Genitourinary Pathology

Sex Cord Stromal Tumor, Most Likely Sertoli Cell Tumor, with Fibroma-like Stroma

Victor E. Reuter
Memorial Sloan-Kattering Cancer Center


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Case History:
Unilateral testicular tumor in a 15 month-old child.


Slide 1
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Figure 1
Gross appearance of the 2.0 cm enucleated testicular mass.
Figure 2
Low magnification view of the lesion.
Figure 3
Two views of the mesenchymal component of the lesion. The image on the left contains primitive-appearing stromal cells and the image on the left appears more fibrous.

Figure 4
Cells forming cords and nests in a fibrous stroma.
Figure 5
Single cells infiltrating a fibrous stroma.
Figure 6
Two tubular structures contain densely eosinophilic hyaline bodies.

Figure 7
Immunohistochemical stain for Inhibin
Figure 8
Immunohistochemical stain for estrogen receptor.

Diagnosis:
Sex Cord Stromal Tumor, most likely Sertoli cell tumor, with fibroma-like stroma.

Discussion:
This is a very unusual case for which I requested input from my pathology colleagues at Memorial, particularly the GYN folks. I also asked Esther Oliva form MGH to take a look at the case and she was kind enough to share it with Dr. Robert Scully. It was reassuring to me that even he found it to be an unusual tumor. So, why did I chose to share something so rare with you? Well, because it allows me to review the differential diagnosis of testicular tumors in very young patients, which I will do at the end of the case discussion.

This 15 month child was found to have a unilateral testicular mass by his mother. Apparently it was not painful. On physical examination the child was found to be normally developed, the testes were descended and the penis was normal. There was no family history of note and no gynecomastia. The scrotum was explored surgically and a 2 cm mass was enucleated and submitted for a frozen section. We rendered a diagnosis of "tumor" so a completion orchiectomy was performed. The slide you have reviewed in entirely, representative of the lesion. The remaining testis and adnexa were unremarkable.

The first look at the microscopic features of the this tumor allows us to rule out a secondary lesion (lymphoma/leukemia) and mesenchymal lesion (sarcoma) and germ cell tumor (yolk sac tumor). The tumor cell are arranged in cords and nests. Rarely collections of single cells are evident. These cells are small, primitive-appearing and fusiform. The nuclear chromatin is fine and nucleoli are absent. These cells were immunoreactive for Inhibin and CD99 but negative for Oct 3/4. In areas these cells are present within tubular stuctures and sometimes associated with germinal cells. These germinal cells were negative for all these markers. We interpreted the germ cells as entrapped germ cells with features of spermatogonia. Alternatively you could interpret them as distorted seminiferous tubules involved by "intratubular" tumor. Some of these tubular structures had densely eosinophilic hyaline bodies reminiscent of Call-Exner bodies. No cysts were present. A surprising finding was the fibroma-like stroma within the lesion. This component was variably cellular and focally it was reminiscent of ovarian-like stroma. In fact, this component was immunoreactive for estrogen receptor. While this finding is not terribly unusual in association with ovaian sex cord stromal tumors, it is very rare in testicular tumors. Obviously, when confronted with this finding we immediately thought of the possibility of a "syndrome" (androgen insensitivity, etc) but given the clinical and overall pathologic features, this possibility was discarded. The possibility of Gonadoblastoma was discarded for similar reasons.

Putting everything together, we concluded that we were dealing with an unusual morphologic manifestation of a sex cord stromal tumor in a child. In a child of this age the most common type would be a Juvenile Granulosa Cell Tumor, but none of the usual morphologic or clinical features were present. The best fit is a Sertoli cell tumor with entrapped germinal cells and fibroma-like stroma. The child is doing well 4 months after surgery. Unusual indeed!

Sex cord-stromal (gonadal stromal) tumors are rare, comprising approximately 4.0% of testicular neoplasms. Similar tumors may arise in the female gonads. The term refers to neoplasms containing Leydig (interstitial) cells, Sertoli cells, granulosa cells, or theca cells. Tumors may be made up of one or a combination of these cell types in varying degrees of differentiation. The terminology used to describe these tumors is confusing and controversial but it is best to adhere to the classification set forth by the World Health Organization. Among the entities I considered in the differential diagnosis I will highlight a few.

Leydig (Interstitial) Cell Tumor:
Leydig cell tumors (LCT) are the most common pure testicular sex cord-stromal neoplasm and account for 1% to 3% of testicular neoplasms. They may occur at any age, though most common between the third and sixth decades of life [1, 2, 3, 4, 5]. Fifteen to twenty percent of cases will present in prepubertal children. Approximately 10% will metastasize with metastasis occurring at an older age. LCTs usually arise in normally descended testes although they have been described in cryptorchid gonads as well as in testes which have undergone orchiopexy. Most, if not all, children with LCT present with isosexual precocity, which is characterized by deepening of the voice, appearance of body hair, penile enlargement and advanced bone age. Often these physical changes are accompanied by excessive aggression or shyness. LCT must be considered in the differential diagnosis in all prepubertal patients with a testicular mass and precocious puberty.

Grossly, LCT is a well-circumscribed, yellow-tan or brown-gray lobulated mass occasionally containing fibrous septae. Macroscopic evidence of hemorrhage or necrosis is rare. Microscopically, the tumor is made up of large polyclonal cells with abundant eosinophilic and granular cytoplasm. Less frequently, the cytoplasm may be clear or vacuolated or microcystic [6, 7]. Nuclei are round or vesicular with delicate chromatin and a single prominent nucleolus. The cells usually exhibit a solid pattern of infiltration although fibrous septae may give them a pseudotubular or trabecular appearance. Crystalloids of Reinke are present in 25% to 40% of cases and may require electron microscopic examination for their identification. On light microscopy they appear as densely eosinophilic needle-like or rhomboid structures within the cytoplasm. LCT are likely to be immunoreactive with inhibin and vimentin but not cytokeratins, CD-30, Oct 3/4, or PLAP. [3, 8, 9, 10, 11]

Sertoli Cell Tumor
Sertoli cell tumors (SCT) are rare, comprising less than 1% of testicular neoplasms [2, 3, 4, 12, 13]. They were first described in the testis by Teilum who recognized their histologic similarity to Sertoli cell tumors of the canine testis. They may occur at any age and approximately 15% develop in children. Patients characteristically present with a painless mass in a normally descended testis. Gynecomastia is evident in one third of patients. Hormonal alterations in patients with SCT have been poorly documented. Nevertheless, SCT should be in the differential diagnosis of all prepubertal patients presenting with a testicular mass and gynecomastia. Cases have been reported in boys with Peutz-Jeghers syndrome [14].

Grossly, SCT are well circumscribed, solid and yellow-white or tan. The lesions may be lobulated and may contain small areas of hemorrhage. Microscopic examination reveals mostly tubules but also cords, nests, and masses of tumor cells in a fibrous stroma. The neoplastic cells may contain abundant intracytoplasmic lipid giving them a clear or vacuolated appearance. Electron microscopy may reveal Charol-Bottcher filaments within the cytoplasm, which are characteristic of Sertoli cells. The classification of SCT should be reserved for tumors composed entirely of Sertoli cells. Those neoplasms composed only partially of these cells should be classified as mixed or incompletely differentiated sex cord-stromal tumors. SCT are immunoreactive for inhibin, vimentin and cytokeratins. [13] Markers typically seen in GCT are negative. [3]

Juvenile Granulosa Cell Tumor
Granulosa cell tumors analogous to juvenile granulosa cell tumors of the ovary are the most common sex cord-stromal tumor of the infantile testis [2, 15, 16]. They are usually present in the first six months of life, the oldest reported case being in a 21-month-old. Two cases have developed in undescended testes. Juvenile granulosa cell tumors may arise in patients with an abnormal karyotype and ambiguous genitalia. Tumors may be solid, cystic or both and the cysts frequently contain a gelatinous material. Microscopically, the tumor exhibits either a follicular or solid pattern and the cells are characterized by a moderate to large amount of eosinophilic cytoplasm and hyperchromatic nuclei. Stromal hyalinization is often extensive. Although mitoses may be plentiful, no testicular tumor of this type has metastasized [3, 17].

Sex Cord-gonadal Stromal Tumors, Mixed or Incompletely Differentiated Forms
As you might expect, these two categories include tumors with more than one identifiable sex cord-stromal element, as well as tumors in which the exact gonadal stromal cell of origin cannot be established with certainty [2, 3, 18]. These neoplasms may occur at any age although more than half of the patients are either children or infants. Painless testicular enlargement is the most common presenting symptom that is infrequently associated with gynecomastia. Grossly, these tumors are similar to other sex cord-stromal neoplasms and their microscopic appearance is quite variable, ranging from predominantly epithelioid to predominantly stromal growth patterns. Frequently the cells are undifferentiated making precise classification impossible. Approximately 30% of tumors presenting in patients older than 10 years of age are malignant whereas tumors presenting in younger patients follow a benign course. Histologic predictors of aggressive clinical behavior have not been established. Radical orchiectomy is the treatment of choice; however, retroperitoneal lymph node dissection should be given serious consideration in patients older than 10 years of age.

Gonadoblastoma:
Gonadoblastomas are rare neoplasms composed of sex cord elements intimately admixed with germ cells [3, 18]. These tumors generally arise in chromosomally abnormal individuals with dysgenetic gonads; 20% of cases occur in phenotypic males. Patients usually present with cryptorchidism, hypospadia, and internal female genitalia, although two cases have been reported arising in a scrotal testis. One third of cases are bilateral and 60% are associated with malignant germ cell elements that are usually seminoma, but may be yolk sac tumor of embryonal carcinoma. While gonadoblastomas do not metastasize, metastasis from the associated germ cell tumor may occur.

The microscopic appearance is distinctive and consists of tumor nests surrounded by connective tissue. The nests contain germ cells with clear cytoplasm and sex cord elements resembling Sertoli cells, granulosa cells or both. The nests may contain hyalinized eosinophilic structures resembling Call-Exner bodies.

References
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