Characterization and management of testicular pathology in McCune-Albright syndrome

Abstract

Context: The testicular phenotype in McCune-Albright syndrome (MAS) has not been well characterized. Boys present with a relatively low incidence of precocious puberty in comparison with girls. Radiographic and histological studies are limited to small series and case reports, which report testicular microlithiasis and Sertoli cell hyperplasia.

Objective: Our objective was to characterize the biochemical, radiological, and histological spectrum and clinical management of testicular pathology in males with MAS.

Patients, design, and setting: Fifty-four males with MAS participated in this prospective cohort study at a clinical research center.

Intervention: Evaluation included testicular exam, pubertal staging, testicular ultrasound, measurement of LH, FSH, and testosterone. Orchiectomies were performed when considered clinically indicated.

Main outcome measure: Prevalence and characterization of ultrasound lesions with correlation to histology were evaluated.

Results: Of 54 males, 44 (81%) presented with ultrasound abnormalities including hyperechoic lesions (49%), hypoechoic lesions (30%), microlithiasis (30%), heterogeneity (47%), and focal calcifications (11%). Eight subjects underwent orchiectomy revealing large foci of Leydig cell hyperplasia, which could not be definitively distinguished from Leydig cell tumor. After no subjects developed clinical malignancy, a conservative approach was instituted, and subsequent subjects were followed with serial imaging. Testosterone and gonadotropins were normal in subjects without precocious puberty or pituitary disease. Eleven (21%) presented with precocious puberty, and a combination of aromatase inhibitors, androgen receptor blockers, and leuprolide resulted in improved predicted adult height. In addition, the first cases of testicular adrenal rest and bilateral germ cell tumors in association with MAS are presented.

Conclusions: Contrary to prevailing thinking, the incidence of gonadal pathology in MAS is equal in males and females. The predominant histopathological finding was Leydig cell hyperplasia, which carries a low risk of malignant transformation and can be managed conservatively.

Fig. 1.

Summary flow diagram describing the US abnormalities, pathological findings, and clinical management of MAS-associated testicular lesions. *, One patient with gonadal involvement on autopsy, US not available; t̄, patient with left-sided embryonal carcinoma resected, followed by subsequent development of right-sided seminoma.

Fig. 2.

Representative US images of testes of males with MAS. A, Right and left testes demonstrating unilateral heterogeneic texture; B, multiple punctate calcifications consistent with testicular microlithiasis; C, multiple large, irregular hyper and hypoechoic lesions; D, heterogeneous hyperechoic lesion in a patient with seminoma; E, multiple hyper and hypoechoic lesions with associated focal calcifications; F, mediastinal hypoechoic lesion consistent with adrenal rest; G and H, a child with unilateral macro-orchidism, a small hypoechoic area with adjacent calcification in a normal-size testicle (G), and punctate calcifications in the enlarged testicle.

Fig. 3.

Representative pathology from testicular lesions in subjects with MAS. A, Leydig cell hyperplasia (LCH). Nests of proliferating cells (asterisk) are pushing aside the testicular parenchyma, where a few remaining atrophic seminiferous tubules can be observed (white arrowheads). The features of the proliferating Leydig cells containing characteristic brown pigment (lipofuscin) are seen in the inset (white arrows). B, LCH compromising the rete testis (arrowheads) and showing some pleomorphism. At a higher magnification (inset), the cytoplasm is seen to contain lipid droplets. C, Malignant germ cell tumor consistent with embryonal carcinoma. The tumor is composed of round to oval highly atypical cells with prominent dark nucleoli. The proliferation infiltrates and destroys the surrounding testicular parenchyma. A distorted and atrophic remaining seminiferous tubule is seen in the center of this picture (white arrow). The inset shows a higher magnification of the neoplastic cells; the white arrowhead points to an atypical mitosis. D, Sertoli cell intraepithelial neoplasia. The tubules are filled with atypical Sertoli cells and are surrounded by a thick basement membrane. The inset shows a higher magnification of the pleomorphic proliferating cells.

Fig. 4.

Median testosterone values by age in subjects with MAS-associated testicular lesions without precocious puberty. Testosterone levels increase appropriately with age and reach normal adult levels.