Large-cell Calcifying Sertoli Cell Tumors Research Articles

Conservative management of gynecomastia in Peutz-Jeghers syndrome: Case series and review of the literature.

Peutz-Jeghers syndrome (PJS) is a childhood-onset cancer predisposition syndrome that is associated with oral freckling and gastrointestinal polyposis. Male patients with PJS are at risk for large-cell calcifying Sertoli cell tumors in childhood. These tumors are estrogen-producing and can cause symptoms of precocious puberty, gynecomastia, and growth acceleration. Here we discuss our experience with spontaneous resolution or stabilization of breast enlargement without medical intervention in three patients with PJS and gynecomastia. These cases indicate that a watchful waiting approach can be considered in the management of gynecomastia in male children with PJS.

Molecular characterization of large cell calcifying sertoli cell tumors: A multi-institutional study of 6 benign and 2 malignant tumors

Large cell calcifying Sertoli cell tumors (LCCSCTs) are rare testicular tumors, representing <1 % of all testicular neoplasms. Almost 40 % of patients with LCCSCTs will present in the context of the inherited tumor predisposition syndrome, the Carney complex. While most LCCSCTs are benign, 10–20 % have malignant behavior. The aim of our study was to analyze LCCSCTs for novel molecular alterations in addition to PRKAR1A mutations and to identify potential drivers for malignant progression. Eight LCCSCTs diagnosed at two institutions were included. Two patients had the Carney complex confirmed on subsequent genetic testing, and two tumors had several adverse pathological findings. One patient presented with metastatic disease at the time of initial diagnosis. Targeted next-generation sequencing detected PRKAR1A alterations in all cases, with heterozygous PRKAR1A mutations in 5 tumors, germline Carney-complex-associated PRKAR1A mutation in 2 patients, and PRKAR1A fusion in 1 tumor. Additionally, sequencing the metastatic case identified CDKN1B and TERT promoter gene mutations. All tumors showed a low tumoral mutational burden and unremarkable copy number alterations except for frequent LOH of 17q24 encompassing the PRKAR1A locus. RNA expression analysis showed increased expression of several markers including novel PRUNE2, and usual markers like inhibin and calretinin. Our study showed that while LCCSCTs have been reported in the setting of cancer predisposition syndromes, the majority of these tumors occur sporadically. PRKAR1A alterations were present in all cases and appear to be the major driver in LCCSCTs. It remains to be determined whether malignant progression may be caused by additional driver mutations.

Large Cell Calcifying Sertoli Cell Tumor: A Clinicopathologic Study of 18 Cases With Comprehensive Review of the Literature and Reappraisal of Prognostic Features.

We present a series of 18 (8 clinically benign, 8 clinically ambiguous [ie, lacking sufficient follow-up to determine behavior], and 2 clinically malignant) large cell calcifying Sertoli cell tumors (LCCSCT) of the testis. The median patient age and size were 15.5 years and 1.9 cm for the benign tumors; 19 years and 1.6 cm for the ambiguous tumors; and 28.5 years and 2.3 cm for the malignant tumors. The most common presentation was a mass (n=12/18, 67%). Two patients (11%) had the Carney complex, and 2 had neurofibromatosis type 1. All tumors showed nodular growth with frequent lymphoid aggregates at the periphery. Within the nodules, there were nests and trabeculae of pale to eosinophilic epithelioid tumor cells with frequent cytoplasmic vacuolization interspersed with hypocellular, often myxoid stroma with conspicuous neutrophils. Spindled tumor cells were a minor component (<5%) in the clinically benign, ambiguous, and malignant tumors, except in 1 malignant tumor where they comprised 50% to 60% of the cellularity. Calcifications were noted in all but 2 benign tumors that were otherwise of typical appearance. Six tumors (3 in the clinically benign, 1 in the clinically ambiguous, and 2 in the malignant groups) were considered potentially malignant based on the presence of ≥1 adverse pathologic features previously recognized (see reference 1)-that is, size>4 cm, extratesticular growth, necrosis, significant atypia, vascular invasion, and >3 mitotic figures/10 HPFs. Of these, 3 tumors had ≥2 adverse features. One in a 7-year-old was clinically benign despite 5 "malignant" features; the remaining 2 in 27- and 30-year-olds, were clinically malignant, with both fulfilling previously suggested criteria for pathologically malignant tumors (age above 25 y and ≥2 adverse pathologic features). No clinically benign or ambiguous tumor met those same criteria. Of the adverse features, each of the 2 clinically malignant tumors showed tumor necrosis and lymphovascular invasion. All patients, except 1 with a clinically malignant tumor, were alive at a median follow-up of 33 months. In addition, in our literature review of 97 additional LCCSCTs, we identified 2 clinically malignant tumors in 42- and 45-year-old men that lacked any documented adverse pathologic criterion and 2 clinically malignant cases in patients with either the Carney complex or Peutz-Jeghers syndrome. In summary, our study and literature review support that all LCCSCTs in patients above 25 years old should be considered potentially malignant, and those in this age group with ≥2 adverse pathologic features warrant aggressive clinical management; furthermore, syndrome-associated cases are not uniformly benign. Tumor necrosis and lymphovascular invasion likely should receive greater adverse prognostic weight. LCCSCTs in young children may show benign outcomes despite several adverse pathologic features.

Protein kinase A drives paracrine crisis and WNT4-dependent testis tumor in Carney complex.

Large-cell calcifying Sertoli cell tumors (LCCSCTs) are among the most frequent lesions occurring in male Carney complex (CNC) patients. Although they constitute a key diagnostic criterion for this rare multiple neoplasia syndrome resulting from inactivating mutations of the tumor suppressor PRKAR1A, leading to unrepressed PKA activity, LCCSCT pathogenesis and origin remain elusive. Mouse models targeting Prkar1a inactivation in all somatic populations or separately in each cell type were generated to decipher the molecular and paracrine networks involved in the induction of CNC testis lesions. We demonstrate that the Prkar1a mutation was required in both stromal and Sertoli cells for the occurrence of LCCSCTs. Integrative analyses comparing transcriptomic, immunohistological data and phenotype of mutant mouse combinations led to the understanding of human LCCSCT pathogenesis and demonstrated PKA-induced paracrine molecular circuits in which the aberrant WNT4 signal production is a limiting step in shaping intratubular lesions and tumor expansion both in a mouse model and in human CNC testes.

Peutz-Jeghers syndrome: Skin manifestations and endocrine anomalies (Review).

Peutz-Jeghers syndrome (PJS), a rare autosomal dominant serine/threonine kinase 11 (STK11)/ liver kinase B1 (LKB1) gene-related genodermatosis, is characterized by oral hyperpigmentation (OHP); multiple gastro-intestinal mucosal benign hamartomatous polyps causing local bleeding, occlusion, intussusception, post-resection small bowel syndrome, associated increased risk of small intestinal cancer (incidence during the third decade); and 76% cumulative higher risk than the global population of developing non-gastrointestinal tumors (female predominance) including ovarian/testicular neoplasia, pancreatic and gynecologic (breast, uterus, ovarian) cancers. Suggestive PJS-associated OHP requires STK11 genetic testing. Abdominal pain in an OHP patient may be related to PJS-associated polyps. Other features include focal depigmentation followed by hyperpigmentation, and xeroderma pigmentosum-like lesions. The severity of the dermatological findings is correlated with gastrointestinal polyps. The STK11 gene is linked to reserve of primordial follicles, polycystic ovary syndrome, female fertility, and spermatogenesis. PJS is associated with 2 types of ovarian sex-cord stroma tumors (SCSTs): annular tubules (SCTATs) and pure Sertoli cell tumors. SCSTs accounts for 8% of ovarian cancer and SCTATs represents 2% of SCST, which may be associated with the overproduction of progesterone. PJS-SCTAT vs. non-PJS-SCTAT reveals bilateral/multifocal, small tumors with a benign behavior vs. a unique ovarian, large tumor with increased malignant/metastasis risk. Male precocious puberty is due to large cell calcifying Sertoli cell tumors (LCCSCTs). Notably, 30-40% of LCCSCTs are caused by PJS or Carney complex. PJS-LCCSCT is not aggressive, but it may be bilateral/multifocal, with the ultrasound hallmark being micro-calcifications. Testicular, intra-tubular large cell hyalinizing Sertoli cell tumor is the second testicle neoplasia in PJS. The skin and mucosal lesions are useful markers of PJS, assisting with the early identification of hamartomatouspolyps and initiation of serial surveillance of ovarian, or testicular neoplasia.

SUN-940 Carney Complex: A Case of a Rare Multiple Endocrine Neoplasia Misdiagnosed as Peutz-Jeghers Syndrome

Carney Complex (CNC) is an extremely rare multiple endocrine neoplasia caused by germline inactivating mutation in protein kinase A type I-alpha regulatory subunit (PRKAR1A gene). Mode of inheritance is mostly autosomal dominant; 25% of cases are due to de novo mutations. Only 750 world-wide cases have been reported. Most patients are diagnosed in the second or third decade. Clinical features include cutaneous myxomas, angiomyxoid nodules, lentiginous skin pigmentation, cardiac myxomas, and benign and rare malignant endocrine tumors. These endocrine tumors include and are not limited to prolactinomas, thyroid tumors, primary pigmented nodular adrenocortical disease (PPNAD), and large cell-calcifying Sertoli cell tumors (LCCSCT). Diagnosis is often challenging as disease manifestations can occur sporadically over a large span of time, and patients may present with various conditions such as Cushing syndrome, like our case. We present a case that demonstrates the importance of early recognition of this rare disorder.A 28-year-old Caucasian male with PMH of HFrEF, HTN, Sertoli cell tumor status post orchiectomy, vertebral fractures, and surgical removal of lip angiomyxoma presented to clinic for hypogonadism. Physical examination revealed marked Cushingoid features and facial lentigines above his eyes and on his lips. His eclectic medical history and unique exam findings lead to finding of a unifying diagnosis. His labs revealed severe Cushing syndrome, and computed tomography (CT) of his abdomen was performed due to ACTH independent hypercortisolism, demonstrating a bilateral lobular appearance of the adrenal glands.Combination of labs and physical exam findings of lentigines, skin myxomas, cushingoid features, rare angiomyxoma, LCCSCT and hypercortisolism lead to diagnosis of Carney Complex. He was misdiagnosed with Peutz-Jeghers in his adolescence due to LCCSCT and mucosal lentigines; therefore, hormonal screening was not routinely performed. Untreated Cushings led to severe osteoporosis with vertebral fractures and heart failure. Treatment included bilateral adrenalectomy. Pathology report confirmed rare PPNAD. PPNAD and LCCSCT are extremely rare tumors almost exclusively linked to Carney Complex. Interestingly, family history did not reveal endocrine disorders, cancers, or severe illnesses. Genetic testing returned positive for the PRKAR1A gene mutation. Given the consequences of untreated hormonal aberrations seen in this disorder, an early and accurate diagnosis is imperative.

Sonographic diagnosis of large-cell calcifying Sertoli cell tumor.

Large-cell calcifying Sertoli cell tumor is a very rare neoplasm of the testis with less than 100 reported cases. It is associated with some genetic syndromes, and it has some features that help to distinguish benign and malign cases. An 11-year-old boy presented with testicular lesions in both testicles. He underwent right radical orchiectomy in another institution and was referred to our hospital for further treatment. The lesions were reported as large-cell calcifying Sertoli cell tumors in our institution. There were multiple hyperechoic lesions with calcifications in the left testis and lesions showed vascularization on Doppler. Sonographic features of these lesions were also suggestive of benign large-cell calcifying Sertoli cell tumor. The lesions were stabile during follow-up. The ultrasonographic appearance of large-cell calcifying Sertoli cell tumor is descriptive and, together with clinical findings, allows differential diagnosis. It can direct patient management, with a more conservative approach. We report a child with large-cell calcifying Sertoli cell tumor who could have been saved from extensive surgery, such as radical orchiectomy, if the tumor had been diagnosed correctly with sonography.

Nuclear Localization of β-Catenin in Sertoli Cell Tumors and Other Sex Cord-Stromal Tumors of the Testis: An Immunohistochemical Study of 87 Cases.

The diagnosis and subclassification of Sertoli cell tumors (SCT) of the testis are often challenging to general surgical pathologists because of the rarity of the tumors. Immunohistochemical study to date has limited diagnostic value. Nuclear localization of β-catenin, which correlated closely with CTNNB1 gene mutation, was recently reported in SCTs. We investigated the utility of β-catenin nuclear localization in diagnosing SCTs and differentiating them from other testicular sex cord-stromal tumors. Immunohistochemical staining for β-catenin was evaluated in 87 cases of testicular sex cord-stromal tumor: 33 SCTs, not otherwise specified (SCT-NOS) (15 with benign and 18 with malignant features), 10 sclerosing SCTs (SSCT), 5 large cell calcifying SCTs (LCCSCT), 6 Sertoli-stromal cell tumors, 10 Leydig cell tumors, 7 juvenile granulosa cell tumors, 4 adult granulosa cell tumors, and 12 sex cord-stromal tumors, unclassified. Twenty-one of 33 (64%) SCT-NOS, 6 of 10 (60%) SSCTs, and 4 of 6 (67%) Sertoli-stromal cell tumors showed strong, diffuse β-catenin nuclear staining. Nuclear β-catenin positivity was more frequent in SCTs-NOS with benign features than in those with malignant features (93% and 39%, respectively, P=0.13) and, in the Sertoli-stromal cell tumors, occurred only in the Sertoli component. All 5 LCCSCTs and all other types of sex cord-stromal tumor were negative for β-catenin nuclear staining. In conclusion, SCT-NOS and SSCT frequently show β-catenin nuclear localization. Positive nuclear staining of β-catenin is specific for SCT-NOS, SSCT, and Sertoli-stromal cell tumor among testicular sex cord-stromal tumors but has limited sensitivity (63%) in this group. The similar reactivity of SCT-NOS and SSCT provides additional support that these 2 variants are not distinct entities.

Use of aromatase inhibitors in large cell calcifying sertoli cell tumors: effects on gynecomastia, growth velocity, and bone age.

Large cell calcifying Sertoli cell tumors (LCCSCT) present in isolation or, especially in children, in association with Carney Complex (CNC) or Peutz-Jeghers Syndrome (PJS). These tumors overexpress aromatase (CYP19A1), which leads to increased conversion of delta-4-androstenedione to estrone and testosterone to estradiol. Prepubertal boys may present with growth acceleration, advanced bone age, and gynecomastia. To investigate the outcomes of aromatase inhibitor therapy (AIT) in prepubertal boys with LCCSCTs. Case series of a very rare tumor and chart review of cases treated at other institutions. Tertiary care and referral center. Six boys, five with PJS and one with CNC, were referred to the National Institutes of Health for treatment of LCCSCT. All patients had gynecomastia, testicular enlargement, and advanced bone ages, and were being treated by their referring physicians with AIT. Patients were treated for a total of 6-60 months on AIT. Height, breast tissue mass, and testicular size were all followed; physical examination, scrotal ultrasounds, and bone ages were obtained, and hormonal concentrations and tumor markers were measured. Tumor markers were negative. All patients had decreases in breast tissue while on therapy. Height percentiles declined, and predicted adult height moved closer to midparental height as bone age advancement slowed. Testicular enlargement stabilized until entry into central puberty. Only one patient required unilateral orchiectomy. Patients with LCCSCT benefit from AIT with reduction and/or elimination of gynecomastia and slowing of linear growth and bone age advancement. Further study of long-term outcomes and safety monitoring are needed but these preliminary data suggest that mammoplasty and/or orchiectomy may be foregone in light of the availability of medical therapy.

Large-cell calcifying Sertoli cell tumors of the testes in pediatrics

The aim of this review is to describe the clinical, biochemical, radiographic, histological, and functional characteristics of large-cell calcifying Sertoli cell tumors of the testes (LCCSCTs). We describe the two main syndromes associated with these tumors: Peutz-Jeghers syndrome (PJS) caused mainly by mutations in the STK11 (aka LKB1) gene, which encodes a serine-threonine kinase, and Carney complex (CNC), which is most often caused by PRKAR1A mutations, the gene encoding regulatory subunit type 1 of protein kinase A. Relatively few patients have been reported in the literature with LCCSCTs. In children they often present as prepubertal and/or peripubertal gynecomastia. Although these tumors are very rare, they occur with higher frequency among patients with PJS and CNC. Orchiectomy was often performed in the past; however, these tumors are overwhelmingly benign and, unless there are significant hormonal changes or pain and/or mass effects, there is no need for surgery. Tumors that lead to hyperestrogenemia may be treated efficiently with aromatase inhibitors; any change in appearance should prompt evaluation for malignancy. The detection of LCCSCTs may point to an underlying genetic multiple neoplasia syndrome such as PJS or CNC. Surgery is rarely indicated and aromatase inhibitors constitute an effective treatment for those cases that are associated with gynecomastia and/or advanced skeletal age.

Frequent Phosphodiesterase 11A Gene (PDE11A) Defects in Patients with Carney Complex (CNC) Caused byPRKAR1AMutations:PDE11AMay Contribute to Adrenal and Testicular Tumors in CNC as a Modifier of the Phenotype

Carney complex (CNC) is an autosomal dominant multiple neoplasia, caused mostly by inactivating mutations of the regulatory subunit 1A of the protein kinase A (PRKAR1A). Primary pigmented nodular adrenocortical disease (PPNAD) is the most frequent endocrine manifestation of CNC with a great inter-individual variability. Germline, protein-truncating mutations of phosphodiesterase type 11A (PDE11A) have been described to predispose to a variety of endocrine tumors, including adrenal and testicular tumors. Our objective was to investigate the role of PDE11A as a possible gene modifier of the phenotype in a series of 150 patients with CNC. A higher frequency of PDE11A variants in patients with CNC compared with healthy controls was found (25.3 vs. 6.8%, P < 0.0001). Among CNC patients, those with PPNAD were significantly more frequently carriers of PDE11A variants compared with patients without PPNAD (30.8 vs. 13%, P = 0.025). Furthermore, men with PPNAD were significantly more frequently carriers of PDE11A sequence variants (40.7%) than women with PPNAD (27.3%) (P < 0.001). A higher frequency of PDE11A sequence variants was also found in patients with large-cell calcifying Sertoli cell tumors (LCCSCT) compared with those without LCCSCT (50 vs. 10%, P = 0.0056). PDE11A variants were significantly associated with the copresence of PPNAD and LCCSCT in men: 81 vs. 20%, P < 0.004). The simultaneous inactivation of PRKAR1A and PDE11A by small inhibitory RNA led to an increase in cAMP-regulatory element-mediated transcriptional activity under basal conditions and after stimulation by forskolin. We demonstrate, in a large cohort of CNC patients, a high frequency of PDE11A variants, suggesting that PDE11A is a genetic modifying factor for the development of testicular and adrenal tumors in patients with germline PRKAR1A mutation.

Prepubertal gynecomastia in Peutz-Jeghers syndrome: incomplete penetrance in a familial case and management with an aromatase inhibitor

Peutz-Jeghers syndrome (PJS) is a rare autosomal-dominant disorder characterized by multiple gastrointestinal hamartomatous polyps, mucocutaneous pigmentation and increased predisposition to various neoplasms. Endocrine manifestations in PJS include gynecomastia due to calcified Sertoli cell testicular tumors usually referred to as large-cell calcifying Sertoli cell tumors (LSCT). To evaluate the value of endocrine markers and aromatase inhibitor treatment in children with PJS and LSCT. Familial cases, followed in a tertiary care center. Two male siblings aged 7 and 9 years with PJS and LSCT. Third generation aromatase inhibitor (anastrozole) in one of the patients. Longitudinal measurements of sex-steroids, gonadotropins, Sertoli cell markers and auxological evaluation. The two male siblings with PJS had similar bilateral multifocal testicular calcifications and biochemical evidence of Sertoli cell dysfunction manifested by elevated plasma inhibin-alpha levels. Only one sibling had gynecomastia. Estradiol levels were normal in both. During treatment with anastrozole, estradiol levels, growth and skeletal maturation, as well as Sertoli cell markers (inhibin B, inhibin-alpha and anti-Mullerian hormone) decreased. Inhibin-alpha may be considered as a marker for LSCT in children with PJS, pointing to a specific defect in inhibin regulation in this condition. Moreover, the decrease in Sertoli cell markers during aromatase inhibitor treatment suggests that increased estrogen production is a primary event regulating downstream production of Sertoli cell peptides. Anastrozole is efficient in controlling the clinical features of the disease and should be proposed as an alternative to bilateral orchidectomy, which is often performed in this condition.

Bilateral testicular large-cell calcifying Sertoli cell tumor and recurrent cardiac myxoma in a patient with Carney’s complex

Large-cell calcifying Sertoli cell tumors are exceedingly rare testicular tumors which can be distinguished from pure Sertoli cell tumors by distinctive microscopic features and multifocal and bilateral calcifications [1]. We describe the characteristic sonographic appearance of the tumor with pathologic correlation. This tumor also constitutes one of the conditions of Carney's complex [2], which includes cardiac and skin myxomas, myxoid mammary fibroadenomas, spotty skin pigmentation, primary pigmented nodular adrenocortical disease, pituitary adenoma and unusual testicular tumors, especially large-cell calcifying Sertoli cell tumor. We report the case of a 10-year-old boy with four of the above conditions. Recognition of this complex is important as cardiac myxomas can lead to lethal complications. Because of a tendency for familial occurrence, family members should be screened carefully [3].

Bilateral Large‐Cell Calcifying Sertoli Cell Tumor of the Testes with Peutz‐Jeghers Syndrome: A Case Report

A 13-year-old boy with Peutz-Jeghers syndrome (PJs), gynecomastia, and bilateral multifocal testicular tumors is described. Histology of the testicular tissue disclosed large-cell calcifying Sertoli cell tumors. Females with PJs are known to be at increased risk of developing gonadal tumors. This case and a review of other reported cases suggest that males with PJs are also at risk for developing gonadal tumors.

Large Cell Calcifying Sertoli Cell Tumor of the Testis: A Clinicopathologic, Immunohistochemical, and Ultrastructural Study of Two Cases

The clinicopathologic, immunohistochemical, and electron microscopic study of two patients with large cell calcifying Sertoli cell tumors (LCCSCT) of the testis is reported to elucidate the histogenesis of this rare tumor. Both tumors occurred in young individuals (16 and 32 years); case 1 was found incidentally, and the patient in case 2 presented with a 3-4-week history of testicular pain. Evidence of testosterone production was demonstrated in one case. In the same case, at the ultrastructural level Charcot-Böttcher crystalloids were observed. These data support previous reports that LCCSCT shows Sertoli cell differentiation.

Evaluation and management of Carney's complex: an illustrative case

Carney's complex is characterized by cardiac and cutaneous myxomas, mammary myxoid fibroadenomas, spotty mucocutaneous pigmentation, primary pigmented adrenocortical disease, large-cell calcifying Sertoli cell tumors of the testis, growth hormone-secreting pituitary adenomas, and psammomatous melanotic schwannomas. We present an illustrative case of Carney's complex in a 26-year-old woman who at age 20 underwent bilateral adrenalectomy for Cushing's syndrome. Six years later, she suffered multiple central nervous system embolic episodes secondary to three cardiac myxomas, which led to her death. Appropriate evaluation and management of patients with Carney's complex is outlined.