Contributed by Melissa Halpern, MD and Ronald Jaffe, MDFINAL DIAGNOSIS:
DISCUSSION:
Large cell calcifying Sertoli cell tumor is an unusual variant of Sertoli cell tumor. Sertoli cell tumors represent less than 1 percent of all testicular neoplasms. A distinct subtype, the large cell calcifying Sertoli cell tumor, was first described in 1980 by Proppe and Scully. The tumors may occur in an isolated form or may be associated with genetic abnormalities, including the Carney complex and Peutz-Jeghers syndrome. Forty-nine of these tumors have been described in the literature, with patients ranging from 2 to 51 years of age (average 21 years). Of the 49 cases described, 41 have been reported as benign and 8 as clinically malignant, with regional lymph node metastasis at presentation or follow-up. There are many features that are helpful in evaluating the likelihood of malignant behavior. Malignant tumors tend to be found in an older population (mean age 39 years versus 17 years for benign tumors) and tend to be larger (mean size 5.4 cm versus 1.4 cm for benign tumors). Benign tumors are more likely to be associated with a syndrome or congenital abnormality (36 % versus 12.5 % of malignant tumors). All of the reported malignant large cell calcifying Sertoli cell tumors are unilateral and unifocal, whereas 28% of the benign tumors are bilateral and/or multifocal. Kratzer et al recommends that tumors be classified as malignant when they demonstrate 2 or more of the following: extra testicular spread, size greater than 4 cm, mitoses greater than 3 per 10 high power fields, significant nuclear atypia, necrosis, or lymphovascular invasion. Immunochemical stains for p53 protein and Ki-67 (MIB-1 antibody) were not shown to correlate with malignant behavior. All of the patients with a diagnosis of malignant tumor developed retroperitoneal lymph node metastases. Many had hematogenous metastases to the bone, liver and lungs as well.
Grossly, these tumors average 2 cm in diameter, are often multifocal, and are bilateral in about 20% of cases. They are well circumscribed and show a white to tan granular cut surface. Microscopically, the tumor is composed of round to polygonal cells arranged in sheets, nests, or trabeculae with central calcification. These cells have abundant eosinophilic and finely granular cytoplasm. The nuclei are round to oval with prominent nucleoli and rare mitotic figures. The stroma varies from myxoid to fibrous. The neoplastic cells are strongly positive for vimentin and S100. Cytokeratin is either negative or only focally positive. Stains for epithelial membrane antigen, alpha-fetoprotein, chorionic gonadotrophin, and smooth muscle actin are negative. Ultrastructural features include irregular nuclei, basal lamina, lipid droplets, and poorly formed cell junctions. Variable amounts of smooth and rough endoplasmic reticulum may be seen. Occasional tumors contain perinuclear bundles of filaments suggestive of Charcot-Bottcher bodies.
The patient described here has a complex personal and family medical history. He has a history of multiple skin myxomas and left orchiectomy at the age of 8 for a previous large cell calcifying Sertoli cell tumor. A stable right testicular mass was also noted at that time. At the age of 12 he underwent right thyroidectomy for a follicular adenoma. Routine surveillance for cardiac myxomas has been negative. His mother has a past medical history significant for numerous cardiac myxomas, follicular thyroid carcinoma, pituitary adenoma, atypical mesenchymal neoplasm with unknown malignant potential of the uterus, adrenal hyperplasia, and multiple skin lesions, including nevi, fibromas, and myxomas. In addition, there are multiple maternal relatives with similar symptoms. The constellation of symptoms seen in both our patient and his mother are consistent with a diagnosis of the Carney complex (Carney syndrome).
The Carney complex (CNC) was first described by JA Carney in 1985, when he reported a series of patients with a "complex of myxomas, spotty pigmentation, and endocrine overactivity." These findings are transmitted in an autosomal dominant fashion. In order to diagnose CNC, two of the eight findings must be present: cardiac myxoma, cutaneous myxoma, myxoid mammary fibroadenoma, spotty pigmentation, primary pigmented nodular adrenocortical disease, testicular tumor, growth hormone secreting pituitary tumor, and psammomatous melanotic schwannoma. The spotty pigmentation in CNC should be multiple, characteristic in its distribution, not related to sunlight exposure, and be histologically consistent with a lentigo. The testicular tumors characteristic of CNC include large cell calcifying Sertoli cell tumors, as seen in this patient, Leydig cell tumors and adrenocortical rest tumors. The Carney complex includes previously diagnosed entities including LAMB (lentigines, atrial myxoma, mucocutaneous myxoma, and blue nevi) syndrome and NAME (nevi, atrial myxoma, myxoid neurofibromata and ephelides) syndrome.
Possible genes associated with CNC have been mapped to chromosome 2p16 and 17q22-24. Genomic amplification of 2p16 in tumors from CNC patients suggests that an oncogene is located at this locus. Loss of heterozygosity studies of 17q22-24 in tumors from CNC patients suggest that this locus contains a tumor suppressor gene. One of the known genes in this region of chromosome 17 encodes the regulatory subunit 1A of the cAMP dependent protein kinase (PRKAR1A). PRKAR1A has been found to be mutated in both CNC families and sporadic cases of CNC.
REFERENCES
Contributed by Melissa Halpern, MD and Ronald Jaffe, MD
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