Testis & paratestis
Sex cord stromal tumors
Intratubular large cell hyalinizing Sertoli cell neoplasia (ITLCHSCN)
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Deputy Editor-in-Chief: Maria Tretiakova, M.D., Ph.D.
Last author update: 2 January 2025
Last staff update: 2 January 2025
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PubMed Search: Intratubular large cell hyalinizing Sertoli cell neoplasia
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Laboratory | Radiology description | Prognostic factors | Case reports | Treatment | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Positive stains | Negative stains | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1Cite this page: Macias V, Kajdacsy-Balla A. Intratubular large cell hyalinizing Sertoli cell neoplasia (ITLCHSCN). PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/testisitlchscn.html. Accessed January 13th, 2025.
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
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
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).
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Reference: Intratubular large cell hyalinizing Sertoli cell neoplasia (ITLCHSCN)
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Reference: Intratubular large cell hyalinizing Sertoli cell neoplasia (ITLCHSCN)
