Sertoli Cell Tumor Causing Prepubertal Gynecomastia in a Boy with Peutz-Jeghers Syndrome: The Outcome of 1-Year Treatment with the Aromatase Inhibitor Testolactone

Abstract

Peutz-Jeghers syndrome (PJS) is a rare disorder characterized by benign intestinal hamartomatous polyps and mucocutaneous pigmentation, and with an increased risk for intestinal and extra-intestinal neoplasms. Sertoli cell tumors in boys with PJS have been increasingly recognized as a cause of prepubertal gynecomastia. However, an association between nephrocalcinosis and PJS has not been reported before. We report on a 7.25-year-old boy with PJS, bilateral gynecomastia, Sertoli cell tumor and nephrocalcinosis, and present the outcome of 1-year treatment with the aromatase inhibitor testolactone. The patient presented with bilateral breast and testis enlargement, and mucocutaneous pigmentation. Testicular ultrasound revealed parenchymal multiple microcalcifications. Histopathological examination was consistent with Sertoli cell tumors. Nephrocalcinosis due to idiopathic renal hypercalciuria was also detected. The aromatase inhibitor testolactone was begun in an attempt to prevent acceleration in skeletal maturation. One-year treatment with testolactone reduced the breast base diameter from 7 to 3 cm, and bone age advanced 1.2 years during this period. Our case demonstrates that waiting for the effect of aromatase inhibitors on gynecomastia before making a decision for mastectomy may be a reasonable option. We also consider that the association between PJS and nephrocalcinosis may be a coincidence.

Teasing out the role of aromatase in the healthy and diseased testis

“…79,80 This clinically induces pre-pubertal gynecomastia with no measurable effect on the testis. 79,80 In comparison, the genetic makeup of PJS frequently comprises inactivating mutations of the serine/threonine kinase 11 (STK11) tumor suppressor gene located on chromosome 19p13.3 which encodes for the protein kinase, LKB1 81 and consequently predisposes individuals to benign and malignant tumors of many organ systems, including the testis. 82 This mutation is presumably playing the pathogenic role in tumor development in patients with PJS however the molecular mechanisms by which this occurs is yet to be founded.…”

“…83 In terms of the testis, the sex cords are the site of tumorigenesis and a total of 35 boys with PJS have presented with testicular Sertoli cell tumors. 36,37,39,59,81,[84][85][86][87][88][89][90][91][92][93][94][95][96][97][98][99][100] In boys with PJS, there is an increase of aromatase expression and activity in these tumors, resulting in excess estradiol production that not only acts to feed local tumor growth, 36,39 but also accelerates testicular and extragonadal morphogenesis. For instance, the obvious clinical manifestations are enlarged testes, pre-pubertal gynecomastia and feminizing precocious puberty, and it has become increasingly numbers and the fact that spermatozoa in these mice display decreased motility, as evidenced by the proven inability to fertilize oocytes in vitro.…”

“…Another related orphan member of the nuclear receptor family, liver receptor homolog-1 (LRH-1; NR5A2), has also been shown to bind to SFRE and recognized that both of these result from the increase in testicular aromatization. 81 The tumors are typically benign and considered the equivalent of the ovarian sex cord tumor with annular tubules (SCTAT), commonly seen in females with PJS. 37 Interestingly, AROM + mice do not develop sex cord tumors, rather Leydig cell adenomas, which are exacerbated as a result of increasing testicular estradiol concentration.…”

Sertoli Cell Tumor of the Testis in Association with Peutz-Jeghers Syndrome Sometimes Requires a High Index of Suspicion

“…Anyway, it should be noted that average age of presentation of these tumors is earlier than in others cancers associated to PJS 1,4,8 . As in our case, diffuse and bilateral testicular involvement can overlook the presence of changes on physical examination 13 and the development of secondary hormonal disturbances may not be present at an early stage.…”

“…Surgery could be indicated in selected cases of unusual invasive tumors, pain or mass effect. Hormonal manifestations could be treated with aromatasa inhibitors 13 , like testolactone and anastrozol. These drugs can be effective in controlling the clinical features of the disease, like breast development, growth velocity and bone maduration 16 but evidence is limited and further studies are required 9 .…”