma

Gross description

Gray-tan mass with hemorrhage and necrosis

Gross images

Contributed by Debra L. Zynger, M.D.

Mixed GCT with predominance of embryonal carcinoma

Mixed GCT with minor component of embryonal carcinoma

Microscopic (histologic) description

Multiple growth patterns usually present (Am J Surg Pathol 2014;38:689)
3 most common growth patterns: solid (55%), glandular (17%) and papillary (11%) (Am J Surg Pathol 2014;38:689)
Rare patterns: nested (3%), micropapillary (2%), anastomosing glandular (1%), sieve-like glandular (Am J Surg Pathol 2014;38:689)
Polygonal cells (Arch Pathol Lab Med 2007;131:1267)
Cells are crowded, have indistinct distinct cell borders and appear to have overlapping nuclei
Moderate amount of amphophilic and granular cytoplasm
Pleomorphic, high grade nuclear features
Mitotic figures are common
Smudgy degenerative appearing nuclei are often seen
Necrosis is common, both as single cell necrosis and larger foci
Often grows admixed with yolk sac tumor and can rarely form polyembryoma-like structures, called embryoid bodies
Residual seminiferous tubules may contain germ cell neoplasia in situ (GCNIS) or intratubular embryonal carcinoma, which entirely fills the tubule
Lymphovascular invasion is common within embryonal carcinoma predominant GCTs, is usually best visualized at the periphery testicle and may entirely occlude vessels, mimicking nodules of tumor

Microscopic (histologic) images

Contributed by Debra L. Zynger, M.D.

Solid growth

Glandular growth

Papillary growth

Cellular overlap

Pleomorphic

Admixed with yolk sac tumor

Intratubular

Lymphovascular invasion

Spermatic cord invasion

OCT 3/4

CD30

PLAP

CD117

D2-40

AE1 / AE3

Virtual slides

Images hosted on other servers:

Mixed GCT with predominance of embryonal carcinoma

CD30

Cytology description

No role in diagnosis of primary testicular GCT

Positive stains

OCT 3/4 (nuclear and cytoplasmic) (Cancer Res 2003;63:2244)
CD30 (Mod Pathol 2007;20:320)
PLAP: heterogenous (Hum Reprod Update 2006;12:303)
SOX2 (Am J Clin Pathol 2009;131:731)
AE1 / AE3 (Am J Clin Pathol 2000;113:583)
SALL4 (Cancer 2009;115:2640)

Negative stains

CD117 / KIT: patchy, weak (Int J Androl 1994;17:85)
D2-40 / podoplanin: patchy, weak, nonmembranous (Mod Pathol 2007;20:320)
Glypican 3: weak, focal (Virchows Arch 2006;449:308)
AFP: 21% positive (Urology 1983;22:649, Acta Pathol Microbiol Immunol Scand A 1983;91:165)
CK7: 52% weak (Hum Pathol 2019;84:254)
Inhibin (Hum Pathol 2019;84:254)
p63 (Hum Pathol 2019;84:254)
GATA3 (Hum Pathol 2016;48:18)
Calretinin (Int J Gynecol Pathol 2001;20:346)
SOX17 (Am J Clin Pathol 2009;131:731)
Beta hCG: caveat that tumors containing choriocarcinoma can have expression that diffuses into all GCT types, requiring careful interpretation and use of more specific markers (Hum Pathol 2019;84:254)

Electron microscopy description

Long tight junctions and telolysosomes (Cancer 1986;57:257)
No microvilli anchoring rootlets (Cancer 1986;57:257)
Frequent desmosomes (Ultrastruct Pathol 1988;12:67)
Electron dense extracellular lumens with microvilli (Ultrastruct Pathol 1988;12:67)
Heterochromatin is often present (Ultrastruct Pathol 1988;12:67)
Within the cytoplasm, glycogen, ribosomes and large numbers of mitochondria are easily visible (Ultrastruct Pathol 1988;12:67)

Molecular / cytogenetics description

Isochromosome 12p: present in most testicular GCT components including embryonal carcinoma (Expert Rev Anticancer Ther 2020;20:75)

Sample pathology report

Left testis, radical orchiectomy:
- Mixed germ cell tumor, teratoma (45%), embryonal carcinoma (25%), yolk sac tumor (15%), seminoma (10%) and choriocarcinoma (5%) types (see synoptic report)
See staging information

Differential diagnosis

Choriocarcinoma:
- Biphasic with large syncytiotrophoblasts and mononucleated cytotrophoblasts
- Distinct cell membranes and pale cytoplasm
- Associated with hemorrhage
- Positive: beta hCG, glypican 3, GATA3, CK7 (strong), inhibin, p63
- Negative: OCT 3/4, CD30
Seminoma:
- Uniform cells with distinct borders and pale clear cytoplasm
- Fibrous septae with lymphocytes
- Positive: CD117 / KIT, podoplanin / D2-40, PLAP (greater reactivity than embryonal carcinoma), OCT 3/4 (both positive)
- Negative: CD30
Yolk sac tumor:
- Variety of growth patterns, usually with flattened cells, paler eosinophilic cytoplasm, frequent hyaline globules and myxoid material and less inconspicuous mitotic figures
- Positive: glypican 3, AFP, GATA3 (weak)
- Negative: OCT 3/4, CD30
Lymphoma:
- Typically 60 years or older
- Color Doppler ultrasound with increased blood flow (Radiographics 2015;35:400)
- Cells are round, with more uniform nuclei and dispersed chromatin
- Positive: CD45, CD20 (usually)
- Negative: SALL4, OCT 3/4, PLAP (Hum Pathol 1987;18:946)
Carcinoma of nongerm cell origin:
- Lacks chromosomal 12p abnormalities
- Positive: site specific markers
- Negative: SALL4 (although can be expressed in certain carcinomas, such as gastric adenocarcinoma), OCT 3/4, CD30 (Am J Surg Pathol 2014;38:410, Cancer Res 2003;63:2244)

Board review style question #1

A 26 year old man presented with a left testicle mass. A radical orchiectomy was performed. Which is the correct diagnosis for the testicular germ cell tumor component shown in the above image?

Choriocarcinoma
Embryonal carcinoma
Seminoma
Teratoma
Yolk sac tumor

Board review style answer #1

B. Embryonal carcinoma

Comment Here

Reference: Embryonal carcinoma

Board review style question #2

The H&E image above is a brain metastasis of testicular germ cell tumor with choriocarcinoma and embryonal carcinoma. Which of the following 2 immunostains will be positive in choriocarcinoma but weak or negative in embryonal carcinoma (one of which is shown above)?

AFP, PLAP
CD30, OCT 3/4
CK7, p63
D2-40, CD117
SALL4, AE1 / AE3

Board review style answer #2

C. CK7, p63. CK7 (shown in the immunostain image above) is strongly and diffusely positive choriocarcinoma. CK7 is weak or negative in embryonal carcinoma. Expression for p63 is seen in mononucleated trophoblast cells in choriocarcinoma. p63 is negative in embryonal carcinoma. AFP is positive in yolk sac tumor and weak to negative in embryonal carcinoma and choriocarcinoma. PLAP is variably positive in embryonal carcinoma and negative in choriocarcinoma. CD30 and OCT 3/4 are positive in embryonal carcinoma and negative in choriocarcinoma. D2-40 and CD117 are positive in seminoma but negative in both choriocarcinoma and embryonal carcinoma. SALL4 and AE1 / AE3 are positive in both choriocarcinoma and embryonal carcinoma.

Comment Here

Reference: Embryonal carcinoma

Board review style question #3

In a testicular mixed germ cell tumor, increased percentage of which component correlates with a worse prognosis?

Embryonal carcinoma
Seminoma
Spermatocytic tumor
Teratoma
Yolk sac tumor

Board review style answer #3

A. Embryonal carcinoma. In a testicular germ cell tumor, higher percentage of embryonal carcinoma and choriocarcinoma are associated with negative outcomes, such as local and distant metastases. Increased proportions of teratoma and yolk sac tumor are associated with better outcomes. In a mixed germ cell tumor, percentage of seminoma usually does not impact prognosis or management. Spermatocytic tumor is a germ cell tumor unrelated to germ cell neoplasia in situ.

Comment Here

Reference: Embryonal carcinoma

Epidermoid cyst

Table of Contents

Definition / general

Rare benign cyst, < 1% of testicular tumors
Usually ages 10 - 39
Unclear if neoplastic - occasionally has allelic losses, favoring neoplasia (Arch Pathol Lab Med 2003;127:858)
Pilomatricoma / pilomatrixoma (histologic changes including shadow cells, which resemble cutaneous piiomatrixoma), is considered a subtype (Am J Surg Pathol 2001;25:788, Arch Pathol Lab Med 1995;119:96)

Case reports

21 and 27 year old men (Cesk Patol 2005;41:102)

Gross description

Intraparenchymal lesion, usually adjacent to tunica albuginea, mean 2 cm, contains white grumous keratin debris

Microscopic (histologic) description

Cyst with keratinized squamous epithelial lining containing a granular cell layer, cyst filled with laminated keratin
Cyst rupture may cause granulomatous reaction
No adnexal structures, no other tissue types
Pilomatrixoma-like variant:
- Adjacent testis does not show intratubular germ cell neoplasia, unclassified type (IGCNU)
- Eosinophilic islands of "shadow" squamous epithelium with focal, peripheral calcification and ossification
- The ghost-like cells are similar to the shadow cells of cutaneous pilomatrixoma (Am J Surg Pathol 2001;25:788)

Microscopic (histologic) images

Contributed by Debra L. Zynger, M.D. and @ThatGlassTho on Twitter

Testicular epidermoid cyst

Cyst wall with adjacent normal seminiferous tubule

Lamellar keratin within the cyst

Stratified squamous epithelium with adjacent keratin

Teratoma - epidermoid cyst

Molecular / cytogenetics description

Isochromosome 12p and other overrepresentation of 12p are present in usual teratoma but not in epidermoid cyst (Clin Cancer Res 2006;12:5668)

Molecular / cytogenetics images

Images hosted on other servers:

Normal FISH for 12p

Differential diagnosis

Teratoma: usually postpubertal testis, IGCNU present, often atypia in teratomatous elements

Epididymitis

Table of Contents

Definition / general | Microscopic (histologic) images

Definition / general

Primary cause of epididymal obstruction
Usually related to cystitis, prostatitis or urethritis that spreads through vas deferens or lymphatics
May cause testicular ischemia and necrosis, later scarring and infertility with preservation of Leydig cells and preserved sexual activity
Acute disease: epididymis enlarged, covered with fibrin, may contain pus and rupture
Brucellosis: affects testis and epididymis in 20% of cases; has granulomatous appearance
Gonorrhea: affects epididymis before testis
Tuberculosis: may cause confluent caseation that spreads into testis and simulates malignancy; may cause scrotal fistula; should culture to rule out M. kansasii and M. avium-intracellulare
Children: usually gram negative rods, congenital genitourinary abnormality
Sexually active men age 35 or less: Chlamydia trachomatis, Neisseria gonorrhoeae
Men age 35+: E. coli, Pseudomonas and other urinary tract infection organisms

Microscopic (histologic) images

Contributed by Veena Maheshwar, M.D., Kiran Alam, M.D., Anshu Jain, M.D.

25 year old man with epididymal mass: filiarial epididymitis

Epithelioid trophoblastic tumor

Table of Contents

Definition / general

Testicular trophoblastic tumors show a morphologic spectrum analogous to the trophoblastic tumors of the female genital tract including choriocarcinoma, epithelioid trophoblastic tumor (ETT) and placental site trophoblastic tumor (PSTT)
Other than choriocarcinoma, these other trophoblastic tumors are very rare in the testis but have been reported on occasion in association with a history of other germ cell tumor types

Essential features

Epithelioid trophoblastic tumor (ETT) is an unusual trophoblastic tumor, distinct from choriocarcinoma and placental site trophoblastic tumor (PSTT) with morphologic features similar to a carcinoma
ETT has a squamoid appearance, with mostly mononucleated trophoblastic cells and a variable amount of fibrinoid material surrounding the tumor clusters and vessels
Both morphologic and immunohistochemical studies show that ETT is mainly composed of chorionic type intermediate trophoblastic cells

Terminology

Atypical choriocarcinoma

ICD coding

ICD-O: 9105/3 - trophoblastic tumor, epithelioid
ICD-11: 2C80.Y & XH8FW3 - other specified malignant neoplasms of testis & trophoblastic tumor, epithelioid

Epidemiology

Rare gestational trophoblastic neoplasm with only 6 ETTs described in men (Am J Surg Pathol 2009;33:1902, Am J Surg Pathol 2015;39:1468, Indian J Urol 2022;38:230)
Typically occurs in young men between 19 and 43 years
Mean age: 44 (range: 20 - 68 years) (Hum Pathol 2024;153:105673)

Sites

Usually at metastatic sites (lymph nodes, lung) (Hum Pathol 2024;153:105673)
Rarely testis (Hum Pathol 2024;153:105673)

Pathophysiology

Pathogenesis is not clear but it has been suggested that the tumor arises within a mixed germ cell tumor after reprogramming in the differentiation of the neoplastic cytotrophoblasts to produce ETT (Lancet Oncol 2007;8:642)
Chemotherapy may contribute to the differentiation of choriocarcinoma into ETT, which is more refractory to chemotherapy owing to its low proliferation activity; consequently, the ETT cells survive after the destruction of choriocarcinoma (Lancet Oncol 2007;8:642, Pathology 2018;50:88)

Etiology

Seems to develop from the neoplastic transformation of cytotrophoblastic cells that assume a differentiation toward the chorionic type intermediate trophoblastic cells that are normally found in chorion laeve (fetal membrane)

Clinical features

Usually found in metastases (Am J Surg Pathol 2015;39:1468, Indian J Urol 2022;38:230, Am J Surg Pathol 2009;33:1902, Hum Pathol 2024;153:105673)
Metastases and recurrence can occur years after orchiectomy despite chemotherapy (mean: 11 years) (Am J Surg Pathol 2015;39:1468, Indian J Urol 2022;38:230, Am J Surg Pathol 2009;33:1902, Hum Pathol 2024;153:105673)

Diagnosis

Based on characteristic morphology and immunoprofile

Laboratory

May be associated with mild elevation of beta human chorionic gonadotrophin (βhCG)

Radiology description

No characteristic features

Prognostic factors

A subset of cases have an aggressive course (Hum Pathol 2024;153:105673)

Case reports

31 year old man with metastatic epithelioid trophoblastic tumor in retroperitoneal nodes (Indian J Urol 2022;38:230)
39 year old man with metastatic epithelioid trophoblastic tumor (Am J Surg Pathol 2009;33:1902)

Microscopic (histologic) description

Several growth patterns may be present including cohesive nests of squamoid cells with abundant pink cytoplasm and lacking associated hemorrhage
Tumor cells have single pleomorphic and hyperchromatic nuclei with prominent nucleoli and occasional multinucleation along with well defined cytoplasmic membranes without discernible intercellular bridges
Intracytoplasmic vacuoles containing fibrinoid cellular debris, sometimes with pyknotic nuclear fragments can be identified
Extracellular hyaline material and lymphocytes at the periphery with Infiltrating tumor nests and single squamoid cells can also be recognized
Mitotic count ranges from few to several in different fields
Occasional central cystic degeneration containing fibrinoid material is noted
Most striking histologic feature is an absent biphasic pattern of cytotrophoblasts and syncytiotrophoblasts

Microscopic (histologic) images

Contributed by Debra L. Zynger, M.D.

Tumor metastatic to shoulder

Mononucleate cells

Prominent cell borders

Positive stains

AE1 / AE3, CAM 5.2
Variable inhibin, p63, GATA3, PLAP, HPL, βhCG, EMA, CD10, SALL4
Reference: Hum Pathol 2024;153:105673

Negative stains

Sample pathology report

Retroperitoneal lymph node, lymph node dissection:
- Metastatic testicular germ cell tumor, teratoma (60%) and epithelioid trophoblastic tumor (40%) (see comment)
- Comment: The epithelioid trophoblastic tumor expresses AE1 / AE3, inhibin, p63 and GATA3.

Differential diagnosis

Choriocarcinoma:
- Very high serum βhCG
- Shows a biphasic pattern of syncytiotrophoblastic and mononucleated trophoblast cells and significant fresh hemorrhage, often with extensive necrosis
- Higher mitotic activity
- βhCG and HPL expression are diffuse rather than focal
Regressing choriocarcinoma:
- Large mononucleated trophoblast cells with pale to eosinophilic cytoplasm
- Absent biphasic pattern of cytotrophoblasts and syncytiotrophoblasts with necrosis and fresh hemorrhage along with hyalinized fibrous background and numerous hemosiderin laden macrophages
- Few mitotic figures
- Prominent Leydig cell hyperplasia in the surrounding testis
Placental site trophoblastic tumor:
- Sheets of discohesive cells with focal hemorrhage
- More infiltrative growth instead of nodules and nests
- Larger cells with more pleomorphic nuclei
- p63 negative
Squamous cell carcinoma, as a component of teratoma with somatic malignancy:
- Also has concurrent testicular germ cell tumor with other components or a history of testicular germ cell tumor with subsequent metastasis
- Keratin pearls or more overt, classic squamous appearance
- Inhibin, βhCG, HPL negative
Squamous cell carcinoma, nontesticular in origin:
- Correlation with history of other malignancies and current imaging required
- Keratin pearls or more overt, classic squamous appearance
- Inhibin, βhCG, HPL negative

Additional references

Mol Carcinog 2017;56:1214, Clin Obstet Gynecol 1984;27:248, WHO Classification of Tumours Editorial Board: Urinary and Male Genital Tumours, 5th Edition, 2022

Board review style question #1

A patient with a history of testicular germ cell tumor treated with chemotherapy now has an enlarged cervical lymph node that is diffusely involved by the tumor (shown above). There is only a minor elevation of serum βhCG. The tumor is formed by large, solid nodules of cells with a squamoid appearance. The cells are homogeneous and intermediate to large in size, consistent with mononucleated trophoblastic cells. The tumor cells express AE1 / AE3, patchy inhibin and p63 and only focal βhCG. What is the best diagnosis?

Choriocarcinoma
Cystic trophoblastic tumor
Epithelioid trophoblastic tumor
Myoid gonadal trophoblastic tumor

Board review style answer #1

C. Epithelioid trophoblastic tumor (ETT). Essential diagnostic criteria of ETT (WHO 5th edition) include squamoid appearing, mostly mononucleated trophoblastic cells with a variable amount of fibrinoid material surrounding the tumor clusters and vessels. Desirable diagnostic criteria of ETT (WHO 5th edition) include positive staining for p63 and Ki67 index > 10%. Answer A is incorrect because choriocarcinoma has a biphasic pattern of syncytiotrophoblastic and mononucleated trophoblast cells and patients with a substantial burden of choriocarcinoma have high serum βhCG. Answer B is incorrect because cystic trophoblastic tumors have a degenerative appearance with cysts lined by squamoid appearing cells with smudged, irregular nuclei, abundant eosinophilic cytoplasm with intracytoplasmic lacunae and associated fibrinoid material. Answer D is incorrect because myoid gonadal trophoblastic tumor is a pure spindle cell tumor lacking sex cord differentiation and is positive for both actin and S100.

Comment Here

Reference: Epithelioid trophoblastic tumor

Fibroma thecoma group

Table of Contents

Definition / general

Sex cord stromal tumors composed of spindle, oval or round cells with varying amounts of collagen present

Essential features

Hemorrhage and necrosis absent
Variable cell density, variable collagen
Usually no Sertoli or granulosa elements present but may have minor aggregates of other sex cord cells (Arch Pathol Lab Med 1999;123:391)
Usually scanty mitoses (≤ 5 mitoses/10 high power fields), can be as high as 10 mitoses/10 high power fields

Terminology

Synonyms:
- Fibrothecoma
- Thecofibroma
- Thecoma / fibroma group
- Testicular fibroma

ICD coding

ICD-O:
- 8600/0 - thecoma, NOS
- 8810/0 - fibroma, NOS
ICD-10: D29.20 - benign neoplasm of unspecified testis
ICD-11: 2F34 & XH34A0 - benign neoplasm of skin of male genital organs & thecoma, NOS

Epidemiology

Rare tumor
Age range: 16 - 69 years; mean age: 44 years (Am J Surg Pathol 2013;37:1208)
Often occurs in third or fourth decade of life

Sites

Testis
Paratestis

Pathophysiology

Unknown
May be associated with Gorlin syndrome (nevoid basal cell carcinoma syndrome), abnormalities of PTCH gene (J Pediatr Surg 2010;45:E1)

Etiology

Unknown

Clinical features

Commonly presents as slowly increasing unilateral testicular mass (Urol Ann 2021;13:308)
Hormonal changes are extremely uncommon
Clinically benign behavior with no reported recurrences or metastases (Urol Ann 2021;13:308)

Diagnosis

Ultrasound
Orchiectomy

Laboratory

Hormone levels are typically within normal range
Serum testosterone and estrogen may be elevated in some secreting tumors
Tumor markers (beta human chorionic gonadotropin [hCG], alpha fetoprotein [AFP], lactate dehydrogenase [LDH]) are within normal range (Urol Case Rep 2020;33:101368, Urol Ann 2021;13:308)

Radiology description

Well defined, hypoechoic, solid mass
Can appear as a heterogeneous mass

Prognostic factors

Benign behavior
Even 10 mitoses per 10 high power fields show no adverse prognosis (Am J Surg Pathol 2013;37:1208)

Case reports

31 year old man with a firm nodule in the right testis and a 14 year old boy with a nontender mass in the left testis (Arch Pathol Lab Med 1999;123:391)
33 year old man with an incidental nodular mass in the left testis (Hum Pathol 2009;40:584)
37 year old man with a firm right testicular mass (Urol Case Rep 2020;33:101368)
51 year old man with a 2 year history of a small painless testicular mass, with recent size increase (Urol Ann 2021;13:308)

Treatment

Diagnostic orchidectomy is curative; observation after orchidectomy is the only necessary treatment

Gross description

Well defined, firm tumors ranging from 0.5 to 7.6 cm in greatest dimension (Am J Surg Pathol 2013;37:1208)
Cut surface is tan, yellow or white and solid to cystic; can have focally hemorrhagic areas

Gross images

Images hosted on other servers:

Well circumscribed intratesticular tumor

Microscopic (histologic) description

Circumscribed but unencapsulated; encapsulated forms are rare
Arranged in fascicles, storiform or a combination pattern in collagenized stroma with small blood vessels
Herringbone pattern may be seen
Variable cell density, variable collagen
Usually scanty mitoses (≤ 5 mitoses/10 high power fields), can be as high as 10 mitoses/10 high power fields
May be infiltrative and entrap seminiferous tubules; this feature has no impact on tumor behavior
Usually no Sertoli or granulosa components are present but may have minor aggregates of other sex cord cells (Arch Pathol Lab Med 1999;123:391)
If > 1 microscopic focus of other sex cord stromal cells, classify as mixed or unclassified since these tumors have metastatic potential unlike the classical fibroma

Microscopic (histologic) images

Contributed by Rafael E. Jimenez, M.D., M.H.A.

Bland nuclei

Fascicular pattern

Encapsulated tumor

Collagenized stroma

Inhibin

SF1

Positive stains

Inhibin, SF1, smooth muscle actin, calretinin, SOX9, FOXL2, CD56, vimentin

Negative stains

MIC2, CD34, KIT, keratin (occasionally positive), HMB45, MelanA, S100
Desmin is typically negative but may be focally positive (Am J Surg Pathol 1997;21:296)

Electron microscopy description

Fibroma cells resemble both fibroblasts and myofibroblasts

Molecular / cytogenetics description

Although loss of heterozygosity at 9q22.3 (PTCH locus) is observed in 40% of sporadic ovarian thecoma fibromas, only one case in testis has been reported (J Pediatr Surg 2010;45:E1)

Sample pathology report

Right testis, orchiectomy:
- Fibrothecoma (see comment)
- Comment: The neoplastic cells showed positivity for inhibin, smooth muscle actin and SOX9 while MelanA, KIT and desmin were negative. This is consistent with the diagnosis above.

Differential diagnosis

Fibrosarcoma:
- Malignant tumor with infiltration, cytological atypia, frequent mitoses, necrosis
Leiomyoma:
- Positive for muscle markers; negative for inhibin and other sex cord stromal markers
Neurofibroma:
- Patchy S100 positive; negative for sex cord stromal markers
Fibrous pseudotumors:
- Less cellular, more inflammatory cells
Solitary fibrous tumor:
- CD34 positive; tends to arise from extratesticular tissues like tunica albuginea, tunica vaginalis, gubernaculum, not testicular stromal cells
Unclassified sex cord stromal tumors:
- Show more than focal incomplete Sertoli cell differentiation; strong positive S100 is useful stain
Myoid gonadal stromal tumor:
- Rare, usually well circumscribed tumor composed of densely packed spindle cells with variable intervening collagen deposits; the nuclei are tapered with inconspicuous nucleoli
- Positive for SMA, S100, FOXL2 and SF1 and negative for SOX9
Granulosa cell tumor:
- Nodular growth pattern with cells showing nuclear grooves; luteinization of cells and mitotic figures are rare
- FOXL2 mutations can be seen
- Reticulin staining shows fibers surrounding aggregates of cells instead of individual cells as in fibrothecoma

Additional references

J Urol 2012;188:1944, Int J Gynecol Pathol 2019;38:143, Int J Gynecol Pathol 2018;37:305, eMedicine: Pathology of Sex Cord Stromal Testis Tumor [Accessed 13 December 2022]

Board review style question #1

A 65 year old man presented with a painless mass in his right testis. An ultrasound demonstrated a solid mass, measuring 5.4 cm in greatest dimension. He was scheduled for a radical orchiectomy. The resected tumor's histology is depicted in the image above. What is the best course of action after this diagnosis?

Chemotherapy
Observation
Orchiectomy
Radiation

Board review style answer #1

B. Observation

Comment Here

Reference: Fibroma thecoma group

Board review style question #2

Which of the following immunohistochemical profiles best supports the diagnosis of a fibrothecoma of the testis?

Calretinin positive, S100 negative, CD34 positive
CD56 negative, inhibin negative, smooth muscle actin negative
Inhibin positive, FOXL2 positive, MelanA negative
MIC2 positive, FOXL2 negative, S100 negative

Board review style answer #2

C. Inhibin positive, FOXL2 positive, MelanA negative

Comment Here

Reference: Fibroma thecoma group

Fibrous pseudotumor

Table of Contents

Definition / general

Diffuse or localized, reactive fibromatous proliferation involving epididymis, tunica or spermatic cord
May simulate a testicular tumor (Arch Surg 1978;113:814)
May cause bowel wall perforation in infants with meconium periorchitis

Terminology

Other terms used:
- Fibroma
- Nonspecific peritesticular fibrosis
- Nodular fibrous periorchitis, chronic proliferative periorchitis, reactive periorchitis or pseudofibrous periorchitis
- Fibrous periorchitis (for diffuse lesions)
- Proliferative funiculitis
- Nodular pseudotumor (if forms a mass)
- Inflammatory fibropseudotumor or pseudotumor (if forms a mass)
- Peritesticular fibromatosis
- Fibrous mesothelioma

Sites

Typically involves tunica albuginea

Case reports

28 year old man with paratesticular fibrous pseudotumor (J Med Case Rep 2013;7:225)
32 year old man with previous idiopathic retroperitoneal fibrosis (Eur Urol 1986;12:64)
Fibrous pseudotumor of epididymis and tunica vaginalis (Can J Urol 2006;13:3279)
Paratesticular fibrous pseudotumor (Front Med 2014;8:484)

Radiology images

Images hosted on other servers:

MRI: polycyclic mass

Clinical images

Images hosted on other servers:

Intrascrotal mass

Gross description

Can show diffuse band-like thickening, often encasing the testis
Localized forms show single or multiple nodules, 2 mm to 9 cm
Cut surface is usually firm, whitish

Gross images

Images hosted on other servers:

Pedunculated mass

Well demarcated margins

Microscopic (histologic) description

Dense fibrosis, focal edema, lymphangiectasis and perivascular round cell infiltration
Active epididymitis and chronic interstitial orchitis present in some cases
Associated with fibrinous or hyalinized loose bodies in cavity
Composed primarily of spindle cells with variable hyalinization and collagenization
Variable component of lymphocytes, plasma cells, histiocytes and scattered eosinophils
Nuclear atypia is usually absent, and if present is usually focal and restricted to the more cellular areas with more florid granulation tissue-like proliferation
May have focal whorled arrangement, focal calcification and ossification
Usually no mitoses
No atypical mitoses

Microscopic (histologic) images

Images hosted on other servers:

Dense fibrotic tissue

Collagen rich hyalinized fibrotic tissue

CD3

IgG4

CD31

Differential diagnosis

Sarcomas: generally are more cellular, with atypical mitoses and pleomorphism

Germ cell neoplasia in situ

Table of Contents

Definition / general

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

Essential features

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

Terminology

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 coding

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

Epidemiology

Found at higher rates in patients with uncorrected cryptorchidism (2 - 4%), ambiguous genitalia (25%) or infertility (1%) (Int J Cancer 1999;83:815)

Sites

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)

Pathophysiology

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

Etiology

Almost universally present in background seminiferous tubules of testis involved by adult germ cell tumor (Cancer 1981;47:2660)
- Occasionally also in contralateral testis (Eur Urol 2007;51:175, Int J Cancer 1999;83:815)
May be seen as residual finding in a setting of burnt out adult germ cell tumor (Ann Oncol 2003;14:1412)

Diagrams / tables

Images hosted on other servers:

GCNIS derived adult germ cell tumors

Clinical features

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)

Diagnosis

Diagnosis requires histologic examination (testicular biopsy, orchiectomy)
Biopsy of contralateral testis in patients with adult germ cell tumor is more common in Europe than North America

Laboratory

There are no specific serum marker findings (World J Urol 1996;14:S55)

Radiology description

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

Prognostic factors

~50% of cases progress to invasive adult germ cell tumor within 5 years and 90% within 7 years (Br Med J (Clin Res Ed) 1986;293:1398)

Case reports

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)

Treatment

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)

Microscopic (histologic) description

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

Microscopic (histologic) images

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.

Prominent, large atypical gonocytes

Pagetoid GCNIS into rete testis

Normal prepubertal testis

GCNIS with adjacent microinvasion

Podoplanin /
D2-40

Membranous
D2-40 IHC

Membranous KIT IHC

Nuclear OCT 3/4 IHC

Virtual slides

Images hosted on other servers:

Peripheral residual seminiferous tubules

Positive stains

OCT 3/4 (Cancer Res 2003;63:2244, Clin Cancer Res 2004;10:8544)
SALL4
Podoplanin / D2-40
KIT / c-KIT / CD117
SOX17 (J Pathol 2008;215:21)
NANOG
LIN28A
AP2 gamma (Clin Cancer Res 2004;10:8521)
PLAP (Mod Pathol 1988;1:475, Int J Androl 2011;34:e160)
IHC can be helpful for diagnosis in difficult cases (Int J Androl 2009;32:666)
Important consideration: c-KIT and PLAP seem to be frequently positive in normal spermatogonia beyond infantile age; therefore, D2-40 and OCT 3/4 are probably better markers for GCNIS given their higher specificity (Pediatr Surg Int 2020;36:1249)

Negative stains

Molecular / cytogenetics description

Aneuploid (polyploid) with gain of additional findings at the time of invasion (e.g., isochromosome 12p is seen in invasive disease but not in GCNIS) (Genes Chromosomes Cancer 2003;38:117)
Aneuploidy, absence of isochromosome 12p can be demonstrated by FISH, single nucleotide polymorphism (SNP) array or karyotype (Am J Surg Pathol 2020;44:e66)

Molecular / cytogenetics images

Images hosted on other servers:

Representative aneuploidy and chromosomal abnormalities

Sample pathology report

Right testicle and spermatic cord, radical orchiectomy:
- Testis with fibrosis, seminiferous tubular atrophy and scattered foci of intratubular germ cell atypia, consistent with germ cell neoplasia in situ (GCNIS)
- No invasive tumor is identified
- Spermatic cord, epididymis and rete testis are negative for tumor
- No lymphovascular invasion is identified
- AJCC classification (8th edition): pTis N0

Differential diagnosis

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

Additional references

WHO Classification of Tumours of the Urinary System and Male Genital Organs, 4th Edition, 2016

Board review style question #1

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

Embryonal carcinoma
Juvenile granulosa cell tumor
Spermatocytic tumor
Teratoma, prepubertal type
Yolk sac tumor, prepubertal type

Board review style answer #1

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.

Comment Here

Reference: Germ cell neoplasia in situ

Board review style question #2

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

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

Board review style answer #2

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.

Comment Here

Reference: Germ cell neoplasia in situ

Gonadoblastoma

Table of Contents

Definition / general

Rare in situ form of a malignant germ cell tumor composed of germ cells and sex cord stromal derivatives resembling immature granulosa cells and Sertoli cells

Essential features

Associated with disorders of sex development (DSD)
Precursor lesion of germ cell tumors with varying risk of malignant transformation depending on the manner in which it develops
Histologically shows nested to corded arrangement of germ cells and small sex cord cells with deposits of basement membrane material
Often discovered incidentally on prophylactic gonadectomy (Klin Padiatr 2012;224:359)

Terminology

First described as gonadoblastoma in 1953 (Cancer 1953;6:455)
- The term gonadoblastoma was selected due to the tumor's more comprehensive replication of gonadal development compared to other tumor types

ICD coding

ICD-O
- 9073/1 - gonadoblastoma
ICD-10
- D40.10 - neoplasm of uncertain behavior of unspecified testis
ICD-11
- 2C73.Y & XH0K61 - other specified malignant neoplasms of the ovary & gonadoblastoma
- 2F76 & XH0K61 - neoplasms of uncertain behavior of female genital organs & gonadoblastoma
- 2F77 & XH0K61 - neoplasms of uncertain behavior of male genital organs & gonadoblastoma

Epidemiology

Rare tumors
Most are discovered incidentally during a gonadectomy in treatment for a disorder of sex development (Klin Padiatr 2012;224:359)
Primarily happens in the malformed gonads of someone with a sex development disorder due to mutations in genes responsible for gonadal embryogenesis (Hum Pathol 2020;100:47)
- 50 - 60% of these patients will development a gonadoblastoma (Cancer 1970;25:1340, Pediatrics 2006;118:753, Pediatr Endocrinol Rev 2011;9:519, Semin Diagn Pathol 2014;31:427)
Rarely can happen sporadically in individuals with a normal peripheral karyotype (Hum Pathol 2020;100:47)
Patient age: ranges from neonatal to the 40s (Cancer 1970;25:1340)
50% present as virilized females (Cancer 1970;25:1340)
30% present as nonvirilized females (Cancer 1970;25:1340)
20% present as males with hypospadias and cryptorchidism (Cancer 1970;25:1340)
25 - 35% of patients with Turner syndrome and Y chromosomal material develop gonadoblastoma (J Pediatr Urol 2016;12:283.e1, Pediatr Dev Pathol 2015;18:117)
TSPY positive with WT1 mutations (Frasier and Denys-Drash syndromes) (Am J Med Genet C Semin Med Genet 2017;175:304)
- 40 - 60% lifetime germ cell neoplasia in situ / gonadoblastoma (GCNIS / GB) risk
TSPY positive gonadal dysgenesis (Am J Med Genet C Semin Med Genet 2017;175:304)
- 12 - 40% lifetime GCNIS / GB risk
Partial androgen insensitivity (Am J Med Genet C Semin Med Genet 2017;175:304)
- 15 - 20% lifetime GCNIS / GB risk
Complete androgen insensitivity (Am J Med Genet C Semin Med Genet 2017;175:304)
- 0.8 - 15% lifetime GCNIS / GB risk
Ovotesticular DSD (Am J Med Genet C Semin Med Genet 2017;175:304)
- 2.6% lifetime GCNIS / GB risk
Associated with gonadal dysgenesis (Am J Med Genet C Semin Med Genet 2017;175:304)
- Can arise from defects in any stage of gonadal development, including
  - Sex determination errors (e.g., mutations in SRY)
  - Androgen production or androgen sensitivity issues (e.g., partial androgen insensitivity syndrome [PAIS] with intra-abdominal gonads)
  - Sex chromosome aneuploidy (e.g., 45,X or 45,X / 46,XY mosaicism)
Refer to Am J Med Genet C Semin Med Genet 2017;175:304 for a more complete list of entities associated with gonadoblastoma and their lifetime risk of development of gonadoblastoma

Sites

Gonads

Pathophysiology

Normal physiological development of germ cells and its relation to gonadoblastoma (Am J Med Genet C Semin Med Genet 2017;175:304)
- Complex coordination in germ cell development
  - Germ cell development requires exact coordination across spatial, temporal and genetic dimensions (Nat Rev Genet 2016;17:585, Clin Genet 2017;91:292)
- Primordial germ cell (PGC) specification
  - In humans, PGCs differentiate from somatic cells around week 2, driven primarily by transcription factors BLIMP1 and SOX17 (Cell 2015;160:253)
- PGC migration to the genital ridge
  - PGCs travel in clusters from the proximal epiblast to the genital ridge, guided by KIT / KITLG signaling and reach their target by weeks 5 - 6
  - Cells that do not successfully migrate to the genital ridge undergo apoptosis
- Preparation for imprinting (licensing)
  - As PGCs migrate, they undergo global demethylation (licensing) in preparation for genomic imprinting
  - Upon reaching the genital ridge, these cells become gonocytes (testicular) or oogonia (ovarian)
- Expression of GCT markers
  - During this phase, PGCs express markers such as OCT 3/4 and PLAP, which are also histopathological markers of germ cell tumors (GCTs)
- Gonadal sex determination and differentiation
  - After migration, signaling cascades determine gonadal sex and direct further differentiation
    - Testicular pathway
      - SRY and SOX9 drive the development of testicular tissue, along with transcription factors like NR5A1 and ZFPM2 (Nat Clin Pract Endocrinol Metab 2006;2:231)
    - Ovarian pathway
      - In the absence of SRY, ovarian differentiation is supported by WNT4 / beta catenin, FOXL2 and RSPO1 (Nat Genet 2006;38:1304, Cell 2009;139:1130, Am J Hum Genet 2008;82:39)
  - Mutations in these pathways are associated with DSD
- Gonadal fate and sex specific development
  - Ultimate fate of the gonad, whether testicular, ovarian or nondimorphic (atypical), determines further sex specific development
  - Nondimorphic gonads, which do not display typical ovarian or testicular morphology, are often linked with DSD
- Differentiation of specialized gonadal cells by week 9
  - By week 9, typical testicular tissue includes differentiated Leydig and Sertoli cells that produce testosterone, INSL3 and AMH
  - By week 11, ovarian tissue includes developing theca and granulosa cells
- Risk of developmental errors leading to tumor formation
  - Each stage in germ cell development presents an opportunity for errors, which can increase the risk of germ cell tumor (GCT) formation, such as gonadoblastoma
- Pluripotency of germ cells
  - Germ cells are highly pluripotent after embryogenesis, sharing similar hypomethylation and gene expression profiles with embryonic stem cells and iPS cells (Clin Genet 2017;91:292, Int J Dev Biol 2013;57:299)
- Oncogenic potential and developmental disruptions
  - Developmental disturbances affecting germ cell location or environment can lead to oncogenic potential if cell survival is maintained
- Identification of precursor lesions
  - GCT precursors are frequently found as gonadoblastoma (GB) in ovaries / nondimorphic gonads or germ cell neoplasia in situ (GCNIS) in the testis, collectively referred to as GCNIS / GB
- TGCT oncogenesis model
  - Some suggest that GCNIS is present from birth due to a fetal developmental defect and will almost inevitably progress to malignancy (mean onset age 20 - 35) (Ann Oncol 2005;16:863)
  - Others suggest GB may be present at birth or develop later in life, with only a 50% likelihood of malignant transformation (Endocr Rev 2006;27:468)
In an individual with a disorder of sex development (Hum Pathol 2020;100:47)
- Phenotypic girl or women often with masculinization
- Less common: phenotypic men or boys with a spectrum of feminization
  - Genetics
    - 45,X / 46,XY partial gonadal dysgenesis
    - 46,XY complete gonadal dysgenesis
    - 46,XY disorder of sex development
    - One case has been reported in a phenotypic woman with androgen insufficiency syndrome; 46,XY peripheral karyotype
  - Molecular
    - Transcription factors SRY box 9 (SOX9) and forkhead box L2 (FOXL2): needed for male and female mammalian gonadal development, respectively
      - SOX9: visualize testicular differentiation in dysgenetic gonads
      - FOXL2: can visualize ovarian differentiation
      - In gonadoblastoma, the sex cord component expresses FOXL2 but lacks SOX9, suggesting abortative ovarian differentiation
    - Gonadoblastoma susceptibility region on the short arm of the Y chromosome
      - Only oncogenic area on human Y chromosome
      - Increases risk of dysgenetic gonads of XY individuals developing a noninvasive tumor
    - TSPY1
      - May cause germ cells with delayed maturation in an individual with a disorder of sex development to transform into a classical gonadoblastoma
    - Germ cells with delayed maturation express OCT4
- Defect in the genetic pathway responsible for Sertoli cell development results in malformed Sertoli cells; this improper formation leads to delayed maturation of gonocytes in the gonad, increasing their susceptibility to malignant transformation (Int J Gynecol Pathol 2014;33:365)
  - Undifferentiated gonadoblastoma comes from undifferentiated gonadal tissue (UGT) within the dysgenetic gonads of individuals with a sex development disorder (J Clin Endocrinol Metab 2006;91:2404)
    - Undifferentiated gonadal tissue: only seen in dysgenetic gonads of someone with a Y chromosome or a part of a Y chromosome and a sex development disorder
    - Proposed as the precursor of classical gonadoblastoma (J Clin Endocrinol Metab 2006;91:2404)
Gonadoblastoma in individuals with normal peripheral karyotype and no sex development disorder
- No explanation in the literature

Etiology

Germline or acquired mutations in the genes WT1 (Denys-Drash syndrome, Frasier syndrome) and SRY (Swyer syndrome)
Must have the GBY region of the Y chromosome, including the candidate TSPY1 gene, in gonadal tissue

Diagrams / tables

Images hosted on other servers:

Gonadoblastoma from UGT

Risk of developing a germ cell tumor

Clinical features

~80% are phenotypic females with subtle abnormalities in sexual development; cases with pure gonadal dysgenesis can be completely normal females
- Patients with clitoromegaly, abnormal hirsutism, etc. are candidates for karyotype analysis to exclude intersex disorders
~20% are phenotypic males with gynecomastia, hypospadias, cryptorchidism; usually 46,XY or 45,X / 46,XY
~33% have bilateral gonadoblastoma
Commonly associated with primary amenorrhea, developmental delay of genitalia and secondary sexual characters
50% have abdominal mass with malignant transformation into seminoma or with metastatic disease
Gonadoblastoma not identified during neonatal period may go undetected until puberty when patients present with primary amenorrhea
Features of intersex disorders
- Presence of inguinal hernia in phenotypically female neonates associated with male pseudohermaphrodites in 1.6%
Patients with complete androgen insensitivity / male pseudohermaphroditism not diagnosed during neonatal period usually go unnoticed until puberty
- Normal breast development but secondary sexual characters like pubic and axillary hair growth are rudimentary; vagina may be hypoplastic
Patients with mixed gonadal dysgenesis (45,XO / 46,XY) have
- Ambiguous genitalia with varying degrees of phallic enlargement
- Undescended testis
- Urogenital sinus with labioscrotal fusion
- Nearly all have a uterus, vagina and fallopian tubes in addition to an ovary / streak and a contralateral testicle
- 50% are short and ~33% appear similar to individuals with Turner syndrome

Diagnosis

Imaging is not helpful in identifying premalignant lesions; ultrasound (US) and MRI are used to localize gonads in DSD (J Pediatr Adolesc Gynecol 2016;29:577)
Often diagnosed at birth
Discovered incidentally during gonadectomy for individuals with DSD (BMC Pediatr 2019;19:143)
Consultation with a geneticist required to calculate risk of developing a gonadoblastoma in individuals with DSD (Am J Med Genet C Semin Med Genet 2017;175:304)

Laboratory

Karyotyping is most important investigation for identifying those with intersex disorders who are at increased risk of developing gonadoblastoma; may have abnormalities in serum electrolytes, may be life threatening
Hormonal evaluation is necessary to rule out other causes of abnormal sexual development and to plan hormonal replacement

Radiology description

Usually microscopic and unable to be seen on imaging
Ovaries with gonadoblastoma typically appear as solid tumors in the lower abdomen on US and CT imaging when macroscopically evident (Cancer Imaging 2009;9:1)

Radiology images

Images hosted on other servers:

CT, abdominal mass, gonadoblastoma

Prognostic factors

Delayed gonadal development and oncologic risk (Am J Med Genet C Semin Med Genet 2017;175:304)
- Genetic disorders, including both DSDs and syndromes such as trisomy 21, can lead to delayed gonadal development and a prolonged immature gonocyte state, which increases oncologic transformation risk (Hum Pathol 2006;37:101)
One study lists a 50% chance of malignant transformation often due to dysgerminoma (Klin Padiatr 2012;224:359)
- Presence of Y chromosome material appears to be related to risk of malignant transformation
Other studies say the rate of malignant transformation of a gonadoblastoma to an invasive tumor is unknown (Klin Padiatr 2012;224:359)

Case reports

11 year old patient diagnosed with a mosaic Turner syndrome karyotype (Ecancermedicalscience 2023;17:1613)
14 year old girl presented with an uncommon cause of virilization due to a virilizing ovarian tumor (J Clin Res Pediatr Endocrinol 2024 Oct 10 [Epub ahead of print])
15 year old phenotypic female presented with primary amenorrhea (Mol Genet Genomic Med 2023;11:e2300)
21 year old woman with a rare case of ovarian gonadoblastoma flourishing into malignant mixed germ cell tumor with review of literature (Int Cancer Conf J 2022;11:114)
21 year old woman presented with primary amenorrhea (Exp Ther Med 2024;28:358)

Treatment

Gonadectomy
- Decision making in gonadectomy (Am J Med Genet C Semin Med Genet 2017;175:304)
  - Gonadectomy decisions in patients with DSD are based on factors including gender identity, gonadal germ cell tumor (GCT) risk and future fertility considerations
  - Optimal decision making involves an interdisciplinary team, ideally composed of geneticists, endocrinologists, behavioral health specialists and urologists (J Pediatr Urol 2012;8:7)
- Benefits of gonadectomy
  - Reduces risk of gonadal GCTs
  - Allows control or reduction of endogenous sex hormone production if misaligned with gender identity
- Benefits of gonadal retention
  - Maintains endogenous hormone production, supporting congruence with gender identity
  - Preserves potential fertility for future family planning
  - Allows decision making to be deferred until the patient can provide informed assent or consent
- Risk assessment parameters
  - Chromosomal complement
    - Presence of Y chromosome material increases GCT risk
  - Gonadal pathology
    - Evaluation through biopsy or gonadectomy may be required to assess tumor risk
  - Genital and reproductive phenotype
    - Physical characteristics of the genitals and reproductive organs are considered
  - Endocrine profile
    - Hormonal status and potential impact on health and gender identity
  - Medical comorbidities
    - Includes risks related to syndromic features, such as adrenal insufficiency or increased risk for cancers in other organs
  - Molecular biology knowledge
    - Understanding the relationship between molecular etiology and GCT risk is essential for risk assessment and treatment planning in DSD

Clinical images

Not relevant

Gross description

Been described as soft, fleshy, firm and cartilaginous, flecked with granules of calcification or almost totally calcified (Cancer 1970;25:1340)

Gross images

Images hosted on other servers:

Gonadoblastoma and dysgerminoma in gonadal dysgenesis

Frozen section description

During an intraoperative consultation, there is a report of using a touch prep to identify a gonadoblastoma (Diagn Cytopathol 2011;39:42)
Otherwise no major role in diagnosing a gonadoblastoma

Frozen section images

Not relevant

Microscopic (histologic) description

Essential WHO diagnostic criteria
- Nested to corded arrangement of germ cells and small sex cord cells with deposits of basement membrane material
Desirable WHO diagnostic criteria
- Frequent background of DSD
- Typical immunophenotype
- Marker positivity for germ cell and sex cord stromal tumors
Features
- Round nests and cords composed of germ cells, small sex cord cells and globoid deposits of hyaline basement membrane material in variable proportions
- Germ cells
  - Large nuclei
  - One or more prominent nucleoli
  - Pale / clear cytoplasm
  - May resemble
    - GCNIS cells
    - Seminoma / dysgerminoma cells
    - Spermatogonia
  - Scattered between sex cord cells
- Sex cord cells
  - Nuclei
    - Angulated
    - Sometimes grooved
  - Similar to Sertoli cells
  - May have Charcot-Böttcher crystals (Cancer 1976;37:1770)
  - May form palisades at the edge of nests
  - May rosette around basement membrane deposits
  - May form circular arrays around germ cells
- Basement membrane material
  - Often develops laminated calcifications like psammoma bodies
    - May coalesce to make mulberry-like structures
    - Rarely, may be so numerous that they obliterate the cellular detail (burn out or regressed gonadoblastoma)
- Scattered Leydig-like cells may be seen in nearby gonadal stroma
- Morphologic features of undifferentiated gonadal tissue can overlap with what is called by Scully a dissecting gonadoblastoma (Am J Surg Pathol 2016;40:1417)
  - Present in ~75% of cases
  - Neoplastic cells here form a cord-like pattern
WHO classification system
- Tumors of the testis
  - Germ cell tumors derived from germ cell neoplasia in situ
    - Noninvasive germ cell neoplasia
      - Gonadoblastoma
  - Germ cell tumors unrelated to germ cell neoplasia in situ
  - Sex cord stromal tumors of the testis
- See also Gonadoblastoma of the ovary

Microscopic (histologic) images

Contributed by Brandon Douglas Metcalf, M.D.

Calcifications and tumor cell nests

Tumor cell nest

Sex cord stromal cells

Seminomatous germ cells

OCT 3/4

SALL4

Inhibin

FOXL2

Virtual slides

Images hosted on other servers:

Ovary, gonadoblastoma

Cytology description

N/A

Cytology images

Not relevant

Immunofluorescence description

Not relevant

Immunofluorescence images

Not relevant

Positive stains

In germ cells (Int J Pediatr Endocrinol 2015;2015:14)
In sex cord cells
- Inhibin
- Nuclear SOX9 (weak)
- FOXL2 (strong)
- SF1 (Int Cancer Conf J 2022;11:114)
In Leydig cells
- Inhibin
- Calretinin
Stromal cells of gonadoblastoma
- Androgen receptor (Am J Clin Pathol 2023;160:S53)

Negative stains

Gonadal sex cord cells
- SOX9 (J Pathol 2008;215:31)
Stromal cells of gonadoblastoma
- Estrogen receptor (Am J Clin Pathol 2023;160:S53)

Electron microscopy description

Tumor composition (Cancer 1976;37:1770)
- Gonadoblastoma is organized into well defined nests containing large germ cells and smaller Sertoli cells
- Surrounding stroma contains Leydig cells, which are endocrinologically active
Germ cells
- Large, pale cells with minimal organelles, round or ovoid nuclei lacking peripheral heterochromatin and prominent nucleoli
- Sparse mitochondria with underdeveloped cristae, along with abundant ribosomes and glycogen granules
- Occasional desmosomal contacts with Sertoli cells, indicative of some cellular interaction
Sertoli cells
- Smaller, polygonal cells with irregular, infolded nuclei, prominent nucleoli and peripheral heterochromatin
- Contain Charcot-Böttcher crystalloids, suggesting a Sertoli cell origin and tonofilament bundles attached to desmosomes
- Some cells exhibit features associated with steroid activity, such as delta 5-3 beta hydroxysteroid dehydrogenase reactivity around lipid droplets and lysosomes
Basal laminae and hyaline bodies
- Multilayered basal laminae around tumor nests and in hyaline bodies mimic the structure of adult testicular seminiferous tubules
- Hyaline bodies exhibit a spiral, multilayered architecture with occasional cell debris, collagen fibers and calcium deposits, likely derived from surrounding stroma
Leydig cells
- Found within the stroma and display a range from poorly differentiated fibroblast-like forms to mature cells
- Well differentiated cells contain round mitochondria, lipid droplets and lysosomes, indicative of steroid production capacity

Electron microscopy images

Images hosted on other servers:

Sertoli cells

Germ cells

Gonadoblastoma and Leydig cells

Leydig cells

Molecular / cytogenetics description

FISH: Y chromosome in tissues or other materials such as urine of phenotypically female patients (Pediatr Dev Pathol 2019;22:380)
- FISH and the inclusion of buccal cells in genetic investigations should be part of the diagnostic workup for TS
- Helps in detecting mosaicism that could affect treatment and genetic counseling, especially with respect to the risk of gonadoblastoma (J Hum Reprod Sci 2023;16:286)

Molecular / cytogenetics images

Images hosted on other servers:

Karyotype, mosaic of 45,X / 46,XY

Videos

Gonadoblastoma and digital pathology by Lewis Hassell, M.D.

Laparoscopic gonadectomy

Classification of ovarian lesions

Sample pathology report

Left testis, resection:
- Testicular gonadoblastoma; no invasive germ cell tumor or sex cord tumor present (see comment)
- Comment: The left testis shows tumor in nested pattern composed of large round immature germ cells (confirmed by positive OCT 3/4 and SALL4) intermingled with oval shaped sex cord stromal cells forming tubular structures (confirmed by positive staining for inhibin, calretinin and FOXL2). These findings are consistent with a gonadoblastoma. The foci of gonadoblastoma are separated by fibrotic septa. Multiple foci of calcifications are noted in the gonadoblastoma. No invasive germ cell tumors or sex cord tumors are identified, therefore the foci of gonadoblastoma are essentially considered as in situ neoplasm.

Differential diagnosis

Fetal gonadoblastoid testicular dysplasia:
- In fetuses and neonates
- Not associated with intersexual states or gonadodysgenesis (Pediatr Dev Pathol 2007;10:274)
Sertoli cell nodules colonized by GNIS (Histopathology 2014;65:861):
- In postpubertal patients
- Sertoli cell nodules
  - FOXL2 negative
  - SOX9 strongly positive
Mixed germ cell sex cord stromal tumor (Pathol Res Pract 2020;216:153198):
- Not associated with gonadal dysgenesis
- Lacks calcification or hyalinization

Additional references

WHO Classification of Tumours Editorial Board: Urinary and Male Genital Tumours, 5th Edition, 2022, Diagn Cytopathol 2019;47:1203, Int J Gynecol Pathol 1989;8:72

Board review style question #1

A 14 year old phenotypic girl presents to the clinic for amenorrhea. Genetic testing results in a diagnosis of turner syndrome with a mosaic of 45,X / 46,XY. An MRI reveals a normal right ovary and a left ovary was not identified. An elective laparoscopic gonadectomy was performed, a streak gonad was identified in the left adnexal space. The streak gonad and right ovary were excised. Permanent H&Es were obtained and the following pathologies were identified in the image above. What immunostain would help you distinguish the entity seen in the picture above from a Sertoli nodule colonized by GCNIS and how does that immunostain stain in this entity?

FOXL2, negative
FOXL2, positive
KIT (CD117), negative
SOX9, positive

Board review style answer #1

A. FOXL2, negative. FOXL2 stains negative in gonadoblastoma. Answer B is incorrect because FOXL2 is positive in Sertoli nodules. Answer D is incorrect because SOX9 is negative in gonadoblastoma. Answer C is incorrect because KIT is positive in gonadoblastoma.

Comment Here

Reference: Gonadoblastoma

Board review style question #2

Gonadoblastoma are most often associated with

Disorders of sex development
Glioblastomas
Neuroblastomas
Smoking

Board review style answer #2

A. Disorders of sex development. Generally, processes that interfere with germ cell development increase the risk of producing a gonadoblastoma, which arises from germ cells that are arrested in development. Answer D is incorrect because gonadoblastoma are generally related to a genetic process that disrupts the normal physiological development of germ cells. Answer B is incorrect because glioblastomas are malignant brain tumors with no direct link to reproductive organs or genetics causing gonadoblastoma. Answer C is incorrect because neuroblastomas develop from immature nerve cells and are not related to glioblastomas.

Comment Here

Reference: Gonadoblastoma

Gonadoblastoma

Table of Contents

Definition / general

Rare benign gonadal tumor composed of germ cells and sex cord stromal derivatives resembling immature granulosa cells and Sertoli cells

Terminology

First described by Scully (Cancer 1953;6:455, Cancer 1970;25:1340)
Resembles normal developing gonad (hence the name)

Epidemiology

Most cases occur within first 2 decades; nearly 94% by age 30
Those with with partial dysgenesis / mosaicism are diagnosed prior to puberty; those with complete androgen insensitivity are diagnosed after puberty
Almost always associated with disorders of sex development
~10% with dysgenetic gonads develop gonadoblastoma / seminoma by age 10 (Obstet Gynecol Surv 1986;41:74)
~25% with mixed gonadal dysgenesis and Y component develop gonadoblastoma and germ cell tumor by age 40 (Am J Obstet Gynecol 1976;124:293)

Sites

Usually abdominal / inguinal undescended gonads / testis
May occur in ovaries of phenotypically and genetically normal females (see ovary tumor chapter)

Pathophysiology and etiology

Disorders of sexual development (DSD) clearly associated with increased risk of gonadoblastoma include:

Complete androgen insensitivity (46,XY) (30 - 66% incidence)
Pure gonadal dysgenesis / Swyer syndrome (46,XY)
Mixed gonadal dysgenesis (45,X / 46,XY) (55% incidence)
Turner syndrome (45,XO) with XY mosaicism
- Molecular presence of Y chromosome (6 - 9% incidence) results in 43% incidence of gonadoblastoma
Frasier syndrome (rare 46,XY DSD caused by mutation in WT1 gene)
Maternal exposure to androgens, drugs, alcohol or illness during first trimester is associated with gonadal dysgenesis and intersex disorders; however, association with gonadoblastoma development is not established

Clinical features

~80% are phenotypic females with subtle abnormalities in sexual development; cases with pure gonadal dysgenesis can be completely normal females
- Patients with clitoromegally, abnormal hirsutism, etc. are candidates for karyotype analysis to exclude intersex disorders
~20% are phenotypic males with gynecomastia, hypospadias, cryptorchidism; usually 46XY or 45X / 46XY
1/3 have bilateral gonadoblastoma
Commonly associated with primary amenorrhea, developmental delay of genitalia and secondary sexual characters
50% have abdominal mass with malignant transformation into seminoma or with metastatic disease
Gonadoblastoma not identified during neonatal period may go undetected until puberty when patients present with primary amenorrhea
Features of intersex disorders:
- Presence of inguinal hernia in phenotypically female neonates associated with male pseudohermaphrodites in 1.6%
Bimanual abdominal palpation can be used to confirm presence of uterus in initial few days of neonatal life (due to effects of maternal hCG)
Patients with complete androgen insensitivity / male pseudohermaphroditism not diagnosed during neonatal period usually go unnoticed until puberty
- Normal breast development but secondary sexual characters like pubic and axillary hair growth are rudimentary; vagina may be hypoplastic
Patients with mixed gonadal dysgenesis (45XO / 46XY) have
- Ambiguous genitalia with varying degrees of phallic enlargement
- Undescended testis
- Urogenital sinus with labioscrotal fusion
- Nearly all have a uterus, vagina and fallopian tubes in addition to an ovary / streak and a contralateral testicle
- 50% are short and ~33% appear similar to individuals with Turner syndrome

Laboratory

Karyotyping is most important investigation for identifying those with intersex disorders who are at increased risk of developing gonadoblastoma
May have abnormalities in serum electrolytes, may be life threatening
Hormonal evaluation is necessary to rule out other causes of abnormal sexual development and to plan hormonal replacement

Prognostic factors

Excellent prognosis prior to malignant transformation, with no deaths reported
30% of patients have malignant germ cell tumor in dysgenetic or contralateral gonad
Cure rates > 80% have been reported, including those with seminomatous overgrowth or metastases

Case reports

10 year old girl, Turner mosaic with Y chromosome material identified by restriction fragment analysis and unilateral microscopic gonadoblastoma (Am J Clin Pathol 1988;90:622)
12 year old girl with minute Y chromosome derived marker (J Med Genet 1992;29:542)

Treatment

Some cases undergo spontaneous involution
Treatment of choice is excision of gonadoblastoma and dysgenetic gonads prior to neoplastic transformation; however, timing of surgery varies with underlying disorder of sexual development
- For mixed gonadal dysgenesis and mosaicism, surgery recommended before puberty, as early as possible
- For complete androgen insensitivity (pure gonadal dysgenesis), surgery recommended after completion of puberty but before age 20:
  - Allows development of female breast by peripheral conversion of testosterone by aromatase into estrogens
  - Incidence of gonadoblastoma or other germ cell tumors before age 20 is negligible in these patients
  - Patients are usually diagnosed at puberty when they present with primary amenorrhea

Gross description

Tumor size varies from microscopic to 8 cm
Yellow to tan nodules with gritty cut surface
No hemorrhage or necrosis unless transformation to malignant germ cell tumor

Gross images

Images hosted on other servers:

Gonadoblastoma and dysgerminoma in gonadal dysgenesis

Microscopic (histologic) description

Three growth patterns
1. Most common: round / irregular clusters of immature Sertoli cells and germ cells surrounded by basement membranes, with Sertoli cells encircling rounded hyaline nodules
2. Sertoli cells surround large germ cells
3. Germ cells occupy center of nests with peripheral ring of Sertoli cells
Stroma may contain large polygonal cells indistinguishable from Leydig cells: common in postpubertal patients
Calcification common: may be focal involving hyaline bodies or extensive
50% have coexisting or subsequent seminoma
8 - 10% develop other germ cell malignancies (Am J Obstet Gynecol 1972;113:410)

Microscopic (histologic) images

Images hosted on other servers:

Gonadoblastoma

Female patient

Positive stains

Germ cells express p53 (Mod Pathol 1997;10:1101), PLAP, CD117 / c-kit, VASA protein (Lab Invest 2002;82:159), testis specific Y protein encoded (Cytogenet Cell Genet 2000;91:160)
Stromal cells express inhibin, WT1

Electron microscopy description

Some cells show Charcot-Böttcher filaments of Sertoli cells

Molecular / cytogenetics description

Germ cells are aneuploid (Histopathology 1997;30:177)
Tsuchiya identified gonadoblastoma locus near Y centromere; TSPY gene is most likely candidate
- TSPY is expressed in adult spermatogonia and fetal gonocytes and has vital functions in male stem / germ cell proliferation
- It is ectopically expressed in gonadoblastoma, seminoma, ITGCN, some nonseminomatous germ cell tumors
- TSPY expression correlates with PLAP, c-kit, OCT3 / 4
Seminomas and nonseminomatous tumors arising within dysgenetic gonad are usually diploid, unlike those arising from normal gonad (Genes Chromosomes Cancer 1999;25:134, Cancer Genet Cytogenet 1991;57:219, Cancer Res 1998;58:3105)

Differential diagnosis

Sertoli cell tumor with nodules with entrapped germ cells in a may be mistaken for a gonadoblastoma

Additional references

eMedicine: Gonadoblastoma, Hum Pathol 1986;17:531

Granulomatous lesions of testis and paratestis

Table of Contents

Definition / general

Rare; usually men 40 - 59 years with sudden onset of tender testicular mass, variable fever
May be a response to acid fast products of disintegrated sperm, postinfectious or due to trauma or sarcoidosis
Resembles pyogenic epididymo-orchitis
Benign, although granulomatous inflammation may be associated with seminoma
Recommend cultures to rule out infectious process (brucellosis, leprosy, sarcoidosis, syphilis, TB)
Granulomatous ischemic lesion
- Usually affects head of epididymis
- May be due to ischemia with secondary granulomatous reaction and scarring
Gross description
- Solid, unilateral nodular enlargement of testis; resembles lymphoma
Microscopic (histologic) description
- Lymphocytes and plasma cells infiltrate interstitium and surround seminiferous tubules
- Giant cells and histiocytes that resemble (but are not) actual granulomas
- Granulomatous ischemic lesion
  - Zone of necrosis involving efferent ducts and interstitial connective tissue, with adjacent lymphocytes and macrophages
  - Macrophages form large clusters with cholesterol crystals and foreign body type giant cells in duct lumen
  - Also intratubular epithelial regeneration and proliferation of small ducts showing epithelial regeneration and numerous spermatozoa in their lumen
  - Associated with ceroid granuloma, spermatic granuloma and epidermoid metaplasia of the efferent ducts
Reference: Am J Surg Pathol 1997;21:951

Infectious causes

AIDS

Associated with markedly reduced spermatogenesis, arrested maturation, germ cell aplasia, tubular hyalinization / thickening of basement membranes, interstitial inflammation and fibrosis, reduction in Leydig cells, Sertoli cell only pattern (J Pathol 1991;163:47, Urology 1999;53:203, Mod Pathol 1989;2:233, Hum Pathol 1989;20:210)
Often other infections in testis or epididymis (Candida, CMV, Histoplasma, mycobacteria, toxoplasmosis)
Testicular atrophy related findings do not appear to be immune mediated (Hum Pathol 1989;20:572)
Testis is an uncommon location for Kaposi sarcoma in AIDS patients

Brucellosis

Zoonotic infection acquired from sheep, camels, cattle, dogs, goats, reindeer, swine via skin / mucous membrane contact or contaminated animal products
Affects testis and epididymis (epididymo-orchitis) in 2 - 20% of cases, causing scrotal pain, swelling, fever
Often diagnosed by laboratory studies
Case report: 32 year old man with painless testicular mass-brucellosis (Int J Urol 2004;11:683)
Micro description: granulomatous or testicular abscess
Treatment: antibiotics; orchiectomy if resembles a neoplasm or refractory to therapy
Additional references: Urol Int 2009;82:158, BMC Res Notes 2011;4:286, Clin Infect Dis 2001;33:2017

E. coli related pyogenic epididymo-orchitis

Usually due to E. coli
Resembles granulomatous orchitis
Complications: venous thrombosis, septic testicular infarct

Gonorrhea

Usually spreads from posterior urethra to prostate, seminal vesicles and epididymis
Testis involved only if untreated

Histoplasma capsulatum

Rarely presents as testicular mass
May resemble sperm granuloma (J Clin Pathol 1974;27:929)
Caseating granulomatous inflammation with giant cells
Small yeast forms (2 - 5 micrometers) are identifiable by silver stain (J Urol 2000;164:1652)

Leprosy

Does not occur in U.S.
Rarely presents with orchitis (Am J Clin Pathol 1980;73:712)
Testicular involvement thought to be facilitated by lower temperature of scrotum
3 phases of testicular involvement
1. Vascular phase: blood vessels show perivascular lymphocytic inflammation and interstitium is filled with macrophages containing mycobacteria
2. Interstitial phase: endarteritis, Leydig cell clusters, interstitial fibrosis, histiocytes containing acid fast bacteria and reduced spermatogenesis
3. Obliterative phase: dense fibrosis, no detectable tubules, reduced vessels, rare acid fast bacteria; associated with gynecomastia and infertility

Mumps

Testicular infections rare in infected children (prepubertal) but occur in 15 - 40% of postpubertal men one week after parotiditis
Usually unilateral (bilateral in 15 - 30%); epididymitis is also common (85%) and often precedes orchitis
33% of infected postpubertal men develop testicular atrophy, 2 - 10% become infertile
Incidence increasing, due to reduced use of vaccine (BJU Int 2010;105:1060)

Syphilis

Testis usually involved first
Discrete gummas contribute to enlarged, irregular testis
Gummas: diffuse interstitial inflammation with edema, lymphocytes and plasma cells, with obliterative endarteritis and perivascular cuffing
Spirochetes usually identified in gummatous but not fibromatous stages

Tuberculosis

Usually begins in epididymis and spreads to testis
Prostate and seminal vesicles are usually also infected

BCG therapy

[Pending]

Sperm granuloma

[Pending]

Malakoplakia

[Pending]

Sarcoidosis

[Pending]

Iatrogenic (injectables)

[Pending]

Nonspecific / unknown cause

[Pending]

Gross images

Contributed by Yale Rosen, M.D. and @SueEPig on Twitter

TB orchitis

Granulomatous orchitis

Images hosted on other servers:

Brucellosis

Microscopic (histologic) images

Contributed by Sean R. Williamson, M.D. and @SueEPig on Twitter

Tuberculosis involving testis and paratestis

Granulomatous orchitis

Differential diagnosis

Granulomatous inflammation associated with seminoma
Infection or inflammation (Hum Pathol 1990;21:1080)
Lymphoma

Grossing and features to report

Table of Contents

Definition / general | Features to report (pending)

Definition / general

Spermatic cord margin (sample before cut into tumor since contamination is a common problem) (Mod Pathol 1996;9:762)
Tumor (1 - 2 section per cm, representing all grossly different features)
Tumor and tunica
Tumor and hilum (site of extratesticular extension in > 90%) (Am J Clin Pathol 1999;111:534)
Tumor and normal testis
Normal testis
Epididymis

Features to report (pending)

Features to report by organization:

Hernia sac with mesothelial entrapment

Table of Contents

Definition / general

Entrapment of mesothelial cells within hernia sac fibroadipose tissue

Essential features

Small glands, clusters, cords or individual mesothelial cells within the hernia sac
Usually no fat, muscle, stromal invasion or necrosis
Lacks grossly visible proliferation (Virchows Arch A Pathol Anat Histopathol 1989;415:283)

Epidemiology

6% of pediatric hernia sacs contained mesothelial proliferation (J Urol 2011;186:1620)
Mean age in adults is 44.5 years (Am J Surg Pathol 2014;38:54)
Incidence in adults unknown

Pathophysiology

Persistent serosal injury causes reactive hyperplasia of the mesothelial lining and submesothelial fibrosis, entrapping mesothelial cells beneath the mesothelial lined surface (Mod Pathol 2005;18:S131, Diagn Pathol 2011;6:78)

Clinical features

Similar clinical presentation as a patient with a hernia sac without mesothelial entrapment (usually hydrocele, also hematocele, cyst adjacent to epididymis, hemorrhagic epididymal cyst, pyocele) (Am J Surg Pathol 2014;38:54)

Prognostic factors

No aggressive behavior has been reported (Am J Surg Pathol 2014;38:54)

Treatment

Similar treatment as a hernia without mesothelial entrapment, i.e. excision of hernia sac (J Urol 2011;186:1620)

Gross description

No grossly visible proliferation; same findings as hernia sac without mesothelial proliferation (Am J Surg Pathol 2014;38:54)

Microscopic (histologic) description

No surface proliferation; surface often partially or completely denuded (Am J Surg Pathol 2014;38:54)
Mesothelial proliferation within fibrotic stroma (Am J Surg Pathol 2014;38:54)
Widely spaced proliferation of mesothelial cells predominately oriented parallel to the surface mesothelium (Am J Surg Pathol 2014;38:54)
Most commonly form small glands and cords; also small nests and individual appearing cells (Am J Surg Pathol 2014;38:54)
Proliferation has a well defined edge of pseudoinvasion within the fibrous stroma (Am J Surg Pathol 2014;38:54)
Usually does not penetrate into muscle (Semin Diagn Pathol 2003;20:272)
Reactive appearing mesothelial cells with large nuclei and prominent nucleoli (Semin Diagn Pathol 2003;20:272)
No to low mitotic activity (Am J Surg Pathol 2014;38:54)
Background of fibrosis and chronic inflammation (Am J Surg Pathol 2014;38:54)

Microscopic (histologic) images

Contributed by Debra L. Zynger, M.D.

Entrapped glands

Cords, glands and small nests

Gland formation

Entrapped mesothelium

WT1

Calretinin

Positive stains

Keratins, AE1 / AE3
CK7
Mesothelial markers: Calretinin, CAIX, CK5 /6, D2-40, CD141, WT1 (Mod Pathol 2005;18:S131, Diagn Cytopathol 2009;37:748, Virchows Arch 2012;460:89)

Negative stains

p53 (Am J Surg Pathol 2014;38:54)
Ki67 (6% in reactive mesothelial cells) (Am J Surg Pathol 2014;38:54)
GLUT1 (0% - 27% in reactive mesothelial cells) (Am J Surg Pathol 2014;38:54)
CK20, p63, PAX8

Molecular / cytogenetics description

9p21 not deleted (Am J Surg Pathol 2014;38:54)

Differential diagnosis

Mesothelioma
- Grossly visible lesion, usually exophytic in this location (Diagn Pathol 2011;6:78)
- Forms a mass with more tightly packed glands
- True invasion
- Haphazard arrangement of glands rather than in a linear arrangement
- More nuclear atypia and mitotic activity
Adenocarcinoma:
- Forms a mass
- Desmoplastic reaction
- Back to back glands
- Mitotic activity (Mod Pathol 2005;18:S131)
- Mesothelial markers usually negative
Adenomatoid tumor:
- Forms a mass lesion near epididymis
- Positive for mesothelial markers (Semin Diagn Pathol 2003;20:272)
Histiocytic inflammation:
- Keratin negative (Am J Surg Pathol 2014;38:54)

Board review style question #1

Glands parallel to surface
GLUT1 and p53 positivity
Homozygous for 9p21 deletion
Invasion into muscle
Prominent mitotic activity

Board review style answer #1

A. Glands parallel to surface

Comment Here

Reference: Hernia sac with mesothelial entrapment

Board review style question #2

Adenomatoid tumor
Diffuse malignant mesothelioma
Hernia sac with mesothelial entrapment
Histiocytic inflammation
Metastatic adenocarcinoma

Board review style answer #2

C. Hernia sac with mesothelial entrapment

Comment Here

Reference: Hernia sac with mesothelial entrapment

Hydrocele

Table of Contents

Definition / general

Accumulation of serous fluid between visceral and parietal layers of tunica vaginalis

Essential features

Accumulation of serous fluid between visceral and parietal layers of tunica vaginalis
Idiopathic or associated with nonneoplastic or neoplastic lesions
Note: thorough macroscopic examination and extensive sampling are needed to rule out mesothelioma (Singapore Med J 2015;56:e53)

ICD coding

ICD-10: N43.3 - hydrocele, unspecified
ICD-11: GB00 - hydrocele or spermatocele

Epidemiology

Prevalence: 6% children, 1% adult men
Any age
Reference: Acta Medica (Hradec Kralove) 2020;63:57

Sites

Scrotum
Rarely, the hydrocele sac may extend beyond the scrotum to the abdomen via the inguinal canal (abdominoscrotal hydrocele) (Urol Case Rep 2020;32:101254)

Pathophysiology

	Encysted variant	Funicular variant
Persistent communication with the peritoneal cavity	No	Yes
Etiology	Defective closure at both proximal and distal ends of processus vaginalis	Defective closure of the distal end of tunica vaginalis
Macroscopic differential diagnosis	Inguinal lymphadenopathy, hernia, tumor of the spermatic cord

Reference: Acta Radiol 2007;48:1138

Etiology

Mostly idiopathic, putative causes: excessive secretion or decreased reabsorption of fluid by parietal mesothelial cells, congenital lack of efferent lymphatics
Association with inguinal hernia, scrotal trauma, inflammation (epididymoorchitis) or tumors of the testis / paratestis (BJU Int 2011;107:1852)
Filarial hydrocele (StatPearls: Filarial Hydrocele [Accessed 2 February 2023]):
- Late and chronic manifestation of filariasis
- Very common in endemic areas (tropical and subtropical countries)
- Due to parasite induced blockage and dysfunction of the lymphatic vessels

Clinical features

Painless scrotal swelling, feeling of heaviness (BJU Int 2011;107:1852)

Diagnosis

Usually diagnosed by physical examination and transillumination

Radiology description

Simple fluid collection at ultrasound; may contain septations, calcifications or cholesterol (Radiographics 2009;29:2017)
Avascular at Doppler evaluation
MRI: low signal on T1, high signal on T2 weighted images

Radiology images

Images hosted on other servers:

Scrotal MRI: cystic lesion

Encysted hydrocele

Case reports

18 year old man with an asymptomatic palpable mass in the left testis growing into the lower abdomen (Pan Afr Med J 2018;31:213)
63 year old man with giant hemorrhagic hydrocele (Urol Case Rep 2018;18:44)
80 year old man with longstanding hydrocele and eggshell peripheral calcifications (BMJ Case Rep 2020;13:e232827)

Treatment

Spontaneous resolution in most cases
Some cases require surgical treatment
Follow up due to possible recurrences (Cheng: Urologic Surgical Pathology, 4th Edition, 2019)

Gross description

Usually unilocular, can be multicameral (Nistal: Atlas of Peculiar and Common Testicular and Paratesticular Tumors, 1st Edition, 2020)

Gross images

Images hosted on other servers:

Abdominoscrotal hydrocele

Microscopic (histologic) description

Loose connective tissue lined by a single layer of cuboidal or flattened mesothelial cells
Lining may show mesothelial hyperplasia (both solid and papillary), squamous metaplasia or prominent atypia
Usually clear luminal fluid
Fibrinous exudate, chronic inflammatory infiltrate and fibrosis in longstanding cases, due to infection or hemorrhage (Cheng: Urologic Surgical Pathology, 4th Edition, 2019)
Occasional presence of florid nodular collections of histiocytes and aggregates of incidental benign small blue cells of possible rete epithelial origin (Hum Pathol 2010;41:88, Am J Surg Pathol 2016;40:1507)

Microscopic (histologic) images

Contributed by Francesca Sanguedolce, M.D., Ph.D.

Connective tissue, mild inflammation

Fibrosis, moderate inflammation

Mesothelial lining

Calretinin

Positive stains

Calretinin, BAP1, MOC31 (Raspollini: Uropathology, 1st Edition, 2020)
Other mesothelial markers: pancytokeratin, CAM 5.2, WT1, D2-40 (podoplanin)

Sample pathology report

Left testis, hydrocelectomy:
- Hydrocele

Differential diagnosis

Testis tumor:
- Solid mass at transillumination
Mesothelioma:
- Thickened tunica vaginalis and small papillary projections at ultrasound (Arch Pathol Lab Med 2012;136:113)
- Extensive growth in tunica with infiltration into underlying connective tissue; frank cytologic atypia (Hum Pathol 2019;92:48)
- Positive for calretinin and D2-40
- Negative for BAP1 and MOC31
Spermatocele:
- Cystic dilatation of the epididymis, efferent ductule or proximal rete testis
- Negative for mesothelial markers
- Spermatozoa and proteinaceous fluid in the lumen
- Often ciliated epithelial lining

Board review style question #1

Which cell type lines a hydrocele?

Endothelial cells
Germinal cells
Mesothelial cells
Urothelial cells

Board review style answer #1

C. Mesothelial cells. Since hydrocele is defined as an accumulation of serous fluid between visceral and parietal layers of tunica vaginalis, its lining is provided by mesothelial cells.

Comment Here

Reference: Hydrocele

Board review style question #2

Which microscopic findings can occur in a hydrocele?

Acute inflammation, mucinous metaplasia
Chronic inflammation, fibrosis, squamous metaplasia
Clear cell hyperplasia
Psammoma bodies

Board review style answer #2

B. Chronic inflammation, fibrosis, squamous metaplasia. Longstanding hydrocele may be complicated by inflammation and hemorrhage, resulting in abnormal findings involving both the lining cells and the connective tissue.

Comment Here

Reference: Hydrocele

Infertility

Table of Contents

Hypospermatogenesis | Infertility | Maturation arrest

Hypospermatogenesis

Definition / general

All stages of spermatogenesis present but reduced to a varying degree
Includes the mixed pattern with some tubules showing Sertoli cells only or hyaline sclerosis with others tubules containing complete spermatogenesis
Mild if changes in occasional tubules; severe if significant reductions in all tubules, moderate in between
Often is thickening of tunica propria, interstitial fibrosis, tubular sclerosis, germ cell disorganization and sloughing into lumina
Many causes of infertility induce hypospermatogenesis, such as diabetes mellitus, toxins, excess heat, varicocele, hypothyroidism, irradiation and others

Additional references

Arch Pathol Lab Med 1982;106:231, Arch Pathol Lab Med 2010;134:1197

Infertility

Definition / general

Causes: pretesticular, testicular, posttesticular
Pretesticular: extragonadal endocrine disorders (hypothalamic, pituitary, adrenal); includes elevated prolactin levels (Arch Pathol Lab Med 1984;108:35)
Testicular: little treatment currently available
Posttesticular: duct obstruction (congenital, inflammatory, postsurgical); surgical treatment often successful since spermatogenesis is normal
- Impaired sperm motility due to epididymal or immunologic factors is considered posttesticular
Evaluation: history and physical examination, semen analysis, white blood cell count in semen, detection of antisperm antibodies, sperm function tests (cervical mucus interaction, ova penetration, hemizonal assay)
Testicular biopsy is helpful for azoospermia without endocrine abnormalities
RNA binding motif: nuclear immunostain identifies spermatogenesis in biopsies that appear to be Sertoli cell only (Hum Pathol 2001;32:36)

Additional references

Am J Surg Pathol 2001;25:71, Arch Pathol Lab Med 1995;119:722, Arch Pathol Lab Med 2010;134:1197

Maturation arrest

Definition / general

Complete maturation arrest: germ cell maturity ceases at a specific point frequently at primary spermatocyte level; sperm counts usually zero
Incomplete maturation arrest: similar to complete but a few late spermatids are present in a few seminiferous tubules, some prefer the term hypospermatogenesis instead of incomplete maturation arrest; patients are usually oligospermic (Arch Pathol Lab Med 2010;134:1197)
Same etiologies as hypospermatogenesis (diabetes mellitus, toxins, excess heat, varicocele, hypothyroidism, irradiation); also postpubertal gonadotropin deficiency, alkylating agents
Nonzero sperm counts indicate late spermatids are present somewhere in testis, although perhaps not in area biopsied
Patients with early maturation arrest have a greater incidence of genetic anomalies and are more likely to have worse reproductive outcomes than are patients with late maturation arrest (Urology 2012;80:826)

Microscopic (histologic) description

Numerous spermatogonia, few spermatocytes, no mature spermatozoa
Sertoli cells prominent since reduced germ cells
Tubules often contain degenerated cells with irregular dense nuclei

Microscopic (histologic) images

Contributed by Asmaa Gaber Abdou, M.D.

Various images

Inflammatory pseudotumor

Table of Contents

Definition / general

Synonyms: chronic proliferative periorchitis, inflammatory pseudotumor, nodular and diffuse fibrous proliferation, paratesticular fibrous pseudotumor
Ages 7 - 95 years, peaks in 20's
Reactive fibrous mass, usually between testicular tunica layers; also involves epididymis and spermatic cord, associated with hydrocele, infection, trauma (Am J Surg Pathol 2010;34:569)
Some cases may be type of IgG4 associated sclerosing disease (Virchows Arch 2011;458:109, Hum Pathol 2012;43:2084)

Case reports

22 year old man with collagen rich stromal tumor attached to testicular tunica albuginea (Hum Pathol 1990;21:866)

Treatment

Excision

Gross description

Multinodular thickening of peritesticular tissue or discrete mass of firm white tissue up to 15 cm
May be an associated hydrocele or hematocele

Microscopic (histologic) description

Dense fibrous tissue, fibroblasts, inflammatory cells, dystrophic calcification
With time, cellularity decreases and fibrosis increases
Usually no necrosis, no pleomorphism, no / rare mitotic activity (Am J Surg Pathol 2010;34:569)

Positive stains

Smooth muscle actin (myofibroblasts); variable keratin

Negative stains

Usually ALK1-, suggesting it is unrelated to inflammatory myofibroblastic tumor of other sites
Beta catenin-, in contrast to fibromatosis
Low Ki67 proliferative index (Am J Surg Pathol 2010;34:569)

Differential diagnosis

Fibromatosis (beta catenin+)
Leiomyoma
Spindle cell mesothelioma

Intratubular large cell hyalinizing Sertoli cell neoplasia (ITLCHSCN)

Table of Contents

Definition / general

Sex cord stromal tumor of the testis that is composed of an intratubular neoplastic proliferation of large Sertoli cells and prominent basement membrane deposits; occurs almost exclusively in patients with Peutz-Jeghers syndrome (PJS)

Essential features

Benign, multifocal and often bilateral testicular lesion
Found in prepubertal male patients, usually associated with gynecomastia
Associated with Peutz-Jeghers syndrome

Terminology

Preferred: intratubular large cell hyalinizing Sertoli cell neoplasia
Accepted: intratubular large cell hyalinizing Sertoli cell neoplasia or intratubular large cell hyalinizing Sertoli cell tumor
Historically: sex cord tumor with annular tubules (not recommended)

ICD coding

ICD-O: 8643/1 - intratubular large cell hyalinizing Sertoli cell neoplasia
ICD-10: D29.20 - benign neoplasm of unspecified testis: Sertoli cell tumor
ICD-11: 2F34 - benign neoplasm of male genital organs: Sertoli cell tumor, unspecified site, male

Epidemiology

Male patients
Age: most are prepubertal
Due to its strong relationship with Peutz-Jeghers syndrome, intratubular large cell hyalinizing Sertoli cell neoplasia (ITLCHSCN) is now allocated within the Genetic Tumor Syndromes chapter of the 5th edition of the WHO Classification of the Urinary and Male Genital Tumours

Sites

Seminiferous tubules

Pathophysiology

Unknown

Etiology

STK11 mutations seen in Peutz-Jeghers syndrome predispose to proliferation (Hum Mutat 2005;26:513, Fam Cancer 2018;17:421, Digestion 2023;104:335)

Clinical features

Bilateral testicular enlargement without a distinct mass (Am J Surg Pathol 2007;31:827)
Hallmarks of increased estrogenic levels (Am J Surg Pathol 2007;31:827, Virchows Arch 2024;484:723)
- Bilateral gynecomastia
- Advanced bone age
Other manifestations of Peutz-Jeghers syndrome

Diagnosis

Testis biopsy or orchiectomy; microscopic diagnosis (Am J Surg Pathol 2007;31:827)

Laboratory

Increased estradiol level (Am J Surg Pathol 2007;31:827)

Radiology description

In situ disease not identified by imaging, except sometimes by ultrasound (Semin Diagn Pathol 2014;31:323)
Ultrasonographic findings (Am J Surg Pathol 2001;25:1237, Am J Surg Pathol 2007;31:827, Semin Diagn Pathol 2014;31:323)
- Bilateral, multiple small areas of echogenicity
- Microscopic calcifications
Can be followed by ultrasound for invasion (Am J Surg Pathol 2007;31:827, Semin Diagn Pathol 2014;31:323)

Prognostic factors

Considered a benign condition; unknown what makes rare cases invasive (Am J Surg Pathol 2007;31:827, Virchows Arch 2024;484:723)

Case reports

4 year old Native American boy with increased serum estrogens, gynecomastia and advanced bone age (J Pediatr Hematol Oncol 2015;37:e184)
4 year old boy with gynecomastia, increased serum estrogens and advanced bone age (N Engl J Med 1991;324:317)
4 - 13 year old boys with Peutz-Jeghers syndrome and gynecomastia (Am J Surg Pathol 2007;31:827)
6 year old boy with increased serum estrogen (first recorded case) (Cancer 1980;46:223)
7 year old boy with left gynecomastia, bilateral testicular enlargement and increased levels of estradiol and inhibin A (Pathology 2020;52:712)
8 year old boy with gynecomastia, advanced bone age, increased growth velocity and increased testicular volume (Acta Clin Belg 2017;72:254)

Treatment

Aromatase inhibitors to suppress the excess of estrogen secondary to high levels of aromatase (Am J Surg Pathol 2007;31:827, Virchows Arch 2024;484:723)
Conservative management with follow up by ultrasound examination (Am J Surg Pathol 2007;31:827)
Orchiectomy in cases with refractory hyperestrogenism (Am J Surg Pathol 2007;31:827)

Gross description

Small scattered solid white foci or areas of ill defined nodularity

Microscopic (histologic) description

Patchy, intratubular growth pattern (Am J Surg Pathol 2007;31:827)
Expanded seminiferous tubules, 2 - 4x the normal size (Am J Surg Pathol 2007;31:827)
Proliferation of enlarged Sertoli cells (Am J Surg Pathol 2007;31:827)
- Abundant cytoplasm, pale to eosinophilic, often vacuolated
- Uniform nuclei, round to oval
- Fine chromatin
- Small to medium nucleoli
Thickened peritubular basement membrane (Am J Surg Pathol 2007;31:827)
Projections of basement membrane forming intratubular globular eosinophilic deposits (Am J Surg Pathol 2007;31:827)
Spermatogonia not present (Am J Surg Pathol 2007;31:827)
Rare, small focal calcifications in basement membrane deposits (Am J Surg Pathol 2007;31:827)
No mitotic figures (Am J Surg Pathol 2007;31:827)
Nonneoplastic tubules with prepubertal histological features (Am J Surg Pathol 2007;31:827)

Microscopic (histologic) images

Contributed by Vikas Mehta, M.D.

Seminiferous tubules

Basement membrane deposition

Calretinin

Inhibin A

Collagen IV

PAS

Positive stains

Tumor cells (J Clin Endocrinol Metab 2013;98:E1979, Pathol Int 2005;55:366)
- Inhibin A
- Aromatase
- Calretinin
- MelanA
- Cytokeratin (AE1 / AE3)
Basement membrane (Am J Surg Pathol 2007;31:827, Virchows Arch 2024;484:723)
- Collagen IV
- Laminin
- PAS

Negative stains

Not well studied in literature

Molecular / cytogenetics description

STK11 mutations in nearly 100% of cases (Hum Mutat 2005;26:513, Am J Surg Pathol 2007;31:827, Fam Cancer 2018;17:421)

Sample pathology report

Testis, right, core needle biopsy:
- Intratubular large cell hyalinizing Sertoli cell neoplasia (see comment)
- Comment: The expanded clusters of seminiferous tubules composed of large Sertoli cells showed strong cytoplasmic reactivity to sex cord markers (inhibin A) and cytokeratins (AE1 / AE3), whereas the distinct thickened peritubular basement membrane and intratubular membrane deposits were highlighted by collagen IV immunohistochemical stain. Nonneoplastic germinal tubules exhibit a prepubertal morphological appearance. Evidence of invasion is not identified.

Differential diagnosis

Large cell calcifying Sertoli cell tumor (Hum Pathol 2010;41:552, Diagnostic Histopathology 2019;25:398, Histopathology 2022;80:677, Histopathology 2023;82:1079):
- Associated with Carney complex and mutations of the PRKAR1A gene
- Multinodular growth pattern
- Large epithelioid Sertoli tumor cells in cords, nests, sheets or solid tubules
- Larger and easily identifiable intra or extratubular calcifications
- Prominent neutrophilic infiltrate
- Variable myxoid or fibrous stroma
- Loss of cytoplasmic PRKAR1A expression by immunohistochemistry
- Charcot-Böttcher filaments (Sertoli cell specific) seen by electron microscopy
- High grade atypia, increased mitotic activity, necrosis, invasion and extratesticular extension may be seen in malignant tumors
Sertoli cell nodules / adenoma (Diagnostic Histopathology 2019;25:398):
- Associated with cryptorchid testes
- Microscopic (< 1 cm), rarely mass forming
- Patchy, intratubular growth pattern
- Nonneoplastic immature Sertoli cells
- May present deposits of globular basement membrane
- Spermatogonia present
- No stromal invasion
Gonadoblastoma (Histopathology 2018;72:545, Hum Pathol 2020;100:47):
- Associated with dysgenetic gonads in cases with disorders of sex development
- Mixture of germ cells and immature sex cord cells
- Tumor cells arranged in round islands or nests
- Globular eosinophilic basement membrane deposits
- Frequent calcifications
- Variable cellular stroma
- May be positive for TSPY1, OCT4, SOX9, SF1, alpha inhibin

Additional references

Moch: WHO Classification of Tumours of the Urinary System and Male Genital Organs, 4th Edition, 2016, WHO Classification of Tumours Editorial Board: Urinary and Male Genital Tumours, 5th Edition, 2022

Board review style question #1

Which diagnosis is associated with a 4 year old boy who presents with pigmented macules around the lips and oral mucosa, gynecomastia and the findings shown on the testis biopsy above?

Gonadoblastoma
Intratubular large cell hyalinizing Sertoli cell neoplasia (ITLCHSCN)
Large cell calcifying Sertoli cell tumor (LCCSCT)
Sertoli cell nodule

Board review style answer #1

B. Intratubular large cell hyalinizing Sertoli cell neoplasia (ITLCHSCN). The patient has Peutz-Jeghers syndrome and the testicle shows intratubular large cell hyalinizing Sertoli cell neoplasia. The image shows a tubule composed of large Sertoli cells without normal spermatogonia and spherules of basement membrane-like material characteristic of this entity (Am J Surg Pathol 2007;31:827, Virchows Arch 2024;484:723). Answer A is incorrect because gonadoblastoma is associated with disorders of sex development. Tumors are characterized by round islands or nests composed of germ cells admixed with immature sex cord elements and basement membrane deposits (Histopathology 2018;72:545, Hum Pathol 2020;100:47). Answer C is incorrect because large cell calcifying Sertoli cell tumor is associated with Carney complex. Tumors are composed of large epithelioid cells arranged in cords, nests, sheets or solid tubules embedded in a myxoid or fibrous stroma with prominent neutrophilic infiltrate and larger, easily visible calcifications (Hum Pathol 2010;41:552, Virchows Arch 2024;484:723). Answer D is incorrect because Sertoli cell nodules are typically identified in cryptorchid testes and show spermatogonia. Histologically the nodules are characterized by nonneoplastic immature Sertoli cells within seminiferous tubules with round shaped hyaline material deposits (Am J Surg Pathol 2007;31:827, Diagnostic Histopathology 2019;25:398).

Comment Here

Reference: Intratubular large cell hyalinizing Sertoli cell neoplasia (ITLCHSCN)

Juvenile granulosa cell tumor

Table of Contents

Definition / general

Neoplasm composed of primitive appearing granulosa cells growing in solid and follicular patterns
Most common neoplasm of the testis during the first 6 months; almost all tumors are seen in first decade of life (J Cancer Res Clin Oncol 2020;146:2829)
No malignant cases reported

Essential features

Juvenile granulosa cell tumor (JGCT) is a rare neoplasm with a wide morphologic spectrum
Solid and reticular patterns may pose diagnostic challenges but the lobular appearance and follicular differentiation are characteristic
Immunostains aid in diagnosis with positive expression of SF1, calretinin, vimentin and inhibin and negative expression of alpha fetoprotein (AFP)

ICD coding

ICD-O: 8622/1 - granulosa cell tumor, juvenile
ICD-11: 2F34 & XH2U25 - benign neoplasm of male genital organs & granulosa cell tumor of the testis, juvenile

Epidemiology

Rare tumors that account for Afflicts patients from 30 weeks gestational age to 10 years old, with 90% occurring in patients ≤ 6 months of age (Am J Surg Pathol 2015;39:1159)
Association with cryptorchoid testis or dysgenetic gonads (Drash syndrome) (Semin Diagn Pathol 2014;31:323, J Cancer Res Clin Oncol 2020;146:2829)
Chromosomal abnormality linked to the Y chromosome is found in 20% of the cases (Am J Surg Pathol 1994;18:316)
Can also occur rarely in undescended testes and dysgenetic gonads

Sites

Almost invariably unilateral

Pathophysiology

Thought to arise from a specialized gonadal stromal cell of the testicle, which is histologically very similar to JGCT of the ovary

Clinical features

Most commonly seen as testicular mass (65%) or enlarging testis (25%)
Testicular masses are asymptomatic and can be present within the abdomen or inguinal region or within the scrotal sac
Can also present with lack of endocrine features
Some cases present with the contralateral testis as clinically normal but undescended

Diagnosis

Imaging: testicular ultrasonography usually reveals a well defined large intratesticular multicystic and solid mass
Pathological findings after orchiectomy are conclusive

Laboratory

Serum alpha fetoprotein (AFP) and beta human chorionic gonadotropin (HCG) are within normal range and do not aid in diagnosis

Radiology description

Multiseptated, cystic intratesticular / intra-abdominal mass observed on ultrasonography

Radiology images

Images hosted on other servers:

Well encapsulated cystic mass

Prognostic factors

Favorable prognosis, with no documented metastasis or relapses
Lymphovascular invasion has been documented in only 2 cases and involvement of rete testis in 4 cases (Am J Surg Pathol 2015;39:1159)

Case reports

Newborn boy with enlarged right testis (Autops Case Rep 2014;4:39)
Newborn boy with left intra-abdominal mass (Urology 2012;79:1152)
Newborn boy with positive alpha fetoprotein immunohistochemical staining of a juvenile granulosa cell tumor (Urol Case Rep 2017;12:49)

Treatment

In circumstances where organ preservation is not possible, total orchiectomy is performed

Gross description

Tumors measure 0.5 - 5 cm (mean: 2 cm; median: 1.5 cm)
Well circumscribed and yellow-orange or tan-white on cut surface
Can have a solid (33% cases) or cystic component (67% cases) or both (Am J Surg Pathol 2015;39:1159)
Watery to mucoid cystic fluid

Gross images

Images hosted on other servers:

Testicle after surgery

Microscopic (histologic) description

Solid, nodular or follicular patterns are the most common and sometimes alternate
Follicles vary from large and round / oval to small and irregular containing basophilic or eosinophilic secretion (mucicarmine+)
In solid or nodular areas, the cells grow in sheets or irregular clusters
Cells have moderate to large amounts of pale to eosinophilic cytoplasm, round to oval hyperchromatic nuclei, some of which contain nucleoli
Mitoses are common, in contrast to adult granulosa cell tumor
Extensive hyalinization (forming nodules) and prominent myxoid background may be seen
Call-Exner bodies are uncommon
Apoptosis, entrapped seminiferous tubules, rete testis involvement and lymphovascular invasion could be seen in rare cases (Am J Surg Pathol 2015;39:1159)

Microscopic (histologic) images

Contributed by Vikas Mehta, M.D.

Variable sized follicles

Follicles with bland cells

Tumor cells with eosinophilic cytoplasm

Round to oval hyperchromatic nuclei

Positive stains

JGCT stains uniformly positively for FOXL2, SF1 and vimentin
Majority JGCT also express inhibin, calretinin, WT1 and SOX9 (Am J Surg Pathol 2015;39:1159)

Negative stains

Glypican 3, SALL4, podoplanin (D2-40), OCT3/4, AFP

Molecular / cytogenetics description

Association with abnormal karyotypes, including mosaics such as 45, X/47, XXY or 45X/46, X.r(Y) have been seen (Pediatr Dev Pathol 2016;19:471)

Sample pathology report

Left testis, radical orchiectomy:
- Juvenile granulosa cell tumor (1.5 cm), confined to the testis (see comment)
- Comment: The tumor is small and well circumscribed and shows variable sized follicles lined by bland appearing, oval, round cells arranged in single or multiple layers with outer layers resembling theca cells. Many mitotic figures are identified. No nuclear grooves or Call-Exner bodies identified.

Differential diagnosis

Yolk sac tumor:
- High elevations of AFP
- Presence of Schiller-Duval bodies
- True follicles are diagnostic of JGCT and are not a feature of yolk sac tumor
- Negative for SF1, FOXL2, inhibin A, calretinin
Teratoma:
- Numerous ectodermal, mesenchymal and endodermal tissues occur
- Virtually all elements lack cellular atypia
Cystic dysplasia of the testicle (Front Pediatr 2022;10:898038):
- Rare and benign cause of testicular swelling in pediatric population
- Irregular cystic spaces in the mediastinum of the testis, displacing the testicular parenchyma
- Cysts lined with flattened cuboidal epithelium and separated by fibrous septa
- Frequently associated with genitourinary anomalies, ipsilateral renal agenesia and multicystic dysplasia of the kidney
Sertoli cell tumor:
- Small size, multifocal, monotonous tubular / cord architecture, associated with androgen insensitivity syndrome and cryptorchidism
Gonadoblastoma:
- Almost always associated with disorders of sex development
- Round nests and cords composed of germ cells, small sex cord cells and globoid deposits of hyaline basement membrane material
- May also show Charcot-Böttcher crystals
Unclassified sex cord stromal tumors:
- Mixture of cell types granulosa cell tumor, Leydig cell tumor, thecoma, etc.
- Variable AE1 / AE3 and Ki67 reactivity for germ cell differentiation
- Variable inhibin A, calretinin, CD99 reactivity for sex cord stromal elements
- S100, smooth muscle actin reactivity for spindle cell elements
Rhabdomyosarcoma:
- More typically in paratesticular location
- Lacks follicle formation; small round blue cells with rhabdomyoblasts
- Positive for desmin, MyoD1 and myogenin

Board review style question #1

A 5 month old boy presented with a left testicular mass. An ultrasound of the testis showed a variably solid cystic mass with internal septations. An image from the resection specimen is shown above. Which of the following features will point toward the diagnosis of juvenile granulosa cell tumor?

Presence of intracellular or extracellular eosinophilic hyaline globules, basement membrane material and Schiller-Duval bodies
Round nests and cords composed of germ cells, small sex cord cells and globoid deposits of hyaline basement membrane material
Variable morphologic patterns with biphasic epithelioid and spindle cell components
Variable sized true follicles lined by bland appearing, oval, round cells arranged in single or multiple layers with outer layers resembling theca cells

Board review style answer #1

D. Variable sized true follicles lined by bland appearing, oval, round cells arranged in single or multiple layers with outer layers resembling theca cells. Answer A is incorrect because the features described are found in yolk sac tumors. Answer C is incorrect because variable morphologic patterns with biphasic epithelioid and spindle cell components are found in a subset of sertoli cell tumors, NOS. Answer B is incorrect because the features described are found in gonadoblastoma.

Comment Here

Reference: Juvenile granulosa cell tumor

Board review style question #2

Which of the following choices represents the immunoprofile of juvenile granulosa cell tumor of testis?

Desmin+, MyoD1+, myogenin+
Glypican3+, SALL4+, OCT3/4+
S100+, SMA+, SF1+
SF1+, FOXL2+, inhibin+

Board review style answer #2

D. SF1+, FOXL2+, inhibin+. Answer B is incorrect because glypican3+, SALL4+, OCT3/4+ can be seen in immature teratoma. Answer C is incorrect because the features listed are consistent with gonadal stromal tumor, myoid. Answer A is incorrect because the features listed are consistent with rhabdomyosarcoma.

Comment Here

Reference: Juvenile granulosa cell tumor

Large cell calcifying Sertoli cell tumor

Table of Contents

Definition / general

Large cell calcifying Sertoli cell tumor (LCCSCT) was first described by Lange et al. in 1960 (J Urol Medicale Chir 1960;66:259)
Published by Proppe and Scully in 1980 (Am J Clin Pathol 1980;74:607)
Approximately 130 cases reported (to date) in English language literature

Essential features

Generally presents as a benign sex cord stromal tumor found predominantly in patients < 20 years old; a subset presents in older patients and may behave aggressively
Associated with Carney complex in 20 - 40% of cases due to alterations in the gene PRKAR1A
Characterized by intratubular and sheet-like growth of large eosinophilic cells with laminated psammomatous, mulberry-like or dystrophic calcifications, a prominent neutrophilic infiltrate and lymphocytic rim

ICD coding

ICD-10: D29.20 - Sertoli cell tumor, male

Epidemiology

Male patients, generally < 20 years old
20 - 40% of cases associated with Carney complex due to mutations in PRKAR1A gene (part of Carney complex with spotty cutaneous pigmentation, primary pigmented nodular adrenocortical disease, atrial myxomas, superficial angiomyxomas, malignant melanocytic nerve sheath tumors, blue nevus and thyroid carcinoma)
Debatable association with Peutz-Jeghers syndrome (rare reports, may represent intratubular large cell hyalinizing Sertoli cell neoplasia) and neurofibromatosis (Am J Surg Pathol 2021 Dec 16 [Epub ahead of print])

Sites

Testis
Multifocal and bilateral testicular involvement in > 50% of patients with Carney complex (J Urol 2002;167:1299)

Clinical features

Majority of cases present as painless testicular mass, and less commonly as testicular pain, gynecomastia or precocious pseudopuberty (Am J Surg Pathol 2021 Dec 16 [Epub ahead of print])

Diagnosis

Definitive diagnosis by histopathological examination

Prognostic factors

Kratzer et al. proposed malignant prognostic features that include age > 25 years old and 2 or more of the following adverse features (Am J Surg Pathol 1997;21:1271):
- Size > 4 cm
- Extratesticular extension
- Mitotic index > 3/10 high power fields (HPFs)
- Coagulative tumor necrosis
- Vascular invasion
- High grade cytologic atypia
Prepubertal status may provide a protective effect (Am J Surg Pathol 2021 Dec 16 [Epub ahead of print])
Tumors associated with Carney complex may behave in biologically indolent fashion compared with sporadic tumors (Eur Urol 2001;40:699)

Case reports

10 year old boy with sporadic bilateral LCCSCT (Ann Clin Lab Res 2015;3:2)
19 year old man with Carney complex treated with partial orchiectomy (BMJ Case Rep 2017;2017:bcr2017219557)
42 year old man with metastatic LCCSCT (J Endocr Soc 2019;3:1375)
62 year old man with locally invasive LCCSCT (J Clin Diagn Res 2016;10:ED03)

Treatment

Partial or radical orchiectomy for organ confined disease
Retroperitoneal lymph node dissection with possible adjuvant chemotherapy or radiation therapy for metastatic disease (benefit unknown)

Gross description

Nodular, yellow-gray, firm to hard gritty tumors generally < 2 cm in diameter
Generally well circumscribed but occasionally infiltrative into adjacent paratestis
Malignant cases more likely to present as fleshy masses with tumor necrosis
References: Am J Surg Pathol 2021 Dec 16 [Epub ahead of print], Histopathology 2022;80:677

Gross images

Contributed by Sara Vargas, M.D.

Ill defined testicular nodules

Images hosted on other servers:

Firm, white tan nodules

Tumor

Microscopic (histologic) description

Laminated psammomatous and mulberry-like calcifications
Prominent neutrophilic infiltrate and lymphocytic rim
Large epithelioid cells with eosinophilic cytoplasm, prominent nucleoli and minimal cytologic atypia
Cords, trabeculae, nests or sheets in a variably myxoid or fibrous stroma
Generally limited to testis with occasional extension into paratesticular tissue, including rete testis and hilar soft tissue
Malignant cases more likely to exhibit solid sheet-like growth and frequent nuclear pleomorphism ranging from mild to prominent

Microscopic (histologic) images

Contributed by Stephanie Siegmund, M.D., Ph.D.

Calcifications, neutrophils, myxoid stroma

Focus of intratubular tumor

Tumor involving rete testis

Mulberry calcifications

Trabecular architecture

Focal nuclear pleomorphism

Neutrophilic infiltrate

Minimal cytologic atypia

Mulberry calcifications

PRKAR1A loss

Virtual slides

Images hosted on other servers:

Multifocal mass in pediatric testis

Dystrophic calcifications

Positive stains

Inhibin, MelanA, vimentin, calretinin, S100 protein, SF1 (Appl Immunohistochem Mol Morphol 2013;21:318)
Alpha-1 antitrypsin / chymotrypsin (71%)
References: Am J Surg Pathol 2021 Dec 16 [Epub ahead of print], Histopathology 2022;80:677

Negative stains

PRKAR1A loss (93%)
OCT 3/4, SALL4, CAM 5.2, CK18 (antibody clone DC10)
Beta catenin (cytoplasmic staining only)
References: Am J Surg Pathol 2021 Dec 16 [Epub ahead of print], Histopathology 2022;80:677

Molecular / cytogenetics description

Frequent biallellic inactivation of PPKAR1A gene, secondary to somatic or germline mutations as part of Carney complex (Hum Pathol 2010;41:552, J Endocr Soc 2019;3:1375, Histopathology 2022;80:677)
No chromosomal abnormalities reported

Sample pathology report

Testis and spermatic cord, radical orchiectomy:
- Large cell calcifying Sertoli cell tumor (1.0 cm) (see comment)
- Tumor is limited to the testicular parenchyma
- No necrosis is identified
- Mitoses number < 1 per 10 HPFs
- The spermatic cord and cord resection margin are negative for tumor
- No lymphovascular invasion is identified
- Background testis with maturing spermatogenesis
- Comment: The slides demonstrate sheets and cords of large epithelioid cells with eosinophilic cytoplasm and prominent nucleoli. Immunohistochemistry demonstrates the following staining profile in lesional cells: positive staining for inhibin, calretinin, S100, MelanA and beta catenin (cytoplasmic, nonnuclear) and negative staining for PRKAR1A (loss), OCT 3/4 and SALL4. Overall, the findings are consistent with large cell calcifying Sertoli cell tumor. Adverse pathologic features are not identified (e.g., > 3 mitoses per 10 HPF, coagulative necrosis, vascular invasion, size > 4.0 cm, high grade cytologic atypia or extratesticular extension) (Am J Surg Pathol 1997;21:1271). Approximately 20 - 40% of cases are associated with Carney complex and genetic counseling is recommended in the appropriate clinical context.

Differential diagnosis

Leydig cell tumor (LCT):
- Usually solitary and unilateral
- Frequent Reinke crystals (diagnostic of LCT)
- Lacks calcifications and neutrophilic infiltrate
- Retains IHC expression of PRKAR1A
Sertoli cell tumor, not otherwise specified (NOS):
- Similar population of large, polygonal Sertoli cells with eosinophilic cytoplasm
- Usually lacks calcifications and neutrophilic infiltrate
- Nuclear localization of beta catenin by IHC
- Retains IHC expression of PRKAR1A
Intratubular large cell hyalinizing Sertoli cell neoplasia:
- Predominantly intratubular process with expanded tubules and thickened basement membrane
- Tubules filled by globular eosinophilic basement membrane-like material
- Generally lacks calcifications
- Retains IHC expression of PRKAR1A

Board review style question #1

Which of the following features is most consistent with sporadic presentation of large cell calcifying Sertoli cell tumor (LCCSCT), shown in the image, versus a syndromic association (e.g., Carney complex)?

Bilateral disease
Loss of PRKAR1A by IHC
Multifocal disease
Pediatric presentation
Sibling(s) with similar presentation

Board review style answer #1

B. Loss of PRKAR1A by IHC. While PRKAR1A alterations are commonly found in patients with Carney complex, the loss of PRKAR1A is seen in most sporadic as well as syndromic LCCSCT and can frequently be demonstrated by as loss of PRKAR1A by IHC in sporadic tumors. All other listed answers (pediatric onset, bilateral and multifocal disease, sibling(s) with similar presentations) are more commonly associated with LCCSCT occurring in Carney complex patients and would suggest a syndromic association.

Comment Here

Reference: Large cell calcifying Sertoli cell tumor

Leiomyosarcoma

Table of Contents

Definition / general

Malignant mesenchymal tumor with smooth muscle differentiation

Epidemiology

Second most common malignant mesenchymal tumor of paratestis, after liposarcoma (Urol Oncol 2014;32:52)
10 - 30% of paratesticular sarcomas are leiomyosarcomas (Int Braz J Urol 2006;32:66, Urol Int 2009;82:448, Urol Oncol 2014;32:52)
5 year and 10 year disease specific survival rates are 77% and 66% (Urol Oncol 2014;32:52)
After 4 year follow up, 30% had metastases (lymph nodes, lungs, liver) (all grade 3 tumors) (Am J Surg Pathol 2001;25:1143)
Median age is 64 years, range 17 - 92 years (Am J Surg Pathol 2001;25:1143, Urology 2002;60:1112)

Sites

Spermatic cord is most common paratesticular site (Am J Surg Pathol 2001;25:1143)
Other sites include epididymis and scrotal sac (Can Urol Assoc J 2011;5:E121)

Pathophysiology

Hypothesized to arise from cremasteric muscle, vas deferens or contractile cells of other structures such as tunica or blood vessels (Urology 2002;60:1112)
Paratesticular tumors belong to "deep type" of leiomyosarcoma
No recurrent genetic abnormality has been documented
Tumor spreads via lymphatic and hematogenous metastases or by local extension
Lymphatic spread is to regional lymph nodes: external iliac, hypogastric, common iliac, retroperitoneal (J Urol 1970;103:628)
Lung is most common site for hematogenous spread

Clinical features

Typically presents with painless, slow growing mass (at least a few months) in scrotal sac
Rarely presents with sudden increase in size of long standing mass
Aggressive tumors may invade dartos muscle and overlying skin, causing a fungating mass

Laboratory

Normal serum tumor markers (LDH, β-HCG, α-fetoprotein) helps exclude a germ cell tumor

Radiology description

Sonography shows a mass with mixed echogenicity and increased vascularity (World J Radiol 2011;3:114)
Color Doppler ultrasonography reveals irregular vascularity, more dominant in periphery, similar to malignant tumors
CT usually shows absence of fat (absence of foci with negative Hounsfield units)
Variable degree of hydrocele may be present

Radiology images

Images hosted on other servers:

Mass posterior superior to right testis

Huge heterogeneous enhancing mass

Heterogenous echogenicity

Prognostic factors

Similar to sarcoma: tumor size, tumor grade, presence of necrosis, mitotic count, completion of resection, local recurrence, distant metastases
Specific prognostic criteria not well established due to rarity of tumor
FNCLCC grading (recommended over NIH system) gives points for:
- Differentiation: 1, well differentiated leiomyosarcoma; 2, conventional leiomyosarcoma; 3, poorly differentiated / pleomorphic / epithelioid leiomyosarcoma
- Mitotic count: 1, 0 - 9 per 10 high powered fields; 2, 10 - 19 per 10 high powered fields; 3, 20 or more per 10 high powered fields
- Necrosis: 0, none; 1, less than or equal to 50%; 2, greater than 50%
- Grade 1 is 2 - 3 points, grade 2 is 4 - 5 points and grade 3 is 6 - 8 points

Case reports

Infant with testicular leiomyosarcoma (J Pediatr Surg 2004;39:e16)
18 year old man with epithelioid tumor (Urol J 2004;1:215)
45 year old man with rapidly enlarging, painless testicular swelling (Case #254)
50 year old man successfully treated with orchiectomy and chemotherapy (Cancer Res Treat 2012;44:210)
53 year old man (Asian J Androl 2013;15:843)
58 and 75 year old men with leiomyosarcoma of epididymis (Can Urol Assoc J 2011;5:E121)
65 year old man (Med Princ Pract 2002;11:157)

Treatment

Radical orchidectomy for resectable tumors
Simple excision is insufficient as residual disease was found in 27% of cases that underwent repeat wide excision (J Urol 1981;126:611)
Uncertain role of adjuvant radiation or chemotherapy; some authors recommend adjuvant therapy in high grade / high risk tumors and others recommend adjuvant radiotherapy for all grades to reduce local recurrence (Cancer 1996;77:1873, J Urol 1991;146:342)
Prophylactic retroperitoneal lymph node dissection may be performed but no survival benefit has been documented, so dissection recommended only if nodes are suspicious for involvement (J Urol 1970;103:628)
Single or multiagent chemotherapy with anthracyclines and if osfamides or gemcitabine for nonoperable or metastatic tumors

Clinical images

Images hosted on other servers:

Ulcerated and
fungating tumor
involving scrotum

Gross description

Tumor typically located outside tunica albuginea, may be centered on epididymis or spermatic cord
Cut surface is usually firm, gray white
Grossly identifiable necrotic and hemorrhagic areas may be seen

Gross images

Images hosted on other servers:

Well defined huge solid mass

Microscopic (histologic) description

Interlacing fascicles of spindle shaped cells with eosinophilic cytoplasm and cigar shaped nuclei
Mitotic activity is usually seen; necrosis may be seen
At least mild atypia; more undifferentiated cases have marked cellular atypia
Variably scattered mast cells, inflammatory cells, hyalinization
Histological variants:
- Epithelioid
- Dedifferentiated / pleomorphic
  - Discrete transition to more pleomorphic tumor (reminiscent of malignant fibrous histiocytoma) without any smooth muscle differentiation
  - Dedifferentiated areas are usually negative for all myogenic markers
  - Heterologous osseous or chondro-osseous elements may be seen rarely
- With osteoclast-like giant cells (Urol Int 1996;56:259)
- Myxoid (Am J Surg Pathol 2000;24:927)
- Inflammatory

Microscopic (histologic) images

Case #254

Various images

Vimentin

Desmin

Alpha smooth muscle actin

PAS

PLAP

Images hosted on other servers:

Pattern of spindle cells - H&E

Mitotic activity and atypical nuclei

Desmin+, SMA+

Desmin+

SMA+

Immunohistochemistry & special stains

Positive:
- Muscle specific actin, smooth muscle actin, h-caldesmon and desmin
- Vimentin
Variable:
- CD34
Negative / focal rare cells:
- Cytokeratin, CD117, myogenin, myoD1, S100

Electron microscopy description

7 nm microfilaments, regular dense bodies, micropinocytotic vesicles, glycogen pools (Ann Diagn Pathol 2003;7:60)

Differential diagnosis

Dedifferentiated liposarcoma with smooth muscle differentiation
- More typical liposarcomatous areas
Fibromatosis: tapered nuclei
Leiomyoma
- No appreciable mitotic activity or necrosis but nuclear atypia may be present
- Scrotal smooth muscle tumors should be classified as potentially malignant if any mitotic activity is seen (Ann Diagn Pathol 2003;7:60)
Malignant peripheral nerve sheath tumor
Mesothelioma
- Associated with hydrocele, asbestos exposure; infiltrative margins; usually keratin+, desmin-
Solitary fibrous tumor
- Disorganized spindle cells, diffusely CD34+ and desmin-
Spindle cell rhabdomyosarcoma
- Usually occurs in children
- Myogenin+, MyoD1+

Leydig cell tumor

Table of Contents

Definition / general

Most common sex cord stromal tumor of the testis; comprised of cells resembling nonneoplastic Leydig cells
A small minority (< 10%) of cases are clinically malignant (World J Urol 2020;38:2857, Int J Urol 2010;17:886)

Essential features

Most common sex cord stromal tumor of the testis
Histology: diffuse / nodular growth of polygonal cells with abundant eosinophilic cytoplasm, uniform round nuclei and prominent central nucleoli; Reinke crystals may be present
Immunohistochemistry: inhibin A+, calretinin+, MelanA+, SF1+, AR+
Features associated with malignant potential include: size > 5 cm, infiltrative borders, cytological atypia, frequent mitoses (> 3/10 high power fields), vascular invasion and necrosis
Treatment: surgical resection, curative for nonmetastasizing tumors
Prognosis: overall 5 year survival after orchiectomy > 90%

Terminology

Interstitial cell tumor - obsolete term

ICD coding

ICD-10: D40.10 - Leydig cell tumor of testis

Epidemiology

1 - 2% of testicular tumors in adults and 3 - 6% of testicular tumors in prepubertal males (J Urol 2009;181:2299, J Pediatr Hematol Oncol 2019;41:74)
Mostly sporadic, rarely associated with hereditary leiomyomatous and renal cell carcinoma syndrome (J Clin Endocrinol Metab 2006;91:3071)
Occurs at any age with 2 peaks: 5 - 10 years and 30 - 60 years (J Urol 2009;181:2299)

Sites

Testicular parenchyma
Rarely in ectopic rests of Leydig cells in the epididymis (Andrologia 2013;45:430)

Pathophysiology

Produces androgen, mainly testosterone, which can cause symptoms described below
Can also produce estrogen by either direct production of estradiol or by peripheral aromatization of testosterone (Arch Pathol Lab Med 2007;131:311)

Etiology

Little is known
Rare association with germline fumarate hydratase mutations in patients with hereditary leiomyomatosis and renal cell carcinoma syndrome and activating mutations of the luteinizing hormone receptor (N Engl J Med 1999;341:1731)

Clinical features

> 90% benign
Usually unilateral, rarely bilateral
Painless testicular enlargement
Children
- Precocious puberty caused by androgen production
- Gynecomastia and breast tenderness due to estrogen production (Arch Pathol Lab Med 2007;131:311)
Adults
- Gynecomastia
- Infertility, loss of libido and erectile dysfunction (Hum Reprod 2019;34:1389)
- Rarely, Cushing syndrome (Urology 2000;56:153)
Malignant Leydig cell tumors may rarely present with metastases, usually to the retroperitoneal lymph nodes or lungs (Am J Surg Pathol 1985;9:177, J Urol 2020;203:949)

Diagnosis

Tumor histology and immunohistochemistry

Laboratory

Serum testosterone and estrogen levels may be elevated
Lower sperm concentration, lower total sperm count and motility (Hum Reprod 2019;34:1389)

Radiology description

Nonspecific
On ultrasound, tumors are generally well defined, homogeneous hypoechoic, small solid masses with hypervascularity (Arch Pathol Lab Med 2007;131:311)
May show cystic areas

Radiology images

Images hosted on other servers:

CT scan: circumscribed mass

MRI: solid enhancing mass

Ultrasound: mixed echogenic mass

Prognostic factors

Benign Leydig cell tumors: excellent prognosis, curative by surgery
Malignant Leydig cell tumors: poor survival, most develop metastatic disease leading to death (J Urol 2020;203:949)

Case reports

6 year old boy with precocious puberty and a left testicular mass (J Indian Assoc Pediatr Surg 2017;22:181)
32 year old man with gynecomastia and a small mass in the right testis (Case Rep Urol 2018;2018:7202560)
45 year old man with a large painless mass in the right testis (Urol Case Rep 2019;28:101064)
62 year old man with a huge painless mass in the right testis (Medicine (Baltimore) 2018;97:e11158)
91 year old man with a malignant Leydig cell tumor in the left testis (Int Braz J Urol 2019;45:1260)

Treatment

Benign Leydig cell tumors
- Orchidectomy
- Testis sparing surgery in small tumors is a safe alternative (Hum Reprod 2019;34:1389, World J Urol 2020;38:2857)
Malignant Leydig cell tumors
- Orchiectomy with retroperitoneal lymph node dissection can be curative
- No significant response to radiation or chemotherapy (Oncology (Williston Park) 2014;28:211,, World J Urol 2020;38:2857)

Gross description

Well circumscribed, solid homogeneous mass
Usually < 5 cm in size
Golden brown or brownish green cut surface
Hyalinization and calcification may be present
Gross features suggestive of malignancy (Arch Pathol Lab Med 2007;131:311)
- Large size: > 5 cm
- Infiltrative margins
- Hemorrhage and necrosis
- Extratesticular extension

Gross images

Contributed by Debra L. Zynger, M.D.

Small tumor

Nodular tumor

High risk tumor

Images hosted on other servers:

Circumscribed brown tumor

Frozen section description

Diffuse sheets of uniform polygonal cells with round nuclei, central nucleoli, abundant granular, eosinophilic cytoplasm and rectangular to club shaped Reinke crystals (Hum Pathol 2015;46:600)
Touch imprint and scrape smear preparations are better to highlight Reinke crystals (Arch Pathol Lab Med 2005;129:e65)

Frozen section images

Images hosted on other servers:

Reinke crystals

Microscopic (histologic) description

Architecture:
- Diffuse or nodular with fibrous bands
- Uncommon patterns: insular, trabecular, pseudotubular, ribbon-like, trabecular, spindled and microcystic (Surg Pathol Clin 2018;11:739)
Cytologic features:
- Polygonal cells with abundant eosinophilic granular cytoplasm, uniform round nuclei and prominent central nucleoli; rarely, nuclei may have a ground glass appearance
- Uncommon cell types: scant cytoplasm, foamy cytoplasm and spindling (Am J Surg Pathol 2002;26:1424)
- Lipofuscin pigment maybe present: golden yellow on H&E stain, red-purple granular appearance on PAS stain
- Binucleated and multinucleated cells may be present
- Reinke crystals: pathognomonic; identified in only up to 30% (degradation / dissolution by formalin fixation); intracytoplasmic, rarely extracellular
- Mitosis: rare
- Mild nuclear atypia permissible
- Occasionally, psammoma bodies, calcification, osseous and adipocytic metaplasia may be identified (Am J Surg Pathol 2002;26:1424)
Microscopic features suggestive of malignancy (most malignant tumors will have more than 2 of these features) (Am J Surg Pathol 1985;9:177):
- > 5 cm
- Infiltrative borders
- Cytological atypia
- Frequent mitoses (> 3/10 high power fields)
- Vascular invasion
- Necrosis

Microscopic (histologic) images

Contributed by Manju Aron, M.D. and Kristine Cornejo, M.D.

Polygonal cells

Eosinophilic cells

Reinke crystals

Inhibin positive

SF1 positive

Cytology description

Fine needle aspiration is rarely performed unless in a metastatic lymph node
Cellular smears with discohesive cells having eccentric round nuclei, evenly distributed chromatin, prominent nucleoli and abundant eosinophilic granular cytoplasm
Naked nuclei are common
Cytoplasm may be vacuolated due to lipid accumulation
Nuclear grooves, binucleation and multinucleation may be identified
Nuclear pseudoinclusions and Reinke crystals can be seen
No cytological features to differentiate Leydig cell tumors from nodular Leydig cell hyperplasia (J Am Soc Cytopathol 2019;8:220)

Positive stains

Inhibin A, calretinin, MelanA, androgen receptor (AR) and steroidogenic factor 1 (SF1)
Insulin-like 3 (INSL3) variably reported to be positive
CD99 (MIC2) membranous staining (Histopathology 2021;78:290)

Negative stains

SALL4, OCT4 and beta catenin (Am J Surg Pathol 2015;39:1390)
Cytokeratin, chromogranin, synaptophysin, S100 and PLAP (rarely focally positive)

Electron microscopy description

Reinke crystals are diagnostic
- Appearance depends on plane of sectioning: prismatics, hexagonal lattices or hexagonal microtubules with parallel lines
- Located in cytoplasm but can be seen in nucleus or interstitium
Abundant smooth endoplasmic reticulum, mitochondria with tubulovesicular cristae, numerous lipid droplets and lipofuscin granules (Case Reports Histol Histopathol 1989;4:247)

Molecular / cytogenetics description

DNA aneuploidy is associated with malignant Leydig cell tumors, benign Leydig cell tumors are diploid
Gain of chromosome X, 19 or 19p and loss on chromosome 8 and 16 are most frequent findings (Oncol Rep 2007;17:585)
Somatic GNAS (guanine nucleotide binding protein, alpha stimulating activity polypeptide 1)
- Activating mutation (R201S) has been reported (J Androl 2012;33:578)

Sample pathology report

Right testicle, radical orchiectomy:
- Leydig cell tumor, 2 cm in greatest dimension (see synoptic report)
- Tumor limited to testis
- Resection margins uninvolved by tumor
Note that benign tumors are not staged

Differential diagnosis

Testicular tumor of adrenogenital syndrome or testicular adrenal rest tumors:
- Arise in males with congenital adrenal hyperplasia
- Hormonal profile with high 17-hydroxyprogesterone and adrenal androgen levels and frequent regression following dexamethasone treatment
- Usually bilateral, dark brown nodules
- Spotty cytological atypia, abundant cytoplasmic lipofuscin pigment but no Reinke crystals, broad bands of hyalinized collagenous stroma
- Androgen receptor and INSL3 negative
- More frequently positive for neuroendocrine markers (synaptophysin and CD56)
- Reference: Histopathology 2017;70:513
Leydig cell hyperplasia:
- Interstitial growth pattern with small nodules < 0.5 cm; usually bilateral and multifocal
- Diffuse positivity for INSL3
- Reference: Appl Immunohistochem Mol Morphol 2019;27:203
Granular cell tumor:
- Abundant granular cytoplasm, no Reinke crystals
- Positive for S100, CD68 and PASD; negative for inhibin A, SF1 and MelanA
Large cell calcifying Sertoli cell tumor:
- Associated with Carney complex
- Sertoli cells with abundant eosinophilic cytoplasm and extensive calcification, variable tubular or intratubular growth, stroma more myxoid and neutrophil rich, no Reinke crystals
- Positive for SMA and desmin, more diffuse S100 positivity
- Reference: Hum Pathol 2010;41:552
Malakoplakia:
- Involves tubules and interstitium with xanthogranulomatous inflammation and Michaelis-Gutmann bodies
Seminoma:
- Is in the differential diagnosis of Leydig cell tumor with clear cytoplasm
- Seminoma is associated with germ cell neoplasia in situ, fibrous septae, lymphocytic infiltrate and granulomas
- Positive for SALL4 and OCT4
- Negative for inhibin A, MelanA and SF1

Board review style question #1

A 21 year old man had a 2 cm painless mass in the left testicle. Histological features are shown in the image above. Which marker will be positive in this tumor?

SALL4
PLAP
OCT4
Inhibin A
Cytokeratin

Board review style answer #1

D. Inhibin A. The diagnosis is Leydig cell tumor.

Comment Here

Reference: Leydig cell tumor

Board review style question #2

Malignant potential in Leydig cell tumor is associated with which of the following factors?

Younger patient age
Diffuse growth pattern
Large tumor size (> 5 cm)
Calcification
Reinke crystals

Board review style answer #2

C. Large tumor size (> 5 cm)

Comment Here

Reference: Leydig cell tumor

Board review style question #3

A 41 year old man was hit in the groin area by a baseball. An ultrasound showed a 3 cm tumor of the testis. On histology, the tumor showed diffuse sheet-like growth of cells with minimal stroma, shown above. The tumor cells were large and polygonal with abundant, slightly granular, eosinophilic cytoplasm. The tumor cell nuclei were round and contained a single prominent nucleolus. Rare intracytoplasmic eosinophilic crystals were identified. The most likely diagnosis of this tumor is which of the following?

Adult granulosa cell tumor
Juvenile granulosa cell tumor
Leydig cell tumor
Sertoli cell tumor

Board review style answer #3

C. Leydig cell tumor

Comment Here

Reference: Leydig cell tumor

Liposarcoma

Table of Contents

Definition / general

Well differentiated and dedifferentiated liposarcomas are characterized by MDM2 amplifications and represent the vast majority of paratesticular liposarcomas
Other liposarcomas (myxoid liposarcoma, pleomorphic liposarcoma) are very rare in this location and are driven by other mechanisms of tumorigenesis

Essential features

Well differentiated liposarcoma (WDLPS)
- Mature adipocytes and stromal cells with at least focal cytologic atypia
- Adipocytic component may be limited in tumors with predominant sclerosing or inflammatory morphology
- Giant ring / marker chromosomes; MDM2 gene amplification
Dedifferentiated liposarcoma (DDLPS)
- Undifferentiated pleomorphic or spindle cell sarcoma that arises in association with WDLPS
- Typically nonlipogenic and high grade; rare heterologous (osteosarcomatous, rhabdosarcomatous, or leiomyosarcomatous) differentiation reported
- Well differentiated component can be minimal or absent
Myxoid liposarcoma (MLPS)
- Small primitive mesenchymal cells and univacuolated (signet ring) lipoblasts
- Myxoid stroma with delicate, thin walled arborizing capillaries
- > 5% high grade features are associated with a worse prognosis
- DDIT3 (12q13) gene rearrangement
Pleomorphic liposarcoma (PLPS)
- Variable amount of pleomorphic lipoblasts, admixed with a high grade sarcoma
- Epithelioid subtype can be positive for keratins
- Important to rule out DDLPS with homologous dedifferentiation

Terminology

Well differentiated liposarcoma
- Deep, centrally located tumors have a significant risk of recurrence and dedifferentiation and should be designated as WDLPS
- Atypical lipomatous tumor (ALT) is used for tumors of the extremities and trunk that are amenable to complete resection
- Subtypes: lipoma-like (adipocytic), sclerosing, inflammatory
- Not recommended: atypical lipoma
Dedifferentiated liposarcoma
- Using FNCLCC criteria, DDLPS should be given a differentiation score of 3
- Low grade differentiation (grade 2 by FNCLCC) is officially recognized but there is no consensus regarding diagnostic criteria and prognostic significance (Am J Surg Pathol 2007;31:1, Am J Surg Pathol 1997;21:271)
Myxoid liposarcoma
- High grade MLPS: > 5% high grade morphology is associated with more aggressive behavior (Ann Surg Oncol 2012;19:1081, Sarcoma 2011;2011:538085)
- Not recommended: round cell liposarcoma
Pleomorphic liposarcoma
- Subtype: epithelioid

ICD coding

Well differentiated liposarcoma
- ICD-O: 8851/3 - liposarcoma, well differentiated
- ICD-10: C49.9 - liposarcoma, well differentiated type
- ICD-11: 2B5H & XH7Y61 - well differentiated lipomatous tumor, primary site & liposarcoma, well differentiated
Dedifferentiated liposarcoma
- ICD-O: 8858/3 - dedifferentiated liposarcoma
- ICD-10: C49.9 - dedifferentiated liposarcoma
- ICD-11: 2B59.Y & XH1C03 - liposarcoma, other specified primary site & dedifferentiated liposarcoma
Myxoid liposarcoma
- ICD-O: 8852/3 - myxoid liposarcoma
- ICD-10: C49.9 - myxoid liposarcoma
- ICD-11: 2B59.Y & XH3EL0 - liposarcoma, other specified primary site & myxoid liposarcoma
Pleomorphic liposarcoma
- ICD-O: 8854/3 - pleomorphic liposarcoma
- ICD-10: C49.9 - pleomorphic liposarcoma
- ICD-11: 2B59.Y & XH25R1 - liposarcoma, other specified primary site & pleomorphic liposarcoma

Epidemiology

Most common paratesticular malignancy in adults but overall exceedingly rare, with Urol Oncol 2014;32:52.e19)
Most common in middle aged and older adults (Am J Surg Pathol 2003;27:40)
Third most common location for WDLPS and DDLPS after retroperitoneum and limbs (10 - 15% of cases) (Am J Surg Pathol 1992;16:1051, Am J Surg Pathol 1997;21:271)
Other liposarcomas are exceedingly rare in this location, particularly as primary tumors; must rule out metastasis and DDLPS

Sites

Majority of cases arise from spermatic cord; less commonly testicular tunica and epididymis (Am J Surg Pathol 2003;27:40)

Pathophysiology

See Molecular / cytogenetics description

Etiology

Mostly sporadic; rarely associated with Li-Fraumeni syndrome (p53 positive, MDM2 negative) (Pediatr Dev Pathol 2010;13:218, Hum Pathol 2024;147:82)

Diagrams / tables

N/A

Clinical features

Painless paratesticular swelling or mass, usually longstanding
Rapidly enlarging mass suggestive of a high grade tumor
Rarely presents as inguinal hernia, inflammatory process or testicular tumor (Case Rep Med 2014;2014:735380, J Clin Diagn Res 2014;8:165)
DDLPS can occur in the primary tumor (90%) or recurrences (10%) of WDLPS (Am J Surg Pathol 1992;16:1051)

Diagnosis

In conjunction with imaging findings, initial diagnosis can be made on targeted biopsy
Due to intratumoral heterogeneity, surgical resection is recommended for definitive classification (AJR Am J Roentgenol 2021;216:997)
Ancillary testing may be needed in difficult cases (see Molecular / cytogenetics description)

Laboratory

No specific laboratory abnormality is known

Radiology description

Well differentiated liposarcoma
- Variable fatty component
- Septal and nodular enhancement, corresponding to areas of stromal fibrosis / sclerosis (Radiographics 2005;25:1371)
Dedifferentiated liposarcoma
- Enhancing nonfatty mass, in association with lipomatous mass or abnormal fat (Radiographics 2005;25:1371, Sarcoma 2020;2020:8363986)
Myxoid liposarcoma
- Subtle fatty component in lacy / linear pattern (Radiographics 2000;20:1007)
- Nodular enhancement represents high grade areas (Radiol Case Rep 2017;12:811)
Pleomorphic liposarcoma
- Heterogeneous enhancing mass with necrosis and hemorrhage; may have small fatty component (Radiographics 2005;25:1371)

Radiology images

Images hosted on other servers:

DDLPS CT abdomen / pelvis

DDLPS scrotal ultrasound

WDLPS CT pelvis

Nonhomogeneous right scrotal mass

No evidence of tissue infiltration

Prognostic factors

Well differentiated liposarcoma
- Local recurrence is common (60%) but time to recurrence is highly variable (Am J Surg Pathol 2003;27:40)
- No metastatic potential (unless dedifferentiation occurs)
- Progression to DDLPS is the most important prognostic factor and a time dependent phenomenon (Am J Surg Pathol 1992;16:1051)
Dedifferentiated liposarcoma
- Relatively better prognosis compared to other high grade sarcomas (Am J Surg Pathol 1994;18:1213, Am J Surg Pathol 1997;21:271)
- Rhabdomyoblastic differentiation associated with significantly higher mortality (5 year survival is 29%; 75% without myogenic differentiation) (Am J Surg Pathol 2015;39:383)
Very few confirmed cases of paratesticular MLPS and PLPS in the literature

Case reports

23 year old man with paratesticular myxoid liposarcoma (Rare Tumors 2010;2:e23)
46 year old man with paratesticular myxoid liposarcoma (Pathol Res Pract 2013;209:124)
50 year old man with paratesticular well differentiated liposarcoma mimicking a testicular tumor (J Clin Diagn Res 2014;8:165)
50 year old man with recurrent paratesticular well differentiated liposarcoma (World J Surg Oncol 2014;12:276)
59 year old man with paratesticular dedifferentiated liposarcoma (Int J Surg Case Rep 2020;72:418)
61 year old man with paratesticular dedifferentiated liposarcoma with osseous metaplasia (Case Rep Urol 2015;2015:965876)
61 year old man with bilateral paratesticular dedifferentiated liposarcoma with homologous differentiation (J Surg Tech Case Rep 2014;6:15)
70 year old man with paratesticular dedifferentiated liposarcoma with osteosarcomatous differentiation mimicking a complex hydrocele (J Surg Case Rep 2020;2020:rjaa342)
70 year old man with paratesticular dedifferentiated liposarcoma presenting as inguinal hernia (Case Rep Med 2014;2014:735380)
75 year old man with paratesticular dedifferentiated liposarcoma and lung metastases (J Med Case Rep 2020;14:86)
77 year old man with paratesticular dedifferentiated liposarcoma with leiomyosarcomatous differentiation (Diagn Pathol 2013;8:142)

Treatment

Well differentiated liposarcoma
- Surgical resection (en bloc excision, including radical orchiectomy, involving high ligation of the spermatic cord) for primary and recurrent tumors (Int J Clin Oncol 2020;25:2099)
- Wide re-resection, including hemiscrotectomy, may be performed to prevent local recurrence in cases with inadequate resection margins (J Surg Oncol 2018;117:1464)
- Radiation therapy for widely positive margins and unresectable tumors (Cancer Radiother 2017;21:16)
Dedifferentiated liposarcoma
- Surgical resection with negative margins, particularly for dedifferentiated component (Int J Clin Oncol 2020;25:2099)
- Neoadjuvant radiation or palbociclib (CDK4 inhibitor) if unresectable or high risk of recurrence (Curr Treat Options Oncol 2020;21:15)
Myxoid liposarcoma
- Surgical resection with negative margins (Int J Clin Oncol 2020;25:2099)
- Neoadjuvant or adjuvant radiation therapy in certain clinical situations (Cancer 2009;115:3254)
- Unresectable tumors can also be treated with trabectedin (Lancet Oncol 2007;8:595)
Pleomorphic liposarcoma
- Surgical resection with negative margins, with adjuvant radiation or chemotherapy (Oncol Res Treat 2022;45:525)

Clinical images

Images hosted on other servers:

Myxoid liposarcoma

Tumor after chemotherapy

Gross description

Well differentiated liposarcoma
- Well defined, multilobulated
- Adipocytic areas are marbled and yellow-white; fibrotic / sclerotic areas are firm and white-gray; myxoid areas are gelatinous (Virchows Arch 2010;456:167)
Dedifferentiated liposarcoma
- Firm, fleshy, tan-gray nodules; occasionally gradual transition or infiltrative (Virchows Arch 2010;456:167)
- Well differentiated component may be limited or absent
Myxoid liposarcoma
- Well circumscribed, multinodular, gelatinous
- High grade areas are tan-gray, firm, fleshy
Pleomorphic liposarcoma
- Variable growth (well defined, infiltrative, multinodular)
- Firm, white-yellow cut surface; often areas of necrosis and hemorrhage

Gross images

Contributed by Sara Moscovita Falzarano, M.D., Ph.D. and Debra L. Zynger, M.D.

Well differentiated liposarcoma

Dedifferentiated liposarcoma

Images hosted on other servers:

Well differentiated liposarcoma

Dedifferentiated liposarcoma

Frozen section description

Not routinely used for diagnosis; may be helpful to evaluate for high grade sarcoma if no prior imaging or biopsy

Frozen section images

N/A

Microscopic (histologic) description

Well differentiated liposarcoma
- 3 main morphologic subtypes, often multiple / mixed patterns; no prognostic significance (Virchows Arch 2010;456:167)
- Lipoma-like
  - Lobules of variably sized mature adipocytes
  - Lipoblasts; not required for diagnosis
  - Thickened fibrous septa containing atypical and multinucleated stromal cells
  - Areas may be indistinguishable from lipoma
- Sclerotic
  - Common pattern in paratesticular tumors
  - Hypocellular dense collagenous stroma with scattered atypical cells
- Inflammatory
  - Prominent chronic mixed inflammatory infiltrate; obscures atypical stromal cells (Am J Surg Pathol 1997;21:518)
  - Can be superimposed on another morphologic subtype
- Other patterns: myxoid and spindle cell (resembling MLPS), metaplastic bone / cartilage
Dedifferentiated liposarcoma
- Wide morphologic spectrum and intratumoral heterogeneity (Virchows Arch 2010;456:167)
- Most commonly high grade with low grade foci; rarely entirely low grade
- High grade
  - Most often resembles undifferentiated pleomorphic sarcoma (UPS)
  - Can also mimic other pleomorphic and spindle cell sarcomas (myxofibrosarcoma, solitary fibrous tumor, leiomyosarcoma and malignant peripheral nerve sheath tumor)
  - Deep tumors previously diagnosed as inflammatory UPS (formerly malignant fibrous histiocytoma); now favored to represent the inflammatory variant of DDLPS (J Pathol 2004;203:822)
- Low grade
  - Usually resembles a low grade spindle cell tumor (fibromatosis, nodular fasciitis, perineurioma / meningioma, low grade fibromyxoid sarcoma)
  - Distinction between cellular WDLPS and low grade DDLPS is controversial (Am J Surg Pathol 2023;47:649)
    - Distinct clonal proliferations with a mitotic rate > 5/10 high power fields are generally considered low grade dedifferentiation
- Heterologous differentiation in 5 - 10% of cases
- Rare cases with homologous differentiation, pleomorphic lipoblasts (Am J Surg Pathol 2010;34:1122)
Myxoid liposarcoma
- Hypocellular lobules with increased cellularity at the periphery
- Prominent myxoid stroma; may form mucin pools (pulmonary edema-like pattern)
- Delicate, thin walled branching capillaries (chicken wire or chicken feet appearance)
- Small spindled to stellate cells with uniform, bland nuclei, scant eosinophilic cytoplasm
- Lipoblasts; often univacuolated (signet ring)
- No significant cytologic atypia or mitotic activity
- Mature adipocytic component in some cases; rarely metaplastic bone or cartilage (Am J Clin Pathol 2012;137:229)
- High grade areas composed of hypercellular sheets of round cells; increased nuclear grade and mitotic activity
Pleomorphic liposarcoma
- Variable number of pleomorphic lipoblasts admixed with high grade sarcoma, most often resembling undifferentiated pleomorphic sarcoma or myxofibrosarcoma (Am J Surg Pathol 2002;26:601, Am J Surg Pathol 2004;28:1257)
- Univacuolated (signet ring) lipoblasts; can be extensive
- Epithelioid morphology in 25%; contains nonlipogenic cells with cytoplasmic vacuolization (Mod Pathol 1999;12:722)

Microscopic (histologic) images

Contributed by Melanie Bourgeau, M.D.

Lipoma-like WDLPS

WDLPS with ropey collagen

Sclerotic WDLPS

Inflammatory WDLPS

Low grade DDLPS, fibromatosis pattern

Low grade DDLPS, whorling pattern

Low grade DDLPS, storiform pattern

Low grade DDLPS, myogenic differentiation

Low grade DDLPS, metaplastic

High grade DDLPS, myxofibrosarcoma pattern

High grade DDLPS, pleomorphic pattern

High grade DDLPS, ectatic vessels

High grade DDLPS, inflammatory pattern

High grade DDLPS, homologous differentiation

Myxoid liposarcoma, low grade

Myxoid liposarcoma, high grade

Pleomorphic liposarcoma

Pleomorphic liposarcoma, epithelioid subtype

Virtual slides

Images hosted on other servers:

Lipoma-like well differentiated liposarcoma

Sclerosing well differentiated liposarcoma

Inflammatory well differentiated liposarcoma

Dedifferentiated liposarcoma

Myxoid liposarcoma

Pleomorphic liposarcoma

Cytology description

Not routinely performed on paratesticular tumors

Cytology images

N/A

Immunofluorescence description

N/A

Immunofluorescence images

N/A

Positive stains

Well differentiated liposarcoma
- MDM2 (89 - 100%), CDK4 (68 - 91%) (Am J Surg Pathol 2005;29:1340, Hum Pathol 2017;59:34)
  - Lower sensitivity (41%) in lipoma-like WDLPS (Am J Surg Pathol 2016;40:1647)
  - Can also stain endothelial cells and histiocytes in areas of fat necrosis (Am J Surg Pathol 2016;40:1647)
- HMGA2 (87%); can be easier to interpret (strong, more diffuse staining versus MDM2) but positive in most lipomas (Mod Pathol 2010;23:1657)
- Variable S100 (adipocytes), CD34 (spindle cells)
Dedifferentiated liposarcoma
- MDM2 (95 - 100%), CDK4 (83 - 92%) (Am J Surg Pathol 2005;29:1340, Hum Pathol 2017;59:34)
- Cases without myogenic differentiation can be focally positive for desmin (Am J Surg Pathol 2007;31:1557)
Myxoid liposarcoma
- S100 (89%): primitive mesenchymal cells and lipoblasts (Am J Clin Pathol 1995;103:20)
- SOX11 (90%): not specific (Histopathology 2019;74:391)
- DDIT3 (98%): 96 - 100% specific but not widely available (Histopathology 2021;79:106)
  - Rare focal staining (up to 40% of cells) in other liposarcomas
Pleomorphic liposarcoma
- Focal S100 (33 - 54%, lipoblasts)
- Focal MelanA in some cases of epithelioid PLPS (Semin Diagn Pathol 2019;36:122)

Negative stains

Well differentiated liposarcoma
- Cytokeratins, melanocytic markers (HMB45) (Case Rep Nephrol 2012;2012:374107)
Myxoid liposarcoma
- MDM2, CDK4 (Am J Surg Pathol 2005;29:1340)
- CD34 (Am J Clin Pathol 1995;103:20)
Pleomorphic liposarcoma
- MDM2, CDK4 (Am J Surg Pathol 2005;29:1340)
- Focal SMA (45% positive), desmin (13% positive) (Am J Surg Pathol 2004;28:1257, Mod Pathol 1999;12:722)
- Focal cytokeratin (21% positive): more common in epithelioid subtype (38 - 45% positive) (Mod Pathol 1999;12:722)

Electron microscopy description

N/A

Electron microscopy images

N/A

Molecular / cytogenetics description

Well differentiated liposarcoma
- Supernumerary ring or giant marker chromosomes with material from 12q13-15 region (Genes Chromosomes Cancer 1999;24:30)
- MDM2 amplification is main driver of tumorigenesis; other genes co-amplified (CDK4, HMGA2) (Clin Cancer Res 2009;15:5696, Int J Cancer 2008;122:2233)
- MDM2, CDK4 amplifications detected by FISH or real time PCR (Am J Surg Pathol 2007;31:1476)
Dedifferentiated liposarcoma
- Often gains additional cytogenetic alterations
- More complex karyotype with high copy number variation but low rate of mutation (Oncotarget 2015;6:42429)
Myxoid liposarcoma
- Alterations involving 12q13 breakpoint, most commonly t(12;16)(q13;p11.2), resulting in FUS::DDIT3 fusion (95% of cases)
- Rarely, t(12;22)(q13;q12.2) EWSR1::DDIT3 or more complex rearrangements (Oncogene 1996;12:489)
- DDIT3 FISH is very sensitive and specific; rare false negatives for non-FUS::DDIT3 fusions (Genes Chromosomes Cancer 2023;62:167)
Pleomorphic liposarcoma
- Complex karyotype, with high intratumoral heterogeneity and copy number variations; similar to undifferentiated pleomorphic sarcoma and high grade myxofibrosarcoma (Diagnostics (Basel) 2021;11:430)

Molecular / cytogenetics images

N/A

Videos

Liposarcoma (general overview)

Well differentiated liposarcoma

Dedifferentiated liposarcoma

Dedifferentiated liposarcoma with osteosarcomatous differentiation

Myxoid liposarcoma, low grade

Myxoid liposarcoma, high grade

Pleomorphic liposarcoma

Pleomorphic liposarcoma, epithelioid variant

Sample pathology report

Testicle, partial orchiectomy:
- Well differentiated liposarcoma (4 cm) (see comment)
- No evidence of dedifferentiation
- Surgical margins are negative for tumor
- Comment: Histologic sections demonstrate a well differentiated adipocytic tumor and fibrous septa containing atypical multinucleated stromal cells. Areas with sclerotic and inflammatory morphology are also seen. Immunohistochemistry for MDM2 is strongly positive in lesional cells, consistent with the above diagnosis.
Note: if resection, the soft tissue synoptic template should be used in addition, with staging performed according to retroperitoneum

Testicle, radical orchiectomy:
- Dedifferentiated liposarcoma (10 cm) (see comment)
- Well differentiated liposarcoma component is present
- Surgical margins are negative for tumor
- Comment: Histologic sections demonstrate a high grade nonlipogenic sarcoma with pleomorphic and spindle morphology, in association with a well differentiated adipocytic tumor. The dedifferentiated (nonlipogenic) component constitutes ~60% of the tumor. Immunohistochemistry for MDM2 is strongly positive in lesional cells, consistent with the above diagnosis.

Testicle, partial orchiectomy:
- Myxoid liposarcoma, low grade (3 cm) (see comment)
- Surgical margins are negative for tumor
- Comment: Histologic sections demonstrate a hypocellular myxoid lesion composed of small, bland, primitive mesenchymal cells and delicate, branching capillaries. There are occasional univacuolated and multivacuolated lipoblasts. No high grade features are identified. FISH is positive for DDIT3 rearrangement, confirming the above diagnosis.

Testicle, radical orchiectomy:
- Myxoid liposarcoma, high grade (5 cm) (see comment)
- Surgical margins are negative for tumor
- Comment: Histologic sections demonstrate characteristic features of a low grade myxoid liposarcoma as well as areas with high grade morphology, which constitutes ~30% of the tumor. FISH is positive for DDIT3 rearrangement, confirming the above diagnosis.

Testicle, radical orchiectomy:
- Pleomorphic liposarcoma (6 cm) (see comment)
- Surgical margins are negative for tumor
- Comment: Histologic sections demonstrate a high grade pleomorphic and spindle cell sarcoma with focal / extensive pleomorphic lipoblasts. FISH is negative for MDM2 amplification, consistent with the above diagnosis.

Differential diagnosis

Well differentiated liposarcoma, lipoma-like subtype
- Lipoma:
  - Most fatty spermatic cord lesions are benign; incidental liposarcomas are exceedingly rare (J Surg Oncol 1999;71:50)
  - MDM2 immunohistochemistry has lower sensitivity in lipoma-like WDLPS with minimal atypia (Am J Surg Pathol 2016;40:1647)
  - MDM2 FISH is recommended in large tumors (> 10 cm) with equivocal atypia, concerning imaging findings or recurrent tumors (Histopathology 2022;80:369, Am J Surg Pathol 2015;39:1433)
- Spindle cell / pleomorphic lipoma and atypical spindle cell / pleomorphic lipomatous tumor (ASPLT):
  - Ropey collagen, myxoid change and floret giant cells can also be seen in some cases of WDLPS
  - Lipoblasts can be seen in ASPLT and WDLPS
  - Typically do not occur in the paratesticular region
  - RB1 loss, 13q14 deletions (Am J Surg Pathol 2012;36:1119, Am J Surg Pathol 2021;45:1282)
  - Rare focal staining for MDM2 or CDK4 in ASPLT; MDM2 not amplified (Am J Surg Pathol 2021;45:1282)
  - More atypia in WDLPS but can be subtle
Well differentiated liposarcoma, sclerotic subtype
- Lipoblastoma:
  - Can demonstrate fatty maturation and stromal fibrosis
  - Occurs in infants and young children
  - PLAG1 gene rearrangements (8q12) (Cancer Res 2000;60:4869)
Well differentiated liposarcoma, inflammatory subtype
- Inflammatory myofibroblastic tumor, chronic inflammatory processes (IgG4 related disease) and lymphoproliferative disorders:
  - MDM2 IHC can be positive in areas of fat necrosis but not MDM2 FISH (no amplification)
  - Stromal cells in WDLPS have greater atypia but may be focal and obscured by inflammation
  - IgG4 positive plasma cells not increased in WDLPS (Mod Pathol 2012;25:1181)
  - ALK rearrangements in ~50% of inflammatory myofibroblastic tumors (Mod Pathol 2001;14:569)
Dedifferentiated liposarcoma
- Leiomyosarcoma and rhabdomyosarcoma:
  - DDLPS with extensive heterologous differentiation may be difficult to differentiate from primary myogenic sarcomas
  - No well differentiated component or MDM2 amplification
  - DDLPS has more morphologic heterogeneity
- Solitary fibrous tumor:
  - Subset has mature adipocytic component (lipomatous variant)
  - Diffusely positive for CD34 and STAT6
    - Rare focal staining for STAT6 in DDLPS (Mod Pathol 2014;27:1231)
  - No MDM2 amplification
- Dermatofibrosarcoma protuberans (DFSP):
  - Infiltrative growth and extensive entrapped nonneoplastic fat may falsely suggest lipomatous differentiation
  - Diffusely positive for CD34
  - t(17;22)(q22;q13) COL1A1::PDGFB gene fusion
- Malignant peripheral nerve sheath tumor (MPNST):
  - MDM2 gene amplification reported in small minority of cases (Arch Pathol Lab Med 2012;136:95)
  - Heterologous differentiation in a subset of tumors, typically rhabdomyosarcomatous (malignant triton tumor); there have been rare reports of liposarcomatous differentiation (Pathol Res Pract 2010;206:138)
  - Unlike DDLPS, typically has a relatively uniform appearance throughout
  - Loss of staining for H3K27me3 in conventional (spindle cell) MPNST
  - Diffuse S100, SOX10 positivity, loss of INI1 in epithelioid MPNST
- Sarcomatoid carcinoma and mesothelioma:
  - At least focal positivity for keratins or EMA; limited staining for mesothelial markers in sarcomatoid mesothelioma
  - No WDLPS component
  - Rare instances of MDM2 amplification reported in some carcinomas, although none in the paratestis (Hum Pathol 2019;87:28)
  - Clinical history, imaging and presence of nonsarcomatoid component may be helpful
Myxoid liposarcoma, low grade
- Extraskeletal myxoid chondrosarcoma:
  - Primitive mesenchymal cells and matrix appear similar to MLPS
  - No lipoblasts or prominent capillary vasculature
  - t(9;22)(q22;q12) EWSR1::NR4A3 fusion
  - Negative for DDIT3 overexpression and DDIT3 gene rearrangement
- Lipoblastoma:
  - Occurs in infants and young children
  - Primitive myxoid areas resemble MPLS
  - PLAG1 gene rearrangements (8q12) (Cancer Res 2000;60:4869)
Myxoid liposarcoma, high grade
- Undifferentiated round cell sarcomas (Ewing, BCOR rearranged, CIC::DUX):
  - May be indistinguishable if no low grade MLPS component
  - DDIT3 immunostain is highly sensitive and specific for MLPS in this context (Histopathology 2021;79:106)
  - All have characteristic gene rearrangements; FISH probes available for most
Pleomorphic liposarcoma
- Undifferentiated pleomorphic sarcoma:
  - Pleomorphic lipoblasts may be limited / focal in PLPS; may require extensive sampling
- Epithelioid variant can resemble melanoma or carcinoma:
  - Melanoma is more diffusely positive for S100 and MelanA as well as other melanocytic markers (SOX10, HMB45)
  - Carcinomas positive for multiple keratins or lineage / site specific markers (PAX8, GATA3, NKX3.1, etc.)
  - Clinical history and imaging may also be helpful for metastasis

Additional references

WHO Classification of Tumours Editorial Board: Soft Tissue and Bone Tumours, 5th Edition, 2020

Board review style question #1

A 70 year old man is found to have an 11 cm cord lipoma during elective surgery for inguinal hernia repair. Representative histologic findings are shown in the image provided above. Which of the following tests would be most helpful in this context?

FISH for DDIT3 rearrangement
FISH for MDM2 amplification
Immunohistochemistry for HMGA2
Immunohistochemistry for MDM2
Immunohistochemistry for RB1

Board review style answer #1

B. FISH for MDM2 amplification. The microscopic image demonstrates variably sized mature adipocytes and small areas of fibrous bands containing spindle cells without significant atypia. MDM2 FISH is recommended for deep / centrally located or large tumors (> 10 cm) with equivocal atypia, concerning clinical / imaging findings and recurrent tumors. Answer D is incorrect because MDM2 IHC has low sensitivity in distinguishing between lipoma and lipoma-like well differentiated liposarcoma (WDLPS). Answer C is incorrect because HMGA2 is positive in both lipomas and WDLPS. Answer E is incorrect because RB1 loss is seen in spindle cell / pleomorphic lipoma and atypical spindle cell pleomorphic lipomatous tumor (ASPLT) and is not a feature of conventional lipomas or WDLPS. Answer A is incorrect because although DDIT3 (12q13) may be amplified in some cases of WDLPS, DDIT3 rearrangements are characteristic of myxoid liposarcoma and do not occur in lipomas or WDLPS.

Comment Here

Reference: Liposarcoma

Board review style question #2

A 75 year old man presents with worsening scrotal swelling. On exam, there is a grossly apparent, large, right inguinal mass with no skin changes or signs of infection. A computerized tomography (CT) scan reveals a right inguinal canal ovoidal soft tissue mass, measuring 6 cm in greatest dimension, that was not present on previous imaging performed 12 months prior for chronic back pain. No other abnormalities are noted. Clinical history is otherwise unremarkable. Representative histologic findings from the resected mass are shown in the provided image. Tumor cells are focally positive for desmin and STAT6. FISH is positive for MDM2 amplification. What is the most likely diagnosis?

Dedifferentiated liposarcoma
Leiomyosarcoma
Sarcomatoid carcinoma
Solitary fibrous tumor
Undifferentiated pleomorphic sarcoma

Board review style answer #2

A. Dedifferentiated liposarcoma (DDLPS). The microscopic image demonstrates atypical spindled and multinucleated cells arranged in short fascicles. In this setting, DDLPS is the most likely diagnosis. Identification of a well differentiated liposarcoma (WDLPS) component is the most specific feature but is not identified in all cases. Answer B is incorrect because leiomyosarcomas do not have MDM2 amplification; in addition, they usually demonstrate more extensive staining for at least 2 myogenic markers. Focal staining for desmin is seen in DDLPS with and without myogenic differentiation. Answer D is incorrect because solitary fibrous tumors are characterized by NAB2::STAT6 fusions and do not have MDM2 amplifications. Focal staining for STAT6 may be related to the close proximity of the STAT6 gene (12q13) to the region amplified in WDLPS / DDLPS (12q13-15). Answer E is incorrect because undifferentiated pleomorphic sarcoma is a diagnosis of exclusion and therefore should be negative for MDM2 amplification. Answer C is incorrect because the lack of any significant clinical history or other imaging findings, together with the typical location and molecular alteration, makes DDLPS the most likely diagnosis in this case.

Comment Here

Reference: Liposarcoma

Liposarcoma

Table of Contents

Epidemiology

Rare; mean 63 years, range 41 to 87 years but younger patients have been reported
Most common malignant tumor involving the spermatic cord (46%) (Urol Oncol 2014;32:52)
Paratesticular liposarcomas account for ~12% of all liposarcomas
Well differentiated tumors tend to recur, often late yet have a good outcome; dedifferentiated tumors have metastatic potential

Sites

Usually arise from spermatic cord; also testicular tunica; rarely epididymis

Pathophysiology / etiology

Recurrent molecular abnormalities have been detected in liposarcomas, which differ between each subtype
Well differentiated liposarcoma is characterized by the presence of amplification involving 12q13-q15, which can be identified using FISH or CGH
- This amplification is associated with the occurrence of supernumerary ring chromosomes or giant rod chromosomes
- The 12q13-q15 region contains multiple genes implicated in the pathogenesis of liposarcoma, including MDM2, CDK4, HMGA2, TSPAN31, OS1, OS9, CHOP, STAT6 and GLI (Virchows Arch 2010;456:277, Genes Chromosomes Cancer 1999;24:30, Genes Chromosomes Cancer 1995;14:8, Cancer Genet Cytogenet 1997;99:14, Mod Pathol 2014;27:1231)
Myxoid liposarcoma is characterized by the presence of t(12;16)(q13;p11), which results in the FUS-CHOP gene fusion that is present in over 95% of cases
- Most often, the amino terminal domain of FUS (also known as TLS) is fused to C/EBP homologous protein (CHOP, also known as DDIT3 or GADD153)
- In rare cases, an alternative translocation event is found, t(12;22)(q13;q12), that results in formation of the novel fusion oncogene where EWS takes the place of FUS
- RET, IGF1R and IGF2 are highly expressed in MLPS and promote cell survival through both the PI3K/Akt and Ras-Raf-ERK/MAPK pathways (Hum Pathol 2009;40:1244, Nat Clin Pract Oncol 2007;4:591) and represent potential therapeutic targets
Pleomorphic liposarcoma shows complex chromosomal abnormalities with gains in 1p, 1q21-q32,2q, 3p, 3q, 5p12-p15, 5q, 6p21, 7p, 7q22 and losses involving 1q, 2q, 3p, 4q, 10q, 11q, 12p13, 13q14, 13q21-qter, 13q23-24
- 60% of pleomorphic liposarcoma show deletion of 13q14.2-q14.3, which houses the RB1 gene
- MAD2 gene is also commonly amplified in pleomorphic liposarcoma (Cancer Res 2007;67:6626, Curr Biol 2010;20:328)

Clinical features

Painless scrotal mass of longstanding duration is the most common presentation
Rarely is of recent duration
May present as an inguinal hernia, hydrocele, hematocoele or other testicular tumor

Diagnosis

Diagnosis requires histological examination
Clinical differentiation from other testicular and paratesticular sarcomas is not possible

Laboratory

No specific laboratory abnormality is known
Serum markers for germ cell tumors and sex cord tumors are negative

Radiology images

Images hosted on other servers:

Nonhomogeneous right scrotal mass

No evidence of tissue infiltration

Large heterogenous extratesticular mass

CT of paratesticular liposarcoma presenting as hernia

Prognostic factors

Recurrence of well differentiated paratesticular liposarcoma after complete resection is extremely rare (Malays J Med Sci 2013;20:95)
Recurrence rate is < 10% when resection margin is 10 mm or greater
Risk factors for local recurrence / progression:
- High grade tumor morphology
- Large tumor size ( > 5 cm)
- Inadequate / suboptimal resection

Case reports

23 year old man with paratesticular myxoid liposarcoma (Rare Tumors 2010;2:e23)
46 year old man with paratesticular myxoid / round cell liposarcoma (Pathol Res Pract 2013;209:124)
50 year old man with recurrence of paratesticular liposarcoma (World J Surg Oncol 2014;12:276)
50 year old man with paratesticular liposarcoma masquerading as a testicular tumor (J Clin Diagn Res 2014;8:165)
65 year old man with bilateral paratesticular liposarcoma (J Surg Tech Case Rep 2014;6:15)
77 year old man with paratesticular dedifferentiated liposarcoma with leiomyosarcomatous differentiation (Diagn Pathol 2013;8:142)
Mixed paratesticular liposarcoma with osteosarcoma elements (Clin Transl Oncol 2010;12:148)
Well differentiated inflammatory liposarcoma (Am J Surg Pathol 1997;21:518)
Dedifferentiated liposarcoma (Am J Surg Pathol 1994;18:1213)

Treatment

Usual treatment is orchidectomy through inguinal approach, with adequate margins
Elective inguinal node dissection is not indicated
Cases with a margin < 10 mm or with residual tumor may benefit from radiotherapy; liposarcoma is radiosensitive and the well differentiated subtype is most sensitive
Radiotherapy also useful for unresectable cases
Role of chemotherapy (ex: doxorubicin) is debated; no clear benefit has been shown
Surgical excision is also the cornerstone of management of recurrent cases

Clinical images

Images hosted on other servers:

Scrotal mass at presentation

Tumor after chemotherapy

Gross description

Tumors are usually large, appear to be relatively circumscribed
Cut surface may be yellow, fatty with interspersed fibrous septae or may be uniformly firm and white
Areas of necrosis and hemorrhage may be seen in high grade tumors

Gross images

Images hosted on other servers:

Tumor mass

Yellow and myxoid areas

White yellow to red brown cut surface, marked necrosis

Right paratesticular mass with solid, yellow white, fatty, myxoid areas

Grossly firm tumor

Microscopic (histologic) description

Mature adipocytes, atypical spindle cells and multivacuolated lipoblasts embedded in a loose myxoid to dense fibrous stroma
All variants of liposarcoma may be seen; well differentiated or dedifferentiated liposarcomas are most common
Heterologous leiomyosarcomatous or osteosarcomatous differentiation (Am J Surg Pathol 2002;26:742) and osseous metaplasia (Case Rep Urol 2015;2015:965876) have been reported but their presence does not appear to affect prognosis
Pleomorphic liposarcoma accounts for < 5% of cases and is characterized by MFH-like histology with a disorderly pattern, pleomorphic cells, multinucleated bizarre giant cells and lipoblasts
Giant lipoblasts have enlarged globular or angular hyperchromatic nuclei
Other variants have also been reported

Microscopic (histologic) images

Images hosted on other servers:

Well differentiated liposarcoma:

Atypical spindle cells and lipoblasts

Mature adipocytes and lipoblasts

Well differentiated with dedifferentiated component:

Hypercellular stroma with atypical adipocytes

Atypical adipocytes with enlarged nuclei

Dedifferentiated with leiomyosarcomatous component:

H&E

MDM2+, CDK4+, alpha smooth muscle actin+, desmin+

Myxoid liposarcoma:

Lipoblasts contain lipid vacuoles

Plexiform arrangement of capillaries

Positive stains

MDM2, CDK4 (usually negative in myxoid / round cell and spindle subtypes)
S100
Heterologous elements may show positivity for desmin, actin, etc., based on the differentiation and dedifferetiated tumors have variable reactivity
STAT6 may rarely be positive (reported in dedifferentiated liposarcoma)

Negative stains

HMB45, CD34, actin, keratins, desmin are negative in the lipoblasts

Differential diagnosis

Aggressive angiomyxoma
Angiomyolipoma: HMB45 positive
Embryonal rhabdomyosarcoma
Fibromatosis: resembles sclerosing liposarcoma but is more cellular, has no atypia, has denser collagen and is CD34 negative
Inflammatory fibrous pseudotumor: resembles inflammatory liposarcoma but has bland spindle cells
Inflammatory myofibroblastic tumor
Lipoma: mimics well differentiated liposarcoma but has no atypical adipocytes and no lipoblasts
Lymphoma: mimics inflammatory liposarcoma but has monoclonal lymphocytes (usually B cell not T cell)
Primary retroperitoneal sarcoma extension
Sclerosing lipogranuloma

Additional references

Liposarcoma of soft tissue - general

Melanotic neuroectodermal tumor

Table of Contents

Definition / general

A rare benign tumor of neuroectodermal origin with biphasic population of neuroblastic cells and pigmented epithelial cells

Terminology

First described by Krompecher in 1918 as congenital melanocarcinoma of alveolar process of maxilla (BMJ Case Rep 2010 Nov 23;2010)
Previously known as: melanotic adamantinoma, melanotic hamartoma, melanotic progonoma, pigmented congenital epulis, pigmented neuroectodermal tumor, retinal anlage tumor, retinoblastic teratoma

Epidemiology

Rare
Usually young infants (mean 7 months, range 3 months to 8 years) but also reported in adults
Most common in maxilla of infants with 2:1 female preponderance (see Mandible - Maxilla Chapter)
Also reported in long bones (Cancer 1983;52:661), uterus, skin and brain
Epididymis is uncommon site

Etiology

Precise origin is unknown but suggested to be of neural crest origin, due to a developmental error in evolution of mesonephric ducts, where neural crest cells migrate (J Pathol Bacteriol 1967;93:549)
A dysembryogenetic neoplasm that recapitulates embryonic retinal development (Am J Surg Pathol 1991;15:233)
Relationship with other neural crest tumors such as PNET, neuroblastoma, etc. is not clear

Clinical features

Firm, rapidly enlarging mass, sometimes associated with hydrocele
Usually noticed at birth or within the first year of life
Lymphatic space invasion is associated with hydrocele formation

Diagnosis

Suspected clinically and confirmed histologically

Laboratory

Urinary vanillylmandelic acid (VMA) / homovanillic acid (HVA) elevated in some cases

Prognostic factors

Good prognosis, rarely metastasizes (Cancer 1983;52:661), does recur (Indian J Pathol Microbiol 2005;48:363)
Local recurrence rate in jaw tumors is ~15%
No reliable histological features predict recurrence or metastasis

Case reports

Infant with tumor of epididymis and testis (Indian J Pathol Microbiol 2005;48:363)
4 month old boy with tumor in epididymis (Urol Int 1996;57:262)
6 month old boys (Urology 1995;46:415, Zentralbl Pathol 1994;140:181)

Treatment

Benign behavior (Hum Pathol 1985;16:416)
Simple orchiectomy is usually curative

Gross description

Round to oval, circumscribed, firm epididymal mass, usually < 4 cm
Cut surface is grey white with areas of pigmentation; color depends on amount of pigmentation

Gross images

Images hosted on other servers:

Maxillary tumors

Microscopic (histologic) description

Appears to recapitulate retina at 5 weeks of gestation
Contains dual population of cells: neuroblastic cells with high nuclear cytoplasmic ratio and epithelioid cells containing melanin
Mitoses may be present, usually in neuroblastic component

Microscopic (histologic) images

Images hosted on other servers:

Maxillary tumor: H&E and stains

Cytology description

Dual cell population with dyscohesive primitive neuroblast like cells in fibrillary background, admixed with clusters of larger cells having melanin pigment (Acta Cytol 2006;50:460)

Positive stains

NSE, synaptophysin, HMB45, keratin
Vimentin, GFAP, chromogranin, dopamine β hydroxylase
Fontana-Masson stain highlights the melanin

Negative stains

AFP, S100 and CEA

Electron microscopy description

Large cells contain melanosomes and premelanosomes with varied maturation while the neuroblastic cells contain neurosecretory granules and neurofilaments

Differential diagnosis

Other round cell tumors
- Ewings / PNET
- Leukemic infiltrate
- Metastatic neuroblastoma
- Rhabdomyosarcoma: desmin, myogenin+, HMB45-

Mesothelioma

Table of Contents

Definition / general

Malignant tumor of mesenchymal origin arising from the serosal membrane of the tunica vaginalis
Usually aggressive, similar to peritoneal cavity tumor (Am J SurgPathol 1995;19:815)

Epidemiology

Extremely rare ( < 1% of all mesotheliomas)
Typically middle aged to elderly men (mean age 53, range 12-76 years) but also children (Am J Surg Pathol 1995;19:815, J Urol 1997;158:198)
Most patients > 50 years old; < 10% cases < 25 years
~1/3 associated with asbestos exposure (Am J SurgPathol 2001;25:1304, Cancer 1998;83:2437, Urol Oncol 2006;24:36)

Sites

Rarely arises from the tunica vaginalis (0.3 - 5% of all tumors), often in relation to the epididymis, testis or spermatic cord
More commonly arises in pleura (68 - 85%) and peritoneum (9 - 24%) (Arch Pathol Lab Med 2012;136:113)

Pathophysiology

Originates from tunica vaginalis, which derives from invagination of the peritoneum into the scrotum

Etiology

Exposure to asbestos (Orphanet J Rare Dis 2008;3:34), trauma, herniorrhaphy and longstanding hydrocele have all been implicated as predisposing factors (Arch Pathol Lab Med 2012;136:113)
Variable latency period from initial asbestos exposure to clinical diagnosis

Clinical features

Usually present with hydrocele - insidious, painless swelling of scrotum
Most cases are unilateral; bilateral tumors are rare, ~4% of cases (Cancer 1998;83:2437)
Other presentations include inguinal hernia, epididymitis or testicular mass
Poor prognosis, even with negative resection margins
Mean disease specific survival of 23 months, range of 2 to 64 months (Arch Pathol Lab Med 2012;136:113)

Radiology description

Scrotal ultrasonography usually reveals hydrocele with thickened wall and hypoechoic nodule over epididymis / tunica vaginalis, or a solid paratesticular mass (Urology 2012;80:e3) Ultrasound reveals hydrocele with thickened wall with hypoechoic nodule over epididymis / tunica vaginalis

Radiology images

Images hosted on other servers:

Increased thickness of the left tunica vaginalis

Small nodules

Border indistinctness in the right scrotum

Prognostic factors

Extent of disease at presentation is important prognostic factor (Cancer 1998;83:2437); metastases at presentation is associated with worse prognosis
Complete / adequate excision improves disease free survival; lower recurrence rate after radical orchiectomy (~10%) versus simple hydrocele sac excision (~30%) (Cancer 1998;83:2437)
Better outcome in younger patients
Well differentiated papillary mesothelioma has better prognosis than undifferentiated spindle cell mesothelioma
Other prognostic factors include tumor size, lymph node metastases, invasion into adjacent structures, degree of differentiation

Case reports

36 year old man with no history of hydrocele, trauma or exposure to asbestos (Urology 2012;80:e3)
53 year old man (World J Surg Oncol 2012;10:238)
57 year old man with mesothelioma of tunica vaginalis of "uncertain malignant potential" (Diagn Pathol 2011;6:78)
59 year old man (Case #148)
64 year old man with malignant mesothelioma of tunica vaginalis testis (Pathol Int 2004;54:930)
65 year old man without asbestos exposure (Cases J 2008;1:310)
70 year old man with well differentiated papillary mesothelioma of tunica vaginalis (Pathol Res Pract 2010;206:105)
Malignant mesothelioma of tunica vaginalis testis (Cancer 1998;83:2437)

Treatment

Radical orchiectomy is standard treatment
If treated with transcrotal surgery, subsequent hemiscrotectomy or hemiscrotal irradiation is often recommended
Retroperitoneal lymph node dissection is recommended only if pre-op workup reveals suspicious nodes
Well differentiated papillary mesothelioma may be treated with only surgery

Clinical images

Case #261

Gross description

Multiple nodules within hydrocele sac, frequently associated with mass infiltrating spermatic cord, epididymis or testis
May be a solitary nodule
Hydrocele sac is thick walled, often containing hemorrhagic fluid and papillary excrescences
Less often, mesothelioma creeps along tunica without forming a mass-like lesion

Gross images

AFIP images

Tunica vaginalis

Images hosted on other servers:

Radical orchiectomy specimen

Nodular mass at spermatic cord

Extracted tumor adhered strongly to scrotum skin

Microscopic (histologic) description

Same as mesothelioma at other sites
Either epithelial (60 - 70%), spindle cell (least common) or biphasic type (30 - 40%)
Epithelial type has epithelioid cells arising from the tunica vaginalis with papillary, tubular, adenomatoid or solid architectural patterns
Biphasic type has fascicles of spindle cells with scanty stroma, often merging with epithelial cells
In well differentiated tumors, neoplastic cells are typically cuboidal with scant to moderate amounts of eosinophilic cytoplasm and bland cytologic features
Tumors may also appear poorly differentiated
Papillae have thick, hyalinized fibrovascular cores lined by a single layer of atypical mesothelium
Stroma may be desmoplastic or show necrosis
Variable psammoma bodies

Microscopic (histologic) images

Contributed by Jennifer Gordetsky, M.D.

Mesothelioma

Case #261

Images hosted on other servers:

Epithelial tumor cells

Glandular pattern in desmoplastic stroma

Malignant mesothelial tubular structures

Biphasic exophytic nodule

Papillary structures

Mesothelioma of uncertain malignant potential

Cells are rounded with nuclear atypia

Cytology description

Moderately cellular smears; well differentiated tumors have papillary clusters of epithelial cells with minimal atypia

Positive stains

AE1 / AE3, EMA, calretinin, D2-40, CK5 / 6
Thrombomodulin. vimentin, WT1, EMA, CK7 (Am J Surg Pathol 2006;30:1)

Negative stains

CEA, B72.3, LeuM1 (CD15), BerEP4, CK20

Electron microscopy description

Cells show epithelial and mesenchymal differentiation
Epithelial cells joined by intercellular junctions, including desmosomes and junctional complexes, with lumen formation
Numerous cytoplasmic filaments including tonofibrils; cytoplasmic glycogen is also present
Long, slender microvilli are typically seen on the surface of the tumor cells as well as in intracellular and intercellular lumina
Microvilli length to diameter ratio > 10 (Ulbright: AFIP Series 3, Vol 25)

Molecular / cytogenetics description

Poorly characterized - mesotheliomas harbor multiple cytogenetic abnormalities with no specific diagnostic characteristics
Losses of chromosomal regions in 1p, 3p, 6q, 9q, 8p, 14q and 22q and gains in 5p, 6p, 8q, 15q, 17q, 20 and monosomy 22 have been reported (Arch Pathol Lab Med 2012;136:113)

Differential diagnosis

Adenomatid tumor
Florid mesothelial hyperplasia
Germ cell tumor
Pleomorphic sarcoma
Adenocarcinoma of rete testis, epididymis
Metastatic adenocarcinoma
Serous papillary tumor
Well differentiated papillary mesothelioma: no atypia or invasion

Additional references

Can Urol Assoc J 2012;6:E238,, Kaohsiung J Med Sci 2009;25:77,, Int J Urol 2008;15:560, Int J Urol 2002;9:602, Urology 2005;66:397

Metastases

Table of Contents

Definition / general

Tumors secondarily involving testis and paratesticular structures from distant sites
Excludes hematopoietic tumors

Essential features

Most have known history of primary but rarely the initial presentation
Histologic features recapitulate their site of origin
Should be differentiated from germ cell tumor, sex cord stromal tumor, malignant mesothelioma and adenocarcinoma of the rete testis or epididymis

Terminology

Also called secondary tumors of the testis

Epidemiology

Occur in 0.7% of patients with solid organ malignancies in autopsy studies (Ann Diagn Pathol 2000;4:59)
Majority are > 50 years old (Am J Surg Pathol 2008;32:1683)

Sites

Most common primary sites include the prostate, lung, skin, colon and kidney (Am J Surg Pathol 2008;32:1683)

Clinical features

Most nonsymptomatic or incidental finding
Most unilateral and solitary
Rarely present as carcinoma of unknown primary

Diagnosis

Clinical information and ancillary investigations can be more helpful than special histological techniques in the differential diagnosis

Radiology images

Images hosted on other servers:

Renal cell carcinoma metastasis to testis

Lung adenocarcinoma metastasis to testis

Colorectal adenocarcinoma metastasis to testis

Case reports

15 year old boy with colorectal carcinoma metastasis to his right testis (J Med Case Rep 2018;12:304)
29 year old man with mucinous lung adenocarcinoma metastasis to testis (Urology 2018;118:3)
35 year old man with testicular metastasis of colorectal carcinoma (BMJ Case Rep 2013; 2013)
53 year old man with uncommon testicular metastasis of a primary neuroendocrine tumour of the lung (Can Urol Assoc J 2013;7:E614)
58 year old man with stage IV squamous cell carcinoma of the lung with metastases to the brain and right testis (Case Rep Oncol 2015;8:133)
65 year old man with simultaneous bilateral testicular metastases from renal clear cell carcinoma (Oncol Lett 2014;7:1273)
69 year old man with metastatic renal cell carcinoma to his left testis (Rare Tumors 2016;8:6471)
78 year old man with metachronous ipsilateral testicular metastasis from renal cell carcinoma 6 years after nephrectomy (Case Rep Oncol 2017;10:388)

Gross description

Localized mass, multiple nodules

Gross images

Contributed by Debra L. Zynger, M.D.

Metastatic prostatic adenocarcinoma

Images hosted on other servers:

Metastatic colorectal adenocarcinoma

Metastatic renal cell carcinoma

Microscopic (histologic) description

Histologic features recapitulate their site of origin
Metastatic prostatic adenocarcinoma tends to involve the tubular system
Other metastatic carcinomas tend to infiltrate the testicular interstitium while sparing the seminiferous tubules
Prominent lymphovascular invasion

Microscopic (histologic) images

Contributed by Gang Wang, M.D., Ph.D.

Metastatic prostatic adenocarcinoma

Involvement of the tubular system

Cribriform pattern
most frequent,
epididymis
involvement

Solid growth pattern

Metastatic ductal adenocarcinoma

Positive for PSA

Positive for ERG

Metastatic renal cell carcinoma, clear cell type

Broad pushing borders

Mixed patterns

Positive for PAX8

Positive for CAIX

Metastatic colorectal
adenocarcinoma

Cystic spaces containing mucin

Metastatic cutaneous squamous
cell carcinoma

Infiltrating and anastomosing nests

Positive for p40

Positive stains

Mucin (teratomatous elements and yolk sac tumors may also be positive)
EMA

Negative stains

PLAP, SALL4

Molecular / cytogenetics description

Detection of isochromosome 12 by fluorescence in situ hybridization would suggest a primary germ cell tumor rather than a metastases

Sample pathology report

Right testis and spermatic cord, radical orchiectomy:
- Metastatic renal cell carcinoma, clear cell type, 2 cm, confined to the testicular parenchyma
- Margins of resection, negative for malignancy

Differential diagnosis

Germ cell tumor:
- Relatively younger age (typically 30s and 40s)
- Background of germ cell neoplasm in situ
- Positive for SALL4 (all germ cell tumors), OCT 3/4 and PLAP (seminoma and embryonal carcinoma), CD30 (embryonal carcinoma), AFP and glypican 3 (yolk sac tumor)
- Presence of isochromosome 12p (Am J Surg Pathol 2009;33:1529, Arch Pathol Lab Med 2012;136:435, Am J Surg Pathol 2014;38:689)
Sex cord stromal tumor:
- Positive for inhibin and calretinin, negative for CK (Mod Pathol 1998;11:77, Am J Surg Pathol 1998;22:615)
Malignant mesothelioma:
- Usually extensively and diffusely involves tunica
- Typically positive for mesothelial markers such as calretinin, CK5/6, D2-40 and WT1 (Mod Pathol 2005;18:S131, Am J Surg Pathol 2006;30:1, Arch Pathol Lab Med 2012;136:113)
Adenocarcinoma of the rete testis or epididymis:
- Has a morphologic transition from nonneoplastic rete or epididymis to adenocarcinoma (including in situ changes)
- Positive for PAX8 (Mod Pathol 2005;18:S131, Am J Surg Pathol 2011;35:1473)

Board review style question #1

Which of the following is the most common primary site of metastatic carcinoma in the testis?

Bladder
Kidney
Prostate
Lung
Colon

Board review style answer #1

C. The most common primary site of metastatic carcinoma in the testis is the prostate

Comment Here

Reference: Metastases to testes

Board review style question #2

Calretinin
CDX2
CK7
CK20
PAX8

Board review style answer #2

E. Primary adenocarcinomas of the rete testis or epididymis are positive for PAX8 while metastatic adenocarcinomas from other sites are usually negative for PAX8 (except kidney and thyroid)

Comment Here

Reference: Metastases to testes

Mixed and other sex cord stromal tumors

Table of Contents

Definition / general

A sex cord stromal tumor of the testis with mixed sex cord stromal elements or undifferentiated features
May contain any combination of cell types, including Sertoli cells, Leydig cells, granulosa cells

Terminology

Also includes undifferentiated stromal tumors with no clearly demonstrable differentiation

Epidemiology

Rare tumor of descended testis; < 1% of testicular tumors (J Urol 2004;172:2370)
Can occur in any age group; 1/3 of cases occur in children
Account for 2/3 of sex cord tumors occurring in children

Etiology

No specific etiology has been reported for the mixed / undifferentiated sex cord stromal tumors

Clinical features

Usually present with a painless testicular swelling
May be painful (Ulster Med J 1997;66:54)
15% present with gynecomastia

Comparison of mixed sex cord stromal tumors with and without gonadoblastoma

Mixed sex cord stromal tumor with gonadoblastoma:
- Associated with disorders of sexual development (gonadal dysgenesis [pure or mixed], altered karyotype, pseudohermaphrodites with streak gonads)
- Leydig-like cells and lutein cells
- Virilization
- Proliferative activity only in germ cells
Mixed sex cord stromal tumor without gonadoblastoma:
- Genetically and phenotypically normal individuals
- No Leydig-like cells and lutein cells
- No endocrine effects usually; if present, usually feminization
- Proliferative activity in sex cord stromal and germ cell components

Laboratory

Germ cell markers beta-hCG, LDH, alpha fetoprotein are within normal limits

Radiology description

Solid tumors but may have cystic areas

Prognostic factors

Similar to other sex cord stromal tumors: poor factors are large size, invasive growth pattern, angiolymphatic invasion, nuclear atypia, mitotic activity, necrosis
These tumors are usually benign in children < age 10 years
~20% in older patients are malignant

Case reports

54 year old man with mixture of granulosa and Sertoli cell tumor (Ulster Med J 1997;66:54)
Included in case series of childhood tumors (J Urol 2004;172:2370)
Adult man (Am J Clin Pathol 1981;75:565)
Incidental finding (J Urol 1995;154:1479)

Treatment

Similar to other sex cord stromal tumors
- High inguinal orchidectomy routinely done
- Testicular sparing surgery may be attempted if tumor is small, well circumscribed without any invasive features, normal tumor markers and frozen section facilities are available for intraoperative diagnosis
- No proven indication for lymph node dissection if nodes are not enlarged

Gross description

Gray, tan or yellow solid nodules
Presence of invasion into tunica, rete testis or adjacent structures predicts malignant / aggressive behavior

Gross images

Images hosted on other servers:

Well circumscribed lower pole testicular tumor

Microscopic (histologic) description

Mixture of cell types granulosa cell tumor, Leydig cell tumor, thecoma, etc
One particular cell type may predominate commonly the spindle cell type (Mod Pathol 1997;10:693, Pathol Res Pract 2007;203:759)

Microscopic (histologic) images

Images hosted on other servers:

Tumor is compressing adjacent tunica

Fascicular and storiform spindle cell arrangement

Insular arrangement of cells in hyaline stroma

Irregular ovoid nuclei with longitudinal grooves

Positive stains

Germ cells: variable AE1 / AE3 in a paranuclear dot pattern; variable Ki67 (depending on grade)
Sex cord stromal elements: variable inhibin, calretinin, CD99
Spindle elements: S100, smooth muscle actin (Mod Pathol 1997;10:693)

Negative stains

Germ cells markers: PLAP, OCT4, c-kit
Germ cells: PAS
Sex cord stromal elements: Ki67

Molecular / cytogenetics description

Ovarian tumors have c-kit mutations (seen in seminomas) and excess genetic material on #12p (seen in all germ cell tumors) but no genetic aberrations identified in testicular tumors (Virchows Arch 2006;448:612)

Differential diagnosis

Pure sex cord stromal tumors: show only one cell type and not more than an occasional microscopic focus of other elements; presence of more than occasional occurrence of two or more sex cord stromal cell types warrants a diagnosis of mixed sex cord stromal tumor
Sex cord stromal tumor with entrapped germ cells (Am J Surg Pathol 2000;24:535) and mixed germ cell sex cord stromal tumors: show clusters of germ cells in the center of the tumor; only one sex cord stromal cell type present

Mucinous borderline tumor

Table of Contents

Definition / general

Primary mucinous tumor of ovarian type surface epithelium with borderline malignant potential

Epidemiology

Extremely rare testicular tumor reported in middle age men (age range 42 - 69) (Am J Surg Pathol 2003;27:1221)

Sites

Intratesticular or paratesticular

Pathophysiology

The histogenesis of the ovarian type surface epithelial tumors of the testis and paratestis remains unclear
These tumors are possibly derived from Müllerian remnants or by metaplasia of the mesothelium of the tunica vaginalis (Hum Pathol 2011;42:1343)

Diagnosis

Clinical evaluation is necessary to rule out metastatic spread from a primary adenocarcinoma of the appendix, colon, stomach, pancreas, lung or prostate

Case reports

55 year old man with primary testicular mucinous neoplasms (Can Urol Assoc J 2010;4:E112)
69 year old man with an ossified intratesticular mucinous tumor (Arch Pathol Lab Med 1999;123:244)

Treatment

Radical orchiectomy

Clinical images

Images hosted on other servers:

Area of curvilinear calcification

Gross description

Paratesticular or intratesticular mucinous cystic mass, most often unilocular
Generally not as large as the ovarian tumor counterpart

Microscopic (histologic) description

Unilocular or multilocular cystic spaces lined by either endocervical or intestinal type mucinous epithelium
Tufting and pseudostratification of cells with mild to severe nuclear atypia
Occasional papillae
Occasional mitotic figures
Goblet cells are common
Mucin extravasation and an associated fibrotic, calcific reaction with foci of dystrophic calcification and ossification
Intracystic complex architecture diagnostic of intraepithelial carcinoma as well as foci of microinvasion have been reported
No intratubular germ cell neoplasia (Am J Surg Pathol 2003;27:1221, Can Urol Assoc J 2010;4:E112)

Microscopic (histologic) images

Images hosted on other servers:

Various images

Positive stains

Differential diagnosis

Metastatic mucinous adenocarcinoma: appendix, colon, stomach, pancreas, lung, prostate
Teratoma

Mucinous cystadenocarcinoma

Table of Contents

Definition / general

Ovarian type surface epithelial carcinoma of the testis with mucinous differentiation

Epidemiology

Extremely rare testicular tumor reported in middle age and elderly men (mean age 62)

Pathophysiology

The histogenesis of the ovarian type surface epithelial tumors of the testis and paratestis remains unclear
These tumors are possibly derived from Müllerian remnants or by metaplasia of the mesothelium of the tunica vaginalis (Hum Pathol 2011;42:1343)

Diagnosis

Clinical evaluation is necessary to rule out metastatic spread from a primary adenocarcinoma of the appendix, colon, stomach, pancreas, lung or prostate

Case reports

55 year old man with primary testicular mucinous neoplasms (Can Urol Assoc J 2010;4:E112)
59 year old man with bilateral mucinous cystadenocarcinoma of the testis and epididymis (Arch Pathol Lab Med 1992;116:1360)
71 year old man with mucinous cystadenocarcinoma of the testis (Hum Pathol 2011;42:1343)

Treatment

Radical orchiectomy

Clinical images

Images hosted on other servers:

Right testicular borderline mucinous tumor

Gross description

Mucinous, cystic mass replacing the testicular parenchyma

Microscopic (histologic) description

Well to moderately differentiated malignant cystic neoplasm with mucinous differentiation
Back to back irregular glands, elongated fine complex papillary structures lined with alternating goblet cells and ciliated cells, with little intervening stroma
Papillary structures have atypical cells with hyperchromatic overlapping elongated nuclei with coarse chromatin and increased nuclear to cytoplasmic ratio
Cystic spaces filled with mucin, fibrinopurulent material, degenerative cellular debris
Psammomatous calcifications can be present as well as mucin extravasation

Microscopic (histologic) images

Images hosted on other servers:

Cyst wall irregularly thickened and fibrotic

Mucinous epithelium
resembling endocervical
type cells

Positive stains

CK20 (+/-), CEA, mucin 2
Focal positivity for ER and p53

Negative stains

Differential diagnosis

Adenocarcinoma of the rete or epididymis
Metastatic mucinous adenocarcinoma (appendix, colon, stomach, pancreas, lung, prostate)
Teratoma with malignant transformation

Myoid gonadal stromal tumor

Table of Contents

Definition / general

A rare testicular neoplasm composed of spindle shaped cells that share features of smooth muscle and gonadal stroma (Virchows Arch 2021;478:727)
Hypothesized to arise from peritubular myoid cells or intertubular primitive mesenchymal cells (Am J Clin Pathol 2014;142:675)
Proposed as an emerging entity in the 2016 WHO classification because of the limited number of cases and the overlapping morphology and immunoprofile with the fibroma thecoma group; distinct entity in the WHO 5th edition

Essential features

A pure spindle cell tumor that lacks sex cord differentiation; positive for both actin and S100
Rare testicular tumor that may originate from intertubular primitive mesenchymal cells that undergo myogenic differentiation
Benign tumor with favorable prognosis
Small, circumscribed and nonencapsulated tumors that contain medium to large sized ectatic blood vessels with spindled tumor cells arranged in short intersecting fascicles
Differential diagnosis includes leiomyoma, testicular fibrothecoma and unclassified spindle cell predominant sex cord stromal tumor

Terminology

Historically, nomenclature includes
- Unusual gonadal stromal tumor
- Testicular stromal tumor with myofilaments
- Unclassified sex cord stromal tumor with predominance of spindle cells

ICD coding

ICD-O: 8590/0 - myoid gonadal stromal tumor
ICD-11: 2F77 & XH9G57 - neoplasms of uncertain behavior of male genital organs & sex cord - gonadal stromal tumor, NOS

Epidemiology

Can occur in any age but typically seen in young to middle aged men between 4 and 59 years (median is 37 years, mean is 43 years) (Am J Clin Pathol 2014;142:675)

Sites

Affects the testis unilaterally

Pathophysiology

Hypothesized to arise from peritubular myoid cells which originate from intertubular primitive mesenchymal cells that undergo myogenic differentiation
Peritubular myoid cells play key roles in the development of the fetal testis and maintenance of testicular function (Hum Pathol 2012;43:144, Arch Histol Cytol 1996;59:1)

Etiology

Unknown

Clinical features

Asymptomatic
Incidental testicular mass
Testicular pain
Infertility
Reference: Am J Clin Pathol 2014;142:675

Diagnosis

Surgical specimen evaluated by H&E and immunohistochemical staining

Laboratory

No abnormalities seen

Radiology description

Ultrasound of testis
- Nonhomogenous: hypoechoeic nodule with hyperechoic spots (Indian J Pathol Microbiol 2022;65:444)

Radiology images

Images hosted on other servers:

Ultrasound features

Prognostic factors

Small tumors (< 4 cm) with low mitotic activity have an extremely favorable outcome
Recurrence or metastasis is rarely seen
Reference: Am J Clin Pathol 2014;142:675

Case reports

25 year old man with right testicular mass (Hum Pathol 2012;43:144)
38, 43 and 59 year old men with singular testicular masses (Am J Clin Pathol 2014;142:675)
41 year old man with infertility (Indian J Pathol Microbiol 2022;65:444)
46 year old man with cytologically bland testicular tumor (Ultrastruct Pathol 1991;15:409)

Treatment

Orchiectomy
Adjuvant therapy generally not required

Gross description

Unifocal and well circumscribed with a yellow / tan appearance
Small sized tumors that range from < 1 cm to 4 cm (Am J Clin Pathol 2014;142:675)

Frozen section description

Spindle cell neoplasm, low grade

Microscopic (histologic) description

Circumscribed and nonencapsulated
Focally contain medium to large sized ectatic blood vessels and can be seen adjacent to the rete testis
Tumor cells are spindled and arranged in short intersecting fascicles, sometimes with a storiform pattern
Scant collagen with thin bands in the background
Nuclei range from elongated to fusiform with inconspicuous to small nucleoli and occasional grooves
Cytoplasm is scant to moderate and ill defined, ranging from pale to lightly eosinophilic
No significant cytologic atypia is seen
Mitotic figures vary from 0 to 5 per 10 high power fields
No necrosis or lymphovascular invasion
No differentiated gonadal stromal cells (Sertoli, Leydig or granulosa cells) are seen
Reference: Am J Clin Pathol 2014;142:675

Microscopic (histologic) images

Contributed by Vikas Mehta, M.D.

Ectatic blood vessels

Spindle arrangement of tumor cells

SF1 positivity

h-caldesmon negativity

SMA positivity

S100 positivity

Positive stains

S100 and SMA strong and diffuse positivity is considered a defining criteria (Hum Pathol 2012;43:144, Arch Histol Cytol 1996;59:1)
FOXL2: strong and diffuse positive
SF1: diffuse positive
Muscle specific actin
Vimentin
Inhibin: focal, weak and variable positive
Desmin: variable positive
Calponin: focal and weak positive
WT1: variable positive

Negative stains

h-caldesmon
Calretinin
SOX9
CD34
Peritubular myoid cells in the adjacent seminiferous tubules can be positive for SMA, desmin, h-caldesmon and calponin but negative for S100 protein, inhibin, calretinin, WT1, SOX9, FOXL2 and SF1
References: Hum Pathol 2012;43:144, Am J Clin Pathol 2014;142:675

Electron microscopy description

Myofilaments and desmosomes
Spindle cells showing lipid vacuoles
Elongated cell with spindle nucleus and small cytoskeletal filaments (Virchows Arch 2021;478:727)

Molecular / cytogenetics description

Recurrent chromosome arm level and whole chromosome level copy number gains indicative of ploidy shifts
Chromosome gains of 3, 6 or 6p, 7, 8, 9 or 9q, 11, 12, 14q, 15q, 17 or 17p, 18q, 20 and 21q and copy number loss 22q (Histopathology 2023;82:431)

Sample pathology report

Testis, biopsy:
- Myoid gonadal stromal tumor (see comment)
- Comment: The biopsy shows a spindle cell tumor with fascicular and storiform architecture. The tumor cells show varying amounts of eosinophilic to amphophilic cytoplasm, round to oval regular nuclei and inconspicuous or small nucleoli. No vascular invasion, foci of necrosis or atypical mitosis are identified. The tumor cells express SMA, S100 protein, inhibin, FOXL2, calretinin and SF1. In contrast, SOX9, WT1, AE1 / AE3 and EMA expression were not detected. The overall morphologic features and coexpression of S100 protein and SMA support the diagnosis above.

Differential diagnosis

Leiomyoma:
- Diffuse broad fascicles
- Abundant eosinophilic cytoplasm
- Cigar shaped nuclei
- Negative S100 reactivity
- Positive h-caldesmon reactivity
Testicular fibrothecoma:
- Collagen bundles are typically thicker and more diffuse, sometimes forming hyaline plaques
- Variable and patchy S100 reactivity
- Positive SOX9 reactivity
Unclassified spindle cell predominant sex cord stromal tumor:
- Subtle sex cord elements identified on H&E
- Darker, tight groupings of cells with rounded nuclei and indistinct, typically pale, often scant cytoplasm; may be arranged in nests or short cords
- Immunohistochemical stain reactivity may show significant overlap

Board review style question #1

Myoid gonadal stromal tumor is a new entity described in the latest WHO classification of testicular tumors. A representative histologic image is shown above. Which of the following is true for these tumors?

Consistent pattern of recurrent chromosome arm level and whole chromosome level copy number gains are indicative of ploidy shifts
Intermixed primitive germ cells and diffuse broad fascicles are present
Mitotic count of > 5/10 high power fields is common
Vascular invasion is a defining characteristic of these tumors

Board review style answer #1

A. Consistent pattern of recurrent chromosome arm level and whole chromosome level copy number gains are indicative of ploidy shifts

Comment Here

Reference: Myoid gonadal stromal tumor

Papillary cystadenoma

Table of Contents

Definition / general

Benign tumor of epididymis characterized by prominent papillary architecture
Often associated with von Hippel-Lindau disease (Hum Pathol 1995;26:1341)
First described by Sherrick (Cancer 1956;9:403)

Terminology

Also called papillary cystadenofibroma

Epidemiology

Second most common benign neoplasm of epididymis after adenomatoid tumor
Sporadic or familial
Unilateral or bilateral (40%)
Mean age 36 years
Associated with von Hippel-Lindau (VHL) disease; 65% with bilateral tumors have VHL vs. 18 - 20% with unilateral lesions (Arch Pathol Lab Med 2010;134:630)

Sites

In male GU, occurs in epididymis (develops within efferent ductules of head of epididymis)
In female GU, occurs in broad ligament, peritoneum; also fallopian tube and uterus

Clinical features

Benign, usually asymptomatic
If symptomatic, typically is slow growing swelling in scrotum, with only rare pain or tenderness
Rarely discovered during infertility workup (Arch Pathol Lab Med 2010;134:630)

Laboratory

No specific laboratory features
Negative for germ cell tumor markers

Case reports

46 year old man (Int J Clin Exp Pathol 2011;4:629)
Vascular endothelial growth factor in von Hippel-Lindau syndrome - associated papillary cystadenoma of epididymis (Hum Pathol 1998;29:1322)
3 cases (Arch Pathol Lab Med 1990;114:672)
Solid variant (Histopathology 2015;67:138)

Treatment

Surgical excision; does not recur
If bilateral, patient should be investigated for VHL syndrome

Clinical images

Images hosted on other servers:

Complex echo pattern

Gross description

Well circumscribed, 1 - 5 cm, gray, brown, yellow tumor nodule
Cut surface may show papillary fronds or may be cystic with areas of hemorrhage

Gross images

Images hosted on other servers:

Epididymal tumor

Microcystic with hemorrhage

Microscopic (histologic) description

Papillary in foldings project into cystic spaces covered by single to double layered cuboidal / columnar cells
Tubules common, colloid type cystic material common
Tumor cells have lightly eosinophilic to clear cytoplasm
May see dilated efferent ductules
May have clear cells resembling metastastic renal cell carcinoma but no mitoses, no necrosis, no pleomorphism
Papillary cystadenofibroma: prominent stroma

Microscopic (histologic) images

Images hosted on other servers:

Cystic space with papillary excrescences

Cilia

Case with clear cells

CK7

CD10

Cytology description

Simple and complex papillary clusters
Tumor cells are monomorphic, with moderate to abundant cytoplasm, well defined cytoplasmic borders; round to oval nuclei, finely dispersed chromatin, inconspicuous nucleoli
Vacuolations may be present
No features of malignancy - i.e. no mitoses, no necrosis, no atypia
Usually no psammoma bodies, but see Cytopathology 2014;25:279, Acta Cytol 2004;48:467

Positive stains

AE1 / AE3, CK7, alpha-1-antitrypsin, alpha-1-antichymotrypsin, CAM5.2, EMA, vimentin, vascular endothelial growth factor
Lectin
PAX8, carbonic anhydrase IX
Variable CEA (Am J Surg Pathol 2014;38:713)

Negative stains

Useful negative stains include AMACR and RCC antigen, to differentiate from clear cell papillary renal cell carcinoma
CD10 is usually negative but focal staining may be noted (Am J Surg Pathol 2005;29:520)

Differential diagnosis

Metastatic renal cell carcinoma
- Other features of malignancy
- CD10, RCC antigen are strongly positive
- Lectin and CK7 are negative
Serous borderline tumors and serous adenocarcinoma of paratestis: atypia, mitotic activity, stratification and detached cell clusters

Placental site trophoblastic tumor

Table of Contents

Definition / general | Case reports | Microscopic (histologic) description | Positive stains

Definition / general

Rare, resembles uterine tumor of same name

Case reports

16 month infant (Am J Surg Pathol 1997;21:282)
24 year old man with placental site trophoblastic tumor and teratoma (Hum Pathol 2010;41:1046)

Microscopic (histologic) description

Proliferation of intermediate trophoblasts, identical to uterine tumor

Positive stains

Polyembryoma

Table of Contents

Definition / general

Mixed germ cell tumor with predominant embryoid bodies (central core of embryonal carcinoma cells, amnion-like cavity and yolk sac tumor component)
Elements other than the embryoid bodies, however, should constitute less than 10% of the tumor for the "polyembryoma" designation to be used (Mod Pathol 2005;18:S61)
Resembles embryonic yolk sac
Behaves like other mixed germ cell tumors

Essential features

Central core of embryonal carcinoma cells, amnion-like cavity and yolk sac tumor component that accounts for approximately 90% of tumor

Epidemiology

Extremely rare, same age as germ cell tumors

Clinical features

Same as germ cell tumors
Elevation of serum AFP and beta HCG

Prognostic factors

Same as mixed germ cell tumors

Treatment

Same as mixed germ cell tumor with teratoma

Gross images

Contributed by Delia Perez-Montiel, M.D.

40 year old man

Microscopic (histologic) description

At low power, the stroma can give the tumor a lobular architecture
Embryoid bodies are composed of a hyperchromatic disc of embryonal carcinoma
Surrounding the disc of embryonal carcinoma is edematous stroma forming a cavity lined by yolk sac epithelium

Microscopic (histologic) images

Contributed by Delia Perez-Montiel, M.D.

Positive stains

OCT3 / 4, CD30 and keratin (embryonal carcinoma component)
Glypican 3, AFP and keratin (yolk sac component)

Negative stains

CD117, PLAP, D2-40

Additional references

Int J Gynecol Pathol 2016;35:93, Mod Pathol 2017;30:908, Am J Clin Pathol 1994;102:402

Board review style question #1

What is the difference between a mixed germ cell tumor with embryoid bodies and a polyembryoma?

Mixed germ cell tumors have components other than embryonal carcinoma and yolk sac tumor, while polyembryomas have only embryonal carcinoma and yolk sac tumor.
Polyembryoma is not a germ cell tumor.
Polyembryomas have many different types of embryoid bodies.
Proportion of embryoid bodies in polyembryomas is 90% or higher of the entire tumor.

Board review style answer #1

D. Proportion of embrioid bodies in polyembryomas is 90% or higher of the entire tumor.

Comment Here

Reference: Polyembryoma

Polyorchidism

Table of Contents

Definition / general

Multiple testes within a scrotal sac
Either one common or separate epididymis

Proliferative funiculitis

Table of Contents

Definition / general

Paratesticular (fibrous) pseudotumor (PFP) / funiculitis is a rare tumor-like lesion of unknown etiology
Variably cellular proliferation of bland fibroblasts and myofibroblasts, fibrous stroma and chronic inflammation

Essential features

Rare, benign, paratesticular lesion, involving epididymis, tunica or spermatic cord
Unknown etiology, associated with hydrocele, trauma, increased number of IgG4 positive plasma cells
Bland spindle cell proliferation within dense fibrous tissue, associated with variable chronic inflammation
Imaging studies, particularly scrotum MRI might show finding suggestive of fibrous pseudotumor
Scrotum exploration with biopsy and intraoperative consultation with frozen section may help differentiate this tumor from a malignant mimic and avoid orchiectomy

Terminology

Paratesticular fibrous pseudotumor, inflammatory pseudotumor, nodular pseudotumor, chronic proliferative periorchitis, fibrous periorchitis, reactive periorchitis, pseudofibromatous periorchitis, nodular and diffuse fibrous proliferation, nonspecific peritesticular fibrosis, fibroma, benign fibrous paratesticular tumor, pseudosarcomatous myofibroblastic proliferation of the spermatic cord, proliferative funiculitis, fibrous mesothelioma (Arch Pathol Lab Med 2003;127:742, Pathol Annu 1990;25:51, Am J Surg Pathol 1997;21:296, Urology 2000;56:670, Semin Diagn Pathol 2000;17:340, Arch Pathol Lab Med 1992;116:277, J Pediatr Surg 2001;36:1057, J Urol 1989;141:376, J Pak Med Assoc 2009;59:47, Urology 2006;67:623.e15, Am J Surg Pathol 1992;16:448, Tunis Med 2012;90:333, Ulbright: Tumors of the Testis, Adnexa, Spermatic Cord, and Scrotum, 1999)
Mostofi and Price proposed the term fibrous pseudotumor to encompass all reactive fibroinflammatory lesions of the testicular tunics (Mostofi: Tumors of the Male Genital System, 1st Edition, 1973)

ICD coding

ICD-10
- N50.89 - other specified disorders of the male genital organs
- N50.9 - disorder of male genital organs, unspecified
ICD-11: GB07.1 & XA9235 - inflammatory disorders of spermatic cord, tunica vaginalis or vas deferens & spermatic cord

Epidemiology

It can occur across all age groups (e.g., 16 - 76); mean age at presentation of 42 years (Am J Surg Pathol 2010;34:569, Am J Surg Pathol 1992;16:448, Ann Surg 1904;39:396)
Rarely seen in children (J Urol 1993;150:1886, Pediatr Dev Pathol 2016;19:460)

Sites

Paratesticular tissue and spermatic cord (involving epididymis, tunica or spermatic cord) (Front Med 2014;8:484, Urology 2000;56:670, Am J Surg Pathol 1992;16:448, J Urol 2004;171:1625)

Pathophysiology

N/A

Etiology

Benign, rare lesion of unknown etiology
May be due to ischemia, torsion, secondary to trauma, hydrocele, infections or inflammation (J Pediatr Surg 2001;36:1057, J Pak Med Assoc 2009;59:47, Virchows Arch 2011;458:109, Front Immunol 2021;12:717902, Basic Res Cardiol 1985;80:260, J Pediatr Surg 2001;36:1057, J Urol 1992;148:1254, J Urol 1989;141:376, Pediatr Dev Pathol 2016;19:460)
Abundance of IgG4 expressing plasma cells in many of these lesions suggests that paratesticular fibrous tumor may be part of the IgG4 related disease family; correlation with clinical findings is essential in the diagnosis of IgG4 related diseases and its distinction from nonspecific inflammatory reactions, particularly in unusual anatomic sites (J Med Case Rep 2013;7:225, Gland Surg 2023;12:426, Virchows Arch 2011;458:109)
Some fibrous pseudotumors have been associated with testicular infarct, Gorlin syndrome (the nevoid basal cell carcinoma syndrome) and Schistosoma haematobium infection (J Pediatr Surg 2001;36:1057, J Urol 1992;148:1254, J Urol 1989;141:376)

Diagrams / tables

N/A

Clinical features

Most patients present with a palpable, painless scrotal mass simulating a testicular tumor (Arch Pathol Lab Med 2003;127:742)
Can be an incidental finding at herniorrhaphy (Am J Surg Pathol 1992;16:448)
May present as a solitary lesion or as multifocal lesions (J Urol 2004;171:1625, Am J Surg Pathol 2010;34:569)

Diagnosis

Imaging studies, particularly scrotum magnetic resonance imaging (MRI) might show finding suggestive of fibrous pseudotumor
Scrotum exploration with biopsy and intraoperative consultation with frozen section will help differentiate this tumor from a malignant mimic and avoid orchiectomy

Laboratory

Testicular tumor marker levels within normal limits (normal levels of alpha fetoprotein, beta human chorionic gonadotropin) (Am J Mens Health 2023;17:15579883231181571, J Urol 2004;171:1625, Rare Tumors 2016;8:6288)
Some patients show elevated serum levels of IgG4 (Front Immunol 2021;12:717902)

Radiology description

Ultrasonographic findings are largely unspecific: the lesion is usually heterogeneous and hypoechoic (Pol J Radiol 2016;81:10)
Computed tomography (CT) imaging studies show a hypodense scrotal mass (Pol J Radiol 2016;81:10)
Scrotal magnetic resonance imaging may help to differentiate between malignant tumors and paratesticular (fibrous) pseudotumors, which in general appear hypointense compared to testicular tissue on T1 and T2 weighted MR imaging and might also show focal enhancement after intravenous injection of contrast material (AJR Am J Roentgenol 1997;168:1586, Pol J Radiol 2016;81:10)

Radiology images

Images hosted on other servers:

Ultrasonographic, T2 weighted MR and CT scan images

Scrotal ultrasound and MR images

Prognostic factors

Can recur locally
Overall excellent prognosis

Case reports

16 year old boy presented with painless enlargement of the scrotum (Ann Surg 1904;39:396)
32 year old man presented with a painless left scrotal mass (Cureus 2023;15:e46768)
36 year old man presented with a small, painless right scrotal mass (Urol Case Rep 2021;36:101584)
38 year old man presented with palpable left scrotal masses (Am J Mens Health 2023;17:15579883231181571)
45 year old man presented with an asymptomatic, slowly growing, palpable right inguinal mass (Gland Surg 2023;12:426)
59 year old man presented with a painless swelling in left scrotum (Urol Case Rep 2022;45:102211)

Treatment

Surgical resection (frozen section assessment and local excision / testicular sparing surgery), whenever technically feasible, is the preferred treatment (Front Med 2014;8:484, Case Rep Urol 2018;2018:6904827, J Med Case Rep 2013;7:225)

Clinical images

Images hosted on other servers:

Multiple paratesticular polypoid masses

Multiple polypoid tunica vaginalis masses

Multiple tunica vaginalis nodules

Gross description

Usually well circumscribed but it can also be ill defined
Single or multiple nodules (J Urol 2004;171:1625)
Firm or gelatinous mass with a gray-white cut surface

Gross images

Images hosted on other servers:

Multiple polypoid tunica vaginalis masses

Well demarcated tan-yellow lesion

Tumor in undescended testis

Frozen section description

Bland spindle cells and variable chronic inflammation in a dense fibrotic background
No significant cytologic atypia, differentiating it from sarcomas

Frozen section images

N/A

Microscopic (histologic) description

Variably cellular proliferation of bland fibroblasts and myofibroblasts with oval to fusiform nuclei, small nucleoli and amphophilic cytoplasm
In some cases, there is also a minor population of myofibroblasts / fibroblasts with abundant basophilic cytoplasm, resembling the ganglion-like cells of proliferative fasciitis (Am J Surg Pathol 1992;16:448)
No nuclear atypia or atypical mitoses
Necrosis might be present (Int J Surg Pathol 2008;16:48)
Dense fibrous stroma with variable, mixed inflammatory infiltrate mainly composed of plasma cells and lymphocytes (mixed small B and T cells) but also histiocytes and scattered eosinophils or even uncommonly, mast cells (Gland Surg 2023;12:426, Pathol Int 2003;53:897)
May have focal dystrophic calcifications and ossification
One study showed presence of malignant appearing glandular structures composed of keratin positive mesothelial cells within paratesticular pseudotumor of the spermatic cord (Int J Surg Pathol 2008;16:48)

Microscopic (histologic) images

Contributed by Veronica Ulici, M.D., Ph.D.

Ill defined fibrous lesion

Paucicellular fibrous lesion

Bland fibroblasts and myofibroblasts

Focal calcifications

Mixed inflammatory infiltrate

Prominent chronic inflammation

Ganglion-like cells

Virtual slides

Images hosted on other servers:

Scrotal mass attached to testis

Cytology description

N/A

Cytology images

N/A

Immunofluorescence description

N/A

Immunofluorescence images

N/A

Positive stains

Smooth muscle actin (SMA)
Sometimes desmin, keratin (AE1 / AE3) or calretinin (which are focally positive but rarely can demonstrate diffuse expression), variable CD34 (Am J Surg Pathol 2010;34:569)
In a proportion of cases, the plasma cells showed positivity for IgG and IgG4, with IgG4 number > 40/high power field (HPF) and proportion of IgG4 / IgG > 40% in some areas (Gland Surg 2023;12:426)

Negative stains

Beta catenin (negative nuclear staining, in contrast to fibromatosis) (Am J Surg Pathol 2010;34:569)
ALK1 (suggesting it is unrelated to inflammatory myofibroblastic tumor [IMT])
Usually negative for S100

Electron microscopy description

No specific findings; can show fibroblasts / myofibroblasts, collagen fibrils

Electron microscopy images

Images hosted on other servers:

Spindle cell in collagenous stroma

Molecular / cytogenetics description

Fluorescent in situ hybridization (FISH) studies will be negative for MDM2 amplification (helping to differentiate from well differentiated / dedifferentiated liposarcoma)

Molecular / cytogenetics images

N/A

Videos

Paratesticular fibrous pseudotumor
pathology mini tutorial

Sample pathology report

Soft tissue, right paratestis, excision:
- Dense fibrous tissue with chronic inflammation, consistent with fibrous pseudotumor
- Negative for malignancy
Right testicle, radical orchiectomy:
- Fibrous pseudotumor of spermatic cord (see comment)
- Comment: Histologic sections show reactive appearing fibroblasts / myofibroblasts, dense fibrous stroma and scattered chronic inflammatory cells. These features are consistent with a nonneoplastic reactive lesion that has been described under a variety of names, including fibrous pseudotumor. Due to the location of the mass, MDM2 FISH was performed and was negative for MDM2 amplification which argues against a very subtle sclerosing / inflammatory variant of well differentiated liposarcoma. In addition, given the increased plasma cells, an IgG4 immunostain was performed and demonstrated increased IgG4 positive plasma cells (up to 50 in a high power field). While recent studies have suggested that paratesticular fibrous pseudotumor might belong to the growing list of IgG4 related diseases, correlation with clinical findings is essential in the diagnosis of IgG4 related diseases and its distinction from nonspecific inflammatory reactions, particularly in unusual anatomic sites (APMIS 2018;126:459).

Differential diagnosis

Dedifferentiated liposarcoma:
- Much more atypical
- Adjacent well differentiated liposarcoma component (Am J Surg Pathol 1992;16:448)
- MDM2 amplification
Well differentiated liposarcoma (sclerosing or inflammatory subtypes):
- Rare atypical, hyperchromatic spindle cells in background of dense fibrosis or a prominent inflammatory infiltrate
- MDM2 amplification
Embryonal rhabdomyosarcoma:
- Younger population (children and adolescents)
- More cellular and atypical (Am J Surg Pathol 1992;16:448)
- Positive for desmin, myogenin, MyoD1
Myxoid leiomyosarcoma:
- Intracytoplasmic glycogen
- Nuclear pleomorphism
- Possible necrosis (Am J Surg Pathol 1992;16:448, Pathol Int 2006;56:625)
Fibromatosis:
- Long, sweeping fascicles
- Beta catenin positive (nuclear staining)
Inflammatory myofibroblastic tumor (IMT):
- ALK gene rearrangements and ALK overexpression in ~50% of cases (Curr Opin Oncol 2012;24:409)
- ALK negative IMTs may show ROS1 and PDGFRB alterations (Am J Surg Pathol 2015;39:957, Cancer Discov 2014;4:889, Mod Pathol 2015;28:732)

Additional references

N/A

Board review style question #1

The spindle cells in the paratesticular pseudotumor shown in the photomicrograph are believed to pertain to which line of differentiation?

Adipocytic
Histiocytic
Myofibroblastic
Nerve sheath
Vascular

Board review style answer #1

C. Myofibroblastic. Paratesticular pseudotumor is thought to be a reactive lesion composed of myofibroblasts / fibroblasts set in a dense fibrous stroma with a variable, mixed inflammatory infiltrate. Answer A is incorrect because while the reactive spindle cells and chronic inflammation can be found infiltrating into adipose tissue, this lesion is not related to an adipocytic proliferation / neoplasm. Answer B is incorrect because while histiocytes are present within the lesion, the main reactive, proliferative population is represented by myofibroblasts / fibroblasts. Answer D is incorrect because this lesion is not related to a nerve sheath proliferation / neoplasm. Answer E is incorrect because this lesion is not related to a vascular proliferation / neoplasm.

Comment Here

Reference: Proliferative funiculitis

Proliferative funiculitis

Table of Contents

Definition / general

Pseudosarcomatous inflammatory lesion involving the spermatic cord (Pathol Int 2003;53:897)
Lesion is composed of fibroblasts and myofibroblasts (Am J Surg Pathol 1992;16:448)

Terminology

Also known as pseudosarcomatous myofibroblastic proliferation of spermatic cord
Some studies mention relationship to: inflammatory myofibroblastic tumor, inflammatory pseudotumor, atypical myofibroblastic tumor, pseudosarcoma (Urology 2009;73:1423)
These terms are often used inappropriately in literature and may not truly be related to proliferative funiculitis

Epidemiology

Older men (ages 52 - 76 years)

Sites

Spermatic cord
Similar lesions in epididymis (Pathol Int 2003;53:897)

Etiology

May be due to ischemia, torsion or extension of vasitis

Clinical features

Swelling in inguinal area; usually found in association with inguinal hernia (Pathol Int 2003;53:897, Cheng Essentials of Anatomic Pathology 2011)
Usually incidental at herniorrhaphy

Laboratory

Normal levels of α-fetoprotein, β-human chorionic gonadotropin

Radiology description

Multicystic mass (ultrasound, Tunis Med 2012;90:333)

Prognostic factors

Can recur locally; excellent prognosis when resected with negative margins

Treatment

Surgical resection

Gross description

Ill-defined, firm or gelatinous mass with a gray-white cute surface
Calcification, hemorrhage, and necrosis are uncommon (Int J Surg Case Rep 2012;3:618, Am J Surg Pathol 1992;16:448)

Gross images

Images hosted on other servers:

Tumor in undescended testis

Microscopic (histologic) description

Infiltrative spindle cell proliferation within a myxoid or loose collagenous stroma
Nuclei are oval to fusiform
Basophilic nucleoli may be present
Mixed inflammatory infiltrate mainly composed of plasma cells and lymphocytes
May contain malignant appearing glandular structures composed of keratin+ mesothelial cells (Int J Surg Pathol 2008;16:48), rarely has proliferation of mast cells (Pathol Int 2003;53:897)

Microscopic (histologic) images

Images hosted on other servers:

Spindle cell proliferation

Positive stains

Vimentin, muscle specific actin, SMA, desmin (Urology 2009;73:1423)
Entrapped mesothelial cells stain with keratins, mesothelial markers (D2-40, WT1)

Negative stains

CD21, CD34, S100 (Urology 2009;73:1423)

Differential diagnosis

Dedifferentiated liposarcoma: much more atypical; adjacent well-differentiated adipocytic component (Am J Surg Pathol 1992;16:448)
Embryonal rhabdomyosarcoma: younger population (children and adolescents); more cellular and atypical; (Am J Surg Pathol 1992;16:448) positive for desmin, myogenin, myoD1
Myxoid leiomyosarcoma: intracytoplasmic glycogen; nuclear pleomorphism; necrosis (Am J Surg Pathol 1992;16:448, Pathol Int 2006;56:625)

Regressed germ cell tumor

Table of Contents

Definition / general

Testicular germ cell tumor presenting with spontaneous complete or partial regression (J Ultrasound Med 2003;22:515, J Urol 2009;182:2303, Case Rep Oncol 2017;10:846)

Essential features

Testicular germ cell tumor presenting with spontaneous complete or partial regression (J Ultrasound Med 2003;22:515, J Urol 2009;182:2303, Case Rep Oncol 2017;10:846)
Presents as metastasis, residual testicular germ cell tumor or both (BJU Int 2004;94:74, Case Rep Oncol 2017;10:846, Am J Surg Pathol 2006;30:858)
Histologic features of testicular tumor regression include fibrous scar and germ cell neoplasia in situ (J Ultrasound Med 2003;22:515, Am J Surg Pathol 2006;30:858)
Most commonly associated with pure seminoma in metastasis and residual testicular tumor (Am J Surg Pathol 2006;30:858, J Urol 2009;182:2303)

Terminology

Regressed germ cell tumor
Burned out germ cell tumor
Burnt out germ cell tumor

Epidemiology

3% of all testicular tumors (J Ultrasound Med 2003;22:515)
Median age of diagnosis is between 28 and 32 (range 17 - 67 years) (Am J Surg Pathol 2006;30:858, J Urol 2009;182:2303)
10% of retroperitoneal germ cell tumors have a regressed testicular primary (J Ultrasound Med 2003;22:515)

Sites

Retroperitoneal metastasis is most common (Am J Surg Pathol 2006;30:858)
Metastasis to liver, lung, bone and brain has been reported (Case Rep Urol 2015;2015:835962)

Pathophysiology

Poorly understood (J Ultrasound Med 2003;22:515)
Proposed mechanisms (J Ultrasound Med 2003;22:515, BJU Int 2004;94:74, Case Rep Oncol 2017;10:846):
- Immune modulated regression
- Ischemic regression

Clinical features

Metastatic symptoms are the most common initial presentation: extragonadal mass, abdominal pain, back pain, lymphadenopathy, weight loss and fever (Am J Surg Pathol 2006;30:858, J Ultrasound Med 2003;22:515, J Urol 1996;156:85)
Less common presentations include: testicular mass, elevated serum tumor markers (AFP, beta hCG and LDH) and testicular pain (J Ultrasound Med 2003;22:515, Am J Surg Pathol 2006;30:858)

Diagnosis

Discovered most commonly as metastatic disease in the absence of palpable testicular mass (J Ultrasound Med 2003;22:515, J Urol 1996;156:85)
Sonographic evidence of testicular abnormality (J Ultrasound Med 2003;22:515, J Urol 2009;182:2303)
Extragonadal germ cell tumor identified (J Ultrasound Med 2003;22:515, J Urol 2009;182:2303)
Histopathologic features of tumor regression within testis (Am J Surg Pathol 2006;30:858, Am J Pathol 1961;38:207)

Radiology description

Sonographic features of tumor regression (J Ultrasound Med 2003;22:515, Am J Surg Pathol 2006;30:858, J Urol 2009;182:2303):
- Macrolithiasis (> 0.2 cm) or microlithiasis (< 0.2 cm)
- Loss of testicular homogeneity
- Nonspecific hyperechoic or hypoechoic lesions
- Testicular atrophy
Computed tomographic (CT) features of metastasis (J Ultrasound Med 2003;22:515):
- Lymphadenopathy
- Extragonadal mass

Radiology images

Images hosted on other servers:

Scrotal ultrasound

Regressed
primary with
retroperitoneal
metastasis

Prognostic factors

Posttreatment disease free survival rate: 29% at 5 years and 12% at 10 years (J Urol 2009;182:2303)
No difference in prognosis between complete and partial regression (J Urol 2009;182:2303)
In context of regressed germ cell tumor with metastasis, pure seminoma has a more favorable prognosis (J Urol 2009;182:2303)
No data is available comparing prognosis of regressed versus nonregressed testicular germ cell tumors

Case reports

24 year old man with brain metastasis (Cureus 2016;8:e551)
43 year old man with retroperitoneal seminoma (Rom J Morphol Embryol 2011;52:193)
45 year old man with retroperitoneal metastasis (Int J Health Sci (Qassim) 2018;12:94)
54 year old man with pancreatic choriocarcinoma (Mod Pathol 2004;17:1573)
54 year old man with pulmonary choriocarcinoma (Intern Med 2016;55:1481)

Treatment

Combination systemic chemotherapy is mainstay of treatment for metastasis (J Ultrasound Med 2003;22:515, J Urol 2009;182:2303)
- Can be combined with radiotherapy for seminoma
Radical orchiectomy for abnormal sonographic features (J Ultrasound Med 2003;22:515, J Urol 2009;182:2303)

Gross description

Fibrous scar displacing normal testicular parenchyma (J Ultrasound Med 2003;22:515, J Urol 2009;182:2303)
Scars appear white to tan in color (Am J Surg Pathol 2006;30:858)
Scars can appear as well demarcated nodular foci or stellate lesions (Am J Surg Pathol 2006;30:858)

Gross images

Contributed by Debra L. Zynger, M.D.

Complete regression (pT0)

Germ cell neoplasia in situ only (pTis)

Partial regression (pT1)

Microscopic (histologic) description

Intratesticular fibrous scar (Am J Surg Pathol 2006;30:858, Am J Pathol 1961;38:207):
- Acellular collagenous tissue with numerous small interspersed vessels
- Foamy or hemosiderin laden macrophages
- Lymphoplasmacytic infiltrate
- May have necrosis or intratubular calcification (microlithiasis)
Residual germ cell tumor may be present if regression is incomplete
- Pure seminoma most common (Am J Surg Pathol 2006;30:858, J Urol 2009;182:2303)
Testicular parenchyma (Am J Surg Pathol 2006;30:858):
- Germ cell neoplasia in situ (50% of cases)
- Remaining parenchyma may be atrophic with:
  - Shrunken seminiferous tubules with decreased spermatogenesis
  - Sertoli cell only lined tubules
  - Thickened peritubular basement membrane

Microscopic (histologic) images

Contributed by Debra L. Zynger, M.D.

Scar

Acellular matrix

Small vessels

Hemosiderin

Germ cell neoplasia in situ

OCT3 / 4

D2-40

CD117

Positive stains

Germ cell neoplasia in situ / seminoma: SALL4, OCT3 / 4, CD117 (c-kit), PLAP, D2-40 (podoplanin)
Embryonal carcinoma: SALL4, AE1 / AE3, CD30, OCT3 / 4, PLAP (variable)
Yok sac tumor: SALL4, AE1 / AE3, glypican 3, AFP
Choriocarcinoma: SALL4, AE1 / AE3, CK7, hCG, glypican 3

Negative stains

Germ cell neoplasia in situ / seminoma: AE1 / AE3, CK7, glypican 3, hCG, AFP

Molecular / cytogenetics description

Identification of isochromosome 12p by FISH can confirm a testicular germ cell tumor metastasis although immunohistochemistry is more commonly used and has wider availability

Sample pathology report

Left testicle and spermatic cord, radical inguinal orchiectomy:
- Scar (1.5 cm) and germ cell neoplasia in situ, consistent with regressed germ cell tumor (see synoptic report, pTis NX)
- Comment: the germ cell neoplasia in situ expresses OCT3/4, D2-40, CD117 and PLAP

Differential diagnosis

Nonneoplastic scar:
- Normal serum tumor markers, no extragonadal metastasis
- Usually multifocal
- No germ cell neoplasia in situ (negative for SALL4, OCT3 / 4, CD117, PLAP and D2-40)
- Intratubular calcification less common
Testicular atrophy:
- Normal serum tumor markers, no extragonadal metastasis
- Usually diffuse, no discrete scar
- No germ cell neoplasia in situ (negative for SALL4, OCT3 / 4, CD117, PLAP and D2-40)
- Intratubular calcification less common
Treatment effect:
- History of chemotherapy for germ cell tumor

Board review style question #1

Germ cell neoplasia in situ is found adjacent to a scar, consistent with regressed germ cell tumor. Positive expression using which of the following can confirm the germ cell neoplasia in situ?

AFP
Beta hCG
CD30
CK7
OCT3 / 4

Board review style answer #1

E. OCT3 / 4

Comment Here

Reference: Regressed germ cell tumor

Board review style question #2

What is the most common tumor subtype in a partially regressed testicular germ cell tumor?

Choriocarcinoma
Embryonal carcinoma
Seminoma
Teratoma
Yolk sac tumor

Board review style answer #2

C. Seminoma

Comment Here

Reference: Regressed germ cell tumor

Rete testis adenomatous hyperplasia

Table of Contents

Definition / general

Uncommon benign lesion; usually an incidental finding
May be similar to papillary adenoma of rete testis
Mean age 59 years, range 30 - 74 years
References: Am J Surg Pathol 1991;15:350, Am J Surg Pathol 1991;15:66

Gross description

May be solid / cystic mass in testicular hilus; usually small, incidental microscopic finding

Microscopic (histologic) description

Tubulopapillary or cribriform proliferations of bland epithelium that projects into dilated channels of rete testis
Associated with hyaline globules (represent proteins absorbed from lumen by epithelial lining cells)

Positive stains

keratin, EMA

Negative stains

vimentin, actin, desmin and S100

Differential diagnosis

Yolk sac tumor

Seminoma

Table of Contents

Definition / general

Most common type of testicular germ cell tumor (up to 50%) and may occur as component of mixed germ cell tumor
Derived from transformed gonocytes
Consists of cells with well defined borders, (usually) clear cytoplasm, round to polygonal nuclei and prominent nucleolus

Essential features

Most frequent germ cell tumor of the testis
Presents in young men (30 - 49) with unilateral palpable mass
Typically a well demarcated, uniform neoplasm with characteristic cytological features and background of fibrous septae and lymphocytes
Germ cell markers (OCT 3/4, CD117) are useful in the diagnosis
Prognosis is stage dependent with excellent 5 year survival when clinical stage 1

Terminology

Seminoma: testicular primary (or mediastinal primary)
Dysgerminoma: same tumor but primary to the ovary
Germinoma: same tumor but primary to extragonadal sites (such as pineal gland)

ICD coding

ICD-O: 9061/3 - seminoma, NOS
ICD-10: C62.90 - malignant neoplasm of unspecified testis, unspecified whether descended or undescended

Epidemiology

Male, age 30 - 49
Rare in > 70 or

Sites

Testicle

Pathophysiology

Arises from germ cell neoplasia in situ (GCNIS)
GCNIS cells are proposed to arise from delayed maturation of primordial germ cells / gonocytes with polyploidization resulting in a transformed germ cell
This progresses post puberty into seminoma (most likely GCNIS evolves into intratubular seminoma and then invasive seminoma) (J Urol 1996;155:1938)

Etiology

Risk factors include: family history, previous germ cell tumor, cryptorchidism, subfertility, immunodeficiency disorders (Br J Urol 1989;64:78, J Urol 1996;155:1938)

Clinical features

Usual presentation is with a mass
Paraneoplastic symptoms are rare (limbic encephalopathy, hypercalcemia, polycythemia, exophthalmus) (BMJ Case Rep 2014;2014:bcr2014206893)
Metastases are initially retroperitoneal and then progress to mediastinal and cervical nodes; visceral metastases develop late

Diagnosis

Testicular ultrasound
Serum LDH, AFP and hCG performed
Chest Xray or CT of abdomen and chest (Cancer Treat Res 2018;175:273)

Laboratory

Serum LDH and PLAP may be elevated
hCG levels are increased in up to 20% of cases but elevation is modest (Pathol Annu 1991;26:59)
AFP should not be increased, if elevated think liver disease or nonseminoma component

Radiology description

Uniform, well delineated and hypoechoic mass on ultrasound
May be microlithiasis

Radiology images

Images hosted on other servers:

Ultrasound with testicle mass

Parietal metastasis

Prognostic factors

Clinical stage 1 has 95 - 98% 5 year survival
- > 40 years and advanced stage are poor prognostic features (nonpulmonary metastases)

Case reports

27 year old man with neoplastic meningitis from testicular seminoma (Oncologist 2018;23:1385)
30 year old man with hemoperitoneum from ruptures intra-abdominal testis (BMJ Case Rep 2018;2018:224898)
34 year old man with mediastinal seminoma presenting as a neck mass (Diagn Cytopathol 2019;47:334)
40 year old man with intra-abdominal seminoma arising in cryptorchid testis (J Med Case Rep 2019;13:2)
44 year old man with limbic encephalitis from metastatic “burned out” seminoma (Front Neurol 2018;9:20)

Treatment

Surgery (radical orchiectomy) for primary
Surveillance protocols used for stage 1 disease
Radiation (very radiosensitive tumor) and chemotherapy (platinum based) used in higher stage disease
Retroperitoneal lymph node dissection used for residual post chemotherapy disease (J Natl Compr Canc Netw 2012;10:502)

Gross description

Well demarcated, homogeneous, solid cream or grey tumors; surface nodularity and lobulation; may be multiple nodules
Necrosis or hemorrhage usually minimal
If regressed, only a scar may be visible
Usually confined to testis (90%)

Gross images

Contributed by Debra L. Zynger, M.D.

pT1a

pT1b

pT2

Images hosted on other servers:

Very large seminoma

Seminoma

Lobulated soft tan to brown tissue

Frozen section description

Fibrous bands with lymphocytes and clear cells
Intra-operative smear / touch prep preparation will show large cells with abundant cytoplasm and admixed lymphocytes; tigroid type pattern (dense and light stripes) in air dried Giemsa smear

Frozen section images

Contributed by Michelle Downes, M.D. and Debra L. Zynger, M.D.

Intraoperative frozen section

Pale, foamy cytoplasm

Microscopic (histologic) description

Sheets or lobular configuration of tumor with fibrous septae
Cells are typically pale (glycogen) but may be eosinophilic
Cell membranes are well defined with distinct cell boundaries
Nuclei are polygonal and may have a flat edge giving a squared off appearance; they contain one or more prominent central nucleoli; no nuclear overlap if well fixed tissue
A lymphocytic infiltrate is present (T lymphocytes) with plasma cells; germinal centers may occur
Granulomas noted in up to 50% of cases
Intercellular edema with microcystic spaces and coagulative type necrosis can be present
Multinucleated syncytiotrophoblasts can be seen in 20% of tumors and can produce hCG
Intratubular seminoma may be adjacent to invasive seminoma (30% cases)
Less frequent growth patterns include intertubular pattern (may not form a mass), corded growth, microcystic, tubular, signet ring appearance
Anaplasia referring to increased mitoses and pleomorphism within a seminoma is no longer reported (no correlation with outcome) (J Urol 1996;155:1938)
Fibrosis and sclerosis can indicate regressed or burnt out seminoma
Lymphovascular invasion is uncommon, especially in tumors under 4 cm, and should be differentiated from artifactual carry over (Am J Clin Pathol 2016;145:341)
Invasion of rete testis can be direct stromal invasion or pagetoid invasion; direct stromal invasion carries prognostic significance in seminoma (Am J Surg Pathol 2017;41:e22)

Microscopic (histologic) images

Contributed by Michelle Downes, M.D. and Debra L. Zynger, M.D.

Fibrous septae

Admixed lymphocytes

Large cells with clear cytoplasm

Coagulative necrosis

OCT 3/4

CD117

Granulomatous inflammation

Granuloma

Intratubular seminoma

Rete testis invasion

Rete testis pagetoid spread

Hilar fat invasion

Epididymal invasion

Syncytiotrophoblasts

hCG

Discontinuous spermatic cord invasion

Cytology description

Discohesive population of large cells with moderate cytoplasm, round slightly irregular nuclei and one or more prominent nucleoli
Background population of small, mature lymphocytes
Classic “tigroid smear” seen mostly in hypercellular aspirates (J Cytol 2011;28:39)

Cytology images

Contributed by Michelle Downes, M.D. and Debra L. Zynger, M.D.

Intraoperative touch prep

Large cells with prominent nucleoli

Tigroid pattern

Positive stains

OCT 3/4, CD117, D2-40, PLAP, SALL4, SOX17 (Am J Surg Pathol 2014;38:e50)
PAS

Negative stains

CD30, AFP, glypican 3, hCG (syncytiotrophoblasts may be positive)
EMA, AE1 / AE3 stains cytoplasm of occasional cells in CK7
Inhibin, p63, PAX8, GATA3

Molecular / cytogenetics description

Isochromosome from the short arm of chromosome 12, i(12p) present
KIT mutations (Cancer Res 2005;65:8085)

Sample pathology report

Right testis, mass, radical orchiectomy:
- Seminoma, 3.6 cm (see synoptic report)
- Comment: Immunohistochemistry was performed and the tumor expresses OCT 3/4 and CD117. The cells are negative with CD30 and AFP. The immunoprofile supports the morphologic interpretation of seminoma.

Differential diagnosis

Embryonal carcinoma, solid pattern:
- Significantly greater atypia with lack of distinct cell borders
- Nuclei overlap and increased mitotic activity
- May have additional growth patterns present
- CD30 and cytokeratin positive
Spermatocytic tumor:
- Older patients (> 50)
- Lack of lymphocytes and fibrous septae, three distinct cell populations
- Absence of GCNIS
- OCT 3/4, D2-40 and PLAP negative (may express CD117 and CD30)
Yolk sac, solid pattern:
- Usually some variability in growth patterns present
- Lacks distinct fibrous septae and abundant lymphocytes
- May have Schiller-Duval bodies and hyaline globules
- Glypican 3 and alpha-fetoprotein (AFP) positive
Sertoli cell tumor:
- Lack fibrous bands, lymphocytes and granulomas
- May have more typical tubular areas in conjunction with sheet like growth
- Absence of GCNIS
- Inhibin and keratin can be positive; negative for SALL4, PLAP and OCT 3/4
Lymphoma:
- Older patients (> 60)
- Predominantly interstitial involvement between seminiferous tubules, may be bilateral (rare for seminoma)
- Absence of GCNIS
- CD45 and CD20 positive; OCT 3/4 and PLAP negative
Granulomatous orchitis:
- Predominantly intratubular involvement, granulomas may be poorly formed
- Absence of GCNIS
- OCT 3/4, CD117 and PLAP negative

Board review style question #1

AFP
CD30
hCG
OCT 3/4
SALL4

Board review style answer #1

B. CD30

Comment Here

Reference: Seminoma

Board review style question #2

Bone
Brain
Groin nodes
Lung
Retroperitoneal nodes

Board review style answer #2

E. Retroperitoneal nodes. This is a photo of seminoma.

Comment Here

Reference: Seminoma

Serous borderline tumor

Table of Contents

Definition / general

Serous epithelial tumor of low malignant potential occurring in paratesticular region

Terminology

Same as ovarian counterparts

Epidemiology

Rare tumor but more common than malignant serous epithelial tumors
Mean patient age in the largest reported series was 56 years, range of 14 - 77 years (Am J Surg Pathol 2001;25:373)

Sites

Tunica is most common site, commonly arising from tunica albuginea
Tunica vaginalis, spermatic cord are other common sites
Tumor may extend to testis

Etiology and Pathophysiology

Postulated cell of origin is Müllerian metaplasia of mesothelial lining
Cases arising in testis are explained by Müllerian metaplasia occurring in mesothelial cell inclusions within testicular parenchyma
Embryological Müllerian remnants within testis and paratestis are also postulated to give rise to these tumors

Clinical features

Painless testicular mass in elderly male is most common presentation

Diagnosis

Suspected clinico - radiologically and confirmed histologically

Laboratory

No specific laboratory abnormality

Radiology description

Cystic lesion arising in paratesticular / testicular region
Broad papillae may be visualized but there are no specific diagnostic criteria

Prognostic factors

No reports of recurrence of serous borderline tumors but lesion is rare and reported follow up is only 2 years

Case reports

59 year old men (Hum Pathol 1992;23:75, Anticancer Res 2012;32:5011)
64 year old man with serous borderline tumor of the paratestis (Pathol Int 2008;58:311)

Treatment

Radical orchidectomy is treatment of choice
No cases reported have recurred with or without chemotherapy but need for adjuvant chemotherapy needs to be assessed for each case

Gross description

1 - 6 cm grossly cystic lesion arising within paratestis / testis
Cyst wall is variably thickened with protrusions
Papillae may be visualized focally but usually are not a prominent feature

Microscopic (histologic) description

Histologically identical to their ovarian counterpart
Tumors are cystic with numerous intracystic blunt papillae lined by ciliated stratified columnar cells with minimal to mild cytologic atypia
Psammoma bodies may be present
Cyst wall shows variable amount of fibrous tissue
Ki67 staining index varies from 1% to 10%

Cytology description

Fluid smears with scattered epithelial cells
Occasional papillary frond may be visualized but is usually not a prominent feature

Positive stains

Diffuse strong staining for CK7, ER, PR, MOC31, BerEP4, CAM5.2 and CD15

Negative stains

CK20, CEA, HER2, calretinin

Molecular / cytogenetics description

No specific cytogenetic abnormality has been documented

Differential diagnosis

Serous cystadenocarcinoma

Table of Contents

Terminology

Same as ovarian counterpart

Epidemiology

Mean age 31 years, range 16 to 42 years (Am J Surg Pathol 1995;19:1359, Hum Pathol 1992;23:75) but can be seen in any age group

Sites

Paratesticular region
Commonly involves paratesticular soft tissue in testicular - epididymal groove, visceral tunica vaginalis and rete testis
Rarely is confined to testicular parenchyma

Pathophysiology

Same as other serous tumors of ovarian type
Possible origin from Müllerian metaplasia of mesothelial lining, testicular mesothelial inclusions, embryonic Müllerian remnants

Clinical features

Most patients present with a scrotal mass with hydrocele of 4 - 6 weeks duration
Less commonly patients present with a hydrocele alone
Presentation with metastases is uncommon

Diagnosis

Suspected clinico - radiologically and confirmed histologically
Clinico - radiological features do not sufficiently distinguish this tumor from other similar tumors in this region, which are more common

Laboratory

CA125 may be elevated but is not a consistent feature

Radiology description

USG: commonly a 2.0 - 3.5 cm paratesticular mass, associated with a hydrocele
If predominantly cystic, may be associated with papillary or solid area at one end

Prognostic factors

Has high progression rate and commonly has late metastases

Case reports

6 year old child with paratesticular papillary serous cystadenocarcinoma (Indian J Pathol Microbiol 2006;49:36)
22 year old man with serous papillary adenocarcinoma of rete testis (J Cancer Res Ther 2007;3:37)
29 year old man with serous papillary adenocarcinoma of tunica vaginalis with metastasis (Cancer 1991;67:1450)
50 year old man with papillary serous carcinoma of tunica vaginalis (Pathol Res Pract 2000;196:781)

Treatment

Treatment of choice is high inguinal orchidectomy, followed by chemotherapy
Role of inguinal lymph node dissection is not established

Gross description

Commonly 1.5 - 3.0 cm
Solid, whitish tan, poorly circumscribed, often gritty masses involving soft tissue between testis and epididymis, paratesticular soft tissue or visceral tunica vaginalis
Papillary fronds may be visible in grossly cystic tumors
Invasive foci are commonly associated with a fibrous reaction

Gross images

Images hosted on other servers:

Intratesticular mass

Microscopic (histologic) description

Invasive, well formed papillae lined by serous cuboidal or columnar cells with eosinophilic cytoplasm and marked atypia
Abundant psammoma bodies
Areas of borderline serous tumor often present and rarely can be the dominant component
Most tumors have nuclear grade II or III

Microscopic (histologic) images

Images hosted on other servers:

WT1+

Positive stains

Mucicarmine highlights intracellular neutral mucin
Cytokeratins, AE 1 / AE3, S100, EMA, BerEP4, LeuM1 (CD15), B72.3
Variable CEA, PLAP, WT1, CA125

Negative stains

Mesothelin, thrombomodulin, HBME1, calretinin

Electron microscopy description

Gland formation with delicate luminal microvilli and cilia

Differential diagnosis

Borderline serous papillary tumor: no invasion
Metastatic carcinoma
Mesothelioma: expresses thrombomodulin, HBME1, calretinin

Sertoli cell nodule

Table of Contents

Definition / general

Nonneoplastic proliferation of immature Sertoli cells within seminiferous tubules
Included in the spectrum of testicular dysgenesis syndrome (Clin Endocrinol (Oxf) 2009;71:459, MacLennan: Urologic Surgical Pathology, 4th Edition, 2019)

Essential features

Usually an incidental finding in adult testis
Commonly seen in cryptorchid testis, also identified in normal testis
Nodule size usually varies from microscopic to 5 mm; rarely can reach up to 10 mm
Comprised of seminiferous tubules containing proliferation of immature Sertoli cells

Terminology

Sertoli cell hyperplasia
Tubular dysgenesis
Hypoplastic zones
Pick adenoma

ICD coding

ICD-10: D29.20 - benign neoplasm of unspecified testis

Epidemiology

Identified in adults with
- Cryptorchid testis (~60%)
- Normal scrotal testes (~22%)
- Occasionally in infertile testis
- Adjacent to germ cell tumor (MacLennan: Urologic Surgical Pathology, 4th Edition, 2019)

Sites

Testes

Pathophysiology

Exact pathophysiology of Sertoli cell nodules is unknown
Proliferation of Sertoli cells has been identified in the setting of
- Sexually immature testis
  - Sertoli cells are mitotically active in sexually immature testis and their numbers remain stable in adults (Am J Anat 1957;100:241)
- Developmental arrest of seminiferous tubules
  - Lack of lengthening of tubules prevents the distribution of Sertoli cells (J Clin Pathol 2004;57:802, Hum Pathol 1982;13:3)
Presence of immature Sertoli cells in cryptorchid testes could be explained by different factors including
- Increased temperature of the undescended testes
- Association with congenital lesions
- Hormonal influences (J Clin Pathol 2004;57:802, Hum Pathol 1982;13:3)

Etiology

Primary testicular lesion
Seen within the spectrum of testicular dysgenesis syndrome
Proliferation of seminiferous tubules which are unable to undergo pubertal development
Reference: Clin Endocrinol (Oxf) 2009;71:459

Clinical features

Usually asymptomatic and an incidental finding (Am J Surg Pathol 2010;34:1874)
Macroscopic lesions can present as a palpable testicular mass or firmness, testicular pain and as a visible mass on ultrasound (Am J Surg Pathol 2010;34:1874)

Diagnosis

Usually an incidental finding on histological examination

Laboratory

No significant laboratory findings

Radiology description

Ultrasound imaging may show a nonspecific hyperechogenic lesion (J Clin Pathol 2006;59:1223)

Radiology images

Contributed by Raman Danrad, M.D.

Ultrasound of left testis

Prognostic factors

Sertoli cell nodules have no malignant potential (J Clin Pathol 2006;59:1223)
Presence of Sertoli cell nodules in a testicular biopsy is an adverse prognostic sign for fertility (MacLennan: Urologic Surgical Pathology, 4th Edition, 2019)
Spontaneous regression may occur with increasing age (J Clin Pathol 2006;59:1223)

Case reports

21 year old man with lower left abdomen pain for 10 months (IAIM 2017;4:64)
31 year old man with right inguinal pain and undescended testis (Grand J Urol 2022;2:33)
33 year old man with a painless, right testicular firmness (J Clin Pathol 2006;59:1223)

Treatment

Incidental finding; hence, no further intervention is necessary after histologic diagnosis (Am J Surg Pathol 2010;34:1874)

Gross description

Well circumscribed, white-tan to yellow-tan nodules
Size ranges from microscopic to 5 mm; may reach up to 10 mm (referred to as macroscopic)
Can be single or multiple
Firm to gelatinous
References: Am J Surg Pathol 2010;34:1874, Pathol Res Pract 2016;212:943, J Clin Pathol 2006;59:1223

Gross images

Images hosted on other servers:

Demarcated, bulging, pale yellowish nodules

Sharply demarcated, yellowish white nodule

Microscopic (histologic) description

Circumscribed, unencapsulated nodules, comprised of
- Prepubertal sized seminiferous tubules
- Profiles of tubules vary from round to oval to hourglass in shape
- Lined by columnar to pseudostratified epithelium composed of Sertoli cells with elongated, hyperchromatic nuclei, 1 or more peripherally located nucleoli and scant cytoplasm
- Tubules are devoid of lumina; however, may contain globular hyaline material deposits, due to invagination of the excess basal lamina produced by Sertoli cells
  - Sertoli cells can be arranged in a ring shaped manner around the hyaline material
  - Basal lamina (basement membrane) type material may undergo calcification
- Isolated spermatogonia may be observed in some nodules
Interstitium varies from scant to well collagenized
- Leydig cells are usually absent or low in numbers
References: MacLennan: Urologic Surgical Pathology, 4th Edition, 2019, Am J Surg Pathol 2010;34:1874, J Clin Pathol 2004;57:802

Microscopic (histologic) images

Contributed by Ritu Bhalla, M.D. and Jian-Hua Qiao, M.D.

Unencapsulated nodule

Seminiferous tubule proliferation

Focal Leydig cells

Hyaline basement membrane deposits

Pseudostratified Sertoli cells

Arrangement of Sertoli cells

Calcification

Hyperplastic Sertoli cells

Atrophic seminiferous tubules

Persistent immature tubules

Hyalinization of basement membrane

Atrophic seminiferous tubules

Positive stains

Immature Sertoli cells
- Vimentin, D2-40, CK8, CK18, calretinin and inhibin (MacLennan: Urologic Surgical Pathology, 4th Edition, 2019, J Clin Pathol 2006;59:1223, Am J Surg Pathol 2010;34:1874)
Occasional spermatogonia seen in some cases can be highlighted by
- NY-ESO-1 (J Clin Pathol 2006;59:1223)
- TSPY (Am J Surg Pathol 2010;34:1874)
Basement membrane material
- PAS
- Type IV collagen (J Clin Pathol 2004;57:802)

Negative stains

Electron microscopy description

Hyaline material in light microscopy shows as compact multilamellar matrix in electron microscopy (J Clin Pathol 2004;57:802)

Electron microscopy images

Images hosted on other servers:

Thickened, multilamellar basement membranes

Hyaline core

Sample pathology report

Testes, radical orchiectomy:
- Sertoli cell nodule (see comment)
- Comment: Minute nodular collection of seminiferous tubules comprised predominantly of Sertoli cells with intratubular eosinophilic basement membrane-like material, with background of benign testicular parenchyma.

Differential diagnosis

Sertoli cell adenoma and tubular hamartoma:
- Usually larger in size
- Almost exclusively seen in patients with androgen insensitivity syndrome (AIS)
- Unencapsulated nodules composed of solid tubules of immature Sertoli cells
- Sertoli cells show spherical nuclei and lack pseudostratification
- Tubular hamartoma has a densely cellular interstitium with fusiform cells and numerous Leydig cells
- Sertoli cell adenoma lacks interstitial Leydig cells
- Absence of intratubular globular basement membrane deposits
Sertoli cell tumor, not otherwise specified:
- Usually larger in size (> 1 cm)
- Larger cells with vesicular nuclei and prominent nucleoli arranged in cords and tubules
- Nuclear atypia and mitotic activity may be present
- Absence of basal membrane thickening and germ cells
Intratubular large cell hyalinizing Sertoli cell neoplasia:
- Multiple nodules composed of tubules with larger diameter
- May show thickening of basal membranes and intratubular globular basement membrane deposits
- Sertoli cells with higher grade of maturation (vesicular nuclei with central nucleoli and large eosinophilic cytoplasm)
- Absence of germ cells
- Associated with Peutz-Jeghers syndrome
Gonadoblastoma:
- Nests consist of Sertoli cells and large, atypical germ cells
- Diffuse nodular distribution
- Germ cells positive for OCT 3/4
Sex cord stromal tumor of testis with entrapped germ cells:
- Usually larger in size
- Tubular and cord-like arrangements of sex cord cells
- Germ cells are mostly present at the periphery and in clusters
- Absence of prominent basement membrane deposits
Testes with focal Sertoli only cell tubules:
- Contain a mix of Sertoli only tubules and tubules with germ cells
- Sertoli only tubules are not clustered
- Size of tubules and degree of Sertoli cell maturations is higher
- Absent intratubular globular basement membrane deposits
References: MacLennan: Urologic Surgical Pathology, 4th Edition, 2019, Am J Surg Pathol 2010;34:1874

Board review style question #1

A 30 year old man presents for evaluation of a nonpainful right testicular firmness. Ultrasound imaging showed a hyperechogenic lesion and orchiectomy was performed to rule out testicular neoplasm. Gross examination reveals a well circumscribed, white-tan, firm nodule measuring 8 mm in its greatest dimension with microscopic appearance as shown in the images above. What additional intervention is necessary after diagnosis?

Chemotherapy
Contralateral orchiectomy
No additional intervention is necessary
Retroperitoneal lymph node dissection

Board review style answer #1

C. No additional intervention is necessary. The image reflects a Sertoli cell nodule, referred by some studies as macroscopic, being identified grossly with a size of 8 mm. Answers A, B and D are incorrect because Sertoli cell nodule is a nonneoplastic proliferation of immature Sertoli cells with no reported malignant potential; hence, no other intervention is required after histologic diagnosis.

Comment Here

Reference: Sertoli cell nodule

Board review style question #2

A 25 year old man presents for evaluation of left lower abdominal pain. Imaging reveals the location of the left testicle in the inguinal canal. Subsequent orchiectomy revealed an unremarkable cut surface. Microscopic findings showed multiple, well circumscribed nodules with the appearance as shown in the images above. Which of the following immunohistochemical stains is expected to be positive?

hCG
Inhibin
OCT 3/4
PLAP

Board review style answer #2

B. Inhibin. Sertoli cell nodule is composed mainly of immature Sertoli cells and inhibin helps to highlight and confirm their presence. Answers C, D and A are incorrect because OCT 3/4, PLAP and hCG are negative in Sertoli cell nodule and are helpful to rule out the presence of germ cell neoplasms.

Comment Here

Reference: Sertoli cell nodule

Board review style question #3

Which of the following is a common finding in Sertoli cell nodules?

Atypical mitoses
Globular hyaline material deposits
Nuclei in a syncytium
Numerous spermatogonia

Board review style answer #3

B. Globular hyaline material deposits. Sertoli cells produce an excess of basal lamina that invaginates into the involved tubules. Answer D is incorrect because spermatogonia, when present, are scattered. Answer A is incorrect because typical mitoses are not a common finding of Sertoli cell nodules and are more common in malignant entities. Answer C is incorrect because nuclei in a syncytium (syncytiotrophoblasts) are usually seen in germ cell tumors and are not an expected finding in Sertoli cell nodules.

Comment Here

Reference: Sertoli cell nodule

Sertoli cell only

Table of Contents

Definition / general

Also known as Sertoli cell only syndrome
First derscribed by Del Castillo et al. (1947)

Etiology

Causes: idiopathic, gonadotropin deficiency, cryptorchidism, orchitis, prostate cancer hormonal therapy, radiation, Klinefelter syndrome (Arch Pathol Lab Med 2010;134:1197)

Germ cell aplasia and focal spermatogenesis

2 populations of tubules; one population with small tubules exhibiting germ cell aplasia, other population has reduced spermatogenesis
Usually very low sperm count
Some prefer the term "hypospermatogenesis" for this setting (Arch Pathol Lab Med 2010;134:1197)

Microscopic (histologic) description

Tubules are reduced in diameter and lined only by Sertoli cells
Sertoli cells are perpendicular to basement membrane; may resemble palm trees waving in a breeze
Cells have nuclear indentations and prominent nucleoli
Charcot-Bottcher crystals sometimes seen as thin eosinophilic lines in various directions
4 types of Sertoli cells have been identified
1. Normal adult mature cells
2. Immature cells
3. Dysgenetic cells
4. Involuting cells (Histopathology 1990;16:173)

Microscopic (histologic) images

Contributed by Asmaa Gaber Abdou, M.D.

Sertoli cell only and Leydig cell hyperplasia

Differential diagnosis

Intratubular germ cell neoplasia

Sertoli cell tumor

Table of Contents

Definition / general

Sex cord stromal tumor of testis composed of cells showing features of fetal, prepubertal, adult or atrophic Sertoli cells, at least focally

Essential features

Second most common type of pure sex cord stromal tumor after Leydig cell tumor
Most are small, unilateral tumors in adults and the vast majority are benign
Characterized by tubular or cord pattern, at least focally
Positive for SF1 and nuclear beta catenin
Variable and inconsistent expression of calretinin, inhibin A, androgen receptor, CD56
Negative for SALL4, OCT4 and other germ cell markers
Poor response to therapy when metastatic

Terminology

Androblastoma (obsolete)

ICD coding

ICD-O:
- 8640/1 - Sertoli cell tumor
- 8640/3 - malignant Sertoli cell tumor

Epidemiology

< 1% of testicular tumors
Rare before age 20; mean age 45 years

Etiology

Risk factors: cryptorchidism, familial adenomatous polyposis (Virchows Arch 2012;461:713)
No known environmental factors

Clinical features

Slowly enlarging unilateral testicular mass
Testicular discomfort, pain or incidental finding
Hormonal manifestations very rare; more common in malignant tumors
Exceptionally, metastases are initial manifestation
References: Histopathology 2017;70:513, Ulbright: Tumors of the Testis and Adjacent Structures (AFIP Atlas of Tumor Pathology, Series 4), 1st Edition, 2014, Am J Surg Pathol 2015;39:1390

Diagnosis

For suspected testicular mass, the first test is scrotal ultrasound (US) (sensitivity 95%, specificity 97%)
If US confirms a lesion, the patient should be immediately referred to a urologist for evaluation and management
Men 15 to 44 years old with retroperitoneal mass / metastases should undergo testicular examination and scrotal US
Evaluate serum markers
Biopsy of testicular tumors is in general not performed, to prevent tumor seeding
Staging:
- In clinically stable patients, imaging may be performed before or after orchiectomy
- Imaging: computed tomography (CT) scan of the abdomen / pelvis with intravenous contrast, chest radiograph (CXR)
- Noncontrast chest CT should be performed if CXR is abnormal
Reference: Med Clin North Am 2018;102:251

Laboratory

Serum tumor markers:
- Beta human chorionic gonadotropin (hCG), alpha fetoprotein (AFP) should be normal and are used to exclude nonseminomatous germ cell tumors
- Lactate dehydrogenase (LDH) to assess global tumor burden

Radiology description

Ultrasound: solitary hypoechoic lesion; not helpful in distinguishing from germ cell tumors

Radiology images

Images hosted on other servers:

Hypoechoic lesion

Prognostic factors

Vast majority are benign, ~ 5% cases are malignant
Tumors with sclerosis > 50% almost invariably benign (Am J Surg Pathol 2014;38:510)
Features associated with malignancy: extratesticular spread, size > 5 cm, lymphovascular invasion, high grade cytological atypia, tumor necrosis, mitotic index > 5/10 high power fields (Am J Surg Pathol 1998;22:709)
Very rarely tumors without malignant histology metastasize

Case reports

23 year old man with small, solid, well demarcated intraparenchymal tumor (Case #18)
23 year old man with sclerosing Sertoli cell tumor (Rev Urol 2014;16:191)
34 year old man with familial adenomatous polyposis and bilateral Sertoli cell tumors (Virchows Arch 2012;461:713)
13 examples of malignant Sertoli cell tumors (Am J Surg Pathol 2002;26:541)

Treatment

Orchiectomy (total or partial) is treatment of choice
Retroperitoneal lymph node dissection for malignant Sertoli cell tumors
No specific therapy; poor response to chemotherapy or radiotherapy
Reference: Med Clin North Am 2018;102:251

Gross description

Cut surface usually homogenous white or yellowish
Cystic component present in ~ 30% of cases (Am J Surg Pathol 1998;22:709)
Benign: well circumscribed, most between 2 - 5 cm (Am J Surg Pathol 2014;38:510)
Malignant: > 5 cm, poor circumscription, extratesticular extension, necrosis, hemorrhage

Gross images

Images hosted on other servers:

Tumor in lower pole

Microscopic (histologic) description

Architecture: tubular (lumen), cords (no lumen), tubulopapillary present at least focally
Other patterns: macro or microcystic, nested, trabecular, whorled, solid, retiform, pseudopapillary; most tumors show mixed patterns
Nuclei: bland, uniform, round to ovoid in benign tumors; small hyperchromatic or large with prominent nucleoli in malignant tumors
Cytoplasm: usually clear and abundant but extremely variable, ranging from scant, foamy, eosinophilic to markedly lipidized; hyaline globules are common
Stroma: variable, basement membrane-like material around tubules, sclerotic, myxoid, edematous, angiomatous
If sclerosis > 50% → sclerotic variant (now considered subtype of Sertoli cell tumor, NOS)
Inflammatory cells usually absent, rarely prominent
References: Histopathology 2017;70:513, Ulbright: Tumors of the Testis and Adjacent Structures (AFIP Atlas of Tumor Pathology, Series 4), 1st Edition, 2014, Am J Surg Pathol 2015;39:1390

Microscopic (histologic) images

Contributed by Thomas Ulbright, M.D. and Case #18

Architectural patterns

Cords

Tubules

Tubopapillary

Macrocystic

Microcystic

Architectural patterns

Whorled

Trabecular

Sclerosing Sertoli cell tumor

Various images

Cells

Abundant clear cytoplasm (most common)

Heavily lipidized

Malignant

Marked cytologic atypia

Tumor necrosis

Lymphovascular invasion

High N/C ratio, increased mitotic / apoptic activity

High N/C ratio,
increased
mitotic / apoptotic
activity

Cytology description

Cytologic samples are from metastatic (malignant) Sertoli cell tumors
Aspirates show branching tubules, microacinar and papillary groups
Numerous individual cells are present in the background
Cells are small, ovoid to plasmacytoid, relatively uniform
Nuclei show smooth cell membranes and granular chromatin pattern
Malignancy evident by nuclear overlap, discordant large nuclei and mitotic activity
Aspirates resemble neuroendocrine tumors or well differentiated adenocarcinomas
References: Histopathology 2017;70:513, Ulbright: Tumors of the Testis and Adjacent Structures (AFIP Atlas of Tumor Pathology, Series 4), 1st Edition, 2014, Am J Surg Pathol 2015;39:1390

Cytology images

Contributed by Indiana University School of Medicine

Tubular formations, monotonous small cells (Pap)

Papillary groups and dyscohesive cells (Pap)

Papillary groups and discohesive cells (Pap)

Positive stains

Consistent markers: SF1, nuclear beta catenin
Inconsistent markers: calretinin, inhibin A, cytokeratins, MelanA, WT1, CD99, SOX9, vimentin, CD56, chromogranin, synaptophysin, nestin, PAX2, PAX8, androgen receptor (Am J Surg Pathol 2015;39:1390, Hum Pathol 2017;68:99, Hum Pathol 2017;61:181)

Negative stains

SALL4, OCT4, PLAP, alpha fetoprotein, hCG, CD30

Electron microscopy description

Prominent Golgi complex, variable smooth endoplasmic reticulum, lipid droplets, glycogen
Cells interconnected by desmosomes, peripheral basement membrane
References: Histopathology 2017;70:513, Ulbright: Tumors of the Testis and Adjacent Structures (AFIP Atlas of Tumor Pathology, Series 4), 1st Edition, 2014, Am J Surg Pathol 2015;39:1390

Molecular / cytogenetics description

CTNNB1 gene mutations (Am J Surg Pathol 2014;38:66)
Negative for isochromosome 12p
Cytogenetics: gains of X chromosome (~ 40% cases), loss of chromosomes 2 and 19 (less common) (Virchows Arch 2007;450:425)

Sample pathology report

Left testis, orchiectomy:
- Sertoli cell tumor, not otherwise specified (see comment and synoptic report)
- Comment: The morphologic features are diagnostic of Sertoli cell tumor, not otherwise specified. No features of malignancy are identified in this tumor (i.e. extratesticular spread, size > 5 cm, high grade cytologic atypia, > 5 mitotic figures per 10 high power fields, necrosis or lymphovascular invasion).

Differential diagnosis

Rete testis adenoma:
- Located at the rete testis
- Strong diffuse positivity for PAX2, PAX8 and pankeratin
Adenomatoid tumor:
- Paratesticular location
- Uniformly positive mesothelial markers: pankeratin, CK7, WT1, CK5/6, calretinin
- Negative for SF1 or nuclear beta catenin
Leydig cell tumor:
- Abundant eosinophilic cytoplasm, absent tubules / cords
- Consistent strong expression of calretinin, inhibin A, SF1
- Negative beta catenin (Am J Surg Pathol 2015;39:1390)
Yolk sac tumor:
- Positive for SALL4, glypican 3, alpha fetoprotein, pankeratin
- Negative for OCT4, SF1, nuclear beta catenin, inhibin A, calretinin
Seminoma:
- Positive for SALL4, OCT4, KIT, D2-40, PLAP
- Negative for SF1, nuclear beta catenin, inhibin A, calretinin
Juvenile granulosa cell tumor:
- Most common in infants; 90% occur before age 10
- Follicles with mucicarmine+ basophilic or eosinophilic secretions
- Variable solid pattern, frequent brisk mitotic / apoptotic activity
- Consistent expression of inhibin A, calretinin, FOXL2
Large cell calcifying Sertoli cell tumor:
- Large epithelioid cells, lamellated calcifications
- Associated with Carney complex
Sertoli cell nodule (Pick adenoma):
- Small size, multifocal, monotonous tubular / cord architecture, associated with androgen insensitivity syndrome and cryptorchidism

Additional references

Molch: WHO Classification of Tumours of the Urinary System and Male Genital Organs, 4th Edition, 2016

Board review style question #1

A 60 year old man presents with a 1.1 cm mass in the left testis. The tumor is positive for SF1, nuclear beta catenin, androgen receptor, variable for inhibin A and calretinin and negative for SALL4. What is the most likely diagnosis?

Adenomatoid tumor
Seminoma
Sertoli cell tumor, NOS
Yolk sac tumor

Board review style answer #1

C. Sertoli cell tumor, NOS

Comment Here

Reference: Sertoli cell, NOS

Board review style question #2

What is the characteristic immunoprofile of a testicular Sertoli cell tumor, NOS?

Positive for SF1, calretinin, chromogranin, synaptophysin; negative for SALL4 and beta catenin
Positive for SALL4; negative for SF1, inhibin A and calretinin
Positive for SF1, calretinin, inhibin A, beta catenin (nuclear); negative for SALL4, chromogranin, synaptophysin
Positive for CD45; negative for SF1, inhibin A and SALL4

Board review style answer #2

C. Positive for SF1, calretinin, inhibin A, beta catenin (nuclear); negative for SALL4, chromogranin, synaptophysin

Comment Here

Reference: Sertoli cell, NOS

Sex cord stromal tumors-general

Table of Contents

Definition / general

Includes neoplasms of pure sex cord and pure stromal type as well as those with admixtures of both components in various proportions and degree of differentiation, each strikingly different in clinical features and biology
Sex cord elements are usually positive for steroid producing immunohistochemical cell markers (e.g., inhibin, SF1); in addition, the presence of stromal elements is easily confirmed by a reticulin stain that shows the framework surrounding individual tumor cells
Some arise in the setting of androgen insensitivity syndrome (AIS) or adrenogenital syndrome (AGS), designated as tumor-like lesion occurring in specific syndrome

Essential features

Includes neoplasms of pure sex cord and pure stromal type as well as those with admixtures of both components
Uncommon testicular tumors with a greater proportion in children (25%)
Typically show indolent behavior; only 5% are malignant
Usually positive for steroid producing immunohistochemical cell markers (e.g., inhibin, SF1)

Terminology

Terminology is analogous to ovarian sex cord stromal tumors but some tumors occur almost exclusively in testis (large cell calcifying Sertoli cell tumor and sclerosing Sertoli cell tumor), while others are extremely uncommon in testis (lipid rich Sertoli cell tumor) (Korean J Pathol 2014;48:50, Mod Pathol 2005;18:S81)
Broadly divided as pure (only 1 type) or mixed (2+ types)
Classification
- Pure tumors
  - Leydig cell tumor
  - Sertoli cell tumors
    - Sertoli cell tumor
    - Large cell calcifying Sertoli cell tumor
  - Granulosa cell tumors
    - Adult granulosa cell tumor
    - Juvenile granulosa cell tumor
- Fibroma thecoma group
- Mixed and other sex cord stromal tumors
  - Mixed sex cord stromal tumor
  - Signet ring stromal carcinoma
  - Myoid gonadal stromal tumor
  - Sex cord stromal tumor, NOS

Epidemiology

Uncommon; accounts for ≤ 5% of all testicular tumors, with a greater proportion (~25%) seen in children (Can Urol Assoc J 2017;11:E344, Urology 2009;73:1165)
- Of these, Leydig cell tumors constitute about 75% and Sertoli cell tumors are the next most common
Wide age range in general but
- Juvenile granulosa cell tumor is the most common congenital testicular tumor; more common in neonates and infants, associated with ambiguous genitalia or abnormalities of sex chromosomes
- Sertoli cell tumors are common before age 1; associated with Peutz-Jeghers syndrome and Carney complex
- Leydig cell tumors are most common in the third to fifth decade of life

Sites

Testis

Pathophysiology

Poor gonadal development may lead to testicular cancer; this follows the hypothesis of testicular dysgenesis syndrome
Various histologic studies show dysgenetic features such as undifferentiated tubules, immature Sertoli cells, etc. in testicular cancer
Altered functioning of somatic cells (Leydig and Sertoli) due to mutations / polymorphism, along with environmental and lifestyle factors, act during early development; these dysfunctioning somatic cells lead to disturbed hormone balance leading to altered germ cell differentiation (Semin Cell Dev Biol 2015;45:124)

Etiology

Usually unknown
Not associated with undescended testicle (Arch Pathol Lab Med 2007;131:311)

Clinical features

Usually presents as testicular mass
Functional tumors are generally uncommon, except for Leydig cell tumors (unlike ovarian sex cord stromal tumors)

Diagnosis

Tumor histology and immunohistochemistry

Prognostic factors

Usually indolent behavior; 5% are malignant
Morphologic prognostic factors include size, mitotic rate, necrosis, cellular atypia, infiltrative borders and vascular invasion
Stage is the most important prognostic factor
Stage with TNM for malignant tumors

Case reports

7 year old boy with malignant large cell calcifying Sertoli cell tumor (Urology 2018;117:145)
22 year old man with adult granulosa cell tumor (Am J Case Rep 2014;15:471)
27 year old man with large mixed sex cord stromal tumor (Pan Afr Med J 2017;27:51)
45 year old man with testicular adult granulosa cell tumor (Urol Case Rep 2021;41:101972)
62 year old man with large cell calcifying Sertoli cell tumor (J Clin Diagn Res 2016;10:ED03)

Treatment

High inguinal orchidectomy is treatment of choice
Testicular sparing surgery may be attempted in small tumors
Retroperitoneal lymph node dissection if clinical / radiological evidence of metastatic disease

Immunohistochemistry & special stains

Vimentin is typically positive but not specific
Keratin is frequently positive in Sertoli cell tumors, while staining is focal / absent in Leydig cell tumors and granulosa cell tumors and typically negative in fibromas
EMA is typically negative
Inhibin positivity has been shown in juvenile granulosa cell tumors and Leydig cell tumors even at metastatic sites but Sertoli cell tumors are not uniformly positive (25 - 90%)
Calretinin in postpuberal testis is expressed in Leydig cells but less commonly in Sertoli cells
SF1 is highly specific (negative in germ cell tumors)
FOXL2 positivity and mutations have been detected in granulosa cell tumors
MelanA is often positive in Leydig cell tumors
CD99 is expressed in normal Sertoli and granulosa cells and in testicular sex cord stromal tumors but it is not a reliable marker for sex cord stromal tumors
S100 may stain normal Sertoli and Leydig cells and rete testis, as well as Sertoli cell tumors (including large cell variant), Leydig cell tumors and sex cord stromal tumors - unclassified
Fibrothecomas are often positive for inhibin (patchy to diffuse), calretinin and keratin; they can also stain for MelanA, BCL2, CD34, S100, muscle specific actin and desmin
PAX2 and PAX8 are typically negative
SALL4 is negative (positive in germ cell tumors)

Immunohistochemistry of sex cord stromal tumors
	Calretinin	Inhibin	S100	Keratin	SF1	Vimentin	SMA	FOXL2	MelanA
Sertoli cell tumor	+ / -	+ / -	+ / -	+	+	+	- / +		-
Large cell calcifying Sertoli cell tumor	+	+	+ / -	+ / -	+	+			+
Leydig cell tumor	+	+	+ / -	+ / -	+	+ / -	-		+
Adult granulosa cell tumor	+	+	+ / -	- / +	+	+	- / +	+ / -	-
Juvenile granulosa cell tumor	+	+			+	+
Fibroma thecoma tumors		+	+ / -	+ / -		+	+
Mixed and unclassified sex cord stromal tumors	+	+	+		+
Sex cord stromal tumor, NOS	+ / -	+ / -	+	- / +	+	+	+	+	+ / -
Myoid stromal tumor		+ / -	+		+		+

Reference: Adv Anat Pathol 2021;28:258

Molecular / cytogenetics description

No pathognomonic findings established
Lack hotspot mutations in DICER1 (in contrast to ovarian sex cord stromal tumors) (Mod Pathol 2015;28:1603)

Smooth muscle hyperplasia

Table of Contents

Definition / general

Benign nonneoplastic smooth muscle hyperplasia involving testicular adnexa around vessels or efferent ducts

Epidemiology

Mean age 63 years (range 46 to 81 years) (Am J Surg Pathol 1999;23:903)

Sites

Epididymis is most common site
Can involve rete testis, tunica vaginalis, tunica albuginea, spermatic cord

Etiology & Pathophysiology

Exact cause not known
Obstruction of epididymis or vas deferens ducts hypothesized to be initiating event

Clinical features

Most common presentation is painless scrotal mass of long standing duration
May have periodic pain but usually not a prominent feature

Diagnosis

Suspected clinico - radiologically and confirmed histologically

Laboratory

No specific laboratory feature
Negative tumor markers for germ cell and sex cord stromal tumors

Radiology description

Ultrasound helps delineate the lesion, though it may be difficult to exclude involvement of adjacent testis
May appear solid or multicystic

Prognostic factors

Benign nonneoplastic lesion
No recurrence or progression has been reported

Case reports

55 year old man with paratesticular mass (Arch Pathol Lab Med 2003;127:E111)
55 year old man with smooth muscle hyperplasia of epididymis (J Surg Case Rep 2011;2011:10)
66 year old man with simultaneous leiomyoma and contralateral smooth muscle hyperplasia of epididymis (Pathologica 2009;101:119)
Complex multilocular cystic lesion of rete testis, accompanied by smooth muscle hyperplasia, mimicking intratesticular Leydig cell neoplasm (Virchows Arch 2005;447:768)
Smooth muscle hyperplasia of epididymis (Pathology 2003;35:454)

Treatment

May be excised for diagnosis and treatment
No further treatment required

Gross description

Mean 2.5 cm, range 6 mm to 7 cm
Discrete or ill defined nodules, fusiform or cordlike masses, thickened or diffusely enlarged paratesticular structures

Gross images

Images hosted on other servers:

Well circumscribed multicystic mass

Microscopic (histologic) description

Irregular fascicles of smooth muscle in periductal, perivascular, interstitial or mixed pattern
No cohesive interlacing growth pattern of leiomyoma
May be associated with secondary myxoid change, calcification, hemorrhage, fibrosis
May be associated with ectasia of involved ducts, microscopic adenomatoid tumor, vasitis nodosa
No cellular atypia, no mitosis, no necrosis

Microscopic (histologic) images

Images hosted on other servers:

Columnar epididymal type epithelium

Cystic duct

Mass blends with ducts in epididymal tail

Immunohistochemistry & special stains

Positive for smooth muscle markers but immunohistochemistry not particularly useful in differential diagnosis

Differential diagnosis

Leiomyoma: well circumscribed interlacing fascicles of smooth muscle, which displace rather than encase / invade the adjoining structures
Leiomyosarcoma: malignant tumor characterized by high cellularity, mitosis, necrosis and cellular atypia and associated with invasive features

Spermatocele

Table of Contents

Definition / general

Benign dilatation of efferent ductules in the rete testis or head of epididymis
Size ranges from a few millimeters up to 2 cm

Essential features

Benign dilatation of the efferent ductules in the rete testis or head of the epididymis
Usually idiopathic but cystic dilation from outflow obstruction may play a role
Diagnose by ultrasound demonstrating a well defined simple cyst
Lined by cuboidal, columnar, ciliated or flattened epithelium
Cystic contents often contain spermatozoa

Terminology

Often indistinguishable from epididymal cyst

Epidemiology

All ages affected but typically occurs in 20 - 50 year old men

Sites

Testis, epididymis

Etiology

Usually idiopathic but cystic dilation from outflow obstruction may play a role (Am J Hematol 1990;34:132)
Higher incidence in cystic fibrosis and diethylstilbestrol exposure in utero (J Pediatr Surg 2013;48:2153)

Clinical features

Painless bulging mass separate from testicle

Diagnosis

Diagnosed by radiological imaging, including ultrasound and less commonly by MRI, followed by pathological evaluation of the resection specimen

Radiology description

By ultrasound, simple cysts are generally well defined and anechoic; however, low level echos (falling snow sign) or sedimentation levels can be seen (Clin Radiol 2008;63:929, Abdom Radiol (NY) 2020;45:587)
Cyst may displace the testis if it is large
Distinct from hydrocele, which envelops the testis but does not displace it

Radiology images

Images hosted on other servers:

Ultrasound images

Case reports

25 year old man with rare acute scrotal pain associated with a spermatocele (Urol J 2008;5:206)
53 year old man with spermatocytes observed in an FNA of a spermatocele (Diagn Cytopathol 2019;47:972)
55 year old man with a giant spermatocele mimicking a hydrocele (Kaohsiung J Med Sci 2007;23:366)

Treatment

Surgical resection, spermatocelectomy

Gross description

Arrives in laboratory as a collapsed, thin walled membrane (Urology 1984;24:372)
Round or ovoid
Cysts may be unilocular or multilocular and translucent (Urology 1984;24:372)
Most commonly arises from the head of the epididymis

Gross images

Contributed by Anil Parwani, M.D., Ph.D., M.B.A.

Orchiectomy
with spermatocele

Microscopic (histologic) description

Initially lined by single layer of cuboidal to ciliated columnar epithelium which becomes flattened as fluid accumulates (Urology 1984;24:372)
Thin wall of fibromuscular soft tissue
Lumen, cyst wall and adjacent soft tissue contains spermatozoa and proteinaceous fluid (Diagn Cytopathol 2010;38:816)
Associated with foreign body giant cell reaction, cholesterol clefts (Diagn Cytopathol 2010;38:816)
Epithelial lining may form papillary structures with fibromuscular cores lined by a single layer of columnar to cuboid epithelium with vacuolated cytoplasm

Microscopic (histologic) images

Contributed by Anil Parwani, M.D., Ph.D., M.B.A.

Spermatocele with adjacent epididymis

Cuboidal epithelium

Ciliated columnar epithelium

Flattened epithelium

Aggregate of spermatozoa

Macrophages containing spermatozoa

Cytology description

Cysts can contain spermiophages, macrophages with abundant distended cytoplasm containing intact spermatozoa (Diagn Cytopathol 2010;38:816)

Positive stains

AE1 / AE3, EMA, vimentin (Anat Rec 1993;235:560)

Negative stains

Calretinin, D2-40, WT1 (Int J Clin Exp Pathol 2011;4:631)

Sample pathology report

Cyst, spermatocelectomy:
- Spermatocele (see comment)
- Comment: A cyst with bland cuboidal lining is present, compatible with spermatocele.

Differential diagnosis

Hydrocele:
- Originates between the parietal and visceral layers of tunica vaginalis
- Lining is mesothelial; lumen does not contain spermatozoa
Mesothelial cyst:
- Usually originates from tunica vaginalis or tunica albuginea
Cystic dysplasia of rete testis:
- Congenital lesion of newborns that is associated with ipsilateral renal agenesis
Sertoliform cystadenoma of rete testis:
- Contains tubules with or without lumen (Am J Surg Pathol 2018;42:141)
Simple cyst of rete testis:
- Bulges into the testis proper
- Common in men undergoing renal dialysis
- Columnar epithelium, calcium oxalate crystals, fibrosis and giant cells
Tubular ectasia of rete testis:
- Has numerous dilated canaliculi
- Can coexist with a spermatocele (Arch Ital Urol Androl 2015;87:5)
Dermoid cyst:
- Rarely presents within the spermatic cord or as a paratesticular mass

Additional references

J Urol 2014;192:1179, Case Rep Urol 2015;2015:731987, Urology 1997;49:926

Board review style question #1

Which of the following is a feature of spermatocele?

Has a lining of mesothelial cells
Is cytokeratin negative
May have papillary infoldings with fibrovascular cores lined by vacuolated cuboidal or columnar cells
Originates from the same membrane as hydrocele

Board review style answer #1

C. May have papillary infoldings with fibrovascular cores lined by vacuolated cuboidal or columnar cells. A benign papilloma consisting of papillary infoldings with fibrovascular cores lined by vacuolated or columnar cells may arise from the epithelial lining of the spermatocele. The lining can be cuboidal, columnar, ciliated or flattened epithelium, not mesothelium (answer A). Spermatocele is cytokeratin positive and can be distinguished from the mesothelial lining of a hydrocele by negative staining for D2-40 or calretinin (answer B). The origin of spermatocele is from rete testis / head of epididymis epithelium, whereas hydrocele originates from the mesothelium of the tunica vaginalis (answer D).

Comment Here

Reference: Spermatocele

Board review style question #2

A paratesticular lesion is identified. Which of the following is the origin of the entity shown above?

Head of the epididymis or rete testis
Pampiniform venous plexus
Totipotential germ cells
Tunica vaginalis

Board review style answer #2

A. Spermatoceles often originate from the epithelial lining of the epididymis. Varicoceles commonly originate from the pampiniform venous plexus (answer B). Dermoid cysts commonly originate from totipotential germ cells (answer C). Hydroceles commonly originate from the tunica vaginalis (answer D).

Comment Here

Reference: Spermatocele

Spermatocytic tumor

Table of Contents

Definition / general

Spermatocytic tumor (ST) is a polymorphous triphasic germ cell neoplasm recapitulating spermatogonia development and unrelated to germ cell neoplasia in situ (GCNIS)

Essential features

Does not arise from germ cell neoplasia in situ
More common in older patients compared with patients with other germ cell tumors
Classically characterized by tripartite tumor cells with 3 different cellular sizes (small, intermediate, giant)
Immunohistochemical phenotype: CD117+, SALL4+, PLAP-, OCT3/4-, CD30-
Excellent prognosis

Terminology

Spermatocytic seminoma (not recommended by the WHO)
Spermatocytoma (not recommended by the WHO)
Spermatocytic variant of classic seminoma (not recommended by the WHO)
Type III germ cell tumor (not recommended by the WHO)

ICD coding

ICD-O: 9063/3 - spermatocytic seminoma
ICD-10: C62.9 - malignant neoplasm of testis, unspecified whether descended or undescended
ICD-11: XH80D1 - spermatocytic seminoma (inclusions: spermatocytic tumor, spermatocytoma)

Epidemiology

~1% of germ cell tumors
Usually affects older men compared with germ cell neoplasia in situ derived tumors (mean age 52 years)
Wide age range, including young patients (range 19 - 92 years)
30% of patients are 30 - 39 years; 35% are 40 - 59 years; 35% are ≥ 60 years (Am J Surg Pathol 2019;43:1)
No ethnic predisposition

Sites

Testes
9% bilateral (synchronous or more frequently, metachronous)
No primitive extragonadal cases reported so far
Only 1 case of an ovarian spermatocytic tumor-like lesion reported in a gonadal mixed germ cell tumor (Am J Surg Pathol 2017;41:1290)

Pathophysiology

Does not arise from germ cell neoplasia in situ (Am J Surg Pathol 2020;44:e30)
Derived from postpubertal type germ cells (spermatogonium / spermatocyte)
Genetically features mainly chromosomal abnormalities
Rate of genetic mutations increase with age

Etiology

Cryptorchidism is not a risk factor
Only 2 cases have been reported of coincidental incidence of spermatocytic tumor in an undescended testis (Am J Surg Pathol 2019;43:1, Br J Urol 1993;72:657)

Clinical features

Usually presents as a painless testicular nodule
Rapid tumoral growth is associated with the presence of sarcomatous differentiation (Int J Surg Pathol 2017;25:559)

Diagnosis

Spermatocytic tumor is diagnosed histologically (see Microscopic (histologic) description)

Laboratory

Not associated with elevated lactate dehydrogenase (LDH), alpha fetoprotein (AFP) or beta human chorionic gonadotropin (beta hCG) blood concentration

Radiology description

Well circumscribed (Radiographics 2017;37:1085)
Predominantly solid with heterogenous signal, including hyperechoic and hypoechoic components
Multiple cystic areas

Radiology images

Images hosted on other servers:

ST (arrow) and testis (*)

Prognostic factors

Excellent prognosis overall
ST with sarcomatous differentiation has a poor prognosis, a high risk of metastasis of the sarcomatous component to the lungs and a high mortality rate
Some early reports of metastatic ST without sarcomatous differentiation have been reconsidered to be lymphomas (Cancer 1965;18:751, Cancer 1969;24:92)
Only rare cases of bona fide metastatic ST without sarcomatous differentiation have been reported with spread to retroperitoneal lymph nodes, to the lungs and to the brain
Intravascular space invasion or infiltration beyond testicular parenchyma were reported in metastatic ST without sarcomatous differentiation (Pathol Oncol Res 2017;23:223)
Anaplastic ST is not currently considered to be a negative prognostic factor

Case reports

25 year old man with synchronous bilateral spermatocytic tumors (Scand J Urol 2017;51:78)
26 - 50 year old men with hybrid genetics in a metastatic spermatocytic tumor carrying 12p amplification (Pathology 2018;50:562)
30 year old man with a spermatocytic tumor (Med J Armed Forces India 2018;74:276)
77 year old man with cerebral metastasis of a spermatocytic tumor without sarcomatous differentiation (Pathol Oncol Res 2017;23:223)
Chrondrosarcomatous differentiation in a spermatocytic tumor (Int J Surg Pathol 2017;25:559)

Treatment

Orchiectomy
Bleomycin, etoposide and cisplatin (BEP) chemotherapy has little effect on metastatic ST without sarcomatous differentiation (Med Oncol 2011;28:S423, Pathology 2018;50:562)

Gross description

Variable size (mean 7 cm; range 1.4 - 28 cm)
Homogenous or lobulated nodule
Grayish white
Edematous or mucoid
Soft
Necrosis and hemorrhage can be present
Extension beyond the tunica albuginea might be present (Am J Surg Pathol 2019;43:1)
Fleshy and firm areas, with or without necrosis, might represent foci of sarcomatous differentiation

Gross images

AFIP images

Mucoid tumor

Images hosted on other servers:

ST (arrow)

Cystic and mucoid tumor

Frozen section description

Recognition of 3 cell types (small, intermediate, giant) is key to the correct diagnosis
Intratubular ST in the surrounding parenchyma might be misinterpreted as germ cell neoplasia in situ
No other types of germ cell neoplasia should be present

Microscopic (histologic) description

Low power magnification

Homogenous lesions show diffuse sheets of cells without evident fibrous septa and lymphocytic infiltrates
Multinodular lesions show bands of loose fibrovascular tissue separating nodules (with or without lymphocytic infiltrates) and without remnants of testicular parenchyma between nodules
Spaces filled with clear to pink fluid can be present and they can have different shapes:
- Irregular pseudocystic areas of variable size
- Pseudofollicular (roundish edematous areas surrounded by neoplastic cells)
- Microcystic spaces which separate ST into anastomosing islands with peripheral palisade of cells
Usually expansive neoplastic profile, although corded pattern of growth with intertubular neoplastic cells can be present at the periphery of the lesion
Neoplastic nodules can be boarded by a rim of fibrin (Am J Surg Pathol 2019;43:1)
Usually confined to testicular parenchyma, although it may involve the rete testis, the epididymis or the tunica albuginea
Nonneoplastic testicular parenchyma can have a mild degree of atrophy

High power magnification

Landmark feature - tripartite cytology with cells of 3 different sizes:
- Small cells (6 - 8 microns)
  - Round dark nuclei
  - Narrow rim of eosinophilic cytoplasm
  - They resemble lymphocytes
- Intermediate size cells (15 - 20 microns)
  - Round nuclei with granular to filamentous chromatin (so called spireme-like chromatin, after the thread-like chromatin at the beginning of prophase)
  - Usually no evident nucleoli, although they might be present
  - Dense eosinophilic to amphophilic cytoplasm with no glycogen
  - Poorly defined cytoplasmatic membranes
  - Clearer cells with distinct membranes can be found close to edematous areas
- Giant cells (50 - 150 microns)
  - 1 or more nuclei with the same features of medium cells
  - Eosinophilic cytoplasm with the same features of medium cells
Size distribution can vary among different cases (usually medium cells > small cells > giant cells)
Mitoses (even atypical) and apoptotic bodies can be abundant
Stroma is scant, with only small strips of connective tissue
Lymphocytic infiltrates are scant to absent, both among neoplastic cells and within connective tissue strips
Granulomas are usually not present and only rarely reported
Intratubular extension of ST can be identified around the main lesion
Germ cell neoplasia in situ is not present
Intravascular invasion can be present
Not associated with other forms of germ cell tumor
Anaplastic spermatocytic tumor:
- Not currently considered a WHO subtype of ST
- No convincing clinical evidence of aggressive behavior
- Characterized by areas of relatively monomorphic intermediate sized cells with prominent nucleoli
- Areas of conventional ST can be found elsewhere in the tumor

Spermatocytic tumor with sarcomatous differentiation

Considered a WHO subtype of ST
Rare occurrence with poor prognosis
Sarcomatous component usually features a high grade spindle cell morphology
Other possible differentiations are rhabdomyosarcoma and chondrosarcoma
Sarcoma cells can interdigitate with ST cells or grow juxtaposed to ST
Sarcoma and ST can represent variable percentages of the lesion
Cases with only a minor ST residual component can be difficult to recognize

Microscopic (histologic) images

Contributed by Maurizio Colecchia, M.D., Case #448 and AFIP images

Lobulated architecture

Tripartite cytology

Prevalent intermediate sized cells

Mitoses and apoptotic bodies

Short fibrous bands

Spireme-like chromatin

Edema and microcysts

Edema and nests

Intratubular growth

OCT3/4

CD45

Diffuse growth pattern

Focal pseudoglandular pattern

Cystic pattern

Polymorphic cell population

Small nests, trabeculae, clusters and single cells

Filamentous chromatin

Normal spermatogenesis

Unusual features

Desmin+

Tumor nests and
cords mixed with
lymphocytes

Prominent
granulomatous
reaction and
lymphoid infiltrate

Intratubular component

Virtual slides

Images hosted on other servers:

Spermatocytic tumor

Cytology description

High cellularity
Predominantly single cells
Tripartite cytology with 3 different sizes of cells (small, intermediate and large), with a preponderance of intermediate sized cells
Absence of tigroid background (foamy material attributed to the fragile glycogen rich cytoplasm of seminomas)
No lymphocytes (Diagn Cytopathol 1999;20:233)

Positive stains

CD117
SALL4
DMRT1
NUT (specificity 100%, sensitivity 41% when positivity is present in ≥ 50% of neoplastic cells with equal intensity to spermatogonia internal control) (Histopathology 2014;65:35)
OCT2
SSX2

Negative stains

PAS
EMA, PLAP, OCT3/4, beta subunit of hCG, AFP, CEA, CD30, LCA (CD45) (Am J Surg Pathol 2019;43:1)
AE1 / AE3: focal cells may have dot-like staining

Electron microscopy description

Intercellular bridges between tumor cells identical to those between spermatocytes and between spermatids (Cancer 1969;24:103)
Syncytial formation
Scanty or absent cytoplasmatic glycogen and lipids

Electron microscopy images

AFIP images

Intercellular bridge

Nest of spermatocytic seminoma

Molecular / cytogenetics description

Aneuploid
Classically without 12p abnormalities
Presence of 12p amplification (hybrid genetics) might be linked to the development of metastases or anaplastic morphology (Pathology 2018;50:562, Hum Pathol 2022;124:85)
Amplification of chromosome 9p is the most frequent genetic abnormality, with a consequent amplification of the DMRT1 gene locus (Cancer Res 2006;66:290, Hum Pathol 2022;124:85)
Other gains include chromosome 1 and 20
Partial loss of chromosome 22 can be present
Mutations are infrequent
Activating mutations of HRAS and FGFR3 can be present, especially in elderly patients (PLoS One 2017;12:e0178169)
Epigenetics: loss of biparental imprinting with re-establishment of paternal imprinting

Sample pathology report

Testicle, partial / radical orchiectomy:
- Spermatocytic tumor
- Immunohistochemistry (supporting the above diagnosis): neoplastic cells are CD117+, SALL4+, OCT3/4-
- Infiltration of rete testis present / absent; infiltration of epididymis present / absent; infiltration of hilar fat present / absent; infiltration of spermatic cord present / absent; infiltration of rete testis present / absent; infiltration of tunica vaginalis / scrotal wall testis present / absent
- Lymphovascular invasion present / absent
- Surgical margin involved / not involved by neoplasia

Differential diagnosis

Diffuse large B cell lymphoma (DLBCL) of the testis:
- DLBCL is the most common testicular neoplasia in the elderly
- Often bilateral
- Diffuse growth of monomorphic cells
- Scant stroma
- LCA (CD45)+, CD20+, PLAP-, OCT3/4-
Seminoma:
- Seminoma is more frequent than ST in the elderly
- Seminoma cells are monomorphic with squared off nuclei
- Fibrous stroma with more prominent lymphocytic infiltrates and often granulomatous reaction
- Germ cell neoplasia in situ present; either pure or mixed with other types of germ cell neoplasia
- PAS+, PLAP+, SALL4+, CD117+, OCT3/4+, D2-40+
Embryonal carcinoma:
- Usually young patients
- Solid type resembles anaplastic ST with markedly atypical cells
- Nuclei have irregular profiles
- Germ cell neoplasia in situ present; either pure or mixed with other types of germ cell neoplasia
- PLAP+, SALL4+, OCT3/4+, CD30+, AE1 / AE3+
Yolk sac tumor with microcystic edema:
- Usually in young patients
- Elevated AFP blood levels
- Schiller-Duval bodies
- Uniform cells with clear or vacuolated to lightly eosinophilic cytoplasm
- Germ cell neoplasia in situ present; rarely pure, usually mixed with other types of germ cell neoplasia
- Glypican 3+, AFP+, SALL4+, AE1 / AE3+
Germ cell neoplasia in situ (GCNIS):
- Intratubular spread of ST can be mistaken for GCNIS
- GCNIS features thickened basement membrane (versus nonthickened in intratubular ST), single layer of monomorphic neoplastic cells above the basement membrane (versus tubules at least partially filled with tripartite cytology in intratubular ST), lack of spermatogenesis (versus spermatogenesis partially retained in some tubules in intratubular ST)
- PLAP+, SALL4+, CD117+, OCT3/4+, D2-40+

Additional references

Pathology 2018;50:88, PLoS One 2017;12:e0178169, Int J Surg Pathol 2011;19:5

Board review style question #1

Which of the following answers is correct about spermatocytic tumor?

It can be either pure or mixed with postpubertal teratoma
It does not derive from germ cell neoplasia in situ
It often presents as an extragonadal neoplasia
The most frequent location is the mediastinum

Board review style answer #1

B. It does not derive from germ cell neoplasia in situ

Comment Here

Reference: Spermatocytic tumor

Board review style question #2

In the case of the above histologic image, which of the following immunophenotypes would confirm a spermatocytic tumor?

CD117+, SALL4+, AFP+
CD117+, SALL4-, CD30+
CD117+, SALL4+, OCT3/4+
CD117+, SALL4+, OCT3/4-

Board review style answer #2

D. CD117+, SALL4+, OCT3/4-

Comment Here

Reference: Spermatocytic tumor

Splenogonadal fusion

Table of Contents

Definition / general

Also called ectopic scrotal spleen, testicular splenic fusion
Rare congenital condition of gonad fusing with ectopic splenic tissue; patients usually present before age 20, 50%+ are less than age 10
In males, involves left testis only; occurs in females also
Fusion may be continuous (attaching to spleen) or discontinuous (intrascrotal splenic nodules attached to testis, spermatic cord, epididymis, appendix of testis or appendix of epididymis)
- Continuous form is associated with limb bud anomalies such as peromelia (severe congenital anomalies of extremities identical to thalidomide embryopathy) and micrognatia (small jaw)
- Discontinuous type is rarely associated with cardiac defects

Case reports

16 year old boy with chronic, painless testicular mass (Case of the Week #309)
27 year old man with associated nonseminomatous germ cell tumor (Arch Pathol Lab Med 2002;126:1222)
56 year old man with scrotal mass (Arch Pathol Lab Med 2003;127:e277)

Gross description

Splenic tissue well demarcated from gonad

Microscopic (histologic) description

Normal splenic parenchyma with variable fibrosis, thrombi, calcification, fatty degeneration, hemosiderin

Microscopic (histologic) images

Case #309

Differential diagnosis

Lymphoproliferative tumor
Sarcoma
Teratoma

Staging

Table of Contents

Definition / general

All testicular postpubertal germ cell tumors and malignant sex cord stromal tumors are covered by this staging system
These topics are not covered: spermatocytic tumor, nonmalignant sex cord stromal tumor, prepubertal germ cell tumor, hematopoietic tumors and paratesticular tumors

Essential features

AJCC 7th edition staging was sunset on December 31, 2017; as of January 1, 2018, use of the 8th edition is mandatory

Primary tumor (pT)

pTX: cannot be assessed
pT0: no evidence of primary tumor
pTis: germ cell neoplasia in situ
pT1: nonpure seminoma confined to testis / tunica albuginea / rete and no lymphovascular invasion (LVI)
pT1a: seminoma < 3 cm confined to testis / tunica albuginea / rete and no LVI
pT1b: seminoma ≥ 3 cm confined to testis / tunica albuginea / rete and no LVI
pT2: lymphovascular, hilar fat, epididymal or tunica vaginalis invasion
pT3: direct spermatic cord soft tissue invasion
pT4: direct scrotum invasion

Notes:

Size
- Largest aggregate tumor size should be obtained, encompassing all adjacent nodules, even with different gross appearances rather than regarding nodules as separate smaller tumors
- Seminoma is subclassified as pT1a / b based on a 3 cm threshold but nonpure seminoma is not
LVI
- Freshly cut or minimally fixed testicular germ cell tumors have frequent tissue displacement artifact ("butter"), which confounds the diagnosis of true LVI (classified as pT2) (Am J Clin Pathol 2016;145:341)
- Care must be taken when grossing to decrease the amount of tissue displacement artifact and overnight fixation of a bivalved specimen may be helpful
- Histologic features supporting true LVI are tumor emboli that are cohesive, have smooth contours and adhere to the vessel wall (Am J Clin Pathol 2016;145:341)
- LVI of the spermatic cord is pT2 not pT3
pT2
- Involvement of the tunica albuginea does not impact pT classification
- Tumor involvement of the tunica vaginalis is classified as pT2 and is rare (4/170, 2% seminoma; 0/148, 0% nonseminoma) (Histopathology 2018;73:741, Mod Pathol 2013;26:579)
- Epididymal invasion is uncommon (6% seminoma, 8% nonseminoma) and is classified as pT2; however, it is not associated with a higher clinical stage (Histopathology 2018;73:741, Mod Pathol 2013;26:579)
- Tumor within the soft tissue below the level of the epididymal head is considered hilar fat invasion and is classified as pT2
pT3
- Tumor within the soft tissue beyond the angle between the epididymis and spermatic cord is classified as pT3

Regional lymph nodes (pN)

pNX: cannot be assessed
pN0: no regional lymph node metastasis
pN1: 1 - 5 involved nodes with node size ≤ 2 cm
pN2: > 5 involved nodes or extranodal extension or involved nodes > 2 cm and ≤ 5 cm
pN3: lymph node mass > 5 cm

Notes:

Regional lymph nodes = interaortocaval, para / periaortic, paracaval, preaortic, precaval, retroaortic and retrocaval nodes
The size used to classify untreated lymph nodes is the overall lymph node size rather than the size of the metastatic deposit
Per the AJCC chapter 1 regarding classification post therapy, "necrotic cells currently play no role in assigning the ypT and ypN"
Therefore, size of the metastatic deposit rather than overall lymph node is recommended for use in classifying lymph nodes after therapy
Additionally, most literature describes residual viable tumor size in lymph nodes post treatment rather than overall lymph node size (World J Urol 2021;39:1969, World J Urol 2021;39:839)

Distant metastasis (pM)

pM1a: nonregional lymph node (e.g., iliac, inguinal, pelvic NOS) or lung metastasis
pM1b: distant visceral metastasis

Notes:

Discontinuous spermatic cord invasion
- As discontinuous spermatic cord invasion is theorized to extend into the soft tissue via lymphovascular invasion and shows a trend towards a worse prognosis compared to pT3, it is now classified as pM1 (Mod Pathol 2022;35:249, Am J Surg Pathol 2018;42:306)
- No subcategorization as pM1a or pM1b for discontinuous spermatic cord invasion is specified in the current AJCC
- The National Comprehensive Cancer Network (NCCN) guidelines do not agree with the designation of discontinuous spermatic cord invasion as pM1 but instead recommend the classification as pT3 (J Natl Compr Canc Netw 2019;17:1529)
- The International Union Against Cancer (UICC) has not adopted the change to pM1 and still regards discontinuous spermatic cord invasion as pT3 (European Association of Urology: Testicular Cancer [Accessed 31 May 2023], Brierley: TNM Classification of Malignant Tumours, 8th Edition, 2017)

Serum markers (S)

SX: serum tumor markers not available or not performed
S0: markers within normal limits
S1: LDH < 1.5 x upper limit of normal, hCG < 5,000 mIU/mL and AFP < 1000 ng/mL
S2: LDH 1.5 - 10 x upper limit of normal or hCG 5,000 - 50,000 mIU/mL or AFP 1,000 - 10,000 ng/mL
S3: LDH > 10 x upper limit of normal or hCG > 50,000 mIU/mL or AFP > 10,000 ng/mL

AJCC prognostic stage groups

Stage group 0:pTis N0 M0 S0
Stage group I:pT1 - 4 N0 M0 SX
Stage group IA:pT1 N0 M0 S0
Stage group IB:pT2 - 4 N0 M0 S0
Stage group IS:pT1 - 4,X N0 M0 S1 - 3
Stage group II:pT1 - 4,X N1 - 3 M0 SX
Stage group IIA:pT1 - 4,X N1 M0 S0 - 1
Stage group IIB:pT1 - 4,X N2 M0 S0 - 1
Stage group IIC:pT1 - 4,X N3 M0 S0 - 1
Stage group III:pT1 - 4,X N0 - 3 M1 SX
Stage group IIIA:pT1 - 4,X N0 - 3 M1a S0 - 1
Stage group IIIB:pT1 - 4,X N1 - 3M0 S2;pT1 - 4,XN0 - 3M1aS2
Stage group IIIC:pT1 - 4,X N1 - 3M0S3; pT1 - 4,XN0 - 3 M1aS3; pT1 - 4,X N0 - 3M1bS0 - 3

Notes:

While discontinuous spermatic cord invasion is classified as pM1 per the AJCC thus rendering the patient stage III, the National Comprehensive Cancer Network (NCCN) guidelines do not agree with the designation of discontinuous spermatic cord invasion as pM1 but instead as pT3 (J Natl Compr Canc Netw 2019;17:1529)

Registry data collection variables

Serum tumor markers (AFP, hCG, LDH)

Histologic grade (G)

Germ cell tumors are not graded

Histopathologic type

Seminoma
Nonseminoma
- Embryonal carcinoma
- Yolk sac tumor
- Teratoma
- Choriocarcinoma
Mixed germ cell tumor
Malignant Leydig cell tumor
Malignant Sertoli cell tumor
Malignant sex cord stromal tumors, other types

Notes:

60% of testicular germ cell tumors are seminoma
Within a mixed germ cell tumor, frequency of tumor type is: embryonal carcinoma > teratoma, yolk sac tumor, seminoma > choriocarcinoma > other rare types (Med Oncol 2018;35:21)

Gross images

Contributed by Debra L. Zynger, M.D.

Complete regression (pT0)

Germ cell neoplasia in situ only (pTis)

Partial regression (pT1)

Teratoma (pT1)

Teratoma and EC (pT1)

Seminoma (pT1a)

Seminoma (pT1b)

Mixed germ cell tumor (pT2)

Seminoma (pT2)

No residual testis tumor (ypT0)

No residual node tumor (ypN0)

Lymph node with residual tumor (ypN1 - 3)

Discontinuous spermatic cord (pM1)

Microscopic (histologic) images

Contributed by Debra L. Zynger, M.D.

Lymphovascular invasion (pT2)

Tunica vaginalis invasion (pT2)

Epididymal invasion (pT2)

Hilar soft tissue invasion (pT2)

Lymph node metastasis (pN1)

Post treatment node (ypN0)

Post treatment node (ypN1)

Discontinuous spermatic cord invasion (pM1)

Board review style question #1

In a postpubertal testicular germ cell tumor, lymphovascular (shown above), hilar fat, epididymal and tunica vaginalis invasion are all a part of which pT category?

pT1
pT1a
pT1b
pT2
pT3

Board review style answer #1

D. pT2. Lymphovascular, hilar fat, epididymal and tunica vaginalis invasion are all a part of the pT2 category for testicular germ cell tumors. Lymphovascular invasion by embryonal carcinoma is shown in the image.

Comment Here

Reference: Testis & epididymis - Staging

Board review style question #2

The postpubertal teratoma shown in the gross photo is 1.7 cm and is confined to the testis and did not have lymphovascular invasion. Which is the correct pT category?

pT1
pT1a
pT1b
pT2
pT3

Board review style answer #2

A. pT1. Postpubertal germ cell tumors that are confined to the testicular parenchyma and lack lymphovascular invasion are pT1, pT1a or pT1b. Pure seminoma is stratified as pT1a and pT1b based on a 3 cm threshold. Nonpure seminomas are not stratified and therefore this tumor is pT1.

Comment Here

Reference: Testis & epididymis - Staging

Teratoma

Table of Contents

Definition / general

Tumor originating from germ cells with more than one embryonic germ layer

Terminology

Prepubertal and postpubertal teratoma: currently accepted categories of teratoma
- Either category may occur in either age group
Teratoma with somatic type malignancy: teratoma with malignant transformation that occupies at least a 4x magnification (0.5 cm) (Moch: WHO Classification of Tumours of the Urinary System and Male Genital Organs (IARC WHO Classification of Tumours), Fourth Edition, 2016)
Do not divide into mature and immature as both are malignant and this nomenclature is misleading, no longer accepted and has no clinical relevance (Med Surg Urol 2014;3:1)

Epidemiology

Teratoma is second most common germ cell tumor type in pediatrics, after yolk sac tumor (Rev Urol 2004;6:11)
Incidence increasing, as testicular germ cell tumors are increasing (Hum Reprod 2001;16:972)
Most commonly presents at age 25 - 35 years
Postpubertal teratoma more frequent that prepubertal teratoma
Pure teratomas (5%) are more rare than mixed germ cell tumors as malignant germ cells differentiate into other malignant phenotypes prior to teratoma (Med Surg Urol 2014;3:1)
Teratoma is a component of 50% of mixed germ cell tumors (Moch:WHO Classification of Tumours of the Urinary System and Male Genital Organs (IARC WHO Classification of Tumours), Fourth Edition, 2016)

Pathophysiology

Postpubertal type associated with germ cell neoplasia in situ (GCNIS) and chromosome 12p amplification (Med Surg Urol 2014;3:1)
- Thought to arise from GCNIS
Prepubertal is not associated with GCNIS or chromosome 12p amplification (Med Surg Urol 2014;3:1)
- Prepubertal type significantly less likely to metastasize or recur

Etiology

Genetic component; higher incidence with family history and Caucasians (Int J Dev Biol 2013;57:201)
Possible contribution of environmental exposures but the data is inconclusive (Arch Environ Occup Health 2006;61:87, PLoS One 2013;8:e77130)
- Animal studies have demonstrated associations with diethylstilbestrol (J Urol 1987;138:1446), other groups have hypothesized links between in utero and early life exposure to endocrine disrupting agents (J Urol 1979;122:36, Int J Androl 2008;31:275)

Clinical features

Most commonly presents with painless swelling of the testicle (Histopathology 1988;12:491)
Pain may be associated with hemorrhage or hematoma (Med Surg Urol 2014;3:1)
About 1/3 of pure testicular teratomas present with advanced disease (Cancer 1995;75:2244)
Mediastinal masses may present with cough, dyspnea or cyanosis (Histopathology 1988;12:491)
Intracranial masses may present with headache, vomiting or visual disturbances (Histopathology 1988;12:491)
Growing teratoma syndrome, an enlarging mass during or following chemotherapy for mixed germ cell tumor, may occur (Case Rep Urol 2014;2014:139425)

Diagnosis

Ultrasound is used to evaluate a testicle mass
Avoid biopsies to prevent cancer seeding
Radical orchiectomy is initial procedure to diagnose a testicular mass in an adult
Increasing rate of antenatal diagnoses (J Pediatr Surg 2006;41:1513)
May use intraoperative frozen sections to guide therapy in pediatric populations

Laboratory

In pure testicular teratomas, serum markers (b-hCG and AFP) are usually normal (Med Surg Urol 2014;3:1)

Radiology description

Ultrasound is used to help exclude benign pathology
Imaging may demonstrate calcifications or predominantly cystic lesions
Computed tomography of the chest and abdomen used for staging purposes

Radiology images

Images hosted on other servers:

Testicular teratoma diagnosed in utero

Demonstrating vascularity of testicular teratoma with calcifications

Prognostic factors

The International Germ Cell Consensus Classification guides prognosis and risk of recurrence for testicular germ cell malignancies (IGCCCG) (J Clin Oncol 1997;15:594, J Clin Oncol 2007;25:1033)
Presence of teratoma is associated with better prognosis and therefore histologic recognition and documentation is required (Eur J Cancer 2001;37:576)
- Germ cell tumors with > 50% teratoma have fewer metastases (J Clin Oncol 1988;6:1467)
- Germ cell tumors with > 25% teratoma have less lymphovascular invasion (pT1) (Am J Clin Pathol 2016;145:341)

Case reports

Antenatal diagnosis of teratoma in an undescended testicle (Ultrasound Obstet Gynecol 2016;47:527)
23 year old man with growing teratoma syndrome (Case Rep Urol 2014;2014:139425)

Treatment

Radical orchiectomy is first line therapy for testicular mass in an adult
Increasing rate of testis sparing surgery for prepubertal tumors (Rev Urol 2004;6:11)
Retroperitoneal lymph node dissection and platinum based chemotherapy are adjunctive therapies for testicular germ cell tumor
Treatment guidelines are based on postorchiectomy TNM stage (NCCN guidelines: Testicular Cancer)
Consider sperm preservation options

Gross description

Lobulated, with cysts of mucinous, gelatinous or serous material

Gross images

Contributed by Debra L. Zynger, M.D.

Teratoma (100%)

Mixed GCT

Microscopic (histologic) description

Postpubertal type
- Recognition is important as the percentage of teratoma must be documented in orchiectomy specimens and metastatic lesions
- Demonstrate varying degrees of atypia
- Any type of tissue may be present, such as gastrointestinal glands, respiratory epithelium, cartilage, squamous epithelium with keratinization, primitive undifferentiated spindle cells, or neuroepithelium
- Will have GCNIS (Med Surg Urol 2014;3:1)
- Associated with atrophic testis with sclerosis and microliths (Ulbright: Atlas of Tumor Pathology, 4th Series - Tumors of the Testis and Adjacent Structures, First Edition, 2013)
Prepubertal type
- More likely to have tissue arrangements mimicking organs (organoid morphology with tissue layers visible such as epithelium, lamina propria and muscularis propria) but any tissue type may be present (Moch: WHO Classification of Tumours of the Urinary System and Male Genital Organs (IARC WHO Classification of Tumours), Fourth Edition, 2016)
- Hair follicles may be seen (not in postpubertal type)
- No cytologic atypia, GCNIS or necrosis; minimal mitoses (Ulbright: Atlas of Tumor Pathology, 4th Series - Tumors of the Testis and Adjacent Structures, First Edition, 2013)
Teratoma with somatic type malignancy
- Sarcoma is most prevalent somatic type malignancy but other tumor types occur, including adenocarcinoma, squamous cell carcinoma and primitive neuroectodermal tumor (PNET) (Moch: WHO Classification of Tumours of the Urinary System and Male Genital Organs (IARC WHO Classification of Tumours), Fourth Edition, 2016, J Urol 1998;159:133, Ulbright: Atlas of Tumor Pathology, 4th Series - Tumors of the Testis and Adjacent Structures, First Edition, 2013)

Microscopic (histologic) images

Contributed by Debra L. Zynger, M.D.

Cartilage surrounded by mitotically active spindle cells

Gastrointestinal epithelium

Squamous epithelium

Cellular mesenchyme

Loose mesenchyme

Neuroectoderm

Molecular / cytogenetics description

12p amplification present in postpubertal teratomas and teratomas with somatic type malignancy (Arch Pathol Lab Med 2012;136:435, Moch: WHO Classification of Tumours of the Urinary System and Male Genital Organs (IARC WHO Classification of Tumours), Fourth Edition, 2016)

Sample pathology report

Right testicle, radical orchiectomy:
- Mixed germ cell tumor, teratoma (55%), seminoma (20%), embryonal carcinoma (10%), yolk sac tumor (10%) and choriocarcinoma (5%) types (see synoptic report)

Differential diagnosis

Dermoid cyst:
- Squamous epithelium, hair follicles / sebaceous glands
- May have adjacent lipogranulomas but no other embryonic germ cell types
- Lacks GCNIS and cytologic atypia (Arch Pathol Lab Med 2012;136:435)
Epidermoid cyst:
- Nonneoplastic squamous epithelium producing keratin with lamellar targetoid appearance
- No other embryonic germ cell types
- Lacks GCNIS and cytologic atypia (Arch Pathol Lab Med 2012;136:435)
Sarcoma:
- Can mimic teratoma with sarcoma as somatic type malignancy
- Lacks GCNIS and other germ cell tumor components
Yolk sac tumor:
- Microcystic, glandular and papillary growth patterns can mimic teratoma
- Positive for AFP and GPC3

Board review style question #1

A 27 year old man presents with a painless enlarging testicular mass. He undergoes appropriate workup and orchiectomy confirms diagnosis of a pure postpubertal teratoma. Which of the following is likely to be true?

AFP is likely elevated
Cytogenetic analysis will reveal chromosomal abnormalities
Few mitotic figures will be identified microscopically
Hair follicles are likely to be seen microscopically
He has a poor prognosis

Board review style answer #1

B. Cytogenetic analysis will reveal chromosomal abnormalities

Comment Here

Reference: Teratoma

Board review style question #2

A 37 year old woman gives birth to a male baby who is diagnosed with an undescended testicle. Further workup reveals a large intra abdominal mass, which is resected. Pathology is consistent with a pure teratoma. Which of the following is most likely present on microscopic examination?

Adjacent areas of germ cell neoplasia in situ
Areas with organoid morphology
Many mitotic figures and cytologic atypia
Sarcomatous elements
Significant areas of testicular tubular atrophy

Board review style answer #2

B. Areas with organoid morphology

Comment Here

Reference: Teratoma

Teratoma with somatic type malignancy

Table of Contents

Definition / general

Testicular germ cell tumor with an area of pure somatic type malignancy that arises from germ cell tumor progenitor cells and occupies ≥ 0.5 cm (approximately ≥ 1 microscopic field using 4x objective)

Essential features

Identified within primary testicular tumor or at a metastatic site
Rhabdomyosarcoma, adenocarcinoma, embryonic type neuroectodermal tumor and sarcoma, NOS are the most frequent histologies (Histopathology 2022;81:84, Am J Surg Pathol 2022;46:11)
Varying morphologies, including neuroglial, neuroendocrine carcinoma and neuroblastoma, may make diagnosis difficult (Histopathology 2022;81:84)
Must be distinguished from sarcomatoid or glandular yolk sac tumor, which represent up to 60% of postchemotherapy sarcomatous tumors (Am J Surg Pathol 2015;39:251)

Terminology

Current terminology: teratoma with somatic type malignancy
Previous terminology: teratoma with malignant transformation, teratoma with somatic malignancy
Currently recommended that embryonic type neuroectodermal tumor should replace primitive neuroectodermal tumor (PNET) when referring to a teratoma with this type of somatic malignancy because although it resembles CNS PNET, it lacks EWSR1 rearrangement (Am J Surg Pathol 2021;45:1299)

ICD coding

ICD-O: 9084/3 - teratoma with malignant transformation
ICD-11: 2C80.Y & XH33E8 - other specified malignant neoplasms of testis & teratoma with malignant transformation

Epidemiology

3 - 6% of testicular germ cell tumors (Cancer 1985;56:860, Cancer 1984;54:1824, J Urol 1994;152:1144, Histopathology 2022;81:84)
Median age of diagnosis within testis: 26 years (range: 17 - 55) (Am J Surg Pathol 2022;46:11)
Median age of diagnosis at metastatic site: 39 years (range: 23 - 62) (Am J Surg Pathol 2022;46:11)

Sites

Testis
Metastatic locations (e.g., retroperitoneum, lungs)

Pathophysiology

3 proposed origins of somatic type malignancy (Eur Urol 2007;51:1306):
- Mature teratoma
- Embryonal carcinoma
- Yolk sac tumor (Am J Surg Pathol 2015;39:251, Am J Surg Pathol 2021;45:463)

Clinical features

More commonly found as metastasis, rather than at initial diagnosis confined to the testis
Most frequently identified after chemotherapy (J Urol 2014;192:1403, Am J Surg Pathol 2022;46:11)

Diagnosis

Found as metastatic disease, within the testis or both (J Urol 1998;159:133)
Histologic features and immunohistochemistry determine type of somatic malignancy

Radiology description

Imaging may suggest specific somatic malignancy in germ cell tumors (Eur J Radiol 2009;69:230)
- Ossified lymph nodes and soft tissue reported in osteosarcoma
- Peritoneal carcinoma seen in adenocarcinoma
- Septal thickening and opacifications reported in a case of bronchoalveolar carcinoma

Prognostic factors

If confined to the testis without synchronous metastasis, somatic malignancy does not appear to confer a worse prognosis Am J Surg Pathol 2022;46:11)
Presence in a metastatic site is associated with poor survival (median survival: 44 months) Am J Surg Pathol 2022;46:11)
Median time from initial diagnosis of testicular germ cell tumor and diagnosis of somatic malignancy at metastatic site: 70 months (range: 0 - 384 months) Am J Surg Pathol 2022;46:11)

Case reports

32 year old man with angiosarcoma (Int J Surg Pathol 2022;30:462)
37 year old man with neuroendocrine carcinoma (Case Rep Oncol 2022;15:191)
40 year old man with rhabdomyosarcoma (Urol Case Rep 2020;33:101385)
50 year old man with sarcoma, NOS (Front Oncol 2021;11:633543)

Treatment

Surgical resection is the mainstay of treatment
Chemotherapy is based on histologic subtype of malignant transformation (J Clin Oncol 2003;21:4285)
Radical surgery is often utilized for advanced disease (J Urol 1998;159:133)

Gross description

No gross findings have been reported in large cases series (Histopathology 2022;81:84, Am J Surg Pathol 2022;46:11)

Gross images

Contributed by Christopher Dall, M.D. and Debra L. Zynger, M.D.

Retroperitoneal sarcoma, NOS

Lung rhabdo-
myosarcoma

Iliac leiomyosarcoma

Embryonic type neuroectodermal tumor

Microscopic (histologic) description

Expansile and infiltrative pure area of atypical mesenchymal or epithelial cells that occupies ≥ 0.5 cm
4 most common histologies (Am J Surg Pathol 2022;46:11, Histopathology 2022;81:84):
- Rhabdomyosarcoma
- Adenocarcinoma
- Embryonic type neuroectodermal tumor
- Sarcoma, NOS
Embryonic type neuroectodermal tumor appears as immature neuroectodermal elements
Neuroglial tumors have CNS-like morphology similar to astrocytoma, glioma, glioblastoma and gliosarcoma (Am J Surg Pathol 2019;43:422)
Nephroblastoma-like histology has been described

Microscopic (histologic) images

Contributed by Christopher Dall, M.D. and Debra L. Zynger, M.D.

Metastatic rhabdomyosarcoma

Metastatic chondrosarcoma

Metastatic sarcoma, NOS

Embryonic type neuroectodermal tumor within testis

Positive stains

Sarcoma:
- Desmin, myogenin, vimentin depending on type of sarcoma
- GPC3 (92% in rhabdomyosarcoma, variable to negative in other types of sarcoma) (Am J Surg Pathol 2014;38:1396)
Adenocarcinoma:
- Cytokeratin, EMA (81%) (Virchows Arch 2012;461:27, Am J Surg Pathol 2014;38:1396)
- BerEP4 (91%), MOC31 (92%) (Am J Surg Pathol 2014;38:1396)
- CDX2 (63%) (Am J Surg Pathol 2014;38:1396)
Embryonic type neuroectodermal tumor:
- Undifferentiated components: SOX11, synaptophysin (Arch Pathol Lab Med 2021;145:953)
- Differentiated components: S100, GFAP (Arch Pathol Lab Med 2021;145:953)
Neuroglial:
- GFAP, ATRX (retained) (Am J Surg Pathol 2019;43:422)

Negative stains

Sarcoma:
- SALL4 (0%) (Am J Surg Pathol 2014;38:1396)
- AFP (0%) (Am J Surg Pathol 2014;38:1396)
Adenocarcinoma:
- CK7 (43%) (Am J Surg Pathol 2014;38:1396)
- SALL4 (36%) (Am J Surg Pathol 2014;38:1396)
- GPC3 (7%), AFP (4%) (Am J Surg Pathol 2014;38:1396)
- TTF1 (0%) (Am J Surg Pathol 2014;38:1396)
Embryonic type neuroectodermal tumor:
- Undifferentiated components: S100, GFAP (Arch Pathol Lab Med 2021;145:953)
- Differentiated components: chromogranin, SOX11 (Arch Pathol Lab Med 2021;145:953)
Neuroglial:
- IDH1 pR132H (wildtype), BRAF p.V600E (Am J Surg Pathol 2019;43:422)

Molecular / cytogenetics description

12p gain or i(12p) is usually present (Histopathology 2022;81:84, Am J Surg Pathol 2012;36:1849)
Clonal relationship to the associated teratoma (Am J Surg Pathol 2012;36:1849)

Sample pathology report

Right testis, radial orchiectomy:
- Mixed germ cell tumor, embryonal carcinoma (75%), yolk sac tumor (10%), teratoma (10%), teratoma with somatic malignancy composed of embryonic type neuroectodermal tumor (5%) (see synoptic report)
Left lung, wedge resection:
- Metastatic rhabdomyosarcoma, 3.2 cm (see comment)
- Comment: The patient has a history of a mixed testicular germ cell tumor. The current tumor is consistent with testicular origin (teratoma with somatic malignancy).

Differential diagnosis

Metastasis of non-germ cell tumor (primary sarcoma or carcinoma):
- History of primary sarcoma or carcinoma
- Both primary sarcoma / carcinoma and somatic malignancies of sarcoma / carcinoma are usually SALL4 negative so this cannot be used to discriminate
- Lack 12p abnormality
Teratoma without somatic type malignancy:
- Malignant appearing somatic cells occupy
- Yolk sac tumor (glandular or sarcomatoid):
  - Mimics adenocarcinoma and sarcoma
  - Should be considered before a postchemotherapy diagnosis of sarcoma as the somatic type is rendered (Am J Surg Pathol 2015;39:251)
  - Sarcomatoid yolk sac tumor: GPC3 (100%), AE1 / AE3 (100%), SALL4 (60%), AFP (0%) (Am J Surg Pathol 2014;38:1396)
  - Glandular yolk sac tumor: GPC3 (86%), EMA (71%), SALL4 (71%), AFP 71%, CK7 (14%) (Am J Surg Pathol 2014;38:1396)
- Choriocarcinoma:
  - Cytotrophoblasts mimic squamous cell carcinoma
  - βhCG positive
- Embryonal tumor with multilayered rosettes, C19MC altered:
  - Mimics embryonic type neuroectodermal tumor
  - C19MC amplification
  - Lack 12p abnormality
- Ewing sarcoma
  - Mimics undifferentiated areas of embryonic type neuroectodermal tumor
  - CD99 membranous; FLI1 and NKX2.2 nuclear positive
  - EWSR1 fusion
  - Lack 12p abnormality

Additional references

WHO Classification of Tumours Editorial Board: Urinary and Male Genital Tumours, 5th Edition, 2022

Board review style question #1

Adenocarcinoma
Embryonic type neuroectodermal tumor
Neuroglial tumor
Rhabdomyosarcoma
Squamous cell carcinoma

Board review style answer #1

D. Rhabdomyosarcoma

Comment Here

Reference: Teratoma with somatic type malignancy

Board review style question #2

Isochromosome 12p
MYC amplification
TERT promoter mutation
Expression of ERG

Board review style answer #2

A. Isochromosome 12p

Comment Here

Reference: Teratoma with somatic type malignancy

Teratoma-dermoid cyst

Table of Contents

Definition / general | Microscopic (histologic) description

Definition / general

Rare form of benign testicular teratoma, characterized by pilosebaceous units arranged around predominantly unicystic lesion, often containing hair
Noncutaneous elements may be present but lack cytologic atypia seen in usual mature teratoma (Am J Surg Pathol 2001;25:788)

Microscopic (histologic) description

Organoid arrangement of pilosebaceous units around epidermal epithelium
Lipogranulatomous reaction in testis parenchyma due to leakage of sebaceous secretion
Other tissue types sometimes present
No intratubular germ cell neoplasia (IGCNU), no immature elements

Teratoma-neuroendocrine tumor

Table of Contents

Definition / general

Well differentiated neuroendocrine tumor (NET) is a low grade epithelial neoplasm with neuroendocrine differentiation

Essential features

Primary testicular NETs can be pure (75%) or associated with teratoma (25%)
Tumors show an insular or trabecular growth pattern with salt and pepper nuclear chromatin pattern
Most are not associated with isochromosome 12p or germ cell neoplasia in situ (GCNIS)

Terminology

Also known as pure NET, testicular NET, prepubertal type or postpubertal type or monodermal teratoma
Terminology not recommended: carcinoid, atypical carcinoid, neuroendocrine carcinoma

ICD coding

ICD-O: 8240/3 - well differentiated neuroendocrine tumor (monodermal teratoma)
ICD-11: 2F77 & XH8DS0 - neoplasms of uncertain behavior of male genital organs & neuroendocrine tumor, NOS

Epidemiology

Extremely rare, accounting for < 1% of all testicular neoplasms (Am J Surg Pathol 2010;34:519)
More common in ovaries than testes (15:1)
Mean age at presentation: 46 years (range: 10 - 83 years)
Most cases are reported in Europe and the U.S. with fewer cases from Asia and Africa
Metastatic neuroendocrine tumor from other sites (e.g., lung or gastrointestinal tract) to the testis has been reported

Sites

NET in the genitourinary tract is rare and can occur in the kidney, bladder, prostate, testicle or urethra

Pathophysiology

Arise in the setting of prepubertal teratoma (testicular NET, prepubertal type)
75% occur as pure NET, with the remaining 25% occurring with other teratomatous components (dermoid and epidermoid cysts) (Cancer 1978;42:2696, Am J Surg Pathol 2010;34:519, Cancer 1993;72:1726)
Most are not associated with GCNIS or isochromosome 12p
Rare cases of postpubertal type testicular NET have been reported (Clin Cancer Res 2008;14:1393)

Etiology

Unknown

Clinical features

Most commonly presents as a testicular mass or swelling, which may or may not be associated with testicular pain
Bilateral involvement is uncommon and association with cryptorchidism is rare
10% of cases occur in association with hydrocele (Cancer 1993;72:1726)
Clinical carcinoid syndrome (hot flashes, diarrhea and palpitations) has been reported in 7 - 12% of cases (Cancer 1993;72:1726, Am J Surg Pathol 2010;34:519)
Metastases occur via hematogenous spread to lungs, liver, bones, soft tissue, skin, heart as well as contralateral testis; however, lymphatic spread is also seen

Diagnosis

Diagnosis of testicular NET is made based on histologic examination of the surgical resection specimen

Prognostic factors

Primary testicular NET associated with testicular teratoma seems to have a better prognosis than pure NET
Metastatic disease is associated with atypical features, including larger tumor size (> 7 cm), increased mitotic activity and carcinoid syndrome (Am J Surg Pathol 2010;34:519, Cancer 1993;72:1726)

Case reports

23 year old man with asymptomatic scrotal swelling (Arch Ital Urol Androl 2016;88:245)
29 year old man with scrotal swelling and pain (Tumori 2019;105:NP20)
34 year old man with chronic right scrotal swelling and pain (Am J Case Rep 2015;16:328)
44 year old man with primary testicular NET (BMC Urol 2020;20:197)
49 year old man with primary testicular NET presenting with carcinoid heart disease (Indian J Urol 2015;31:65)

Treatment

Orchiectomy
In a metastatic setting, retroperitoneal dissection and receptor targeted radiotherapy may be used; however, chemotherapy and radiotherapy are reported to provide minimal benefits

Gross description

Well circumscribed, solid, yellow-tan to brown and ranging in size from 0.5 cm up to 11 cm (Cancer 1993;72:1726)
Cystic changes or calcifications can be seen in association with teratomatous component
Extratesticular growth with involvement of spermatic cord occurs uncommonly

Gross images

AFIP images

Solid tan mass

Microscopic (histologic) description

Growth pattern
- Mostly solid nests, insular or trabecular growth patterns
- Acinar and glandular growth pattern with luminal mucin admixed with other growth patterns may be seen (Am J Surg Pathol 2010;34:519, Clin Cancer Res 2008;14:1393)
Stroma
- Delicate fibrous or hyalinized stroma (Tumori 2019;105:NP20)
Neoplastic cells
- Monomorphic with abundant granular eosinophilic to pale cytoplasm
- Uniform round nuclei with fine or salt and pepper chromatin (Am J Surg Pathol 2010;34:519)
Most cases are unassociated with GCNIS (Am J Surg Pathol 2010;34:519)
Mitotic figures, necrosis and vascular invasion are infrequently seen (Am J Surg Pathol 2010;34:519)
Atypical features include necrosis, nuclear atypia and > 2 mitoses per 10 high power fields (HPF) (Am J Surg Pathol 2010;34:519, Am J Clin Pathol 2003;120:182)

Microscopic (histologic) images

Contributed by Sounak Gupta, M.B.B.S, Ph.D. and Rafael E. Jimenez, M.D.

Epidermoid cyst and NET

Retraction artifact

Multiple solid nests

Insular growth pattern

Nests of tumor cells

Cytology description

Isolated or sheets of neoplastic cells with granular cytoplasm, uniform round nuclei and uniformly distributed fine nuclear chromatin

Positive stains

Cytokeratins, synaptophysin, chromogranin A and CD56 are mostly positive (Cancer 1993;72:1726, Oncol Lett 2015;9:2017)
Substance P, gastrin, VIP and neurofilaments are less frequently expressed (Am J Clin Pathol 1982;78:860)

Negative stains

OCT 3/4, CD30, KIT, TTF1, SF1, SOX2, alpha inhibin and CDX2 (Clin Cancer Res 2008;14:1393)

Electron microscopy description

Pleomorphic to more regular round to oval neurosecretory granules

Molecular / cytogenetics description

DNA ploidy studies show a near diploid profile (Cancer 1993;72:1726)
As most cases are not associated with GCNIS, they do not show isochromosome 12p or numerical aberrations in the X chromosome, which are commonly seen in GCNIS derived germ cell tumors
- In rare cases, assessment of isochromosome 12p may be indicated if the postpubertal type is suspected

Videos

Testicular NET

Sample pathology report

Testis and spermatic cord, left, radical orchiectomy:
- Testicular well differentiated neuroendocrine tumor, prepubertal type (monodermal teratoma) and epidermoid cyst (see comment)
- Comment: No germ cell neoplasia in situ (GCNIS) is identified in the background seminiferous tubules.

Differential diagnosis

Metastatic neuroendocrine tumor to testis:
- Usually presents with bilateral involvement, multifocality, vascular invasion and extratesticular localization
Sertoli cell tumor:
- Lacks prominent cytoplasmic granularity and salt and pepper pattern of nuclear chromatin
- Expresses alpha inhibin, calretinin, SF1 and beta catenin (nuclear) and sometimes chromogranin and synaptophysin
Granulosa cell tumor:
- Neoplastic cells have scant cytoplasm, elongated nuclei with nuclear grooves
- No expression of synaptophysin or chromogranin

Additional references

WHO Classification of Tumours Editorial Board: Urinary and Male Genital Tumors, 5th Edition, 2022, Ulbright: Tumors and Tumor-Like Lesions of the Testis and Adjacent Tissues, 5th Edition, 2022

Board review style question #1

A 35 year old man underwent a left radical orchiectomy that demonstrated a 4.0 cm cystic mass (see image). No serological markers (alpha fetoprotein [AFP], beta human chorionic gonadotropin [beta hCG] or lactate dehydrogenase [LDH]) were elevated. Regarding this entity, which of the following statements is true?

CDX2 is usually positive in testicular neuroendocrine tumor
Cystic changes can be seen with teratomatous components
Cytokeratins are usually negative in testicular neuroendocrine tumor
Glandular growth pattern is not observed
These tumors are mostly found in association with germ cell neoplasia in situ (GCNIS) / isochromosome 12p

Board review style answer #1

B. Cystic changes can be seen with teratomatous components. Primary testicular neuroendocrine tumor (NET) can occur as pure NET (75%) or in association with testicular teratoma (25%). Cystic changes in these lesions can be seen with teratomatous components. Answer D is incorrect because these tumors mostly exhibit an insular or trabecular growth pattern that can be intermixed with glandular / acinar structures with luminal mucin. Answer E is incorrect because most of these cases are not associated with GCNIS and do not show isochromosome 12p or numerical aberrations in the X chromosome, which are commonly seen in GCNIS derived germ cell tumors. Answers C and A are incorrect because testicular NET expresses cytokeratins and is negative for CDX2.

Comment Here

Reference: Teratoma - neuroendocrine tumor

Testicular adrenal rest tumor / tumor of adrenogenital syndrome

Table of Contents

Definition / general

Testicular tumor associated with congenital adrenal hyperplasia and chararacterised by benign behavior and typical hormone sensitivity

Terminology

Testicular tumors of Adrenogenital syndrome (TTAGS)
Also know as Testicular adrenal rest tumors (TARTs)
Biologically, the lesions represent hyperplasia of aberrant rests rather than a true neoplastic tumor

Epidemiology

Can present at any age but commonly present in pubertal and postpubertal males, mean age ~15 years
Incidence and prevalence vary based on patient age (prevalence increases with age), geography:
- Often clinically undetected (Radiology 1992;183:425)
- Detected at autopsy in 3 of 7 patients with CAH who were < 8 weeks old (Am J Dis Child 1963;106:243)
- 24% prevalence in 34 children with CAH (age range 2 - 18 years, Eur J Endocrinol 2007;157:339)
Associated with congenital adrenal hyperplasia - 21 hydroxylase deficiency (Urol Clin North Am 2000;27:519, Indian J Endocrinol Metab 2013;17:S14); 27 - 47% develop testicular adrenal rest tumors (J Clin Endocrinol Metab 2001;86:3070, J Clin Endocrinol Metab 2001;86:5721, J Clin Endocrinol Metab 2012;97:4429)
Other conditions associated with testicular adrenal rest tumors include Nelson syndrome, Cushing disease, Addison disease

Sites

Normaly descended testis and adjacent tissues

Etiology and Pathophysiology:

Development and pathogenesis
- Development of TTAGS is dependent on two factors:
  1. Presence of adrenal rests in and around the testis
  2. Abnormal growth stimulated by excess ACTH or Angiotensin II levels
  3. Duration and concentration of exposure to growth stimulating hormones
- Aberrant adrenal rests in and around the testis have been demonstrated at autopsy in ~7.5% of infants without any pathological significance (Am J Pathol 1962;40:587) and in 15% of healthy neonates (BJU Int 2005;95:407, Eur Radiol 2000;10:1165)
- Probably under reported due to difficulty in identifying adrenal rests
- Tumors more common in patients with congenital adrenal hyperplasia who are noncompliant with treatment
- Tumor's adrenal origin and functional status has been inferred from in vitro and in vivo studies:
  1. Adrenal specific enzyme CYP11B1 (11b-hydroxylase) present in tumor tissue of CAH patient with TTAGS (J Clin Endocrinol Metab 1990;70:1408)
  2. Adrenal specific steroids present (J Steroid Biochem Mol Biol 2005;93:67)
  3. Adrenal specific 11b-hydroxylated steroids present in blood from gonadal veins (J Steroid Biochem Mol Biol 2005;93:67, J Clin Endocrinol Metab 1994;79:1390, J Clin Endocrinol Metab 1991;73:1129)
  4. mRNA expression seen of adrenal specific enzymes CYP11B1 (expressed by zona fasciculate and zona reticularis) and CYP11B2 (expressed by zona glomerulosa), as well as of ACTH and angiotensin II (AII) receptors (Best Pract Res Clin Endocrinol Metab 2009;23:209)
- However, persistence of tumors despite ACTH suppression indicates role played by other factors
- TTAGS also reported in patients with adequately controlled hormone levels (J Clin Endocrinol Metab 2001;86:3070)
- Angiotensin II may have role in growth of TTAGS (Regul Pept 2003;110:249)
- TTAGS have not been reported in late onset CAH without clearly elevated ACTH or Angiotensin II levels
- LH may have role in development and growth of TTAGS (Eur J Endocrinol 1999;141:231)
Effects of TTAGS:
- Mechanical effects: size and duration dependent blockage of rete testis with resulting atrophy of seminiferous tubules
- Paracrine effects: steroids produced by tumor cells may be toxic to Leydig cells or germ cells (Hum Reprod 2001;16:263)
- The irreversible end stage of longstanding TART is tubular hyalinization with obstruction of the lumen and complete loss of germ cells and Sertoli cells; differs from ischemic hyalinization by relative preservation of Interstitial Leydig cells

Clinical features

Most tumors are detected on ultrasound screening of patients with Congenital adrenal hyperplasia
Symptoms of congenital adrenal hyperplasia:
- Severe forms: critical adrenal insufficiency with salt losing form present in shock very early in childhood
- Milder forms: present with varying degrees of virilization and sexual precocity in a young child, adolescent or adult
Most common presentation of TTAGS is bilateral presence of palpable nodules in both testes with testicular enlargement
Though varying degree of testicular atrophy is common, presentation with infertility is rare (Actas Urol Esp 2003;27:234)

Diagnosis

Diagnosis is suspected on clinical features and ultrasound examination of scrotum (Radiology 1996;198:99) and confirmed with a biopsy / surgical excision

Laboratory

Increased blood levels of 11-β-OH steroids in effluent testicular blood
Increased 11-β-hydroxylase activity in tumor tissue
Low α-fetoprotein, LDH and β-HCG

Radiology description

Tumors are uniformly hypoechoic with well defined margins
Multifocally and bilaterality is common (~75%)
Mean diameter ~16 mm (range, 2 - 28 mm, Radiology 1992;183:425)

Prognostic factors

Tumors are uniformly benign in behavior and many respond to ACTH suppression by glucocorticoid therapy
No reports of malignant transformation or recurrence after complete excision

Case reports

19 year old man with testicular mass (Arch Pathol Lab Med 2000;124:785)
19 year old man with CAH, Leydig Cell Tumor and TART (Case Rep Urol 2012;2012:648643)
37 year old man with hyperplasia of adrenal rests in testis (Actas Urol Esp 2003;27:234)
Bilateral tumors of testis in 21-alpha hydroxylase deficiency without adrenal hyperplasia (Urol Oncol 2005;23:178)

Treatment

Early tumors are responsive to glucocorticoid therapy, which suppresses ACTH levels
Surgery for tumors nonresponsive to glucocorticoid therapy, large tumors or if differential diagnosis with other tumors exists
Testicular sparing surgery is preferred to preserve fertility, as tumor is benign

Staging / staging classifications

Claahsen-van der Grinten et al (Best Pract Res Clin Endocrinol Metab 2009;23:209) proposed a staging system for TART development and progression, with an intent to guide treatment
- Stage 1: presence of adrenal rest cells within the rete testis, not detectable by scrotal ultrasound
  - In healthy boys, probably regress in utero or in first year of life
- Stage 2: adrenal rest cells may proliferate in the presence of increased concentrations of ACTH (and possibly also of Angiotensin II)
  - The adrenal rest cells may become visible by ultrasound as one or more small hypoechogenic lesions
  - Age of onset of cell growth may depend on the cumulative exposure to ACTH (and angiotensin II) concentrations over time and the number of ACTH (and angiotensin II) receptors on the adrenal rest cells
  - Complete regression of tumors with ACTH suppression by glucocorticoid therapy is possible
- Stage 3: further growth of the adrenal rest cells will compress the rete testis
  - In pubertal or postpubertal CAH patients, oligo or azoospermia may already be found due to obstruction of the seminiferous tubules
  - Signs of gonadal dysfunction: decreased inhibin B and increased follicle stimulating hormone (FSH) and LH levels may also be present
  - Tumors are responsive to ACTH suppression, however the tumors relapse after discontinuation of ACTH suppression
  - Hence, glucocorticoid therapy is only a temporary solution
- Stage 4: further hypertrophy and hyperplasia of the adrenal rest cells with progressive obstruction of the rete testis, leads to induction of fibrosis within the tumor and focal lymphocytic infiltration
  - Several small tumors within the rete testis will conflate, forming a single lobulated tumor, separated from the residual testicular tissue by fibrous strands
  - Differentiation of adrenal cells with loss of ACTH and angiotensin II receptors
  - Loss of response to ACTH suppression by glucocorticoids
  - Surgical excision of TTAGS could prevent further decline of testicular function
- Stage 5: chronic obstruction subsequently will lead to destruction of the surrounding testicular parenchyma with irreversible damage of the testis
  - Only indication for surgery is the relief of pain and discomfort caused by TTAGS
This staging system has not been validated
Early treatment of CAH with adequate suppression of ACTH levels by glucocorticoid treatment from childhood, may prevent development of TTAGS
However, the benefit needs to be balanced against the effect of growth suppression by excess glucocorticoid therapy

Clinical images

Images hosted on other servers:

Dexamethasone treatment

Large TTAGS

Gross description

Usually bilateral, commonly located in hilar region of testis
Well circumscribed yellow to tan nodules separated by dense fibrous bands

Gross images

Images hosted on other servers:

Well circumscribed,
noncapsulated, solid
and lobulated brown lesion

Microscopic (histologic) description

Resemble adrenocortical cells
Sheets, cords or lobules of large, polygonal cells with abundant, finely granular eosinophilic cytoplasm, often with lipochrome pigment
Round, giant and hyperchromatic nuclei; nuclear pleomorphism can be prominent with presence of varying sized intranuclear inclusions
Thin fibrovascular strands run through the tumor tissue but zonation is absent
Mitoses are usually absent
Reinke crystals are absent and help to differentiate from Leydig cell tumors to an extent
Adjacent testicular tissue may be normal or may show evidence of atrophy in the form of reduced / absent spermatogenesis with reduced diameter of the seminiferous tubules, thickened basal membranes and deposition of fibrohyaline tissue
The changes are more marked with tumors of long duration

Microscopic (histologic) images

Images hosted on other servers:

H&E

H&E, IHC, CD56

H&E

Cytology description

Cellular smears with large polygonal to round cells with foamy cytoplasm, round centrally placed nuclei with prominent nucleoli
Abundant lipochrome pigment is characteristic
Reinke crystals are absent
No cytological feature to reliably distinguish from Leydig cell tumor in the absence of Reinke crystals

Immunohistochemistry & special stains

Positive: CD56 strong, synaptophysin strong but can be focal or diffuse
Inhibin positive but not useful to differentiate from Leydig cell tumor (Histopathology 2011;58:1013)
Negative: androgen receptor

Electron microscopy description

Abundant smooth endoplasmic reticulum, a moderate number of mitochondria with tubulovesicular cristae, lipid droplets and lipofuscin granules in the polygonal cells
No Reinke crystals

Differential diagnosis

Leydig cell tumor
- Less commonly bilateral (3% compared to 75% in TTAGS, Pathologica 1994;86:557, Urol Clin North Am 2000;27:519)
- Gynecomastia is more common (~30%), while it is rare in CAH (Urol Clin North Am 2000;27:519)
- Associated with Peutz-Jeghers syndrome, not associated with adrenal hyperplasia
- Nonresponsive to corticosteroid therapy
- Presence of Reinke crystals is diagnostic but seen in just 40 of cases.
- Malignancy related changes are seen in 10% of Leydig cell tumors while they never occur in TTAGS
- Absence of adipocyte metaplasia and extensive fibrosis
- Androgen receptor positive and weak reactivity / negative for CD56 and synaptophysin
Biochemical features are NOT useful to differentiate (Urol Clin North Am 2000;27:519)

Testicular regression syndrome / anorchia

Table of Contents

Definition / general

Anorchism: absence of both testis
Monoorchidism: absence of one testis
Testicular regression syndrome: phenotypically normal male with vas deferens is present

Etiology

Causes: cryptorchidism, possibly testicular infarct, infection, trauma, torsion or prenatal hormone induced atrophy due to overproduction of androgens

Testicular regression syndrome

Either no gonadal or testicular formation or regression of testicular tissue with residual fibrovascular nodule (mean 1.1 cm), calcification and hemosiderin
Rudimentary epididymis and spermatic cord are present
External genitalia depends on chronology of gonadal injury

Case reports

1 year old boy with undescended testis and firm nodule near external inguinal opening (Case of the Week #279)

Microscopic (histologic) description

Regressed testis indicated by fibrosis, hemosiderin, calcification or Leydig cells near epididymis or proximal vas deferens (Arch Pathol Lab Med 2000;124:694)
Presence of only fat and connective tissue does not rule out an intraabdominal testis

Microscopic (histologic) images

Case #279

Torsion

Table of Contents

Definition / general

Twisting of the spermatic cord and its contents
Surgical emergency
Reference: Am Fam Physician 2013;88:835

Essential features

Vascular congestion, edema and interstitial bleeding
Hemorrhagic infarction of the testis

ICD coding

ICD-10: N44.00 - torsion of testis, unspecified

Epidemiology

Annual incidence: 3.8 per 100,000 in boys younger than 18 years
2 peaks of incidence: perinatal and puberty
Up to 14% of cases occur in adults
12 - 21% of neonatal cases are bilateral
References: Am Fam Physician 2013;88:835, Am J Emerg Med 2023;66:98

Sites

Testis

Pathophysiology

Twisting of the testicle along the spermatic cord results in reduced venous outflow and vascular congestion
Prolonged twisting impairs arterial flow and ischemia
Prolonged ischemia can result in necrosis
Reference: Am J Emerg Med 2023;66:98

Etiology

Abnormal or absent fixation of testicle and tunica vaginalis
Tunica vaginalis contains the spermatic cord and normally adheres to the posterolateral part of the testicle
Absent or abnormal fixation can result in twisting of the testicle, compromising the blood flow
2 classic anatomic forms
- Intravaginal (more common)
  - Puberty and adulthood
  - Abnormalities in tunica vaginalis attachment
  - Bell clapper deformity: abnormally high reflection of tunica vaginalis, allowing the spermatic cord to twist inside the tunica
- Extravaginal
  - Infancy and childhood
  - Tunica vaginalis is not adhered to the gubernaculum
  - Both the tunica vaginalis and spermatic cord are prone to torsion
References: Am J Emerg Med 2023;66:98, J Ultrasound Med 2022;41:271

Diagrams / tables

Images hosted on other servers:

Bell clapper deformity
leading to intravaginal
testicular torsion

Clinical features

Intravaginal
- Sudden or insidious onset of pain
- Nausea and vomiting
- Followed by swelling of the ipsilateral scrotum
- Most commonly, these symptoms occur several hours after minor trauma or physical activity
- In some instances, history of previous pain
Extravaginal
- May be entirely asymptomatic
- Sole clinical manifestation may be unilateral mass in the inguinal region or in the superior aspect of the scrotum
Reference: Clin Radiol 1999;54:343

Diagnosis

Imperative to rule out testicular torsion in a patient presenting with acute scrotum
High index of suspicion on the part of the physician is needed
Scrotal Doppler ultrasonography is the imaging study of choice (Am Fam Physician 2013;88:835)

Radiology description

Scrotal Doppler ultrasonography
- Flow in the symptomatic testis may be absent, reduced or have abnormally high resistance
- In bell clapper deformity, testis can rotate
  - Doppler ultrasound flow abnormalities can differ depending on the degree of rotation, which ranges from 180° to 270°
- Venous outflow occlusion precedes arterial inflow occlusion
  - Early or partial torsion can result in areas with high resistance flow rather than absent flow owing to compromised venous outflow
- If spontaneous detorsion occurs, Doppler ultrasound flow within the involved testis may increase
Reference: Radiographics 2020;40:529

Radiology images

Contributed by Raman Danrad, M.D.

Ultrasound of bilateral testis

Ultrasound of right normal testis

Ultrasound of left torsed testis

Case reports

13 year old boy with torsion of biolobed testis (Can Urol Assoc J 2010;4:E67)
15 year old boy with testicular cavernous hemangioma associated with testicular torsion (Int J Surg Case Rep 2018;49:247)
16 year old boy with torsion of right undescended testis (Urol Case Rep 2023;50:102480)
57 year old man presented with 9 day history of testicular pain following lawnmowing (J Am Coll Emerg Physicians Open 2021;2:e12545)

Treatment

Prompt restoration of blood flow is critical in cases of testicular torsion
Typically, there is a 4 - 8 hour window before significant ischemic damage occurs
Viability of testicle is difficult to predict, hence emergent surgical management is indicated
Reported testicular salvage rates are 90 - 100% if surgical exploration is performed within 6 hours of symptom onset
Orchiectomy is performed if the affected testicle appears grossly necrotic or nonviable
If the affected testicle is deemed viable, orchiopexy with a permanent suture should be performed to permanently fix the testicle within the scrotum
Contralateral orchiopexy should be performed regardless of the viability of the affected testicle
Reference: Am Fam Physician 2013;88:835

Clinical images

Images hosted on other servers:

Twisting of spermatic cord

Gross description

Depends on the degree of torsion and the time lapse since onset of symptoms
Dark red testis with smooth external surface and solid consistency

Gross images

Images hosted on other servers:

Smooth external surface of torsed testis

Dark red hemorrhagic cut surface

Microscopic (histologic) description

Edema, congestion and interstitial hemorrhage with venous outflow obstruction
Early conservation of germ cells, which later disappear
Initial phase ( Followed by pronounced hemorrhage and sloughing of all germ cells
Necrosis of the seminiferous epithelium
Hemorrhagic infarction of testicle
References: Maclennan: Urologic Surgical Pathology, 4th Edition, 2019, Amin: Urological Pathology, 1st Edition, 2014

Microscopic (histologic) images

Contributed by Ritu Bhalla, M.D.

Congestion

Hilar hemorrhage

Sloughing of cells

Interstitial hemorrhage

Residual germ cells

Infarcted tubules

Necrotic parenchyma

Sample pathology report

Testicle, left, orchiectomy:
- Testicular parenchyma with hemorrhagic infarction, consistent with testicular torsion

Differential diagnosis

Systemic vasculitides:
- Can present in 1 of 2 patterns
  - Polyarteritis nodosa pattern
    - Fibrinoid necrosis of medium sized arteries
    - Dense transmural neutrophilic infiltrates
    - Testicular infarct and hemorrhage
  - Granulomatosis with polyangiitis pattern
    - Destructive granulomatous vascular inflammation
Germ cell neoplasia in situ (GCNIS):
- Presence of undifferentiated germ cells within seminiferous tubules; the cells possess
  - Large, hyperchromatic nuclei, with 1 - 2 prominent nucleoli
  - Clear cytoplasm
- Spermatogenesis is usually absent
- Thickened peritubular basement membrane
- OCT 3/4 positive
Regressed germ cell tumor:
- Vascularized fibrotic scar with inflammation
- Surrounding hyalinized or atrophic seminiferous tubules
- Psammomatous calcifications
- Residual germ cell neoplasm or GCNIS may be present
Choriocarcinoma:
- Hemorrhage and necrosis surrounded by cytotrophoblasts and syncytiotrophoblasts
Lymphoma:
- Clonal population of lymphoid cells
Reference: Am J Surg Pathol 2014;38:34

Board review style question #1

A 14 year old boy presents to emergency room with severe left sided testicular pain associated with nausea and vomiting. A Doppler ultrasound shows loss in blood flow in the affected testis. Subsequent orchiectomy reveals red-tan, smooth surfaced testis, with microscopic appearance as seen in the image above. Which of the following can be seen in this condition?

Clonal population of lymphoid cells
Elevated alpha fetoprotein (AFP) levels
Hemorrhage surrounded by trophoblastic cells
Initial preservation of germ cells
Undifferentiated malignant cells within seminiferous tubules

Board review style answer #1

D. Initial preservation of germ cells. The patient's presentation, including imaging and pathology, is diagnostic of testicular torsion. Testicular infarct following torsion is initially associated with conservation of germ cells; however, as congestion and hemorrhage increase, these cells slough into the lumens of seminiferous tubules and ultimately the entire tubule undergoes necrosis. Answer C is incorrect because hemorrhage surrounded by trophoblastic cells is typically observed in choriocarcinoma. Answer E is incorrect because germ cell neoplasia in situ (GCNIS) is associated with undifferentiated malignant cells within seminiferous tubules. Answer A is incorrect because clonal population of lymphocytes is seen in lymphoma. Answer B is incorrect because although AFP can be elevated in several conditions, including yolk sac tumor and teratoma, it is usually not elevated in torsion.

Comment Here

Reference: Torsion

Board review style question #2

Which of the following is the most common cause of testicular torsion?

Bell clapper deformity
Choriocarcinoma
Cryptorchidism
Mumps orchitis
Varicocele

Board review style answer #2

A. Bell clapper deformity is the most frequent cause of testicular torsion. Tunica vaginalis is normally attached to the testis posterolaterally. In this anomaly, the attachment is abnormally high, which allows the spermatic cord to twist itself within the tunica vaginalis, resulting in testicular torsion. Answer C is incorrect because cryptorchidism may also be associated with torsion but not as frequently as bell clapper deformity. Answers B, D and E are incorrect because varicocele, mumps orchitis and choriocarcinoma are typically not associated with testicular torsion.

Comment Here

Reference: Torsion

Varicocele

Table of Contents

Definition / general

Mass of tortuous and dilated veins of pampiniform plexus and internal testicular vein of spermatic cord
Occurs posterior and superior to the testis, may extend into the inguinal ring

Essential features

Probably due to incompetent valves of left internal spermatic vein as it empties into renal vein
90% on left
10% bilateral
Right internal spermatic vein is less often involved since it empties directly into the inferior vena cava and tends not to have incompetent valves

Epidemiology

Affects 15% of adults (Ultrastruct Pathol 2010;34:260) and 13% (Fertil Steril 2017;107:74) to 40% (J Assist Reprod Genet 2017;34:839) of men seeking fertility treatment
Only 20% of men with a varicocele will have lowered fertility (Asian J Androl 2016;18:276)
Associated with decreased sperm count and motility (J Assist Reprod Genet 2017;34:839)
Testicular atrophy is the main indication for surgical repair

Sites

Right sided varicocele is unusual; isolated right sided varicocele is associated with situs inversus, venous thrombosis or inferior vena cava compression from space occupying lesion such as soft tissue sarcoma; less commonly paraganglioma (Ann Saudi Med 2016;36:148)
It suggests the presence of a vascular abnormality (Urology 2015;85:e39)

Etiology

Most cases are idiopathic
Renal tumor may invade the left renal vein and block the drainage of the spermatic vein
Possible association with maternal exposure to diethylstilbestrol (Am J Obstet Gynecol 1981;140:186)
Rare association with sertoliform cystadenoma (Am J Surg Pathol 2018;42:141)
Kidney donation usually involves a left kidney; a study showed left pampiniform venous plexus diameter increased after kidney donation in men, suggesting that this can predispose to varicocele (Transplant Proc 2009;41:2738)
Can be caused by May-Thurner syndrome, which is reflux in the left spermatic vein caused by iliac vein compression between the right iliac artery and the spine [Ann Vasc Surg 2017;42:305)
Certain genetic and epigenetic changes are associated with varicocele (J Assist Reprod Genet 2017;34:839)

Clinical features

Often associated with infertility; after treatment, 40 - 55% recover fertility
Testicular pain may be associated with sexual activity
If longstanding, testicular atrophy and infertility of the affected testis may result

Diagnosis

Based on palpation while patient is at rest compared to during Valsalva
Graded based on physical exam findings:
- Grade 1: palpable only during Valsalva
- Grade 2: palpable at rest but not visible
- Grade 3: visible and palpable at rest
Ultrasound if physical exam is inconclusive (J Ultrason 2016;16:359)

Laboratory

May decrease Leydig cell function, causing a lower serum testosterone, which can be improved after varicocelectomy (Urology 2013;81:1213)

Radiology description

Ultrasound can demonstrate vessel size, reversal of blood flow and testicular volume

Radiology images

Images hosted on other servers:

Left sided grade 3 varicocele

Color Doppler ultrasonography of varicocele

Case reports

64 year old Asian man with varicocele due to renal arteriovenous malformation (J Med Case Rep 2018;12:2)
68 year old man with thrombosed varicocele (BMC Urol 2018;18:34)
Fighter pilot with an asymptomatic varicocele precipitated by centrifuge training (Aerosp Med Hum Perform 2015;86:1063)

Treatment

Varicocelectomy
Some patients have improved fertility after microsurgery, perhaps because DNA fragmentation is reduced / DNA integrity is improved (Syst Biol Reprod Med 2012;58:274)
Ligation or occlusion of left spermatic vein at the internal inguinal ring
Motile sperm were found in 11 of 19 patients after varicocele repair; testicular histology was also improved (Biomed Res Int. 2015;2015:709452)

Gross description

Thin walled cystically dilated membrane

Microscopic (histologic) description

From inside to outside, changes include (Ultrastruct Pathol 2010;34:260)
- Narrowing or obliteration of the vein lumens
- Segmental obliteration and occasional thrombi
- Internal elastic lamina fragmentation and invagination of intima
- Variable thickening of vein wall; the media contains hypertrophied smooth muscle fibers and deposition of collagen bundles (Ultrastruct Pathol 2012;36:201)
If a testis is included: decreased spermatogenesis in tubules with germ cell degeneration and increased Leydig cells
Adolescent varicocele: pathologic changes found at or soon after puberty, consisting of tubular sclerosis, premature germ cell sloughing, small vessel sclerosis and variable hypospermatogenesis (Am J Clin Pathol 1988;89:321)

Microscopic (histologic) images

Contributed by Kenneth A. Iczkowski, M.D.

Orchiectomy specimen in a 30 year old with atrophic testis and varicocele

Positive stains

CD31 (stains endothelial layer)

Negative stains

Calretinin

Electron microscopy description

Endothelial cell damage and loss of internal elastic lamina (Ultrastruct Pathol 2010;34:260)

Differential diagnosis

Hydrocele is lined by tunica vaginalis mesothelium (calretinin+, CD31-) whereas varicocele is lined by endothelium (CD31+, calretinin-)

Board review style question #1

Which of the following is not associated with varicocele?

Destruction of vessel's external elastic lamina
Endothelial cell damage
Narrowing or obliteration of the lumen of the vein
Thickening of the media by collagen deposition

Board review style answer #1

A. Destruction of vessel's external elastic lamina. It is the internal elastic lamina that is destroyed

Comment Here

Reference: Varicocele

Board review style question #2

In this orchiectomy specimen in a 30 year old with atrophic testis and varicocele, what is illustrated?

Hematoma on the left and vas deferens on the right
Hydrocele on the left and testis tubules on the right
Spermatocele on the left and rete testis on the right
Varicocele on the left and rete testis on the right

Board review style answer #2

D. Varicocele on the left and rete testis on the right

Comment Here

Reference: Varicocele

Vasculitis

Table of Contents

Definition / general

Polyarteritis nodosa (PAN) is the most common form of testicular vasculitis, predominantly seen in the fourth to sixth decades of life; often associated with hepatitis B virus and human immunodeficiency virus; although 60% to 86% of patients with PAN show testicular involvement at autopsy (ScientificWorldJournal 2010;10:1915), testicular symptoms are present in less than 20% of patients (Hum Pathol 1988;19:186)
Necrotizing vasclulitis: systemic disease which manifests as inflammation of arteries with fibrinoid necrosis and fibrosis of the vascular wall
- May be associated with polyarteritis nodosa or an isolated finding; can be associated with a variety of other entities or may be idiopathic (Cardiovascular Pathology 1994;3:197)
- While necrotizing vasculitis can involve any organ, isolated testicular involvement is rare and can pose diagnostic difficulties, especially in the absence of clinical and laboratory evidence of systemic involvement (World J Surg Oncol 2011;9:63)
Other vasculitides that may involve the testes include Granulomatosis with polyangiitis (Wegener's), Henoch-Schönlein purpura, giant cell arteritis and various autoimmune connective tissue disorders such as systemic lupus erythematosis (J Urol 2006;176:2682)

Clinical features

Can present with acute onset of pain and swelling, presumably related to intratesticular hemorrhage (Ir Med J 2006;99:27)
Systemic disease is frequently already present at the time of initial presentation of testicular vasculitis or develops shortly thereafter
Some cases, however, remain isolated to the testes with no evidence of progression to systemic disease (J Clin Pathol 1994;47:1121)
It is, therefore, unclear whether isolated testicular vasculitis represents an early site of involvement by systemic disease or a separate entity (World J Surg Oncol 2011;9:63)
Only several cases of isolated testicular vasculitis were reported in the literature and a presentation suggestive of a testicular neoplasm is even less common (J Clin Pathol 1994;47:1121)
Since testicular biopsy is contraindicated when malignancy is suspected, the diagnosis is usually reported postorchiectomy in these cases (ScientificWorldJournal 2010;10:1915, Urology 2003;61:1035)
Biopsy most likely diagnostic in patients with testicular symptoms (pain, enlargement or shrinking)
Wedge biopsy should contain capsule, tunica vasculosa and testicular parenchyma

Radiology images

Case #328

Testicular heterogeneous hypoechoic lesion

Case reports

34 year old man with hypoechoic testicular lesion (Case #328)

Treatment

Treatment options are still debated and frequently hinge on individual factors which need to be carefully considered in each patient
Immunosuppressive therapy has been administered to some of the patients
In other cases, careful follow up to exclude progression to systemic disease was preferred (J Clin Pathol 1994;47:1121)
Some authors have even postulated that the excision of the affected organ might be curative, obviating the need for pharmacologic therapy (ScientificWorldJournal 2010;10:1915)
Close follow up, including serology, is recommended since the risk of progression to systemic disease is unknown (J Clin Pathol 1994;47:1121)

Gross description

Testis was bivalved to show a hemorrhagic, well defined, soft, dark red lesion (Case of the Week #328)

Gross images

Case #328

Microscopic (histologic) description

Focal hemorrhage with early organization and small arteries around the area of hemorrhage (Case of the Week #328)

Microscopic (histologic) images

Case #328

Differential diagnosis

Although uncommon, isolated necrotizing testicular vasculitis remains in the differential diagnosis of hypovascular testicular lesions; long term follow up and additional research is needed in order to further elucidate the pathogenesis of isolated organ vasculitis and the subsequent risk of disease progression

Vasitis nodosa

Table of Contents

Definition / general | Microscopic (histologic) description | Microscopic (histologic) images | Differential diagnosis

Definition / general

Granulomatous condition of vas deferens that resembles spermatic granuloma of epididymis
Usually post vasectomy or herniorrhaphy
Occasionally associated with recanalization

Microscopic (histologic) description

Proliferating ductules and dilated tubules containing spermatozoa in wall of vas deferens
Also associated with small bundles of hyperplastic smooth muscle
Vas deferens may show irregular thickening
Ductules may connect with vas deferens (like diverticula or salpingitis isthmica nodosa but with inflammation and less smooth muscle hypertrophy)
May see perineural or vascular invasion by proliferating ductules

Microscopic (histologic) images

Images hosted on other servers:

Vasitis nodosa

Differential diagnosis

Adenocarcinoma of epididymis and adenocarcinoma of rete testis: no history of prior surgery, no intraluminal spermatozoa

Well differentiated papillary mesothelial tumor

Table of Contents

Definition / general

Well differentiated papillary mesothelial tumor is a neoplasm of uncertain malignant potential that originates from the mesothelium of the pleura, peritoneum or tunica vaginalis

Essential features

Mesothelial tumor without significant cytologic atypia (Ann Diagn Pathol 2019;38:43, Ann Surg Oncol 2019;26:852)
Composed entirely of papillary structures and tubules lined by a single layer of bland cuboidal cells with no identifiable invasion
Positive staining for mesothelial markers (calretinin, WT1)
BAP1 and MTAP immunohistochemical staining should be retained

Terminology

Well differentiated papillary mesothelioma (Eur Urol 2022;82:458)

Epidemiology

Tumors arising from tunica vaginalis are rare and comprise Mod Pathol 2022;35:1327)
Age range is 18 - 70 years

Sites

Peritoneum
Tunica vaginalis
Pleura
Pericardium
References: Mod Pathol 2022;35:1327

Pathophysiology

Unknown

Etiology

Unknown

Clinical features

Pleural cases are often symptomatic and associated with a pleural effusion (Mod Pathol 2022;35:1327)
Peritoneal cases are typically identified incidentally during surgery (Mod Pathol 2022;35:1327)
Cases involving the tunica vaginalis are associated with hydrocele and testicular pain (Mod Pathol 2022;35:1327, Clin Genitourin Cancer 2016;14:e435, Can Urol Assoc J 2018;12:E425)

Diagnosis

Histologic diagnosis is required

Radiology description

No specific imaging findings (Radiographics 2023;43:e220128, Adv Anat Pathol 2023;30:280)
There may be no imaging abnormalities (Radiographics 2023;43:e220128)
Sometimes there may be small peritoneal nodules, a single nodule or scattered areas of peritoneal thickening (Radiographics 2023;43:e220128)
Calcifications may be present (Radiographics 2023;43:e220128)

Prognostic factors

This tumor is likely benign in nature but is often morphologically identical to mesothelioma in situ, which may explain the rare reports of recurrence as mesothelioma (Am J Surg Pathol 2023;47:611)

Case reports

18 year old man with hydrocele (J Clin Pathol 1992;45:1029)
35 year old man with bilateral hydroceles (Urol Oncol 2006;24:36)
47 year old man with a testicular tumor found after an episode of acute epididymitis (Int J Surg Pathol 2023;31:1126)
48 year old man without asbestos exposure (Korean J Pathol 2014;48:225)
55 year old man with chronic testicular pain, epididymitis and a hydrocele (Int J Surg Pathol 2023;31:1126)

Treatment

Complete excision

Gross description

Peritoneal surfaces with small nodules or papillary excrescences, single to innumerable (Mod Pathol 2022;35:1327)

Frozen section description

These tumors are often found incidentally during other procedures, prompting frozen section evaluation
Expanded papillary structures with edema or myxoid change, lined by a single layer of bland mesothelial cells
Invasion should be excluded
Reference: Int J Surg Pathol 2021;29:844

Microscopic (histologic) description

Papillary structures with expansile cores showing myxoid features
Papillary structures are lined by a bland simple layer of flattened to cuboidal cells
Fibrovascular cores generally lack inflammation and psammoma bodies
Occasional gland-like or tubulocystic areas may be seen
There should be a lack of stromal invasion, significant atypia and mitotic activity (Mod Pathol 2022;35:1327)

Microscopic (histologic) images

Contributed by Aida Valencia, M.D. and Jennifer Gordetsky, M.D.

Numerous fibrovascular cores

Background macrophages

Broad papillae

Papillae with myxoid stroma

Nonpsammomatous calcifications

Calretinin

WT1

D2-40

Mesothelioma

Virtual slides

Images hosted on other servers:

Diagnostic features

Retained BAP1 expression

Retained MTAP expression

Cytology description

Clusters of uniform mesothelial cells without atypia

Positive stains

MTAP retained (Mod Pathol 2020;33:245)
BAP1 retained (Am J Surg Pathol 2018;42:256)
PAX8 may have aberrant expression (pitfall) (94%) (Hum Pathol 2018;72:160)
WT1
D2-40
CK5/6
Calretinin

Negative stains

Molecular / cytogenetics description

Still being studied, information based on small series
- 2 cases of CDC42 missense mutations (Mod Pathol 2019;32:88)
- 8 cases of TRAF7 missense mutations localized at the C terminus of the protein (Mod Pathol 2019;32:88)
- 5 cases of recurrent missense mutations of EHD1, ATM, FBXO10, SH2D2A, CDH5, MAGED1 and TP73 (Cancers (Basel) 2020;12:1568)

Molecular / cytogenetics images

Images hosted on other servers:

TRAF7 and CDC42 somatic mutations

Sample pathology report

Scrotum, hydrocelectomy:
- Well differentiated mesothelial tumor

Differential diagnosis

Mesothelioma:
- Cytologic atypia, mitoses and invasion
- Loss of BAP1
Mesothelioma in situ:
- Cytologic atypia and mitoses
- Loss of BAP1
- Invasion will not be present
Serous cystadenoma:
- May have similar morphologic features
- Negative for calretinin, D2-40
Serous borderline tumors:
- Architectural complexity of papillae or epithelial proliferation
- Negative for calretinin, D2-40
Low grade serous cystadenocarcinoma:
- Invasion is present
- Negative for calretinin, D2-40
Adenomatoid tumor:
- Tubules, cysts and cords without papillae
- Infiltrative growth is common
- Also mesothelial in origin; both express CK5/6, WT1, calretinin, D2-40

Board review style question #1

Well differentiated papillary mesothelial tumor

The following tumor is incidentally found on the peritoneum during a cholecystectomy. This tumor should show which immunophenotype?

BAP1 loss, calretinin+, WT1+
BAP1 retained, MTAP retained, calretinin+, WT1+
Cytokeratin 5/6-, D2-40+
p53 null, AE1 / AE3+, PAX8+

Board review style answer #1

B. BAP1 retained, MTAP retained, calretinin+, WT1+. These images show a well differentiated mesothelial tumor, which should have retained BAP1 and MTAP. Mesothelial markers will be positive. Answer A is incorrect because while a well differentiated mesothelial tumor will express mesothelial markers, BAP1 should be retained. Answer C is incorrect because mesothelial tumors will express both CK5/6 and D2-40. Answer D is incorrect because this immunophenotype is more in keeping with an ovarian type serous tumor.

Comment Here

Reference: Well differentiated papillary mesothelial tumor

Board review style question #2

A patient presents with scrotal swelling that has been persistent over the last few years. An orchiectomy is done. Which of the following immunophenotypes would favor a mesothelioma over a well differentiated papillary mesothelial tumor?

BAP1 loss, calretinin+, WT1+
BAP1 retained, MTAP retained, calretinin+, WT1+
Cytokeratin 5/6-, D2-40+
p53 null, AE1 / AE3+, PAX8+

Board review style answer #2

A. BAP1 loss, calretinin+, WT1+. These images show a tumor with significant cytologic atypia and invasion into the testis. This is a mesothelioma of the tunica vaginalis. Mesotheliomas will express mesothelial markers and have BAP1 loss. Answer B is incorrect because this immunophenotype is in keeping with a benign mesothelial lesion. Answer C is incorrect because mesothelial tumors will express both CK5/6 and D2-40. Answer D is incorrect because this immunophenotype is more in keeping with an ovarian type serous tumor.

Comment Here

Reference: Well differentiated papillary mesothelial tumor

WHO classification

Table of Contents

Definition / general

WHO classification of tumors of the urinary and male genital organs
Currently on 5th edition, published in 2022

Major updates

Germ cell tumors derived from germ cell neoplasia in situ:
- Teratoma with primitive neuroectodermal tumor (PNET) is now called teratoma with embryonic type neuroendocrine differentiation
Sex cord stromal tumors:
- Signet ring pattern of Sertoli cell tumor is now listed as a separate tumor called signet ring stromal tumor
- Myoid gonadal stromal tumor changed from a provisional entity to a confirmed entity
Paratesticular mesothelial tumors:
- Well differentiated papillary mesothelioma was renamed well differentiated papillary mesothelial tumor

WHO (2022) (ICD-O morphology terms if different)

Germ cell tumors derived from germ cell neoplasia in situ

Noninvasive germ cell neoplasia
- Germ cell neoplasia in situ
- Specific forms of intratubular germ cell neoplasia
  - Intratubular seminoma
  - Intratubular embryonal carcinoma
  - Intratubular trophoblast
  - Intratubular yolk sac tumor
  - Intratubular teratoma
- Gonadoblastoma
The germinoma family of tumors
- Seminoma
  - Seminoma with syncytiotrophoblast cells
Nonseminomatous germ cell tumors
Mixed germ cell tumors
- Mixed germ cell tumors
  - Polyembryoma
  - Diffuse embryoma
Germ cell tumors of unknown type
- Regressed germ cell tumors

Germ cell tumors unrelated to germ cell neoplasia in situ

Spermatocytic tumor
- Spermatocytic tumor with sarcomatous differentiation
Teratoma, prepubertal type
- Dermoid cyst
- Epidermoid cyst
Yolk sac tumor, prepubertal type
Testicular neuroendocrine tumor, prepubertal type (well differentiated neuroendocrine tumor [monodermal teratoma])
Mixed teratoma and yolk sac tumor, prepubertal type

Sex cord stromal tumors of the testis

Leydig cell tumor
- Leydig cell tumor
- Malignant Leydig cell tumor
Sertoli cell tumor (Sertoli cell tumors)
Granulosa cell tumors
- Adult granulosa cell tumor
- Juvenile granulosa cell tumor
Tumors in the fibroma thecoma group (the fibroma thecoma family of tumors)
- Thecoma
- Fibroma
Mixed and other sex cord stromal tumors
- Mixed sex cord stromal tumor
- Signet ring stromal tumor
- Myoid gonadal stromal tumor
- Sex cord stromal tumor, NOS

Ovarian type tumors of the collecting ducts and rete testis

Serous cystadenoma (serous cystadenoma, NOS)
Serous tumor of borderline malignancy (serous borderline tumor, NOS)
Serous cystadenocarcinoma
Mucinous cystadenoma
Mucinous borderline tumor
Mucinous cystadenocarcinoma
Endometrioid tumor, borderline
Endometrioid adenocarcinoma
Clear cell adenocarcinoma
Brenner tumor

Tumors of the collecting duct and rete testis

Adenoma of the collecting ducts and rete testis (adenoma)
Adenocarcinoma of the collecting ducts and rete testis (adenocarcinoma)

Paratesticular mesothelial tumors

Tumors of the epididymis

Cystadenoma of the epididymis
Papillary cystadenoma of the epididymis (papillary cystadenoma)
Adenocarcinoma of the epididymis
Squamous cell carcinoma of the epididymis (squamous cell carcinoma)
Melanotic neuroectodermal tumor of the epididymis (melanotic neuroectodermal tumor)

Metastatic tumors

Additional references

WHO Classification of Tumours Editorial Board: Urinary and Male Genital Tumours, 5th Edition, 2022

Board review style question #1

Spermatocytic tumor, shown in the image above, is an example of which of the following categories of testicular tumors?

Germ cell tumors derived from germ cell neoplasia in situ
Germ cell tumors unrelated to germ cell neoplasia in situ
Sex cord stromal tumors
Tumor containing both germ cell and sex cord stromal elements

Board review style answer #1

B. Germ cell tumors unrelated to germ cell neoplasia in situ. Spermatocytic tumor is a germ cell tumor that is not derived from germ cell neoplasia in situ. Most germ cell tumors such as seminoma are thought to be derived from the precursor lesion germ cell neoplasia in situ. Spermatocytic tumor is not a sex cord stromal tumor and does not have sex cord stromal elements.

Comment Here

Reference: Testis & paratestis - WHO classification

Board review style question #2

Seminoma, shown in the image above, is an example of which of the following categories of testicular tumors?

Germ cell tumors derived from germ cell neoplasia in situ
Germ cell tumors unrelated to germ cell neoplasia in situ
Sex cord stromal tumors
Tumor containing both germ cell and sex cord stromal elements

Board review style answer #2

A. Germ cell tumors derived from germ cell neoplasia in situ. Seminoma is thought to be derived from the precursor lesion germ cell neoplasia in situ. It is not a sex cord stromal tumor and does not contain sex cord stromal elements.

Comment Here

Reference: Testis & paratestis - WHO classification

Yolk sac tumor

Table of Contents

Definition / general

Germ cell neoplasm composed of cells / structures reminiscent of embryonic / fetal yolk sac, allantois and extraembryonal mesenchyme

Essential features

2 biologically distinct entities:
- Postpubertal type (germ cell neoplasia in situ [GCNIS] related and usually as part of mixed tumor)
- Prepubertal type (unrelated to germ cell neoplasia in situ and usually pure)
Multiplicity of histological features with various mimickers
Most overlooked germ cell tumor subtype
Elevated serum alpha fetoprotein (AFP) should raise the suspicion for a yolk sac component

Terminology

First described / studied by Gunnar Teilum and later by Aleksander Talerman (Am J Surg Pathol 1981;5:719)
Complex nomenclature over time, reflecting the remarkable heterogeneity: primitive endodermal tumor, yolk sac carcinoma, endodermal sinus tumor, mesoblastoma vitellinum, orchioblastoma, polyvesicular vitelline tumor, adenocarcinoma of the infant testis, extraembryonic mesoblastoma; malignant endothelioma of perithelioma type (currently less used and not recommended by WHO 2016) (Int J Surg Pathol 2014;22:677, Histopathology 2012;60:1023)

ICD coding

ICD-O:
- 9071/3 - yolk sac tumor, postpubertal type
- 9071/3 - yolk sac tumor, prepubertal type

Epidemiology

Postpubertal type:
- Almost always part of mixed tumors (44% of nonseminomas); pure form exceedingly rare (0.6% of testicular germ cell tumors)
- Epidemiological trends common to all germ cell neoplasia in situ related tumors (15 - 40 years, rising incidence, environmental, genetic and epigenetic triggers) (Int J Mol Sci 2019;20:258)
Prepubertal type:
- Rare (2 - 3 cases/year/1 million) and usually pure (mixed forms with teratoma are the exception)
- Children < 6 years (median age 16 - 20 months)
- Does not follow epidemiological trends / associations of postpubertal type tumors

Sites

Testis
Also found in ovary, extragonadal (along midline of the body)

Pathophysiology

Postpubertal type:
- Derived from germ cell neoplasia in situ (primordial germ cells / gonocytes arrested in maturation → germ cell neoplasia in situ → reprogramming → extraembryonal differentiation)
- Type II germ cell tumor (Nat Rev Cancer 2019;19:522)
Prepubertal type:
- Not derived from germ cell neoplasia in situ
- Hypothesis: derived from teratoma
- Type I germ cell tumor

Etiology

Postpubertal type:
- Environmental factors: testicular dysgenesis syndrome, subfertility
- Genetic factors: single nucleotide polymorphism (SNP) variants (KITLG, SPRY4, DMRT1)
Prepubertal type:
- Unknown
References: Int J Mol Sci 2019;20:258, Nat Rev Cancer 2019;19:522

Clinical features

Unilateral testicular mass, often painless (World J Surg Oncol 2014;12:400)
Postpubertal type:
- More aggressive (compared to prepubertal): around 40% stage I disease; metastatic rate of 33%; stage III patients with yolk sac elements display poorer prognosis; increased prevalence in late recurrences (chemoresistance)
Prepubertal type:
- Less aggressive (compared to postpubertal): 80% stage I disease; of these 6% relapse on surveillance only
- Higher tendency to bypass retroperitoneal lymph nodes and spread hematogenously (compared to postpubertal)

Diagnosis

Physical examination
Testicular ultrasound
Serum tumor markers
Definitive diagnosis: histological examination of orchiectomy specimen
References: Surg Pathol Clin 2015;8:687, Hum Pathol 2018;82:113

Laboratory

Elevated alpha fetoprotein in 95 - 98% of the cases (may also be elevated in 20 - 25% of teratomas via hepatoid differentiation, mucinous glands) (Open Access J Urol 2011;4:1)
Care in interpretation in neonates (physiologically elevated alpha fetoprotein until 6 months)

Radiology description

Ultrasound: heterogenous echogenicity, frequently with cystic spaces, ill defined margins and calcifications (Radiographics 2017;37:1085)

Prognostic factors

Classical factors for testicular germ cell tumors in general, including staging and International Germ Cell Cancer Collaborative Group grouping
In postpubertal mixed tumors, higher percentage of yolk sac tumor is associated with lower stage (Am J Clin Pathol 2016;145:341)
For stage I prepubertal type tumors: size > 4.5 cm, invasion of rete testis / epididymis and necrosis (Am J Surg Pathol 2015;39:1121)

Case reports

7 month old child with bilateral synchronous testicular prepubertal type and teratoma (Urology 2018;117:142)
2 year old boy with yolk sac tumor of cryptorchid testis, diagnosed by fine needle aspiration (J Cytol 2015;32:53)
30 year old man with metastatic yolk sac tumor descending from an intra-abdominal testis (Oncol Lett 2015;10:3647)
46 year old man with postpubertal type, arising from cryptorchid testes (BMJ Case Rep 2019;12:e229541)
50 year old man with pure yolk sac tumor of testis (Med J Dr DY Patil Univ 2016;9:499)

Treatment

Orchiectomy, with or without adjuvant (cisplatin based) chemotherapy

Gross description

Postpubertal type:
- Poorly circumscribed, nonencapsulated, predominantly solid
- Gray to white to yellow to tan, gelatinous surface
- Hemorrhage, necrosis and cystic areas are common
Prepubertal type:
- More homogeneous, gray to yellow, solid or mucoid, bulging and lobulated
- Hemorrhage and necrosis are uncommon
References: Surg Pathol Clin 2015;8:687, Hum Pathol 2018;82:113

Gross images

Contributed by Debra L. Zynger, M.D.

Mixed germ cell tumor, postpubertal with varying % of yolk sac tumor

Mixed germ cell tumor, postpubertal with varying % of yolk sac tumor

Microscopic (histologic) description

Most overlooked subtypes of germ cell tumors (dedicated sampling is key) (Pathology 2018;50:88, Hum Pathol 2018;82:113)
Remarkable heterogeneity, multiple patterns, often combined:
- Microcystic / reticular pattern:
  - Most common
  - Anastomosing cords of flattened cells forming a honeycomb / spider web meshwork, forming spaces enclosing mucoid / basophilic material
- Macrocystic pattern:
  - Coalescence of smaller cystic spaces described in the microcystic pattern
- Myxomatous pattern:
  - Resembles the microcystic pattern
  - Sparse dispersed spindled / stellate cells in a myxoid background that often contains a prominent capillary network (also called angioblastic pattern)
  - Focal differentiation into cartilage or skeletal muscle may be rarely seen and should not elicit diagnosis of teratoma
- Sarcomatoid / spindle cell pattern:
  - Progression of the myxomatous pattern (increase in number / density of spindled / stellate cells retaining cytokeratin positivity)
  - Some cases regarded as somatic malignancy in the form of sarcoma may actually represent sarcomatoid pattern of yolk sac tumor (Am J Surg Pathol 2014;38:1396)
- Solid pattern:
  - Sheets of polygonal clear to amphophilic cells form nodules
  - Distinct cell membrane (like in seminoma)
- Glandular / alveolar pattern:
  - Glands or tubular structures, sometimes with subnuclear vacuoles resembling secretory endometrium or resembling intestinal epithelium
- Endodermal sinus / perivascular pattern:
  - Predominance of Schiller-Duval bodies (see below)
- Hepatoid pattern:
  - Sheets, solid nests or trabeculae of polygonal eosinophilic cells, with large nuclei and prominent nucleoli, resembling hepatocytes
  - Strongly alpha fetoprotein positive
- Papillary pattern:
  - Papillary formations with or without fibrovascular cores projecting into cysts
  - Often hobnail morphology, high nuclear to cytoplasmic ratio
  - Exfoliated cells forming clusters may be seen in the vicinity
- Parietal pattern:
  - Abundant, dense, eosinophilic basement membrane material surrounding tumor cells
- Polyvesicular vitelline pattern:
  - Always occurs with other patterns
  - Vesicles, sometimes with constrictions (forming figure 8 shaped structures), in an edematous to fibrous stroma
Cytological atypia is variable across patterns; it is most significant in solid, sarcomatoid and glandular patterns
50% of tumors contain Schiller-Duval bodies (papillary structures within cystic spaces, lined by cuboidal to columnar cells with a distinct central vessel)
Characteristic (but not pathognomonic) hyaline globules (within and outside cytoplasm), refractile and eosinophilic, which are alpha-1 antitrypsin+ and PAS diastase+

Microscopic (histologic) images

Contributed by João Lobo, M.D. and Rui Henrique, M.D., Ph.D.

Microcystic pattern

Hyaline globules

Glandular pattern

Schiller-Duval bodies

Metastasis

Virtual slides

Images hosted on other servers:

Yolk sac tumor

Cytology description

Variably sized cell clusters, occasional glomeruloid structures, metachromatic basement membrane material, large cells with high nuclear to cytoplasmic ratio, mucoid background, PAS positive hyaline globules (J Cytol 2015;32:53)

Positive stains

Alpha fetoprotein (more specific but less sensitive: variable, often focal, in many cases entirely absent) (Histopathology 2014;65:51)
Glypican 3 (more sensitive, staining almost all cases but less specific) (Am J Surg Pathol 2006;30:1570, Histopathology 2011;58:312)
SALL4 (sensitive and specific for most germ cell tumor types including yolk sac tumor) (Am J Surg Pathol 2009;33:1065)
Pancytokeratin (uniformly positive)
Villin (usually positive)
CK7 (84%) (Hum Pathol 2019;84:254)

Negative stains

OCT 3/4
CD30 (weak / focal staining can be seen)
CD117 (usually negative but variable; 60% in solid patterns) (Am J Surg Pathol 2012;36:360)
PLAP and podoplanin (D2-40) (rarely positive)
Inhibin (Hum Pathol 2019;84:254)
p63 (Hum Pathol 2019;84:254)
GATA3 (12%, may be expressed in primitive patterns) (Hum Pathol 2016;48:18, Histopathology 2016;68:613)

Electron microscopy description

Epithelial cells with tight junctional complexes, apical microvilli, extracellular deposits of basal lamina, glycogen

Molecular / cytogenetics description

Postpubertal type:
- Gain of 12p (usually isochromosome 12p)
- Erased genomic imprinting
Prepubertal type:
- Multiple gains (1q, 20q, 22) and losses (1p, 4, 6q) but no 12p gain
- Biparental genomic imprinting
References: Int J Mol Sci 2019;20:258, Nat Rev Cancer 2019;19:522

Sample pathology report

Right testicle, right radical orchiectomy:
- Mixed germ cell tumor, postpubertal type, 40% teratoma, 30% embryonal carcinoma, 15% yolk sac tumor and 15% seminoma (see synoptic report)

Differential diagnosis

Teratoma (versus glandular pattern of yolk sac tumor):
- Encircling smooth muscle layer, no evidence of glandular branching
Seminoma (versus solid pattern of yolk sac tumor):
- Presence of fibrovascular septa filled with prominent lymphocytic infiltrate
- OCT 3/4+, CD117 diffusely +; AFP-, glypican 3-, AE1 / AE3- to weak / focal
Embryonal carcinoma (some patterns, such as papillary or glandular):
- Higher cytological atypia, extensive necrosis, brisk mitotic activity
- OCT 3/4+, CD30 diffusely +; AFP-, glypican 3- (Pathology 2018;50:88)
Rete testis hyperplasia with hyaline globules:
- Lacks atypia and mitoses
- SALL4-, AFP-, glypican 3- (Am J Surg Pathol 1991;15:66)
Microcystic Leydig cell tumor:
- No recurrence or metastasis
- Calretinin+, inhibin+, MelanA+; AFP-, glypican 3-; cytokeratin and CAM 5.2 focal (Am J Surg Pathol 1999;23:546)

Board review style question #1

A 2 year old boy is submitted to orchiectomy. In the figure you may appreciate a histological section of the lesion. Which sentence is true?

Most likely the tumor has gain of 12p
Most likely this tumor is present in its pure form and not mixed with other subtypes
Negative AFP excludes a yolk sac tumor
OCT 3/4 staining will be positive in this tumor
Schiller-Duval bodies are present and are definitive proof of a postpubertal type yolk sac tumor

Board review style answer #1

B. The picture represents a prepubertal type yolk sac tumor. This entity does not show 12p gain (contrarily to postpubertal type tumors of the testis). Schiller-Duval bodies are present but may be seen (or not) in both prepubertal type and postpubertal type yolk sac tumors. AFP is variably positive (but many times negative) in yolk sac tumors and OCT 3/4 is invariably negative. Prepubertal type yolk sac tumor is almost always seen in its pure form (contrarily to postpubertal type tumors, which are frequently mixed).

Comment Here

Reference: Yolk sac tumor

Board review style question #2

Which of the following is true regarding yolk sac tumor of the testis?

Differential diagnosis with seminoma is particularly problematic in the microcystic pattern
Glypican 3 is the most specific marker of this tumor subtype
Can be germ cell neoplasia related or unrelated depending on pubertal status
Only occurs in adolescents
Serum AFP levels are not relevant for the diagnosis

Board review style answer #2

C. Yolk sac tumor of the testis can be germ cell neoplasia in situ related (postpubertal type) or germ cell neoplasia in situ unrelated (prepubertal type), showing a bimodal epidemiology (young adults and young children, respectively). Glypican 3 is sensitive but not a specific marker of this tumor type. Differential diagnosis with seminoma occurs when a solid pattern is extensive. There is a strong correlation between the finding of elevated serum AFP and presence of yolk sac tumor elements.

Comment Here

Reference: Yolk sac tumor

Recent Testis & paratestis Pathology books

Amin: 2022

Behnke: 2018

Cheng: 2019

Colecchia : 2016

IARC: 2022

Manuel: 2019

Nistal: 2017

Ulbright: 2022

VandenBussche: 2022

Wobker: 2021

Yang: 2020

Zhou: 2022

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