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TESTICULAR TUMORS IN CARNEY’S COMPLEX
0022-5347/02/1673-1299/0 THE JOURNAL OF UROLOGY® Copyright © 2002 by AMERICAN UROLOGICAL ASSOCIATION, INC.®
Vol. 167, 1299 –1302, March 2002 Printed in U.S.A.
TESTICULAR TUMORS IN CARNEY’S COMPLEX ROBERT WASHECKA, MARTIN I. DRESNER
AND
STACEY A. A. HONDA
From the Departments of Urology and Pathology, Hawaii Kaiser Permanente Medical Center, Honolulu, Hawaii, and Urology Section, Surgical Care Line, Southern Arizona VA Health Care System, Tucson, Arizona
ABSTRACT
Purpose: Bilateral sex cord stromal testicular tumors are common in the syndrome of myxoma, spotty pigmentation and endocrine overactivity (Carney’s complex). Large cell calcifying Sertoli cell tumor is the particular testicular tumor found in Carney’s complex. A clinicopathological review of 26 patients is presented. Materials and Methods: We report 2 cases of Carney’s complex with testicular tumors. An additional 24 patients with Carney’s complex and testicular tumors were identified by MEDLINE search and review of the literature. Results: Bilateral testicular tumors were found in 16 patients (61%) with a familial occurrence in 10 (38%). A testicular mass was the most common presentation. The associated findings of Carney’s complex included cardiac myxoma in 16 patients, skin myxoma in 16, skin pigmentation in 15, Cushing’s syndrome in 8, acromegaly in 3 and schwannoma in 3. Excisional biopsy, surveillance, bilateral orchiectomy and unilateral orchiectomy were performed in 7, 4, 7 and 8 patients, respectively. Conclusions: No local tumor recurrence or metastasis has developed in patients with bilateral and/or multifocal testicular tumors. Excisional biopsy or surveillance only are treatment options for bilateral testicular tumors in Carney’s complex. KEY WORDS: cells, Sertoli; testicular neoplasms; gland, endocrine
Syndromic testicular tumors are rare. The rare stromal tumor, large cell calcifying Sertoli cell tumor, commonly occurs in Carney’s complex. This disorder is a familial (autosomal dominant) multisystem tumor syndrome in which the tumors are multicentric in affected organs and bilateral in paired organs. Bilateral testicular stromal tumors present a therapeutic dilemma. At issue is whether to recommend complete testicular ablation (inguinal orchiectomy) or organ sparing surgery (tumor enucleation). Bilateral orchiectomy provides excellent local control of the neoplasms but is associated with negative quality of life, hypogonadism and necessity for lifelong hormonal replacement. Tumor enucleation has both endocrinological and psychological advantages. However, since no single histological criterion has proved reliable in distinguishing benign from malignant sex cord stromal tumors, tumor enucleation has the potential for incomplete or inadequate resection of primary tumor, which may result in local recurrence or possible diminished disease-free and cause specific survivals. We report 2 cases of bilateral testicular tumors in Carney’s complex and review reported cases of stromal tumors in the disorder to define the natural history of testis tumor in this syndrome. PATIENTS AND METHODS
We treated 2 patients with bilateral stromal testis tumors and Carney’s complex, and identified 24 additional cases with testis tumors as a component of Carney’s complex by MEDLINE search and review of the literature. The surgical specimens were fixed in 10% neutral buffered formalin and embedded in paraffin for routine histology processing. Sections were stained in hematoxylin and eosin. For electron microscopic evaluation 1 mm. cubes of fresh tissue from case 1 (right testis) were fixed in 2.5% glutaraldehyde, post-fixed
in osmium tetroxide and embedded in Epon 812. Areas for study were selected from toluidine blue stained thick sections. Ultrathin sections were stained with uranyl acetate and lead acetate, and examined with an electron microscope. CASE HISTORIES
Case 1. A 45-year-old Chinese-Hawaiian man, presented in 1993 with a symptomatic testicular mass. In 1971 when he was 19 years gigantism developed due to a pituitary adenoma, which was treated with cryohypophysectomy. At that time an asymptomatic left testicular mass was detected and left orchiectomy was performed for a Leydig cell tumor. In 1981 a 2.5 cm. fibromyxoma was removed from the left flank. In 1988, the patient was operated on for a left atrial myxoma. On physical examination the patient was obviously acromegalic, displaying marked prognathism, frontal bossing and prominent zygomatic arches. Tiny dark pigmented spots were present on the lips, buccal mucosa and face. The patient had no clinical stigmata of Cushing’s syndrome. The right testis was atrophic but had 3 distinct nontender, rock hard nodules, each approximately 1 cm. in largest diameter. Scrotal sonogram showed numerous hyperechoic areas with shadowing in the right testis (fig. 1). Chest radiographs and serum levels of ␣-fetoprotein and -human chorionic gonadotropiin were normal. The 3 testicular masses were enucleated. There was no evidence of recurrence or metastasis of the lesions 6 years later. The left testis (removed in 1971) had a 1.5 cm. hard globular mass with areas of hemorrhage. The nodules removed from the right testis in 1993 measured 0.7 ⫻ 0.5 ⫻ 0.3 cm. and 2.2 ⫻ 1.0 ⫻ 0.9 cm. (the latter mass was composed of 2 nodules), were rock hard and had gray-yellow cut surfaces. Histologically, the left testicular tumor featured monotonous cells with eosinophilic cytoplasm and uniform large nuclei. Brown cytoplasmic pigment was seen throughout the tumor. No Reinke crystals, capsular invasion or blood vessel invasion was seen. No germ cell tumor elements were noted.
Accepted for publication September 28, 2001. Read at annual meeting of Western Section, American Urological Association, San Diego, California, July 1996. 1299
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FIG. 1. Case 1. Sonogram of large cell calcifying Sertoli cell tumor hyperechoic areas (arrows) with shadowing represent tumor calcification.
The findings were those of a Leydig cell tumor. In addition, a focus of large cell calcifying Sertoli cell tumor and an adrenal rest were present. The 3 nodules from the right testis were largely fibrotic with scattered aggregates of lymphocytes and extensive laminated foci of calcification admixed with nests, cords and sheets of Sertoli cells (fig. 2). The cells had large, round-tooval vesicular nuclei, eosinophilic, granular and occasionally vacuolated cytoplasm, and well-defined cytoplasmic membranes. The cell aggregates were separated by fibrocollagenous stroma. No Reinke crystals, cytological atypia, mitoses, or vascular or lymphatic invasion was seen. No associated germ cell tumor elements or intratubular neoplasia were identified. Histologically, the lesions were large cell calcifying Sertoli cell tumor. Groups of closely apposed polygonal cells with round-tooval nuclei and moderate amounts of cytoplasm were present on electron microscopy. Nuclei exhibited prominent nucleoli and occasional nuclear envelope indentation. Free ribosomes and smooth endoplasmic reticulum were abundant. There were no Reinke crystalloids. The appearances were consistent with Sertoli cells. Case 2. A 12-year-old white male presented for evaluation of a testicular mass found on sonographic examination. He had an established diagnosis of Carney’s complex. Previously, he had had an atrial myxoma excised. On physical examination there were multiple facial lentigines (fig. 3). The
FIG. 2. Case 1. Photomicrograph of large cell calcifying Sertoli cell tumor shows calcification. H&E, reduced from ⫻100.
FIG. 3. Case 2. Facial lentigines include vermilion border of lips and eyelids (not shown).
testes were normal on palpation. The patient had no stigmata of Cushing’s syndrome or acromegaly. Scrotal sonogram revealed bilateral hyperechoic masses with shadowing. Chest radiography, b-HCG, and ␣-fetoprotein were normal. The patient and family declined further treatment. One year later there was no evidence of local tumor progression, metastatic disease or gynecomastia. DISCUSSION
Testicular sex cord stromal tumors are uniquely associated with the syndrome of cardiac myxomas, spotty pigmentation and endocrine overactivity (Carney’s complex). The typical testis tumor in the syndrome, the large cell calcifying Sertoli cell tumor, is a distinctive neoplasm with unique morphological, histochemical, and clinical features that clearly differentiate it from germ cell tumors. Carney’s complex is a heritable condition transmitted as an autosomal dominant trait. Although an array of phenotypes have been described in the complex, it is not known whether they are a result of the loss of a gene function that is needed at multiple independent stages of development (a pleiotropic syndrome) or arise as a secondary consequence of a single primary defect (a sequence syndrome). Testicular tumors were found in 26 patients ranging in age from 4 to 51 years.1–22 The tumors were bilateral in 16 of 26 patients (61%) and appeared metachronously in 2 with a gap of up to 21 years. Familial occurrence was noted in 10 patients (38%). An asymptomatic testicular mass varying from minute size at autopsy to 6.5 cm. in greatest dimension was the most common presentation. Gynecomastia (5 patients), precocious puberty (4) and infertility (2) were additional presentations. Testis tumors were identified prospectively by ultrasound in 4 patients with Carney’s complex. There was no reported history of cryptorchidism, irradiation or germ cell tumor. Initial treatment of the testicular tumors included bilateral orchiectomy in 6 patients, unilateral orchiectomy in 6,
TESTICULAR TUMORS IN CARNEY’S COMPLEX
excisional biopsy in 6, and orchiectomy and contralateral excisional biopsy in 1. Four patients did not receive treatment. One patient whose bilateral tumors were originally diagnosed as embryonal carcinoma underwent bilateral orchiectomy, irradiation and pelvic lymphadenectomy and later pathological review revealed large cell calcifying Sertoli cell tumor. Autopsy examination showed bilateral tumors in 1 patient and confirmed contralateral large cell calcifying Sertoli cell tumor in another who had undergone previous orchiectomy for another such tumor. Followup information extends up to 25 years. There were 2 deaths from cardio embolism from myxoma and 2 patients had a cerebrovascular accident from a myxoma embolism. There has been no development of metastatic disease in any patient with multifocal and/or bilateral testicular tumors including those treated with surveillance only. No local recurrence has developed in patients treated with excisional biopsy. One patient who presented initially with metastatic disease died of tumor 5 months after orchiectomy for a malignant large cell calcifying Sertoli cell tumor. This patient did not fulfill criteria for Carney’s complex but he was presumed to have the syndrome.18 Large cell calcifying Sertoli cell tumor is the characteristic sex cord stromal testis tumor present in Carney’s complex. Although it has been reported without Carney’s complex, the syndrome accounts for the majority of cases. Large cell calcifying Sertoli cell tumor may occur alone or be associated with Leydig cell tumor, hyperplasia or adrenal rest components. Consequently, its presence warrants careful clinical investigation for other signs of the syndrome since the presence of 1 additional component is suggestive of the syndrome while 2 stigmata confirm the presence of Carney’s complex. None of the multifocal and/or bilateral tumors in Carney’s complex exhibited lymphatic or vascular invasion, necrosis, high mitotic index, or tunica albuginea or spermatic cord involvement. There were no associated germ cell tumor elements or intratubular germ cell neoplasm present. Followup of sex cord stromal tumors in Carney’s complex indicates that they have an apparent indolent natural history and low metastatic potential. In a descriptive analysis of a small number of patients, definite treatment recommendations are difficult to establish. Nonetheless, with serological exclusion of germ cell tumors, bilateral occult and/or multifocal testis tumors in patients with Carney’s complex may be observed. Excisional biopsy or orchiectomy should be considered in Carney’s complex to confirm large cell calcifying Sertoli cell tumor in potential candidates of the syndrome for symptoms and cosmesis, or to prevent premature epiphyseal closure in those with precocious puberty. In patients with Carney’s complex an enlarging solitary testicular tumor greater than 4 cm. is suspicious of malignancy and orchiectomy is recommended. Moreover, although most unilateral solitary large cell calcifying Sertoli cell tumors are benign, those exhibiting extratesticular growth and occurring in older patients (mean age 39 years) warrant orchiectomy because of the risk of malignancy. The findings of Carney’s complex in 26 patients with testis tumors included cardiac myxomas in 16, skin myxomas in 15, skin pigmentation in 15, Cushing’s syndrome in 8, acromegaly in 3 and psammomatous melanotic schwannoma in 3.1–22 Since cardiac myxoma and Cushing’s syndrome have potential for serious morbidity, recognition and followup examination of the individual components of Carney’s complex, such as large cell calcifying Sertoli cell tumors, are important. It is unknown if all manifestations of the syndrome will appear with adequate longitudinal evaluation. Cardiac myxomas have caused death of 20% of patients with Carney’s complex and possess distinctive features that may suggest the syndrome. The tumors present in patients at a young age (range 10 to 49 years), are multiple and occurr in
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atypical locations including the left atrium, right atrium, right ventricle and left ventricle in order of decreasing frequency. In contrast, nonsyndromic cardiac myxomas involve the left atrium (75%) and right atrium (20%).23 Depending on size, mobility and location, myxomas may mimic several cardiac conditions in addition to causing embolism, intracardiac obstruction and constitutional symptoms. Echocardiography is the most important means of diagnosis but computerized tomography and magnetic resonance imaging can detect tumors measuring at least 0.5 to 1 cm. in diameter.23 Endocrine overactivity may be manifested by Cushing’s syndrome (primary pigmented nodular adrenal disease), acromegaly (pituitary adenoma) or isosexual precocious puberty (large cell calcifying Sertoli cell tumor). A unifying hypothesis for the diverse forms of endocrine overactivity may be a hormone receptor signal transduction gain-offunction mutation as exemplified by a G protein mutation in the McCune-Albright syndrome.24 Moreover, an activating mutation of the luteinizing hormone receptor gene in Leydig cell tumors has been reported recently.25 Also, a somatic mutation of the follicle-stimulating hormone receptor has been identified in ovarian sex cord tumors.26 How such a change in cell function contributes to tumor formation or growth is not known. Onset of acromegaly ranged from 11 to 27 years in 3 patients. Plasma somatomedin C is the best screening test for patients suspected of having subclinical acromegaly. Evaluation of precocious puberty in boys includes serum follicle-stimulating hormone, luteinizing hormone and testosterone, in addition to gonadotropin releasing hormone stimulation test and scrotal sonogram. Northern blot and in situ hybridization revealed abundant expression of inhibin ␣,  A and  B subunit messenger RNA in large cell calcifying Sertoli cell tumor in a 12-year-old boy with Carney’s complex.20 Serum inhibin levels were increased and may be a potential tumor marker. Primary pigmented nodular adrenocortical disease is a recent addition to the pathological spectrum of conditions causing Cushing’s syndrome, although it accounts for only 1% of cases of the syndrome of primary adrenal origin.27 Age presentation ranged from 8 to 19 years.7 The variability of Cushing’s syndrome, its occurrence in children and the heightened tendency for osteoporosis are recognizable clinical characteristics of primary pigmented nodular adrenocortical disease.27 Clinically, plasma cortisol elevation is mild to moderate and fails to suppress following high dose dexamethasone administration.27 Plasma adrenocorticotropic hormone levels are low or undetectable, and the sella turcica is not enlarged. Bilateral adrenalectomy is curative with no development of Nelson’s syndrome postoperatively. Nelson’s syndrome is hyperpigmentation and third nerve damage due to an enlarging sella turcica caused by pituitary adenoma after adrenalectomy. Skin pigmentary abnormalities (lentigines and blue nevi) and skin tumors (myxomas and psammomatous melanotic schwannoma) are often the earliest signs of Carney’s complex. Cutaneous manifestations are usually present in the first decade and found in more than 50% of patients before detection of other signs of the complex.28 The cutaneous pigmented lesions are lentigines, which are small (less than 2 mm.), brown to dark brown, round, nonelevated spots resembling freckles, and blue nevi, which are larger (up to 8 mm.) blue to black domed lesions. They occur characteristically on the face (periocular, bridge of the nose, perioral zones), vermilion borders of the lips, conjunctiva, eyelids (including lid margins), ears, trunk, neck, limbs and back of the hands.28 Hyperpigmentation has been associated with bilateral multifocal Sertoli cell tumors in Carney’s complex and the Peutz-Jeghers syndrome. Although Carney’s complex and the Peutz-Jeghers syndrome are genetically distinct, they share phenotypic similarities and require clinical recognition
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to establish the correct diagnosis.29 Primary pigmented nodular adrenocortical disease, schwannoma acromegaly, skin and cardiac myxomas are exclusive features of Carney’s complex. In the Peutz-Jeghers syndrome, symptomatic gastrointestinal presentations due to intestinal polyps such as obstruction, abdominal pain, and hematochezia are useful clues. Moreover, in the Peutz-Jeghers syndrome, the aromatase producing testicular tumors cause feminization and account for a significant proportion of all reported cases of prepubertal gynecomastia.30, 31 A relationship between multiple atypical nevi with testicular germ cell tumors has been reported but needs to be confirmed in a population not at risk for solar induced skin damage.32 Thus, skin pigmentation may be an important clue to the presence of a testis tumor. Cutaneous myxomas presenting as symptomatic sessile papules or subcutaneous nodules with smooth, nonulcerated surfaces are found in a third of the patients. Age of affected patients range from birth to 38 years. The lesions are multiple in 75% of the patients. In order of decreasing frequency, the myxomas occur on the head (eyelid, ear canal, scalp and cheek) and neck, trunk (nipples, chest, back and flank), perineum and genitalia, buttock and groin, and lower limb.28 None occurred on the hands and feet. Treatment is simple excision.
10. 11. 12. 13. 14.
15. 16.
17.
CONCLUSIONS
Sex cord stromal tumors in Carney’s complex are commonly bilateral and multifocal. Conversely, the diagnosis of a large cell calcifying Sertoli cell tumor should prompt a clinical investigation for other stigmata of Carney’s complex. In the absence of metastatic disease, tumor progression or local recurrence, observation of the small multifocal and/or bilateral testis tumors in patients with the syndrome is a treatment option in view of their indolent clinical behavior and low malignant potential. A malignant large cell calcifying Sertoli cell tumor in Carney’s complex is rare but is suggested by occurrence in an older patient (greater than 39 years), unilateral, solitary tumor size (greater than 4 cm.) and extratesticular extension.
18.
19. 20. 21. 22.
Dr. J. A. Carney reviewed the histological materials and manuscript, and provided personal followup on patients and editorial assistance.
23. 24.
REFERENCES
25.
1. Ruder, H. J., Loriaux, D. L. and Lipsett, M. B.: Severe osteopenia in young adults associated with Cushion’s syndrome due to micronodular adrenal disease. J Clin Endocrinol Metab, 39: 1138, 1974 2. Fligiel, Z., Kaneko, M. and Leiter, E.: Bilateral Sertoli cell tumor of testes with feminizing and masculinizing activity occurring in a child. Cancer, 38: 1853, 1976 3. Chandraratna, P. A. N., San Pedro, S., Elkins, R. C. et al: Echocardiographic, angiocardiographic and surgical correlations in right ventricular myxoma simulating valvar pulmonic stenosis. Circulation, 55: 619, 1977 4. Laboux, L., Mussini-Montpellier, J., Michaud, J. L. et al: Myxome du ventricule droit chez deux jumeaux monozygotes. Ablation chirugicale. Arch Mal Coer, 71: 953, 1978 5. Proppe, K. H. and Scully, R. E.: Large-cell calcifying Sertoli cell tumor of the testis. Am J Clin Pathol, 74: 607, 1980 6. Rosenzweig, J. I., Lawrence, D. A., Vogel, D. L. et al: Adrenocorticotropin-independent hypercortisolemia and testicular tumors in a patient with a pituitary tumor and gigantism. J Clinc Endocrinol Metab, 55: 42, 1982 7. Carney, J. A., Gordon, H., Carpenter, P. C. et al: The complex of myxomas, spotty pigmentation and endocrine overactivity. Medicine, 64: 270, 1985 8. Gaillard, F., Bouc, M., Dejarte, A. Y. et al: Le Complexe de Carney (myxomas, tache pigmentaires et hyperactivite endocrinienne. Ann Pathol, 8: 239, 1988 9. Leedman, P. J., Cohen, A. K. and Matz, L. R.: The complex of
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myxomas, spotty pigmentation, and endocrine overactivity. Clin Endocrinol, 25: 527, 1986 Handley, J., Carson, D., Sloan, J. et al: Multiple lentigines myxoid tumors and endocrine overactivity; four cases of Carney’s complex. Br J Derm, 126: 367, 1992 Thornton, C. M., Handley, J., Bingham, E. A. et al: Psammomatous melanotic schwannoma arising in the dermis in a patient with Carney’s complex. Histopathology, 20: 71, 1992 Martin-Reay, D. B., Shattuck, M. and Guthrie, F.: Psammomatous melanotic schwannoma: an additional component of Carney’s complex. Am J Clin Path, 95: 484, 1991 Kennedy, R. H., Flanagan, J. C., Eagle, R. C. et al: The Carney complex with ocular signs suggestive of cardiac myxoma. Am J Ophthal, 111: 699, 1991 Cheung, P. S. and Thompson, N. W.: Carney’s complex of primary pigmented nodular adrenocortical disease and pigmentous and myxomatous lesions. Surg Gynec Obstet, 168: 413, 1989 Manthos, C., Sutherland, R., Sims, J. et al: Carney’s complex in a patient with hormone-producing Sertoli cell tumor of testicle. J Urol, 150: 1511, 1993 Carney, J. A.: Psammontous melanotic schwannoma: a distinctive heritable tumor with special association including cardiac myxoma and the Cushing syndrome. Am J Surg Pathol, 14: 206, 1990 Nozian, I. M., Balonk, R., Eitelberger, F. G. et al: Bilateral testicular large cell calcifying Sertoli cell tumor and recurrent cardiac myxoma in a patient with Carney’s complex. Pediatr Radiol, 25: 236, 1995 Kratzer, S. S., Ulbright, T. M., 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 J Surg Pathol, 21: 1271, 1997 Radin, R. and Kempf, R. A.: Carney complex: report of three cases. Radiology, 196: 383, 1995 Toppari, J., Kaipia, A., Kaleva, M. et al: Inhibin gene expression in a large cell calcifying Sertoli cell tumor and serum inhibin and activin levels. APMIS, 106: 101, 1998 Tanaka, Y., Sano, K., Ijiri, R. et al: A case of large cell calcifying Sertoli cell tumor in a child with a history of nasal myxoid tumor in infancy. Pathol Int, 49: 471, 1999 Bleasel, N. R. and Stapleton, K. M.: Carney complex in a patient with multiple blue naevi and lentigines, suspect cardiac myxoma. Aust J Dermatol, 40: 158, 1999 Reynen, K.: Cardiac myxomas. N Engl J Med, 333: 1610, 1993 Weinstein, L., Shenker, A., Gejonan, P. et al: Activating mutations of the stimulation G protein in the McCune-Albright syndrome. N Engl J Med, 325: 1688, 1991 Liu, G., Duranteau, L., Carel, J. C. et al: Brief Report: Leydig cell tumors caused by an activating mutation of the gene encoding the luteinizing hormone receptor. N Engl J Med, 341: 1731, 1999 Kotlar, T. J., Young, R. H., Albanese, C. et al: Mutation in the A follicle-stimulating hormone receptor occurs frequently in human ovarian sex cord tumors. J Clin Endocrinol Metab, 82: 1020, 1997 Kannan, C. R.: Cushing’s syndrome. In: The Adrenal Gland. New York: Plenum, chapt. 3, pp. 97–175, 1988 Carney, J. A.: The Carney complex with myxomatous, spotty pigmentation, endocrine overactivity and schwannomas. Dermatol Clin, 13: 19, 1995 Stratakis, C. A., Kirschner, L. S., Taymans, S. E. et al: Carney complex, Peutz-Jeghers syndrome, Cowden’s disease, and Bannayan-Zonana syndrome share cutaneous and endocrine manifestations, but not genetic loci. J Clin Endocrinol Metab, 83: 2972, 1998 Young, S., Gooneratne, S., Straus, F. H. et al: Feminizing Sertoli cell tumors in boys with Peutz-Jeghers syndrome. Am J Surg Pathol, 19: 50, 1995 Hertl, M. C., Wiebel, J., Schafer, H. et al: Feminizing Sertoli cell tumors associated with Peutz-Jeghers syndrome: an increasingly recognized cause of prepubertal gynecomastia. Plas Reconstr Surg, 102: 1151, 1998 Raghavan, D., Zalcberg, J. R., Grygiel, J. J. et al: Multiple atypical nevi: a cutaneous marker of germ cell tumors. J Clin Oncol, 12: 2284, 1994
Vol. 167, 1299 –1302, March 2002 Printed in U.S.A.
TESTICULAR TUMORS IN CARNEY’S COMPLEX ROBERT WASHECKA, MARTIN I. DRESNER
AND
STACEY A. A. HONDA
From the Departments of Urology and Pathology, Hawaii Kaiser Permanente Medical Center, Honolulu, Hawaii, and Urology Section, Surgical Care Line, Southern Arizona VA Health Care System, Tucson, Arizona
ABSTRACT
Purpose: Bilateral sex cord stromal testicular tumors are common in the syndrome of myxoma, spotty pigmentation and endocrine overactivity (Carney’s complex). Large cell calcifying Sertoli cell tumor is the particular testicular tumor found in Carney’s complex. A clinicopathological review of 26 patients is presented. Materials and Methods: We report 2 cases of Carney’s complex with testicular tumors. An additional 24 patients with Carney’s complex and testicular tumors were identified by MEDLINE search and review of the literature. Results: Bilateral testicular tumors were found in 16 patients (61%) with a familial occurrence in 10 (38%). A testicular mass was the most common presentation. The associated findings of Carney’s complex included cardiac myxoma in 16 patients, skin myxoma in 16, skin pigmentation in 15, Cushing’s syndrome in 8, acromegaly in 3 and schwannoma in 3. Excisional biopsy, surveillance, bilateral orchiectomy and unilateral orchiectomy were performed in 7, 4, 7 and 8 patients, respectively. Conclusions: No local tumor recurrence or metastasis has developed in patients with bilateral and/or multifocal testicular tumors. Excisional biopsy or surveillance only are treatment options for bilateral testicular tumors in Carney’s complex. KEY WORDS: cells, Sertoli; testicular neoplasms; gland, endocrine
Syndromic testicular tumors are rare. The rare stromal tumor, large cell calcifying Sertoli cell tumor, commonly occurs in Carney’s complex. This disorder is a familial (autosomal dominant) multisystem tumor syndrome in which the tumors are multicentric in affected organs and bilateral in paired organs. Bilateral testicular stromal tumors present a therapeutic dilemma. At issue is whether to recommend complete testicular ablation (inguinal orchiectomy) or organ sparing surgery (tumor enucleation). Bilateral orchiectomy provides excellent local control of the neoplasms but is associated with negative quality of life, hypogonadism and necessity for lifelong hormonal replacement. Tumor enucleation has both endocrinological and psychological advantages. However, since no single histological criterion has proved reliable in distinguishing benign from malignant sex cord stromal tumors, tumor enucleation has the potential for incomplete or inadequate resection of primary tumor, which may result in local recurrence or possible diminished disease-free and cause specific survivals. We report 2 cases of bilateral testicular tumors in Carney’s complex and review reported cases of stromal tumors in the disorder to define the natural history of testis tumor in this syndrome. PATIENTS AND METHODS
We treated 2 patients with bilateral stromal testis tumors and Carney’s complex, and identified 24 additional cases with testis tumors as a component of Carney’s complex by MEDLINE search and review of the literature. The surgical specimens were fixed in 10% neutral buffered formalin and embedded in paraffin for routine histology processing. Sections were stained in hematoxylin and eosin. For electron microscopic evaluation 1 mm. cubes of fresh tissue from case 1 (right testis) were fixed in 2.5% glutaraldehyde, post-fixed
in osmium tetroxide and embedded in Epon 812. Areas for study were selected from toluidine blue stained thick sections. Ultrathin sections were stained with uranyl acetate and lead acetate, and examined with an electron microscope. CASE HISTORIES
Case 1. A 45-year-old Chinese-Hawaiian man, presented in 1993 with a symptomatic testicular mass. In 1971 when he was 19 years gigantism developed due to a pituitary adenoma, which was treated with cryohypophysectomy. At that time an asymptomatic left testicular mass was detected and left orchiectomy was performed for a Leydig cell tumor. In 1981 a 2.5 cm. fibromyxoma was removed from the left flank. In 1988, the patient was operated on for a left atrial myxoma. On physical examination the patient was obviously acromegalic, displaying marked prognathism, frontal bossing and prominent zygomatic arches. Tiny dark pigmented spots were present on the lips, buccal mucosa and face. The patient had no clinical stigmata of Cushing’s syndrome. The right testis was atrophic but had 3 distinct nontender, rock hard nodules, each approximately 1 cm. in largest diameter. Scrotal sonogram showed numerous hyperechoic areas with shadowing in the right testis (fig. 1). Chest radiographs and serum levels of ␣-fetoprotein and -human chorionic gonadotropiin were normal. The 3 testicular masses were enucleated. There was no evidence of recurrence or metastasis of the lesions 6 years later. The left testis (removed in 1971) had a 1.5 cm. hard globular mass with areas of hemorrhage. The nodules removed from the right testis in 1993 measured 0.7 ⫻ 0.5 ⫻ 0.3 cm. and 2.2 ⫻ 1.0 ⫻ 0.9 cm. (the latter mass was composed of 2 nodules), were rock hard and had gray-yellow cut surfaces. Histologically, the left testicular tumor featured monotonous cells with eosinophilic cytoplasm and uniform large nuclei. Brown cytoplasmic pigment was seen throughout the tumor. No Reinke crystals, capsular invasion or blood vessel invasion was seen. No germ cell tumor elements were noted.
Accepted for publication September 28, 2001. Read at annual meeting of Western Section, American Urological Association, San Diego, California, July 1996. 1299
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FIG. 1. Case 1. Sonogram of large cell calcifying Sertoli cell tumor hyperechoic areas (arrows) with shadowing represent tumor calcification.
The findings were those of a Leydig cell tumor. In addition, a focus of large cell calcifying Sertoli cell tumor and an adrenal rest were present. The 3 nodules from the right testis were largely fibrotic with scattered aggregates of lymphocytes and extensive laminated foci of calcification admixed with nests, cords and sheets of Sertoli cells (fig. 2). The cells had large, round-tooval vesicular nuclei, eosinophilic, granular and occasionally vacuolated cytoplasm, and well-defined cytoplasmic membranes. The cell aggregates were separated by fibrocollagenous stroma. No Reinke crystals, cytological atypia, mitoses, or vascular or lymphatic invasion was seen. No associated germ cell tumor elements or intratubular neoplasia were identified. Histologically, the lesions were large cell calcifying Sertoli cell tumor. Groups of closely apposed polygonal cells with round-tooval nuclei and moderate amounts of cytoplasm were present on electron microscopy. Nuclei exhibited prominent nucleoli and occasional nuclear envelope indentation. Free ribosomes and smooth endoplasmic reticulum were abundant. There were no Reinke crystalloids. The appearances were consistent with Sertoli cells. Case 2. A 12-year-old white male presented for evaluation of a testicular mass found on sonographic examination. He had an established diagnosis of Carney’s complex. Previously, he had had an atrial myxoma excised. On physical examination there were multiple facial lentigines (fig. 3). The
FIG. 2. Case 1. Photomicrograph of large cell calcifying Sertoli cell tumor shows calcification. H&E, reduced from ⫻100.
FIG. 3. Case 2. Facial lentigines include vermilion border of lips and eyelids (not shown).
testes were normal on palpation. The patient had no stigmata of Cushing’s syndrome or acromegaly. Scrotal sonogram revealed bilateral hyperechoic masses with shadowing. Chest radiography, b-HCG, and ␣-fetoprotein were normal. The patient and family declined further treatment. One year later there was no evidence of local tumor progression, metastatic disease or gynecomastia. DISCUSSION
Testicular sex cord stromal tumors are uniquely associated with the syndrome of cardiac myxomas, spotty pigmentation and endocrine overactivity (Carney’s complex). The typical testis tumor in the syndrome, the large cell calcifying Sertoli cell tumor, is a distinctive neoplasm with unique morphological, histochemical, and clinical features that clearly differentiate it from germ cell tumors. Carney’s complex is a heritable condition transmitted as an autosomal dominant trait. Although an array of phenotypes have been described in the complex, it is not known whether they are a result of the loss of a gene function that is needed at multiple independent stages of development (a pleiotropic syndrome) or arise as a secondary consequence of a single primary defect (a sequence syndrome). Testicular tumors were found in 26 patients ranging in age from 4 to 51 years.1–22 The tumors were bilateral in 16 of 26 patients (61%) and appeared metachronously in 2 with a gap of up to 21 years. Familial occurrence was noted in 10 patients (38%). An asymptomatic testicular mass varying from minute size at autopsy to 6.5 cm. in greatest dimension was the most common presentation. Gynecomastia (5 patients), precocious puberty (4) and infertility (2) were additional presentations. Testis tumors were identified prospectively by ultrasound in 4 patients with Carney’s complex. There was no reported history of cryptorchidism, irradiation or germ cell tumor. Initial treatment of the testicular tumors included bilateral orchiectomy in 6 patients, unilateral orchiectomy in 6,
TESTICULAR TUMORS IN CARNEY’S COMPLEX
excisional biopsy in 6, and orchiectomy and contralateral excisional biopsy in 1. Four patients did not receive treatment. One patient whose bilateral tumors were originally diagnosed as embryonal carcinoma underwent bilateral orchiectomy, irradiation and pelvic lymphadenectomy and later pathological review revealed large cell calcifying Sertoli cell tumor. Autopsy examination showed bilateral tumors in 1 patient and confirmed contralateral large cell calcifying Sertoli cell tumor in another who had undergone previous orchiectomy for another such tumor. Followup information extends up to 25 years. There were 2 deaths from cardio embolism from myxoma and 2 patients had a cerebrovascular accident from a myxoma embolism. There has been no development of metastatic disease in any patient with multifocal and/or bilateral testicular tumors including those treated with surveillance only. No local recurrence has developed in patients treated with excisional biopsy. One patient who presented initially with metastatic disease died of tumor 5 months after orchiectomy for a malignant large cell calcifying Sertoli cell tumor. This patient did not fulfill criteria for Carney’s complex but he was presumed to have the syndrome.18 Large cell calcifying Sertoli cell tumor is the characteristic sex cord stromal testis tumor present in Carney’s complex. Although it has been reported without Carney’s complex, the syndrome accounts for the majority of cases. Large cell calcifying Sertoli cell tumor may occur alone or be associated with Leydig cell tumor, hyperplasia or adrenal rest components. Consequently, its presence warrants careful clinical investigation for other signs of the syndrome since the presence of 1 additional component is suggestive of the syndrome while 2 stigmata confirm the presence of Carney’s complex. None of the multifocal and/or bilateral tumors in Carney’s complex exhibited lymphatic or vascular invasion, necrosis, high mitotic index, or tunica albuginea or spermatic cord involvement. There were no associated germ cell tumor elements or intratubular germ cell neoplasm present. Followup of sex cord stromal tumors in Carney’s complex indicates that they have an apparent indolent natural history and low metastatic potential. In a descriptive analysis of a small number of patients, definite treatment recommendations are difficult to establish. Nonetheless, with serological exclusion of germ cell tumors, bilateral occult and/or multifocal testis tumors in patients with Carney’s complex may be observed. Excisional biopsy or orchiectomy should be considered in Carney’s complex to confirm large cell calcifying Sertoli cell tumor in potential candidates of the syndrome for symptoms and cosmesis, or to prevent premature epiphyseal closure in those with precocious puberty. In patients with Carney’s complex an enlarging solitary testicular tumor greater than 4 cm. is suspicious of malignancy and orchiectomy is recommended. Moreover, although most unilateral solitary large cell calcifying Sertoli cell tumors are benign, those exhibiting extratesticular growth and occurring in older patients (mean age 39 years) warrant orchiectomy because of the risk of malignancy. The findings of Carney’s complex in 26 patients with testis tumors included cardiac myxomas in 16, skin myxomas in 15, skin pigmentation in 15, Cushing’s syndrome in 8, acromegaly in 3 and psammomatous melanotic schwannoma in 3.1–22 Since cardiac myxoma and Cushing’s syndrome have potential for serious morbidity, recognition and followup examination of the individual components of Carney’s complex, such as large cell calcifying Sertoli cell tumors, are important. It is unknown if all manifestations of the syndrome will appear with adequate longitudinal evaluation. Cardiac myxomas have caused death of 20% of patients with Carney’s complex and possess distinctive features that may suggest the syndrome. The tumors present in patients at a young age (range 10 to 49 years), are multiple and occurr in
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atypical locations including the left atrium, right atrium, right ventricle and left ventricle in order of decreasing frequency. In contrast, nonsyndromic cardiac myxomas involve the left atrium (75%) and right atrium (20%).23 Depending on size, mobility and location, myxomas may mimic several cardiac conditions in addition to causing embolism, intracardiac obstruction and constitutional symptoms. Echocardiography is the most important means of diagnosis but computerized tomography and magnetic resonance imaging can detect tumors measuring at least 0.5 to 1 cm. in diameter.23 Endocrine overactivity may be manifested by Cushing’s syndrome (primary pigmented nodular adrenal disease), acromegaly (pituitary adenoma) or isosexual precocious puberty (large cell calcifying Sertoli cell tumor). A unifying hypothesis for the diverse forms of endocrine overactivity may be a hormone receptor signal transduction gain-offunction mutation as exemplified by a G protein mutation in the McCune-Albright syndrome.24 Moreover, an activating mutation of the luteinizing hormone receptor gene in Leydig cell tumors has been reported recently.25 Also, a somatic mutation of the follicle-stimulating hormone receptor has been identified in ovarian sex cord tumors.26 How such a change in cell function contributes to tumor formation or growth is not known. Onset of acromegaly ranged from 11 to 27 years in 3 patients. Plasma somatomedin C is the best screening test for patients suspected of having subclinical acromegaly. Evaluation of precocious puberty in boys includes serum follicle-stimulating hormone, luteinizing hormone and testosterone, in addition to gonadotropin releasing hormone stimulation test and scrotal sonogram. Northern blot and in situ hybridization revealed abundant expression of inhibin ␣,  A and  B subunit messenger RNA in large cell calcifying Sertoli cell tumor in a 12-year-old boy with Carney’s complex.20 Serum inhibin levels were increased and may be a potential tumor marker. Primary pigmented nodular adrenocortical disease is a recent addition to the pathological spectrum of conditions causing Cushing’s syndrome, although it accounts for only 1% of cases of the syndrome of primary adrenal origin.27 Age presentation ranged from 8 to 19 years.7 The variability of Cushing’s syndrome, its occurrence in children and the heightened tendency for osteoporosis are recognizable clinical characteristics of primary pigmented nodular adrenocortical disease.27 Clinically, plasma cortisol elevation is mild to moderate and fails to suppress following high dose dexamethasone administration.27 Plasma adrenocorticotropic hormone levels are low or undetectable, and the sella turcica is not enlarged. Bilateral adrenalectomy is curative with no development of Nelson’s syndrome postoperatively. Nelson’s syndrome is hyperpigmentation and third nerve damage due to an enlarging sella turcica caused by pituitary adenoma after adrenalectomy. Skin pigmentary abnormalities (lentigines and blue nevi) and skin tumors (myxomas and psammomatous melanotic schwannoma) are often the earliest signs of Carney’s complex. Cutaneous manifestations are usually present in the first decade and found in more than 50% of patients before detection of other signs of the complex.28 The cutaneous pigmented lesions are lentigines, which are small (less than 2 mm.), brown to dark brown, round, nonelevated spots resembling freckles, and blue nevi, which are larger (up to 8 mm.) blue to black domed lesions. They occur characteristically on the face (periocular, bridge of the nose, perioral zones), vermilion borders of the lips, conjunctiva, eyelids (including lid margins), ears, trunk, neck, limbs and back of the hands.28 Hyperpigmentation has been associated with bilateral multifocal Sertoli cell tumors in Carney’s complex and the Peutz-Jeghers syndrome. Although Carney’s complex and the Peutz-Jeghers syndrome are genetically distinct, they share phenotypic similarities and require clinical recognition
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to establish the correct diagnosis.29 Primary pigmented nodular adrenocortical disease, schwannoma acromegaly, skin and cardiac myxomas are exclusive features of Carney’s complex. In the Peutz-Jeghers syndrome, symptomatic gastrointestinal presentations due to intestinal polyps such as obstruction, abdominal pain, and hematochezia are useful clues. Moreover, in the Peutz-Jeghers syndrome, the aromatase producing testicular tumors cause feminization and account for a significant proportion of all reported cases of prepubertal gynecomastia.30, 31 A relationship between multiple atypical nevi with testicular germ cell tumors has been reported but needs to be confirmed in a population not at risk for solar induced skin damage.32 Thus, skin pigmentation may be an important clue to the presence of a testis tumor. Cutaneous myxomas presenting as symptomatic sessile papules or subcutaneous nodules with smooth, nonulcerated surfaces are found in a third of the patients. Age of affected patients range from birth to 38 years. The lesions are multiple in 75% of the patients. In order of decreasing frequency, the myxomas occur on the head (eyelid, ear canal, scalp and cheek) and neck, trunk (nipples, chest, back and flank), perineum and genitalia, buttock and groin, and lower limb.28 None occurred on the hands and feet. Treatment is simple excision.
10. 11. 12. 13. 14.
15. 16.
17.
CONCLUSIONS
Sex cord stromal tumors in Carney’s complex are commonly bilateral and multifocal. Conversely, the diagnosis of a large cell calcifying Sertoli cell tumor should prompt a clinical investigation for other stigmata of Carney’s complex. In the absence of metastatic disease, tumor progression or local recurrence, observation of the small multifocal and/or bilateral testis tumors in patients with the syndrome is a treatment option in view of their indolent clinical behavior and low malignant potential. A malignant large cell calcifying Sertoli cell tumor in Carney’s complex is rare but is suggested by occurrence in an older patient (greater than 39 years), unilateral, solitary tumor size (greater than 4 cm.) and extratesticular extension.
18.
19. 20. 21. 22.
Dr. J. A. Carney reviewed the histological materials and manuscript, and provided personal followup on patients and editorial assistance.
23. 24.
REFERENCES
25.
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