Case 3 -

Intratubular Large Cell Sertoli Cell Neoplasia in Peutz-Jeghers Syndrome Thomas M. Ulbright Indiana University School of Medicine Indianapolis, IN

Virtual Slides as well as Still Images are displayed below.
For the fastest viewing of virtual slides, click:



under each thumbnail image below. You must have Aperio ImageScope installed on your PC.

If you do not already have Aperio ImageScope, Windows users with administrator privileges may download and install a free version in order to view USCAP Virtual Slides. Click the icon on the right to get your free copy:

Or, click on slide thumbnail images to view each slide
in a Web-based slide viewer, which is somewhat slower.

If you have any difficulties viewing these slides, email or call George Clay at +1.724.449.1137.

Case History: A 6-year-old boy presented with bilateral gynecomastia. Serum estradiol was elevated (30 pg/ml). On physical examination, both testes were firm, without discrete masses. Testicular ultrasound showed multiple, small (< 3 mm) echogenic foci in both testes. Bilateral testicular biopsy was performed. The slide is from the left testicular biopsy. Case 3 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 3 - Figure 1 - There are lobular clusters of enlarged seminiferous tubules scattered in the testicular parenchyma. Case 3 - Figure 2 - In this cluster of abnormal tubules the diameters are enlarged up to 4 times those of adjacent normal tubules. The abnormal tubules contain a cellular proliferation as well as numerous round deposits of eosinophilic matrix. Case 3 - Figure 3 - At higher magnification it is apparent that the basement membrane around the tubules is thickened and projects into the lumen as globular extensions. The cells in the tubules represent large Sertoli cells with pale, eosinophilic cytoplasm. Case 3 - Figure 4 - The large intraluminal Sertoli cells have uniform, round nuclei with fine chromatin and small nucleoli. Their cytoplasm is eosinophilic and vacuolated. Mitotic figures are not seen. Pathologic Findings: On microscopic examination, the testicular biopsy shows clusters of seminiferous tubules with enlarged profiles, 2 to 4x the diameter of the adjacent, noninvolved tubules. The abnormal tubules are expanded by an intratubular proliferation of large Sertoli cells with vacuolated to eosinophilic cytoplasm and round nuclei having small to moderate-sized nucleoli. Mitotic activity is inconspicuous. The tubules are surrounded by a prominently thickened basement membrane that projects as round deposits into the tubular lumen where they are surrounded by the proliferated, large Sertoli cells. Diagnosis: Intratubular large cell Sertoli cell neoplasia in Peutz-Jeghers syndrome. Discussion: This is an example of the intratubular neoplasia that occurs in the testis of Peutz-Jeghers patients. It has such a distinctive morphology that the diagnosis of Peutz-Jeghers syndrome should be strongly suggested when this lesion is encountered and the patient appropriately evaluated, including genetic testing. Peutz-Jeghers syndrome is a relatively rare genetic disease with an autosomal dominant pattern of inheritance. It has a variable estimated prevalence in the United States, 1:25,000 – 1:280,000. A majority of the cases, 69%, are associated with a germline mutation in the STK11 (serine-threonine kinase 11) gene (also known as LKB1) located on chromosome 19p13.3, [1] and these may either be missense or truncating mutations or deletions. [11, 19] The patients, usually during early childhood, commonly develop melanocytic macules of the oral mucosa and digits and hamartomatous polyps involving the GI tract. They also have an increased frequency of nasal polyps and a variety of cancers. It is thought that they acquire a functional loss to the second allele of the STK11 gene that causes the development of the tumor, with the STK11 gene, therefore, having the role of a tumor suppressor gene. The patient under discussion, after the testicular biopsy, had genetic testing performed on peripheral blood and he was found to have a heterozygous mutation in codon 237 of exon 5 of the STK11 gene, resulting in an asparagine codon instead of the normal aspartic acid codon. A number of different cancers occur with greatly increased frequency in Peutz-Jeghers patients. One study estimated that 93% of Peutz-Jeghers patients would develop some form of cancer by age 64 years, [10] but the methodology of this study has been criticized and felt to overstate the cancer frequency. Nonetheless, it is clear that Peutz-Jeghers patients do have a greatly increased cancer risk, with the most increased risk being in the GI tract, including small intestine, stomach, pancreas and colon. In general discussions of cancer risks in Peutz-Jeghers patients, the testis is often mentioned as being one of the sites at increased risk, with a cited figure of 9% for the number of Peutz-Jeghers patients to develop a testicular "cancer" by age 64. [10] In my opinion, however, there is no evidence for an increased risk of testicular cancer in Peutz-Jeghers patients. The testicular lesions referred to in Peutz-Jeghers syndrome are either similar to the one presented here or, less commonly, an invasive tumor in conjunction with intratubular large cell Sertoli cell neoplasia, with no reports of metastasis. Twenty-six Peutz-Jeghers patients with testicular tumors have been reported in the literature; they ranged from 1.8 – 14 years of age (mean, 6.8 years) at presentation with more than 90% coming to medical attention because of gynecomastia. [17] Most showed perioral pigmentation as well, and relatively few had known GI polyps. On physical examination, the testes were usually enlarged and firm but lacked discrete masses, and ultrasound showed small, multifocal echogenic foci. Of the 26 patients, 19 had only intratubular lesions that were very similar to those seen in the patient under discussion. Some patients had both intratubular and invasive tumors, with the latter showing the same cytological features as the former. Calcifications in these intratubular lesions were uncommon, being described in six of the 26 cases, but all had prominent intraluminal globular deposits of basement membrane. The pathologic features of the few invasive tumors are less well-defined, most resembling the intratubular tumor and consisting of microfoci, but two tumors, occurring in one patient, had the features of the large cell calcifying Sertoli cell tumor. [8] Immunohistochemical study in a few intratubular tumors showed strong reactivity for inhibin-alpha and AE1/AE3 cytokeratin in the tumor cells and positivity of the basement membrane deposits for collagen IV and laminin. [17] Some cases stained positively for aromatase, [4, 5, 7] the enzyme responsible for the conversion of testosterone and androstenedione to estradiol and estrone, respectively, and offering an explanation for the gynecomastia and advanced bone age commonly seen in these patients. Follow-up data are available for 11 patients with intratubular neoplasia (one also having microinvasive tumor foci) whose surgical treatment consisted only of biopsy, and all are alive and well at 0.3 – 19 years (mean, 4.5 years). [17, 18] Three patients with five invasive tumors were alive and well at 2 – 11 years after orchiectomy. This information permits conservative management, without orchiectomy, in young boys with Peutz-Jeghers syndrome who have multifocal, small echogenic foci on testicular ultrasound and are judged to have no good evidence for an invasive tumor. This approach will permit normal puberty without the need for hormonal replacement in many patients. For those with invasive tumors, orchiectomy should be performed, but the patients may be reassured that a benign outcome is anticipated for tumors having the usual features. The differential diagnosis includes the large cell calcifying Sertoli cell tumor, [13, 14] a lesion associated with a different genetic condition, the Carney syndrome. [6] The Carney syndrome is associated with a different mutation involving the PRKAR1A gene at 17q23-24. [13, 14] In my experience, most patients with the large cell calcifying Sertoli cell tumor have an invasive tumor at diagnosis, rather than solely an intratubular one, unlike those with the Peutz-Jeghers syndrome. The intratubular component, therefore, is much less conspicuous and often shows more prominent calcifications and decreased basement membrane deposits compared to the Peutz-Jeghers lesion. Sertoli cell nodules, relatively common non-neoplastic lesions that are seen with increased frequency in cryptorchid testes, share with the Peutz-Jeghers lesions the presence of tubules filled with globular basement membrane deposits and Sertoli cells, but the latter are smaller, "fetal-type" Sertoli cells rather than the large cells seen in the Peutz-Jeghers syndrome, and there are commonly admixed germ cells, unlike the Peutz-Jeghers lesion, which lacks a germ cell component. Finally, the term "sex cord tumor with annular tubules" has been applied to this lesion [9, 12] but unlike the ovarian sex cord tumor with annular tubules, [16, 20] the intratubular process in the testis of Peutz-Jeghers patients lacks the antipodal arrangement of tumor cells around basement membrane deposits, although the multifocal and bilateral nature of the process and the benign outcome are similar to the findings in ovarian sex cord tumor with annular tubules of female patients with the Peutz-Jeghers syndrome. This case of intratubular large cell Sertoli cell neoplasia of the testis provides us an opportunity to briefly review some additional intratubular lesions of the testis. The most common of these is intratubular germ cell neoplasia of the unclassified type (IGCNU), sometimes also termed carcinoma-in-situ. It is the common precursor to almost all the germ cell tumors of the adult testis (with the notable exceptions of spermatocytic seminoma and dermoid cyst) and consists of a proliferation of seminoma-like cells in the basal aspect of seminiferous tubules. Unlike seminoma, however, it lacks evidence of 12p amplification. [15] It is highlighted by immunostains directed against placental alkaline phosphatase, CD117 (kit), and OCT3/4. Intratubular seminoma represents filling and distention of seminiferous tubules by similar cells and is common, as is intratubular embryonal carcinoma, which characteristically shows a comedo-like pattern of necrosis. Coarse intratubular calcifications represent a hallmark of regressed intratubular embryonal carcinoma. [2] Intratubular spermatocytic seminoma is common adjacent to invasive spermatocytic seminoma and usually shows the characteristic "tripartite" morphologic spectrum of tumor cells. Individual syncytiotrophoblast cells occur surprisingly commonly (approximately 17% of cases) adjacent to seminomas but are less commonly encountered associated with the non-seminomatous germ cell tumors. [3] Intratubular teratoma and yolk sac tumor are distinctly rare. Occasional testicular lymphomas may have a prominent intratubular component; the most striking example that we have seen was in an anaplastic large cell lymphoma that had central necrosis of the intratubular tumor and therefore closely resembled intratubular embryonal carcinoma. Metastatic tumors to the testis may also have prominent intratubular growth; we have seen this most commonly in prostatic carcinomas. Primary paratesticular mesotheliomas may display prominent intratubular growth when the testis is involved. Idiopathic granulomatous orchitis shows a prominent intratubular component and should be considered when dealing with intratubular granulomatous inflammation, but intratubular granulomatous reactions are also commonly seen in cases of germ cell tumors, especially seminoma, and so it is necessary to exclude this possibility, which can be difficult in cases where the invasive tumor has undergone spontaneous regression. References Amos CI, Keitheri-Cheteri MB, Sabripour M, et al. Genotype-phenotype correlations in Peutz-Jeghers syndrome. J Med Genet 2004;41:327-33. Balzer BL, Ulbright TM. Spontaneous regression of testicular germ cell tumors: an analysis of 42 cases. Am J Surg Pathol 2006;30:858-65. Berney DM, Lee A, Shamash J, et al. The frequency and distribution of intratubular trophoblast in association with germ cell tumors of the testis. Am J Surg Pathol 2005;29:1300-3. Brodie A, Inkster S, Yue W. Aromatase expression in the human male. Mol Cell Endocrinol 2001;178:23-8. Bulun SE, Rosenthal IM, Brodie AM, et al. Use of tissue-specific promoters in the regulation of aromatase cytochrome P450 gene expression in human testicular and ovarian sex cord tumors, as well as in normal fetal and adult gonads. J Clin Endocrinol Metab 1993;77:1616-21. Carney JA, Gordon H, Carpenter PC, et al. The complex of myxomas, spotty pigmentation, and endocrine overactivity. Medicine 1985;64:270-83. Coen P, Kulin H, Ballantine T, et al. An aromatase-producing sex-cord tumor resulting in prepubertal gynecomastia. N Engl J Med 1991;324:317-22. Dreyer L, Jacyk WK, du Plessis DJ. Bilateral large-cell calcifying Sertoli cell tumor of the testes with Peutz-Jeghers syndrome: a case report. Pediatr Dermatol 1994;11:335-7. Dubois RS, Hoffman WH, Krishnan TH, et al. Feminizing sex cord tumors with annular tubules in a boy with Peutz-Jeghers syndrome. J Pediatr 1982;101:568-71. Giardiello FM, Brensinger JD, Tersmette AC, et al. Very high risk of cancer in familial Peutz-Jeghers syndrome. Gastroenterology 2000;119:1447-53. Hemminki A, Markie D, Tomlinson I, et al. A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature 1998;391:184-7. Hertl MC, Wiebel J, Schafer H, et al. Feminizing Sertoli cell tumors associated with Peutz-Jeghers syndrome: an increasingly recognized cause of prepubertal gynecomastia. Plast Reconstr Surg 1998;102:1151-7. Kratzer SS, Ulbright TM, Talerman A, et al. Large cell calcifying Sertoli cell tumor of the testis: contrasting features of six malignant and six benign tumors and a review of the literature. Am J Surg Pathol 1997;21:1271-80. Proppe KH, Scully RE. Large-cell calcifying Sertoli cell tumor of the testis. Am J Clin Pathol 1980;74:607-19. Rosenberg C, van Gurp RJ, Geelen E, et al. Overrepresentation of the short arm of chromosome 12 is related to invasive growth of human testicular seminomas and nonseminomas. Oncogene 2000;19:5858-62. Scully RE. Sex cord tumor with annular tubules: a distinctive ovarian tumor of the Peutz-Jeghers syndrome. Cancer 1970;25:1107-21. Ulbright TM, Amin MB, Young RH. Intratubular large cell hyalinizing Sertoli cell neoplasia of the testis: a report of 8 cases of a distinctive lesion of the Peutz-Jeghers syndrome. Am J Surg Pathol 2007;(in press). Venara M, Rey R, Bergada I, et al. Sertoli cell proliferations of the infantile testis: an intratubular form of Sertoli cell tumor? Am J Surg Pathol 2001;25:1237-44. Ylikorkala A, Avizienyte E, Tomlinson IP, et al. Mutations and impaired function of LKB1 in familial and non-familial Peutz-Jeghers syndrome and a sporadic testicular cancer. Hum Mol Genet 1999;8:45-51. Young RH, Welch WR, Dickersin GR, et al. Ovarian sex cord tumor with annular tubules: review of 74 cases including 27 with Peutz-Jeghers syndrome and four with adenoma malignum of the cervix. Cancer 1982;50:1384-402.