Case 3 -
Intratubular Large Cell Sertoli Cell Neoplasia in
Thomas M. Ulbright
Indiana University School of Medicine
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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
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.
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.
Intratubular large cell Sertoli cell neoplasia in
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,  and these may either be missense
or truncating mutations or deletions.
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,  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.  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.  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.  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.  Some cases stained positively for
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).
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,
lesion associated with a different genetic condition, the Carney syndrome.  The Carney
syndrome is associated with a different mutation involving the PRKAR1A gene at 17q23-24.
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
but unlike the ovarian sex cord tumor with
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.  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.  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.  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.
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