Intratubular Large Cell Hyalinizing and Calcifying Sertoli Cell Neoplasia of the
Testis in a child with Peutz-Jeghers Syndrome
Assistance Publique-Hopitaux de Paris
Click on each slide thumbnail image for an enlarged view
A boy born in March 1999 presented at age 4 with learning difficulties, attention deficit disorder and
was treated for 2 years by Ritaline. At age 5, resection of a nasal polyp was performed. At age 7, a
unilateral localized left gynecomastia associated with acceleration of growth velocity led to endocrine
evaluation and testicular ultrasonography. Both testes were moderately and equally hypertrophied. At
ultrasonography, multiple, bilateral dot-like calcifications were present in the 2 testes, associated
with a nodule of larger confluent calcifications (7x5mm) in the right testis (the slides submitted are
from the right testicular nodule). Small bilateral cysts into the epididymis were also noted. Endocrine
evaluation showed: low testosterone (< 0, 10 ng/ml), high estradiol (32,4 pg/ml) and markedly
elevated inhibin-α (156 pg/ml).
Immediately after ablation of the testicular nodule, estradiol levels began to lower and testosterone
to rise but testosterone levels lowered again soon.
On account of the low risk of malignant transformation of the intra tubular LCH Sertoli cell
neoplasia, a conservative treatment was decided. Medical treatment was warranted to reduce the effects
of elevated estrogens on the breast and bone maturation. Aromatase inhibitors are the best option,
according to the recent literature. Anastrazole (3rd generation inhibitor of estrogen
synthesis) was given 4 months after surgery. Within the next 4 months, estradiol reached normal range
and gynecomastia disappeared. Growth velocity and skeletal maturation have decreased under this
At low power, cluster of expanded seminiferous tubules with thickened peritubular basement membrane. The stroma is denser than that associated with normal tubules at bottom right
Intratubular proliferation of large Sertoli cells, with eosinophilic or clear cytoplasm, replacing all germ cells and filling the lumen.
On the right, two seminiferous tubules that are filled by large Sertoli cells, with eosinophilic or vacuolated cytoplasm and euchromatic, ovoid nuclei. Their thickened basement membrane extends and invaginates into the lumen.
Among normal seminiferous tubules, one tubule with a PAS-positive, thickened and invaginated basement membrane
A small cluster of expanded seminiferous tubules with intratubular Sertoli cell proliferation and globular eosinophilic basement membrane deposits, partially calcified in the larger tubule.
A group of expanded tubules with numerous intraluminal psammomatous calcifications replacing the large proliferated Sertoli cells.
(Inhibin) Strong inhibin reactivity of the intratubular large proliferated Sertoli cells. In normal seminiferous tubules, weaker reactivity of normal Sertoli cells.
At the time the testicular nodule was resected (May 2006) the diagnosis of Peutz-Jeghers Syndrome was
highly suspected in the presence of perioral pigmentation, and calcifying testicular lesion with
gynecomastia but the search for mutation for the STK11/LKB1 gene was only under scrutiny. Blood samples
had been sent for molecular testing.
Standard techniques checking for STK1 gene mutations covering 70% of mutations present in
Peutz-Jeghers Syndrome (exons 2 and 5-8) were initially negative (October 2006). A few months later,
results from White Blood Cells examination in another institution were positive for molecular diagnosis
of McCune-Albright Syndrome (somatic mutation of arginin 201 with positivity from protein G as).
Therefore for a few months, and despite clinical manifestations more in favor of Peutz-Jeghers Syndrome,
McCune-Albright Syndrome was the considered diagnosis until in September 2007 a different technique for
the study of STK1 mutation was performed (MLPA = Multiple Ligation-dependent Probe Assay) and found a
deletion limited to promotor and exon 1 of gene STK11. This deletion had been described previously with
Peutz-Jeghers Syndrome in the literature and Peutz-Jeghers Syndrome diagnosis was therefore ascertained.
The resected nodule measured 1cm diameter. Among normal prepubertal testicular tubules, there were
patchy distributed expanded tubules, solitary or in clusters. These tubules were filled with enlarged
Sertoli cells and surrounded by a thickened peritubular basement membrane which could be invaginated into
the tubules. Sertoli cells had a large pale or eosinophilic cytoplasm with ovoid, uniform nuclei.
Mitosis were scarce. These tubules did not contain germ cells. There was no definite neoplastic
Sertoli cell cords as seen in Sertoli cell tumors.
The basement membrane appeared multilayered and intensely PAS positive, invaginating into hyalinized,
PAS positive cores. Numerous foci of dystrophic calcifications were present within many of the enlarged
tubules, apparently developed from this thickened, invaginated basement membrane. Immunohistochemical
stains were performed with appropriate reactive controls. Inhibin-α was strongly positive in large
proliferated Sertoli cells.
Peutz-Jeghers Syndrome is a rare autosomal dominant disorder characterized by the association of
benign gastrointestinal hamartomatous polyps, mucocutaneous pigmentation and increased risk of developing
various neoplasms, including gonadal sex cord tumors. In the present case, GI tract polyps were not
present (ileocoloscopy and oesogastroduodenoscopy were normal).
Nasal polyps and Peutz-Jeghers Syndrome
One nasal polyp had been removed in our case, in 2004, 2 years prior to the apparition of
gynecomastia. In the title of Dr Peutz's initial report in 1921, nasal polyps were mentioned as part of
the entity, but had seldom been described in the following decades. In a recent publication, nasal
polyps have been reported in 16% of Dutch patients with Peutz-Jeghers Syndrome. According to this study,
nasal polyps in Peutz-Jeghers Syndrome present with less eosinophilia than sporadic nasal polyps. Within
polyp tissue, LOH at 19p. 13.3 indicating inactivation of the wild type STK11/LKB1tumor suppressor gene
has been found in 50% of PJ patients but not in 28 sporadic nasal polyps studied as control. Therefore
nasal polyps must not be forgotten as a possible clinical manifestation of Peutz-Jeghers Syndrome.
Sertoli Cell proliferations of the testis and Peutz-Jeghers Syndrome
Mutations of the STK11 tumor suppressor gene located on the short arm of chromosome 19 predispose
patients with Peutz-Jeghers Syndrome to different type of neoplasms. In boys, testicular lesions
involving Sertoli cells have been increasingly recognized as a cause of prepubertal gynecomastia and
other estrogenic manifestations.
This process has been described in sporadic cases or short series as Sertoli Cell Tumors (including
Large Cell Calcifying Sertoli Cell Tumor), Intra Tubular Sertoli Cell Tumors(or neoplasias, or
proliferations), sex cord tumor with annular tubules, "aromatase producing sex cord tumor". The variety
of terminology reflects the doubt to whether these entities are true neoplasms and what are their
prognostic significance. Their presumed neoplastic nature has led in the past to recommend bilateral
orchidectomy (Young S 1995, Am J Surg Pathol). The true nature of this lesion is therefore of great
importance due to the potential consequence of the choosen treatment.
A recent publication by Ulbright et al with review of 26 cases including 8 from their own files allows
a more clear view of the true nature and potential of these Sertoli Cell proliferations. The distinctive
clinical background presented a unique clinico-pathological profile : gynecomastia and advanced bone
age, both linked to increased serum estradiol levels often associated with perioral pigmentation.
All boys were young (mean: 6,8y), all had gynecomastia, most often the presenting symptom, with high
estradiol levels. Most of the patients had perioral pigmentation and many Evidence of Evidence of
familial Peutz-Jeghers Syndrome was available in only 8 cases. 20 patients had bilateral enlarged testis,
with no discrete mass, and multiple echogenic foci on testicular ultrasound. 2 patients has unilateral
enlarged testis, with discrete mass. In 19 patients, Sertoli Cell lesions were entirely intratubular,
whereas 7 patients had 9 invasive Sertoli Cell Tumors, associated to Intratubular neoplasia. When extra
tubulat foci were present they were similar to intratubular foci, and when performed, stained positively
for antimullerian hormone and inhibin. Follow up was not available for all 26 patients but when
available was indolent with no metastasis.
Pathology of Sertoli Cell proliferations in boys with with Peutz-Jeghers Syndrome
Sertoli cell proliferation of the testis is totally different from sex cord tumor observed in the
ovary of girls with Peutz-Jeghers Syndrome.
Venara et al (2001) prefer to term the intra tubular lesion "intra tubular Sertoli cell proliferations", due to their indolent course. Ulbright et al consider these
lesions as "Intratubular Large Cell Hyalinizing Sertoli Cell neoplasms of
the testis " because of their occasionsal progression to an invasive tumor, but agrees that conservative
management is possible in most.
The congenital gene defects might trigger a cascade of intracellular events that leads to
overexpression of aromatase in Sertoli cells, favoring the development of Intratubular Large Cell
Calcifying Sertoli Cell Neoplasia. Overexpression of aromatase in Sertoli cells is responsible for
estrogenic manifestations. Aromatase has the capacity to use testosterone as substrate for the synthesis
of estradiol, leading to elevation of its serum level and gynecomastia as its usual presenting feature.
High growth velocity and advanced skeletal maturation are also consequence of estradiol elevation and
important to reduce by treatment. Surgical treatment of gynecomastia can be necessary in some cases.
Scattered giant seminiferous tubules, often in clusters, contain proliferating large Sertoli cells
which replaced all germ cells and fill in the lumen. Enlarged Sertoli cells have pale to eosinophilic
cytoplasm, round, regular nuclei, small nucleoli. The affected tubules are surrounded by thickened multi
layered basement membrane, sending invaginations into the lumen, causing round hyalinized deposits.
Focal intratubular calcifications were present in only 6 intratubular proliferations, but raise the
question of Large Cell Calcifying Sertoli Cell tumors. 6/9 invasive tumors reported in the literature had
foci of calcifications but differed from Large Cell Calcifying Sertoli Cell tumors. It appeared to
Ulbright that only 2 tumors in one patient had the morphology of Large Cell Calcifying Sertoli Cell
tumors. Others had closely packed tubules but lacked a conspicuous stroma.
Our case presents with only intratubular Sertoli cell proliferation, no extra tubular foci.
Whatever the denomination of the Sertoli Cell proliferation, all patients with Peutz Jeghers Syndrome
and Sertoli cell lesions whose follow up was known did well, with a very long follow up for some of them.
It leads to conclude that Sertoli Cell proliferations in Peutz-Jeghers Syndrome are remarkably
indolent and justify conservative management by careful follow up rather than orchidectomy.
1) Other intratubular testicular tumors are present in Carney Syndrome but
there are some differences. Both in Peutz-Jeghers Syndrome and in Carney Syndrome, patients may develop
bilateral multifocal intratubular proliferations of Large Sertoli Cells but Peutz-Jeghers patients have a
greater degree of tubular enlargement, have more frequent basement membrane deposits and do not show as
frequent or extensive calcifications.
2) Sertoli cell nodules (non neoplastic lesions commonly identified in
cryptorchid testis) share patchy distribution, intratubular proliferation, and globular basement membrane
deposits. But proliferation consists of small fetal Sertoli cells and contain spermatogonia (germ cells
are absent in the Peutz-Jeghers lesion).
3) Gonadoblastoma usually develop on dysgenetic gonads. 40% are bilateral.
The tumor is composed of germ cells with seminoma-like features intermixed with immature Sertoli cells.
Rounded deposits of basement membrane are surrounded by the sex cord cells.
4) Sex cord tumor with annular tubules is the term used to describe the
distinctive ovarian tumors in Peutz-Jeghers patients. The antipodal arrangement of sex cord cell around
basement membrane deposits and typical calcifications present in the ovarian tumor is lacking in the
testicular tumor of the boys with this syndrome. Nevertheless there are similarities between these 2
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