Medical and Pediatric Oncology 21:362-364 (1993)

PROCEEDINGS OF THE TUMOR BOARD OF THE CHILDREN’S HOSPITAL OF PHILADELPHIA Giulio J. D‘Angio, MD, Series Editor, and Audrey E. Evans, MD, Associate Editor

Gonadal Stromal Tumor of the Testis in an Infant’

Michael Schneider, BA, R. Beverly Raney, MD, and Antonia K. Uri, MD

Key words: androblastoma, Sertoli cell tumor, cancer in infants, yolk sac tumor r CLINICAL SUMMARY

Michael Schneider, BA (Medical Student, University of Pennsylvania)

A seven-month-old white male infant was well until his mother noted that the left testicle was larger than the right, due to the presence of a nontender, hard, grape- sized nodule on the left. She reported no constipation or urinary symptoms. The child had normal activity and an otherwise normal appearance. He was seen by a urologic surgeon at another hospital, who performed an ultrasound examination of both testicles. A solid nodule was seen in the left testicle; there was no abnormality on the right. Subsequently, a radical left orchidectomy was per- formed, followed by a retroperitoneal node dissection. The chest roentgenograms showed no evidence of me- tastases. Serum levels of alpha-fetoprotein and human chorionic gonadotropin were normal. The pathologic di- agnosis was malignant stromal tumor of the testis.

The parents were farmers in a Mennonite community in Pennsylvania, and the parents’ grandfathers were brothers. However, there was no history of cancer in siblings or uncles, and there are no known genetic dis- eases in the family.

Upon referral to the Children’s Hospital of Philadel- phia, the child was alert and playful. His height was in the 95th percentile for age and weight between the 75th and 90th percentile for age. Physical examination was unre- markable except for well-healed scars on the abdominal wall and absence of the Ieft testicle. There was no evi- dence of sexual precocity or gynecomastia.

This case is presented in order to discuss this very rare tumor and to decide whether chemotherapy is appropriate for his management.

PATHOLOGY REPORT

Antonia K. Uri, MD (Pediatric Pathologist)

The referring pathologist noted that the left testicle was enlarged and grossly abnormal. It was yellowish-tan and cystic in appearance. Histology shows that the tumor cells are replacing the normal testicular structures and 0 1993 Wiley-Liss, Inc.

forming solid sheets and cords of primitive cells which have delicate, fibrous stroma (Fig. 1). Abundant mitoses are present in every high power field, and venous inva- sion by the tumor cells is evident. The regional lymph nodes have no evidence of tumor involvement. The his- tology is characteristic of a malignant gonadal stromal tumor.

Howard Snyder, MD (Pediatric Urologist)

Did you see any Leydig cells? Dr. Uri. There may be Sertoli cell differentiation in

this tumor, but Leydig cells are not apparent either in the tumor or in the adjacent testis. Normally, no Leydig cells are expected to be seen at this age. Although present during fetal growth, Leydig cells disappear after birth and do not return until just before puberty.

R. Beverly Raney, MD (Pediatric Oncologist)

Is the appearance of Leydig cells during fetal life and their disappearance after birth related to the influence of maternal hormones?

Dr. Uri. Yes, this is thought to be true under normal circumstances. However, in pathological conditions,

From the Children’s Cancer Research Center, Children’s Hospital of Philadelphia, Philadelphia, PA 19104.

Received November 30, 1992; accepted December 11 , 1992

Address reprint requests to Giulio J. D’Angio, MD, Department of Radiation Oncology, Hospital of the University of Pennsylvania. 3400 Spruce Street, Philadelphia, PA 19104.

‘These proceedings were prepared some time ago by Dr. Raney, who was then Editor of this series. The case is of interest because of the rarity of the condition, and because there have since been reports of responses to chemotherapy, which were scant at the time the case was under consideration. The discussion and reference list have been up- dated to include this information.

Michael Schneider, MD, is presently at the Baylor College of Medi- cine, Houston, TX.

R . Beverly Raney is now at the U.T.M.D. Anderson Cancer Center, Houston, TX. Antonia K. Uri is currently at the Department of Pathology, Children’s Hospital of Philadelphia, Philadelphia, PA.

Testicular Stromal Tumor 363

Fig. 1. Light microscopy of malignant gonadal stromal tumor show- ing solid sheets and cords of primitive cells with delicate stroma and mitotic figures. x400 (Hematoxylin-eosin).

Leydig cells may proliferate or become neoplastic. Some of those conditions are associated with endocrine distur- bances. This tumor shows no features of Leydig cell differentiation.

Dr. Snyder. Dr. K. Mostofi at the Armed Forces Insti- tute of Pathology also reviewed sections of this tumor, and agreed with the diagnosis of malignant gonadal stro- ma1 tumor. He stressed the point that this tumor is very primitive, since there are no evident hormonal changes in this child. He also thought that the presence of venous invasion was ominous.

Dr. Raney. Did he comment on whether the mitotic rate influences the likelihood of metastatic disease?

Dr. Snyder. He mentioned that there is no known correlation between the degree of mitosis and biologic behavior.

DISCUSSION Mr. Schneider and Dr. Raney. Gonadal stromal tu-

mors form up to 1.5% of all testicular tumors, and there are approximately 80 cases reported in the literature. This entity has also been called a Sertoli cell tumor or andro- blastoma, and can occasionally be admixed with Leydig cell elements [ 1-71. These tumors are believed to develop from the primitive germinal epithelium, mesenchyme, or both, since they may contain elements that morphologi- cally resemble both the sex cord and the supporting tis- sues found in the gonads of both males and females [8] . A bimodal distribution of age incidence has been noted, with most cases occurring in children younger than one year of age and in early adulthood. The usual presenting findings in males are similar to those in this case, which include a testicular mass with or without hormonal changes. Feminization and gynecomastia are more com-

monly noted in postpubertal patients, and in those males with malignant tumors.

Metastases from gonadal stromal tumors appear to be unusual in childhood. Of 27 children younger than fifteen years at the time of diagnosis, 17 were under one year of age, and none of these infants developed metastatic dis- ease [3]. Some authors insist that malignancy can be proven only by the presence of histologically verified tumor in retroperitoneal lymph nodes, lung, or other structures [3,6,8,9]. Madsen and Hultberg summarized the literature in 1990 and found 21 well-documented cases of metastasizing Sertoli cell tumors of the testis. Only three occurred in patients less than 20 years of age (ages 8, 12, and 16 years); two patients were alive at six months and two years after diagnosis, and the third pa- tient died 13 months later [9]. Only five of the 18 older patients were alive at the time of the report [9].

Dr. Snyder. I question whether retroperitoneal lymph node dissection is even appropriate in an infant diagnosed with this pathologic variety of testicular tumor. As with yolk sac tumors of the infant testicle, regional nodal metastases are uncommon, and thus routine lymph node dissection in infants may not be indicated. However, we would explore the retroperitoneum if there were evidence of nodal enlargement by ultrasound examination or com- puterized tomographic examination of that region.

Anna T. Meadows, MD (Pediatric Oncologist)

What are your plans for this child now, Dr. Raney? Dr. Raney. This boy clearly needs to have a CT scan

of the chest in order to look for the presence of pulmonary parenchymal nodules.

Ciulio J. D‘Angio, MD (Pediatric Radiation Therapist)

What will you do if the CT scan shows one or more pulmonary nodules?

Dr. Raney. If only one nodule is found, I will recom- mend that it be removed surgically, in order to determine its nature. If it proves to be malignant or if many typical metastatic nodules are found radiographically, I will con- sider the use of some form of chemotherapy.

Dr. D’Angio. What would you use? For example, would you employ a single agent, or would you use a combination of medications?

Dr. Raney. Little information in the literature ad- dresses effective chemotherapeutic agents for this rare disease. Madsen and Hultberg’s review indicates that the drugs commonly employed for malignant germ-cell tu- mors of the testis, namely cisplatin (CDDP), vinblastine (VBL), bleomycin (Bleo), and etoposide (VP-16), are not effective. However, one patient developed complete remission of lung metastases for 20 months while receiv- ing CDDP, doxorubicin, and cyclophosphamide, and re-

364 Schneider et al.

sponded later to intensified chemotherapy with CDDP, Bleo, and VP-16 [9]. Sharma and colleagues recently reported a dramatic but short-lived complete response lasting three months following CDDP, Bleo, and VBL in a nine-year-old boy with widespread metastases [ 101. Thus, given a choice of possible agents, I would select the latter regimen and would also consider adding doxo- rubicin and cyclophosphamide, perhaps in alternating cy- cles.

Dr. Meadows. How do you plan to follow this pa- tient’s progress?

Dr. Raney. I think repeated physical examination at two-month to three-month intervals would be appropri- ate, along with a chest X-ray film at that time and an abdominal ultrasound examination.

Dr. Meadows. Do you think it would be worthwhile to ascertain the levels of circulating sex hormones?

Dr. Raney. No, because this child has no external evidence of sex hormone excess. He is otherwise healthy and has no evidence of secondary sexual characteristics. If precocious puberty is noted, I would recommend ob- taining the appropriate blood levels and other investiga- tions at that time.

A D D E N D U M

The boy was followed expectantly, without further treatment. He was clinically free of tumor when he died of injuries after being struck by a truck two years after diagnosis.

REFERENCES

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Rosvoll RV, Woodard JR: Malignant Sertoli cell tumor of the testis. Cancer 22:8-13, 1968. Exelby PR: Testicular cancer in children. Cancer 4S:1803-1809, 1980. Gabrilove JL, Freiberg EK, Leiter E, Nicolis GL: Feminizing and non-feminizing Sertoli cell tumors. J Urol 124:757-767, 1980. Campbell CM, Middleton AW Jr: Malignant gonadal stromal tumor: Case report and review of literature. J Urol 125:257-259, 1981. White JM, McCarthy MP: Testicular gonadal stromal tumors in newborns. Urology 20:121-124, 1982. Kaplan GW, Croniie WJ, Kelalis PP, Silber I , Tank ES Jr: Go- nadal stromal tumors: A report of the prepubertal testicular tumor registry. J Urol 136:300-302, 1986.

7.

8.

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Young RH, Talerman A: Testicular tumors other than germ cell tumors. Semin Diagn Pathol4:342-360, 1987. Eble JN, Hull MT, Warfel KA, Donohue JP: Malignant sex cord- stromal tumor of testis. J Urol 313:546550, 1984. Madsen EL, Hultberg BM: Metastasizing Sertoli cell tumours of the human testis-A report of two cases and a review of the litera- ture. Acta Oncol 29:94&949 1990. Sharma S, Seam RK, Kapoor HL: Malignant Sertoli cell tumour of the testis in a child. J Surg Oncol 44:129-131, 1990.

SERIES EDITOR’S N O T E

Gonad derives from the Greek “gone” (seed), and ap- plies to both males and females. The etymological sprouts from the male seed-bearer are interesting, many and varied.

The Greek “orchis” (testicle) provides the root for the many combination forms; e.g., orchiopexy (“pexis” = fixation). “Orchido-”, the other common and equally cor- rect prefix, is from the diminutive of “orchis.” Orchid, the flower, is so named because its root resembles the “orchis.” To some, the bulbous blossom of many species recalls to some the scrotum (Latin: ultimately, “bag” via scrautum [quiver]), so, both above and below ground, this plant has become associated with the male genital apparatus. Interestingly, the combination form for mat- ters relating to the scrotum derives not from the Latin but the Greek word for scrotum, “osche,” e.g., oscheitis.

“Testis” has interesting connotations. The Latin word originally meant the testicle, (from the diminutive of testis, “testiculus”). “Testiculus” perhaps was adopted for anatomic use because “testis” itself came to mean “witness,” in the legal sense. This developed from the practice of placing the hand over the male genitals when swearing. This transposition of meaning has had ever- widening ripples that include “testimony,” “testament” and “test” itself, among many others. “Tester,” however, has two meanings: (a) one who tests, and (b) something overhead. The second meaning derives from “testa,” Latin for “brick,” and then, via obvious or devious routes, to “hard shell,” “tile,” and “head.” The last was extended in the term “tester” to indicate a helmet (ar- mory), a canopy over a bed or pulpit, a headboard, etc.

Starting with the name of a specific part of the anat- omy, Latin subverted “testis” to nonanatomic uses; con- trariwise, starting with the utilitarian “testa,” the lan- guage found its way to an anatomic part, the head.