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

Abstract

Purpose of review

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.

Recent findings

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.

Summary

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.

INTRODUCTION

Sertoli cells are the supporting cells of the testicles. Early in fetal development, Sertoli cells secrete anti-Müllerian hormone (AMH), which leads to regression of Müllerian ducts, whereas formation of internal male genital organs is the result of the action of testosterone secreted by fetal Leydig cells. The major role of Sertoli cells is to promote the differentiation of spermatocytes. Aromatase is the enzyme that converts testosterone to estradiol. Aromatase is barely found in prepubertal testes; its expression increases in late puberty. In normal testes, aromatase is predominantly present in Leydig cells, but in testicular tumors of Sertoli cell origin the neoplastic Sertoli cells of the tumor express aromatase [1]. There are four main histological types of Sertoli cell tumors of the testicles: large-cell calcifying (LCCSCT), sclerosing, sex cord with annular tubules, and tumors that are not otherwise specified. LCCSCTs occur with a frequency of 0.4–1.5% among testicular tumors [2^▪]. They are sporadic in 60% of the reported cases, but in the remaining cases they are linked to multiple neoplasia syndromes such as Peutz–Jeghers syndrome (PJS) and Carney complex (CNC) [3].

In this review, we used computerized, English-only literature searches to identify all published literature related to LCCSCTs. The search strategy for articles between 1990 and 2010 included various combinations of the following terms: Sertoli, Leydig, testes, testicular, tumor(s), PJS, large-cell calcifying, Carney complex, and gynecomastia. Bibliographies of both eligible and closely related articles were searched for other potentially contributing references.

CLINICAL CHARACTERISTICS

LCCSCTs are first detected in the young: from pre-pubertal boys to young adults. Tumors have been described as early as at 2 years of age, with a mean age of presentation at 30 years [2^▪]. Due to the frequent higher expression of aromatase within these tumors, there is higher conversion of testosterone to estradiol. As estrogens advance skeletal maturation, LCCSCT in a prepubertal boy may present by acceleration of his growth. This might not be considered initially as a worrisome clinical sign in a peripubertal child, as this is an expected pattern of growth when a child enters puberty. However, the continuous effects of estrogens will eventually be noticed, as Rgynecomastia may also develop. This is often what brings the child to a physician’s attention [ gynecomastia may also develop. This is often what brings the child to a physician’s attention [4,5^▪,6–11]. Gynecomastia is caused by stimulation of breast tissue from estrogens and is distinct from lipomastia, which is fat tissue around the breast, often seen in overweight boys. With palpation, gynecomastia has the glandular feeling of the breast tissue and, unlike in lipomastia, the areola can be stimulated (Fig. 1a).

FIGURE 1.

(a and b) A 5-year-old boy with Peutz–Jeghers syndrome and gynecomastia due to large-cell calcifying Sertoli cell tumors of the testes. He had a deletion of the STK11/LKB1 gene and is currently on an aromatase inhibitor (his bone age was consistent with that of a 9-year-old boy). (c) Classic ‘Christmas tree-like’ appearance of the testes in an ultrasound of a patient with CNC and extensive microcalcifications due to LCCSCT. (d) Hematoxylin and eosin (H&E) staining of LCCSCT from a patient with CNC; the tumor is composed of sheets, cords, and solid tubules of cells with abundant fibrous tissue that contains large areas of calcification. CNC, Carney complex; LCCSCT, large-cell calcifying Sertoli cell tumors of the testes.

In contrast to other types of testicular tumors, which are usually detected as singular, unilateral distinct hard masses, LCCSCTs are often bilateral, present with an increase in the overall testicular volume, and their calcifications are palpable irregularities in the shape and texture of the glands. Macrocalcifications within the tumor are responsible for the coarse texture, but microcalcifications (which are far more frequent) can be hard to detect by physical examination. Because LCCSCTs are bilateral in 20% of the reported cases [12], they are often missed by physical examination, unless calcifications are palpable.

Hormonal abnormalities and effects on fertility

LCCSCTs express aromatase, which leads to high serum estradiol levels. Aromatase also converts androstenedione to estrone; in prepubertal years, estrone elevation outweighs the estradiol increase, as the adrenal-derived androstenedione is the major source of androgens in these years (due to adrenarche). As only minimal elevations of estrogens are needed to advance the bone maturation and cause gynecomastia, physicians should take into consideration the sensitivity of the assay used to measure estrogens. As gynecomastia may occur first in adrenarche, testosterone levels may be within the normal range or even low. It is always important in the interpretation of the biochemical data to correct for age-specific normal ranges. During the evaluation for testicular enlargement and accelerated growth, the possibility of precocious puberty in a boy needs to be ruled out. Prepubertal levels of follicle stimulating hormone (FSH), luteinizing hormone, and a prepubertal response to gonadotropin releasing hormone stimulation test are all consistent with the diagnosis of a LCCSCT in a prepubertal boy. Secondary central precocious puberty occurs often in children who have been exposed to high levels of androgens of adrenal or testicular tumor origin, and it is also seen in children with congenital adrenal hyperplasia [13]. Clinicians should monitor periodically the testicular size, bone age advancement, growth velocity and gonadotropin levels. When the LCCSCT presents after puberty (or in adult men), the gonadotropin levels can be normal or even slightly elevated.

LCCSCTs can gradually increase in size, block the seminiferous tubules, and lead to decreased fertility. There are only few studies that have examined the role of inhibin in LCCSCTs. Inhibin regulates FSH secretion, which plays a major role in spermatogenesis. Inhibin A has been proposed to be a marker of activity of these tumors, but larger studies are needed to confirm this finding [7].

Clinical imaging (sonography)

Testicular ultrasound can demonstrate bilateral enlargement in testicular volume, with or without microcalcifications [6]. Microcalcifications are not specific to LCCSCTs, but the characteristic ‘Christmas tree-like’ appearance of multiple lesions in syndromic LCCSCTs is almost pathognomonic for this tumor (Fig. 1c). Calcifications in LCCSCTs need to be differentiated from those in teratoma, teratocarcinoma, seminoma, embryonic carcinoma, and Leydig cell tumors and from those in infectious or inflammatory lesions such as in tuberculosis, filariasis, and posttraumatic scars and other inflammations [7,14,15]. Microcalcifications can be more suggestive of LCCSCTs when a color Doppler examination shows increased vascular flow in proximity to the calcified area, along with the absence of soft or cystic tissues. LCCSCTs can also be seen as a round, smooth, and hyperechogenic area, or multiple hyperechogenic spots [2^▪].

As mentioned above, due to increased estrogen levels, bone age films are also abnormal and often show advanced skeletal maturation.

Histology

Macroscopically, the tumors are usually smaller than 4 cm and have well-defined margins. The color is yellowish, while cysts can be found. Tumors can be multifocal and bilateral in 20–40% of cases, with higher incidence of bilateral disease in syndromic cases. In addition to calcifications, necrosis can also be found. Microscopically, tumor cells are organized in sheets, nests, cords, ribbons, and trabeculae and there is usually focal solid tubule formation (Fig. 1d) [2^▪,3]. Another feature supporting the Sertoli versus the Leydig cell origin of a tumor is the formation of a pseudolumen lined by basal lamina and the absence of crystalloids of Reinke [16]. The presence of intra-tubular tumor is also suggestive of the Sertoli cell origin of a tumor. The cytoplasm of the tumor cells is eosinophilic and the surrounding stroma can be myxoid to collagenous with occasionally neutrophilic infiltration. Calcifications are usually prominent with large laminated calcific nodules. Psammoma bodies and rarely ossification can be seen. Sometimes, Charcot–Böttcher filament bundles can be seen, which are characteristic of Sertoli cell differentiation. The Sertoli cell tumors of patients with PJS frequently do not have extensive calcifications [2^▪,3].

Malignancy is found in approximately 17% of patients with LCCSCTs. Malignant LCCSCTs usually occur in older patients (mean age 39 years) and those who have unilateral and unifocal disease (for comparison, the mean age of presentation for benign tumors is 17 years) [17–21]. Indices of malignancy include mitotic count greater than 3 per 10 high-power fields, size larger than 4 cm, significant nuclear atypia, tumor necrosis, and angiolymphatic invasion [3,21]. Immunochemistry can show diffused immunoreactivity for inhibin, vimentin, calretinin, and S100 protein [21,22]. Transforming growth factor β1 immunostaining has also been found to be higher in interstitial cells in LCCSCT [23].

The Peutz–Jeghers syndrome

PJS is an autosomal-dominant inherited syndrome with variable penetrance. Most patients have mutations in the STK11 (for serine/threonine kinase 11; also known as LKB1), a tumor suppressor gene on chromosome 19p13.3 [24] that predisposes patients to the development of different types of cancers [25^▪]. Multiple hamartomatous polyps along the whole gastrointestinal tract are the main characteristic of PJS. In addition, patients have mucocutaneous hyperpigmented macules. Typical areas of bluish pigmentation in PJS include the vermillion border of the lips and the oral and bowel mucosa (Fig. 1b), as well as around the eyes, nares, axilla, palms, and soles. The macules appear in childhood, but are less visible over time in PJS [26]. Patients have higher relative risk to develop colorectal cancer, followed by breast, small bowel, gastric, and pancreatic cancers. Their lifetime risk for all cancer ranges between 37 and 93% [27^▪▪]! Periodic surveillance recommended by expert panels consists of video capsule endoscopy and MRI enteroclysis starting at age 10 years, gastroduodenoscopy at age 20 years, colonoscopy at age 25–30 years, MRI of pancreas at age 30 years, breast MRI at age 25 years, mammography and breast MRI at age 30 years, pelvic ultrasound, cervical smear, CA-125, and transvaginal ultrasound at age 25 years [27^▪▪]. The cumulative cancer risk for ovarian cancer (21%) is higher than the risk for testicular cancer (9%). Annual testicular palpation is recommended in boys with PJS for earlier detection of testicular Sertoli cell tumors [27^▪▪]. Conservative management is indicated [12]. Several cases of LCCSCTs treated with aromatase inhibitors have been reported [5^▪,7,9,28].

The pathogenesis of LCCSCTs in patients with PJS is not completely understood. Inactivating mutations in STK11/LKB1 inhibit AMP-activated protein kinase (AMPK), which normally acts to inhibit mammalian target of rapamycin (mTOR). mTOR is a pathway that favors orderly growth of cells and when dysregulated leads to tumor formation in PJS. STK11 inhibits mTOR directly via alteration of the TSC1–TSC2 complex upstream of mTOR. The mTOR inhibitors, such as rapamycin and CCI-779, inhibit mTOR and could be used potentially as agents for the treatment of PJS [29]. STK11/LKB1 mutations are not involved in the pathogenesis of sporadic sex cord stromal tumors, although loss of heterozygosity at 19p13.3 has been reported in their DNA [30].

Carney complex

CNC is an autosomal-dominant multiple neoplasia syndrome, which was first reported in 1985 [31]. Definite diagnosis can be made if two or more of the major clinical manifestations are seen [32,33]. These include

1. spotty skin pigmentation with typical distribution (lips, conjunctiva and inner or outer canthi, vaginal and penile mucosa);

2. myxoma (cutaneous and mucosal);

3. cardiac myxoma;

4. breast myxomatosis or fat-suppressed MRI findings suggestive of this diagnosis;

5. primary pigmented nodular adrenocortical disease or paradoxical positive response of urinary glucocorticoid excretion to dexamethasone administration during Liddle’s test;

6. Acromegaly due to GH-producing adenoma;

7. LCCSCTs (or characteristic calcification on testicular ultrasound) (Fig. 1c);

8. thyroid carcinoma or multiple, hypoechoic nodules on thyroid ultrasound in a young patient;

9. psammomatous melanotic schwannomas;

10. blue nevus, epithelioid blue nevus;

11. breast ductal adenoma; and

12. osteochondromyxoma.

Alternatively, the diagnosis can be established if a patient has one major feature in addition to an affected first-degree relative or an inactivating mutation of the PRKAR1A gene [33]. PRKAR1A-inactivating mutations have been reported in 45–80% of kindreds with CNC. The molecular mechanism of CNC involves alterations in the protein kinase A (PKA), a key regulator of the cyclic AMP-dependent signaling pathway. PKA is a serine–threonine kinase that is involved in the regulation of metabolism, cell proliferation, differentiation, and apoptosis [34]. Most variants in PRKAR1A lead to increased cAMP-stimulated total kinase activity, but how tumors form is not well understood [35]. In addition, in a large cohort of patients with CNC due to PRKAR1A mutations, a higher frequency of PDE11A variants was found, raising the possibility that other genes may act as modifiers of this phenotype [36].

LCCSCTs are estimated to occur in about 50% of men with CNC [37^▪▪]. Impaired fertility, defective sperm, and oligospermia have been found in men with CNC [38,39]. The pathway that leads to fertility seems independent of the presence of sex cord testicular neoplasm, but it is still unclear. It is our clinical impression that LCCSCTs in CNC have more benign characteristics when compared with those in PJS, at least as far as aromatization is concerned [40].

CONCLUSION

LCCSCTs are typically benign tumors of children and young adults. Pharmacotherapy is only needed for symptomatic relief of gynecomastia and/or advanced puberty. Surgery is only required for malignant tumors, which fortunately are rare.

KEY POINTS.

• LCCSCTs are often linked to syndromes such as CNC and PJS that lead to multiple other neoplasias. Periodic screening for other tumors is recommended for these patients.

• Gynecomastia, advanced skeletal maturation, and bilateral testicular enlargement are the main clinical manifestations of LCCSCTs.

• Most LCCSCTs have a benign clinical course, but malignancy can occur especially in older ages.

• Conservative management is indicated as a first approach, if no worrisome signs for malignancy are present. Annual physical and ultrasound examination are warranted, as part of the follow-up.

• Aromatase inhibitors may be an effective mode of therapy for patients with increased aromatization; currently, only a limited number of patients have been treated, and data from clinical trials are needed.