Conference 11 - 2011 Case: 02 20111214

Signalment:

6-year-old, male, domestic rabbit (Oryctolagus cuniculus)A male, sexually intact pet rabbit presented for enlargement of the left testicle in the scrotum. No other symptoms were found at clinical examination. Bilateral orchiectomy was performed.

Gross Description:

The enlarged left testicle was firm and globular, in contrast to the elongated right one, and approximately 1.7 cm in diameter. The cut surface was flat, smooth and gray-white in color.

Histopathologic Description:

The left testicle was almost entirely replaced by tumoral tissue. The tumoral tissue consisted of discrete tubular structures separated by a fibrous stroma. Tubular structures were composed of an intermixture of large round cells similar to germ cells and spindle cells with elongated nuclei similar to Sertoli or granulosa cells. The spindle cells mainly located at the periphery of tubular structures formed a palisade surrounded by basement membrane (coronal pattern). Spindle cells sometimes surround an isolated or collected large round cell similar to a germ cell and took an appearance like follicular epithelium surrounding the ovum of the primary follicle (follicular pattern). Arrangement of a microfollicular pattern containing eosinophilic amorphous material (Call-Exner-like pattern) was also seen. The central eosinophilic amorphous material was PAS-positive. The large round cells (germ cell components) had abundant clear cytoplasm and round, vesicular nuclei with prominent nucleoli. The spindle cells (sex cord components) had scant clear cytoplasm and small oval or elongated nuclei with indiscernible nucleoli. Mitotic figures were occasionally observed in the germ cell components, but were not detected in the sex cord components. Aggregates of Leydig cells were present within the intertubular stroma. These cells were non-neoplastic and lacked crystals of Reinke. Immunohistochemically, the germ cell components were positive for c-kit and placental alkaline phosphatase (PLAP). The sex cord components stained for vimentin and Wilms tumor-1 (WT-1). Electron microscopic examination revealed that the germ cell components had abundant cytoplasm within a few organelles and large round nuclei with dispersed chromatin and prominent nucleoli in the neoplastic lesion. The sex cord components had many organelles composed predominantly of mitochondria in the primarily scant cytoplasm. The nuclei of cells of the sex cord components were irregular or oval shaped and contained few or modest nucleoli. Amorphous materials surrounded by sex cord components consisted of duplicated basal laminae.

Morphologic Diagnosis:

Testicle: Gonadoblastoma

Condition:

Gonadoblastoma

Contributor Comment:

Tumors arising in testis of rabbits have rarely been reported. In domestic rabbits, one of the most common testicular tumors is the interstitial (Leydig) cell tumor(3). Gonadoblastoma rarely develops, almost exclusively in dysgenetic gonads, or in those with an intersex syndrome in humans(5). On the other hand, gonadoblastomas can be found in apparently normal ovaries and testes6. In animals, gonadoblastomas have only been reported in two dogs(4,7).

Gonadoblastoma is histomorphologically defined as a tumor composed of two principal cell types: germ cell components similar to those of seminoma and sex cord components similar to Sertoli cells. In this case, immunohistochemical examination revealed both the germ cell derivative of the large round cells (c-kit and PLAP positivity) and the sex cord nature of the spindle cells (vimentin and WT-1 positivity) in addition to characteristic morphological features. Furthermore, the ultrastructural pattern of eosinophilic amorphous bodies that are comprised of whorled laminae is already verified in canines(6) and those of human gonadoblastomas.

The differential diagnosis includes mixed germ cell-sex cord-stromal tumor (MGSST) and sex cord tumor with annular tubules (STAT). MGSST generally lacks the discrete tubular structures seen in gonadoblastoma, and usually shows proliferative activity in the sex cord component, , because unlike in gonadoblastoma, germ cells in MGSST are thought to be non-neoplastic and entrapped by neoplastic sex cord-stromal tumor. The histomorphological features showing characteristic three typical patterns (i.e.coronal, follicular, and Call-Exner-like) of sex cord elements within the discrete tubules is most characteristic and diagnostic for gonadoblastoma. In a gonadoblastoma, more than one pattern is usually found in an individual tubule(6). The presence of these patterns supports the diagnosis of gonadoblastoma in this case. STAT has a growth pattern similar to gonadoblastoma and contains eosinophilic amorphous bodies and frequently calcified material, but lacks a germ cell component. Our case is conclusively distinguished from these diagnoses.

Gonadoblastoma typically occurs within dysgenic gonads in children or young adults. Approximately 80% of cases occur in phenotypic females, and most of the remaining 20% are in phenotypic male pseudohermaphrodites(6). In more than 90% of patients with gonadoblastoma, a Y chromosome or fragment can be identified(6). However, it has been found in the testes of normal men(2). Our rabbit has no clinical symptoms such as alopecia, feminization, or cryptorchidism. Our case was apparently sexually intact judging from the intact right testis and normal development of genital organs, and has no dysgenic gonads. However, it remains unclear whether this rabbit had Y chromosome fragments or not, because karyotypic analysis was not done.

JPC Diagnosis:

Gonad: Gonadoblastoma

Conference Comment:

This neoplasm was considered benign because the tumor showed no evidence of invasive germ cells. It is postulated that gonadoblastomas result from abnormal proliferation of germ cells, which induce the sex cord mesenchymal cells around the germ cells to differentiate into granulosa-Sertoli-like cells(8). A CallExner body surrounded by sex cord stromal cells indicates areas of the collection of degenerate and necrotic debris, similar to the phagocytosis of apoptotic spermatogenic cells by Sertoli cells in normal testicles, suggesting that sex cord components may have a tendency to assemble in the area of cell dissolution9.

Placental alkaline phosphatase (PLAP) only stains neoplastic germ cells, in addition to rare somatic epithelial malignancies, and not normal germ cells, which is useful in distinguishing this neoplasm from a mixed germ cell-sex cord-stromal tumor(11). The transcription factor Wilms tumor-1 (WT-1) protein, in addition to staining nephroblastomas, is a marker of M+â-+llerian epithelial origin, and regulates the k-ras oncogene, which plays an important role in tumor suppression. Loss of WT-1 drives cells expressing oncogenic k-ras toward a senescence program, and inhibits the progression of certain types of neoplasia(10). Sex cord stromal tumors are among several neoplasms in veterinary medicine that co-express vimentin and cytokeratin (AE1/AE3); others include canine prostatic carcinoma, feline bronchogenic adenocarcinoma, synovial cell sarcoma, ciliary body adenoma, renal carcinoma, amelanotic melanoma, meningioma, mesothelioma, and anaplastic carcinoma. However, due to the growing list of neoplasms that can express both cytokeratin and vimentin, the diagnostic utility of vimentin is increasingly coming into question(1).

References:

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9. Suzuki M, et al. Testicular gonadoblastoma in two pet domestic rabbits (Oryctolagus cuniculus domesticus). J Vet Diag Invest. 2011;23(5):1028-32.
10. Vincent S, et al. Wilms tumor 1 (WT1) regulate KRAS-driven oncogenesis and senescence in mouse and human models. J Clin Invest. 2010;120(11):3940-52.
11. Wick MR. Immunohistology of melanocytic neoplasms. In: Dabbs DJ. Diagnostic Immunohistochemistry, Theranostic and Genomic Applications. 3rd ed. Philadelphia, PA:Saunders Elsevier; 2010:191.