Peutz-Jeghers syndrome with feminizing sertoli cell tumor

Pe u tz- Jeg h ers Syndrome with Feminizing Sertoli Cell Tumor

JOSE MARIA CANTU, MD, HORACIO RIVERA, MD, RENE OCAMPO-CAMPOS, MD, NORMA BEDOLLA, MSC, VINCENTE CORTES-GALLEGOS, MD, AMADO GONZALEZ-MENDOZA, MD, MIGUEL DfAZ, MD,

AND ALEJANDRO HERNANDEZ, MD

A case involving a 6-year-old boy with Peutz-Jeghers syndrome and an unilateral feminizing Sertoli cell tumor is described. Endocrinologic studies revealed consistently high plasma and urine levels of estrogens and normal levels of testosterone and dihydrotestosterone. The increased levels of estrogens did not show changes that could be correlated with exogenous gonadotropin administration, thus in- dicating an autonomous nature. The histopathologic studies of nontumorous testicular tissue revealed changes in the seminiferous tubules which suggested that estrogens, directly or indirectly, may have had both stimulating and atrophying effects. It is concluded that gonadal tumors are an additional mani- festation of the Peutz-Jeghers syndrome gene in both male and female patients.

Cancer 46:223-228, 1980.

N 1921, P E U T Z ~ ~ observed oral melanosis associated I with nasal and intestinal polyps in several members of a Dutch family. In 1949, Jeghers et al.I3 described additional cases and provided evidence of autosomal dominant inheritance. Since then, there have been reports of many other cases of this disorder, which is currently known as Peutz-Jeghers syndrome. The in- testinal polyps are of an hamartomatous nature1*z’fi,29,30 whose propensity for malignancy is still uncer- tain.6Jfi~17~z0~2Y Ovarian tumors are more common in women with Peutz-Jeghers syndrome than in the general female p ~ p u l a t i o n ; ~ ~ ~ * ~ ~ ~ ~ ~ however, no associ- ation between Peutz-Jeghers syndrome and gonadal tumors has been reported in the male patient. The pur- pose of this report is to describe for the first time, the association of Peutz-Jeghers syndrome with a Sertoli cell tumor, to emphasize the variable expres- sivity and pleiotropism of the causal gene, and to cor- relate the testicular histopathologic findings with the tumoral endocrine dysfunction.

From the Divisiones deGenetica y Hematologia, Patologia Experimental y Biologia de la Reproduccion (CMN), Subjefatura de Investigacion Cientifica, Unidad de Investigacion Biomedica, y Hospitales de Pediatria y Gineco-Obstetricia, Centro Medico de Occidente, Instituto Mexican0 del Seguro Social, Guadalajara, Jalisco, Mexico.

Supported in part by a grant from the Ford Foundation. Address for reprints: J. M. Cantu, MD, Apartado Postal 1-3838,

Guadalajara, Jalisco, Mexico. The authors thank Drs. Gregorio Perez-Palacios and Tomas Morato

for LH and FSH determinations and Dr. Enrique Corona-Rivera for his help in the clinical studies.

Accepted for publication July 6, 1979.

Case Report

Clinical and Familial Data

The 6-year-old patient was the second child of noncon- sanguineous parents; aged 27 (father) and 28 (mother) years at his birth. The pregnancy, delivery, and psychomotor development were normal. An urethral meatotomy was per- formed when he was four years old because of congenital stenosis. At five years of age, medical consultation was sought for bilateral gynecomastia with an evolution of about two years; it was progressive, painless, without galactorrea, with slight predominance on the right side and associated with a rapid increase in stature. He also had numerous small (1-4mm) blackish macules on the lips and the buccal mucous membranes, without any additional symptoms. Upon physi- cal examination at five years; seven months of age, the fol- lowing somatometric data were found: height, 119 cm (above the 97th percentile corresponding to about the 50th percentile for seven and a half years); weight, 24 kg; arm span, 119 cm; upper to lower segment ratio, 1.05; and cephalic, thoracic and abdominal circumferences of 5 2 , 68, and 59 cm respec- tively. The clinical features included melanosis oris (Fig. l) , severe bilateral gynecomastia (Tanner’s Stage 111) with im- mature nipples, and large testes for his age (Tanner’s Stage 11-111) measuring 3.5 x 2.0 cm, but with normal morphology and consistency. The penis was normal without evidence of precocious virilization. Ophthalmologically , the pro- positus showed nonaccomodative alternate esotropia.

Laboratory Studies

Laboratory studies including urinalysis, blood cell count, plasma glucose, urea and creatinine, liver and thyroid function tests, screening tests for metabolic defects

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224 CANCER July 1 1980 Vol. 46

TABLE 1. Urinary Excretion (24 Hours) of Total Estrogens (EJ, 17-Ketosteroids (17-0), 17-Hydroxysteroids (17-OH),

and Creatinine

17-0 17-OH E, Creatinine Volumen Sample (mg) (mg) (PSI (g) (ml)

1. Basal 2.5 3.0 15.3 0.85 978.0 2. Basal 2.2 0.7 14.03 0.5 635.0 3. DST 0.8 13.3 0.54 630.0 4. DST 0.4 18.6 0.65 750.0 5 . DST ND 11.7 0.59 640.0

DST = dexamethasone suppression test; ND = not detectable.

(Phenistix, glucose oxidase, Millon, anthrone, ferric chloride, DNPH, nitrosonaphthol, acid albumin turbidity, CTA, methylmalonic acid, Benedict, and cyanide nitroprusside), brain gammagram, urocystogram, and x-chromatin and karyo- type, all yielded normal results. Determinations of total estrogens (EJ, 17-ketosteroids (17 = 0) and 17-hydroxy- steroids (17-OH) in 24-hour urine studies, basal as well as after adrenocortical inhibition with dexamethasone (500 mg every 6 hours for four days), showed consistently high levels of estrogens and a normal decrease in the levels of 17-OH (Table 1).

Radiologic Studies

Results of a barium-meal examination, barium-enema studies, and intravenous pyelography with retroperitoneal insufflation were normal. The radiologic bone age was increased by about two years.

Familial Data

Familial studies revealed that the propositus' 7-year-old only brother had melanosis oris. The mother, born to a 38- year-old father, also showed melanosis oris as well as blackish macules on the palms (Fig. 1). None of the patients presented symptoms or radiologic evidence of polyposis.

FIG. 1. Melanosis oris in the propositus (top left) and in his mother (bottom left ). Melanosis of the palmar side of the mother's thumb is also shown (right).

No other relative had antecedents of mucocutaneous melanosis or gastrointestinal disorders suggestive of polyposis.

Materials and Methods

Plasma luteinizing hormone (LH) and follicle stimu- lating hormone (FSH) were measured by means of a double-antibody radioimmunoassay;** samples were assayed in duplicate at two different dilutions in order to ascertain parallelism with the standard curves. Results were expressed as ImU/ml of the second IRP- HMG preparation. Plasma testosterone (T), dihydro- testosterone (DHT), estradiol (E2), and Et deter- minations were carried out by means of radioim- m u n o a s ~ a y ~ , ~ ~ and the results expressed as pglml.

Hypothalamic Pituitary Studies

Pituitary gonadotropin reserve and responsiveness were evaluated by measuring the plasma concentra- tions of LH and FSH in samples taken every 20 minutes for 3 hours and then in two further samples with a 40- minute interval; an intravenous bolus of synthethic LH-RH (100 pg) was administered immediately after the fourth sample.

Gonadal Studies

Biopsy specimens of both testes were obtained and histologically examined. After the biopsy was done, the

10

8 g1 7

LH-RH

i

0 ' I I I I I I I I I 1 20 40 60 80 100 120 160 180 220 260

M I N U T E S - L H } I m U / m l 2nd I R P - H M G o----o F S H

FIG. 2. Plasma LH and FSH values and pituitary responsiveness to synthetic LH-RH administration.

No. 1 PEUTZ- JEGHERS SYNDROME .

HCG 2500 IU F$ ,&ol,!,u m n

Cantu et a1

f

225

2 4 92 199 250 279 501 342 412 3 5 ' 7 9 162330343g 38 132 251 272 2O6 328 380 454

1 D A Y

FIG. 3. Plasma T, DHT, E,, and Et levels before and after stimulation with gonadotropins and orchiectomy. Note the increase of T and DHT values. E2 and Et levels were consistently high without response to stimulation with gonadotropins and decreased to normal limits after orchiectomy.

testicular responsiveness was evaluated through the administration of human chorionic gonadotropin (hCG) at a dose of 2500 IU/day for four consecutive days, and 26 days later by the administration of 150 IU of both FSH and LH for 4 consecutive days. A left orchiectomy was performed after the diagnosis was made. Plasma T, DHT, E, and E, levels were measured before, during, and after the stimulations and after the orchiectomy. The excised testis was also histopathologically studied.

Mammary Studies

Biopsy specimens of the left mammary gland were histologically examined. The evolution of gyneco- mastia was evaluated through the measurement of the thoracic circumference at the nipple level every month during 15 months.

Results

Levels of plasma LH and FSH before and after the LH-RH injection are depicted in Fig. 2 . The levels of plasma T, DHT, E2 and E, before, during, and after

stimulations with hCG and FSH-LH, as well as before and after orchiectomy, are shown in Fig. 3 . The T and DHT values were considered within normal limits for his sex and age, whereas E, and E, values were very high, corresponding to those of a normal woman in the secretory phase.21 After the left orchiectomy, E, and E, levels decreased to normal, thus indicating their tumorous origin.

The histopathologic studies of the left testis revealed a well defined tumor approximately 7 mm in diameter, formed by tubules filled with Sertoli cells (Fig. 4). The cells were large, polymorphic, and arranged in nests or cords; some scattered luminae were also observed (Fig. 5 ) . The nuclei were generally large and vesicular, with prominent nucleoli. Mitotic figures were rarely seen and the basement membranes were intact. Leydig cells could not be identified within the tumor, but they were found in some areas of the nontumorous testicular tissue from both right (in which no tumoral evidence could be found) and left testis, whose seminiferous tubules showed diverse characteristics. Some appeared to be typically infantile immature tubules (normal for

226 CANCER July 1 1980 Vol. 46

Frp. 4. Photomicrograph of Sertoli cell tumor. Note the Sertoli cells proliferation filling the tubules and the absence of germinal epithelium ( ~ 8 0 ) .

age), others like those observed at the initiation of puberty with mitotic activity of spermatogoniae and some primary spermatocytes up to pachytene, and others were atrophied with a gross basement mem- brane and hialinization. No calcification could be found within the tumor.

The histopathologic studies of the mammary tissue showed fibrosis with ductal proliferation and periductal edema, typical findings in gynecomastia. The thoracic circumference remained constant (68 cm) during the 15 months despite body growth, thus indicating slight involution. Nevertheless, bilateral mastectomy was performed for both psychologic and esthetic reasons. Two years after orchiectomy, he has not presented any sign of puberty and the right testis remains of the same size.

Discussion

The diagnosis of Peutz-Jeghers syndrome in the propositus, his brother, and mother was based on the finding of dominantly inherited typical melanosis. Since the mother was the only affected member of her sib-

ship and her parents were both normal, she is probably the result of a de n o w mutation; this is further sup- ported by the increased paternal age at her birth. In- testinal polyposis could not be demonstrated in any of the patients, either because of technical radiologic limitations2'j or because of the variable expressivity in Peutz-Jeghers s y n d r ~ r n e . * ~ ~ ~ * ~ ~ ~ ~ ~ ~ ~ ~ ~

The diagnosis of Sertoli cell tumor was made on the basis of the histopathologic testicular findings, as well as the clinical and endocrinologic data. Although it is difficult to establish whether a 7 mm lesion is a tumor or a nodular hyperplasia, the following data supported the diagnosis of Sertoli cell tumor: 1) it was a solitary unilateral lesion; 2) the microscopic features cor- responded to those in the medical literature for Sertoli cell tumor; and 3) it showed an autonomous nature and function. Sertoli cell tumor is a neoplasm that belongs to the group of specialized gonadal stroma tumors. 18319

It represents less than 2% of all testicular neoplasmsl0 and to date, approximately 70 cases have been de- scribed,28 24 of which have occurred in ~ h i l d r e n . ~ ~ ~ ~ The great majority of Sertoli cell tumors have shown benign evolution in both clinical and histopathologic

No. 1 PEUTZ-JEGHERS SYNDROME . Cantu et al. 227

paremeters;8,28 the Sertoli cell tumor in the patient reported here corresponds to this variant, since there was neither clinical nor histopathologic evidence of malignancy. Also, the lack of calcifications makes the present tumor different from the Sertoli cell tumor variant recently defined by Proppe and S c ~ l l y . ~ ~ Sertoli cell tumors arise from testicular blastomas, from which Sertoli cells are derived."I9 A predominance of Sertoli cells results in increased production of

as first demonstrated by Huggins and Moulder" in Sertoli cell tumors in the dog. In humans, approximately 20% of Sertoli cell tumor cases present abnormal hormonal activity which in general is clini- cally manifested by gynec0mastia.l" In the present case, the hyperestrogenism was also manifested by accelerated growth and development with Concomitant advanced bone age and elevated serum and urine estrogens. The nongonadotropin dependency of the tumor was evidenced by the sustained high levels of E2 and E, with variations not correlated to exogenous gonadotropin administration. The pituitary response to LH-RH administration may be considered abnormal

since the first significant rise of both LH and FSH occurred 80 minutes after stimulation, thus indicating a delayed response, if any. Furthermore, the post- stimulation LH peaks are similar to that observed prior to the administration of LH-RH, suggesting that LH variations are spontaneous pulses rather than re- sponses to the synthetic hypothalamic hormone. These pulsations are usually seen in boys in midpuberty;' therefore, this finding in the present case could suggest an advanced hypothalamus maturation probably caused by the chronic hyperestrogenism. Neverthe- less, it would be difficult to explain the lack of, or the delayed response to, LH-RH, unless a post-pulsation insensitivity pituitary period or a technical error are invoked. It is currently accepted that no hormone is necessary in order to promote differentiation from spermatogonia type A up to the meiotic profase of primary ~permatocytes . '~ However, the symmetrical enlargement of both testes and the nontumorous testicular histopathologic findings in the present case indicate that, in some way, the tubular activity is re- lated to the hyperestrogenism. The mechanism by

FIG. 5. Photomicrograph of Sertoli cell tumor. Note the packed Sertoli cells, the disrupted tubular architecture, and a tubular lumen (arrow) ( X 160).

228 CANCER July I 1980 Vol. 46

which estrogens induced these changes can not be definitely established with the present data. Never- theless, an early maturation of the gonadostat or a direct effect of estrogens on germinal epithelium (or both), could be speculated.

Oncologically , an association between ovarian neo- plasms and Peutz-Jeghers syndrome of about 14% has been found.5 Some of them are granulosa cell tumors5 whose embriologic origin is identical to that of Sertoli cell tumors. Furthermore, the ovarian neoplasm which Scully termed “sexual cordon tumor with annular tubule^''^^ probably originated in the granulosa cells, shows a growth pattern very similar to that of Sertoli cell tumors. Of the 13 cases reported by this investigation, 6 patients were women with corrobora- ted Peutz-Jeghers syndrome.25

The association in Peutz-Jeghers syndrome of polyp- osis and ovarian tumors or Sertoli cell tumors could be explained on the basis of the defective action of a single gene during differentiation of the corresponding mesodermal and endodermal derivates. It may be con- cluded that gonadal tumors in Peutz-Jeghers syndrome have the same biologic significance in male and female patients and are additional evidence of pleiotropism.

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