Peutz-Jeghers syndrome

An 18-year-old African American man presented to his primary care physician for a routine physical examination. The examination was unremarkable with the exception of an enlarged right testis. A scrotal ultrasound showed 3 nodules in the right testis, ranging from 1.7 to 3.1 cm in largest dimension, and 2 nodules in the left testis, each measuring 1.3 cm. The impression was bilateral nonseminomatous germ cell tumor of testis. A computed tomographic scan of the chest and abdomen showed no evidence of metastasis. The laboratory results, including [alpha]-fetoprotein and human chorionic gonadotropin levels, were within normal limits. The past medical and family history for this patient was unremarkable. He underwent right radical and left partial orchiectomy.

On gross examination of the excised specimen, we noted bilateral, multiple, tan, partially cystic, and focally firm tumor nodules measuring up to 3.5 cm in largest dimension (Figure 1). Microscopically, the tumor was composed of solid nests and cords of large polygonal cells with abundant eosinophilic cytoplasm, uniform nuclei, and prominent nucleoli (Figures 2 and 3). There were scattered calcifications. The stroma was loose and focally myxoid, with foci of lymphocytic and neutrophilic infiltration. Intratubular tumor associated with lamellar calcifications was also identified (Figure 4). No necrosis was evident and mitotic figures were very rare. The tumor infiltrated but did not perforate the tunica albuginea. The epididymis, rete testis, and spermatic cord were free of tumor. The uninvolved testicular parenchyma showed decreased spermatogenesis.

Immunohistochemical stains showed that the tumor cells were positive for inhibin (Figure 2, inset), vimentin, and S100, and negative for cytokeratins CAM 5.2 and AEl/AE3. The postoperative course was uneventful. The patient was discharged with strong emphasis on followup. However, he did not fully adhere to his schedule and did not return until 10 months later. At this time, he had an unremarkable chest and abdominal computed tomographic scan and a normal cardiac echography. An ultrasound of the remaining left testis showed 3 tiny nodules. It was not clear if this finding represented previously unrecognized tumor or a recurrence. The patient was advised to seek further follow-up.

What is your diagnosis?

Pathologic Diagnosis: Large Cell Calcifying Sertoli Cell Tumor

Approximately 3% to 4% of testicular neoplasms fall into the category of sex cord-stromal tumors, the most common subtype being the Leydig cell tumor.1 Much less frequent are pure Sertoli cell tumors, which account for less than 1%. Most Sertoli cell tumors belong to the "not otherwise specified" type; however, 2 distinct and rare variants have been described, namely, the sclerosing Sertoli cell tumor and the large cell calcifying Sertoli cell tumor (LCCSCT).

Large cell calcifying Sertoli cell tumors are seen most commonly in the second decade of life.2 While the not otherwise specified Sertoli cell tumors are usually unilateral, LCCSCTs are frequently bilateral (40%) and multi-focal (60%).2 Large cell calcifying Sertoli cell tumor was first described in 1980 by Proppe and Scully.2 They studied 10 cases of Sertoli cell tumor that had distinctive histology and that were associated with unusual clinical features. Since these tumors characteristically contained calcifications and large cells, the descriptive term large cell calcifying Sertoli cell tumor was preferred. The neoplastic cells of LCCSCT are arranged in solid tubules, trabeculae, cords, and clusters in a loose myxoid stroma. The cells are generally large and have abundant, finely granular, eosinophilic cytoplasm, morphologically resembling Leydig cells. Thus, the differential diagnosis includes mainly Leydig cell tumor and tumors of the androgenital syndrome. Large cell calcifying Sertoli cell tumors frequently show an intratubular growth pattern, as depicted in the current case. To our knowledge, this characteristic has not yet been described in Leydig cell tumors. Calcifications will also favor an LCCSCT, whereas lipofuscin and Reinke crystalloids may be seen in Leydig cell tumors. Tumors of the androgenital syndrome are also commonly bilateral; however, they are seen in patients with the salt-losing form of androgenital syndrome (21-hydroxylase deficiency). Therefore, clinical information is essential in reaching the correct diagnosis.

Immunohistochemically, these tumors are positive for vimentin and SlOO, and negative for keratins. They also can be positive for inhibin, as found in our case. Ultrastructurally, LCCSCTs show cell junctions, variable amounts of smooth and rough endoplasmic reticulum, prominent Golgi, and variable amounts of lipid.3-6 Charcot-Bottcher filaments, the perinuclear intermediate filaments that occur in nonneoplastic mature Sertoli cells, have been identified in only a few cases of LCCSCT.3-6

The malignancy rate in LCCSCT is relatively low. Of a total of 47 reported cases, only 8 were malignant.5 Since the malignant tumors tend to be reported more frequently, the actual percentage may be lower. The malignant tumors were unilateral, solitary, and seen in older patients (mean age, 39 years). The benign tumors were rather multifocal and bilateral (28%), were more commonly associated with an endocrine abnormality or a syndrome (36%), and were seen in younger patients (mean age, 17 years).5 Tumor size greater than 4 cm, extratesticular extension, increased mitotic activity, necrosis, vascular invasion, and high-grade cytologie atypia were features suggesting malignant behavior.5 Malignant tumors usually metastasize to the retroperitoneal lymph nodes; however, hematogenous spread to the bone, liver, and lungs has also been reported.5

Clinically, LCCSCTs may be associated with endocrinologie abnormalities, such as gynecomastia, acromegaly, and sexual precocity.2,5 Other associations include Peutz-Jeghers syndrome and, more importantly, Carney syndrome and sudden death secondary to cardiac myxomas.2 Therefore, patients with LCCSCT should be carefully evaluated and informed about the potential associated risks to ensure proper follow-up and early intervention. In some instances, elevated preoperative estrogen levels returned to normal following orchiectomy, suggesting that these tumors are responsible for at least some of the endocrinologic abnormalities seen in these patients.6 The treatment for primary testicular tumor is surgical. Chemotherapy or radiotherapy can be offered for nonresectable cases.5

References

1. Mostofi FK, Price EB. Tumors of the Male Genital System. Washington, DC: Armed Forces Institute of Pathology; 1973. Atlas of Tumor Pathology; 2nd series, fascicle 8.

2. Proppe KH, Scully RE. Earge-cell calcifying Sertoli cell tumor of the testis. Am J Clin Pathol. 1980;74:607-619.

3. Tetu B, Ro JY, Ayala AC. Large cell calcifying Sertoli cell tumor of the testis: a clinicopathologic, immunohistochemical and ultrastructural study of two cases. Am I Clin Pathol. 1999;96:717-722.

4. Proppe KH, Dickersin CR. Large-cell calcifying Sertoli cell tumor of the testis: light microscopic and ultrastructural study. Hum Palhol. 1982;13:1109-1114.

5. Kratzer SS, Ulbright TM, Talerman A, et al. Large cell calcifying Sertoli cell tumor of the testis: contrasting features of six malignant and six benign tumors and a review of the literature. Am I Surg Pathol. 1997;21:1271-1280.

6. Waxman M, Damjanov I, Khapra A, et al. Large cell calcifying Sertoli tumor of testis: light microscopic and ultrastructural study. Cancer. 1984;54:1574-1581.

Hakan Aydin, MD; Gulbeyaz Omeroglu, MD; Atilla Omeroglu, MD

Accepted for publication January 2, 2004.

From the Departments of Pathology, Johns Hopkins Hospital, Baltimore, Md (Dr Aydin); Loyola University Medical Center, Maywood, III (Dr G. Omeroglu); and Memorial Sloan-Kettering Cancer Center, New York, NY (Dr A. Omeroglu). Dr Aydin is currently with the Department of Pathology, Baskent University, Ankara, Turkey. Dr A. Omeroglu is currently with the Department of Pathology, McGill University, Montreal, Quebec, Canada.

Corresponding author: Gulbeyaz Omeroglu, MD, Department of Pathology, Loyola University Medical Center, EMS Bldg, 2nd Floor, 2160 S First Ave, Maywood, IL 60153.

Reprints not available from the authors.

Copyright College of American Pathologists May 2004
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