Spermatocytic Tumor Pathology

A spermatocytic tumor is an uncommon neoplasm unique to the testis with clinicopathologic features distinctive from classic seminoma, and is not considered a variant of the latter. It was first recognized and described by Masson ("le seminome spermatocytaire") in 1946. ^{[1, 2, 3]} Until the 2016 update of the World Health Organization (WHO) Classification of Tumours of the Urinary System and Male Genital Organs, spermatocytic tumor was known as spermatocytic seminoma. ^[4]

See an example of a spermatocytic tumor depicted in the histologic image shown below.

Spermatocytic Tumor Pathology. At low power, the tumor shows a sharp demarcation to the testicular parenchyma, which is edematous. There are subtle fibrous bands within the tumor.

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Spermatocytic tumor has an annual incidence of approximately 0.2 per 100 000, comprising no more than 2% of all testicular germ cell tumors (TGCTs), with no clear rise during recent decades. ^[5] A population-based study has shown that spermatocytic tumors represent about 1% of all seminomas, with an increase in incidence over the past decades. ^[5] In a series from Pakistan, there were 16 spermatocytic tumors and 486 classic seminomas in a 21-year span. ^[6]

Patients with spermatocytic tumors are usually older than patients with other testicular germ cell tumors, with most cases presenting in the sixth decade. However, age at diagnosis ranges from 19-92 years (mean, 53.5 y); therefore, spermatocytic tumor should be considered in the differential diagnosis of testicular germ cell tumors presenting in young adults. ^{[7, 8, 9]}

Unlike other testicular tumors, spermatocytic tumors does not appear to be linked to cryptorchidism and is not associated with intratubular germ cell neoplasia, unclassified type (IGCNU), or other testicular germ cell tumor subtypes. ^{[10, 11]} One study made an attempt to link human spermatogonial stem cells as the cell of origin for this tumor, ^[12] evidence that was reinforced by the expression of OCT2, SSX, and SAGE1, which point to a spermatogonia as a cell of origin in a different study. ^[13] An immunohistochemical and molecular study supports that these tumors are likely to originate in a cell farther along the developmental pathway than those that give rise to other germ cell tumors. ^[14]

The primary tumor site is limited to the testis and, unlike classic seminoma, spermatocytic tumors have never been reported as primary at extragonadal sites. Bilateral involvement occurs in less than 5% of cases and is usually asynchronous. ^{[15, 16, 17]} They rarely involve the rete testis and may compress the epididymis without invading it.

Most spermatocytic tumors present with painless testicular enlargement, which can be referred to several years before the diagnosis. Spermatocytic tumors are not associated with any serum marker elevation. ^{[2, 18]}

Spermatocytic tumors are usually multinodular, with a cut surface that varies from gray-white and fleshy to tan and gelatinous. Hemorrhage and necrosis may be present as well as extratesticular extension. The size varies from 1.0 to 20 cm, with more than 70% measuring 3-8 cm. Microcysts are common. Necrosis and hemorrhage are rare, and if present, these features may suggest associated sarcoma. ^[19]

Nodules of diffuse sheets of cells in spermatocytic tumors are usually interspersed by edema. If extensive, the edema can give rise to a nested, pseudoglandular or trabecular pattern. Fibrous septa, clear cytoplasm and associated granulomatous reaction, present of classic seminoma, are virtually lacking in spermatocytic tumors. Likewise, lymphoid infiltrate is scant to absent, and usually limited to a perivascular distribution at the periphery of the tumor. See the images below.

Spermatocytic Tumor Pathology. At low power, the tumor shows a sharp demarcation to the testicular parenchyma, which is edematous. There are subtle fibrous bands within the tumor.

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Spermatocytic Tumor Pathology. The tumor cells are displayed in sheets that are loosely cohesive in a mucoid stroma. The vascularity can be prominent. Although the typical lymphocytic infiltrates of the classic seminoma is usually absent, one can usually find focal clusters of small lymphocytes.

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The most distinctive feature of spermatocytic tumors is cellular variation. Cells with uniformly round nuclei but with variation in diameter (6-100 µm) are distributed in three distinctive populations: small lymphocytelike cells (6-8 µm) with smudged chromatin and slightly more cytoplasm than a lymphocyte; intermediate-sized cells (15-20 µm), the most common cell type; and large cells (50-100 µm), that may be mono- or multinucleated. The chromatin is dense in small cells and filamentous in the intermediate and large ones, with a "spireme" appearance, reminiscent of primary spermatocytes, hence the name. The mitotic rate is often high and apoptosis is prominent. The cytoplasm is eosinophilic to amphophilic and lacks glycogen (periodic acid Schiff [PAS] negative). See the following images.

Spermatocytic Tumor Pathology. The 3 typical cell types are seen: large and intermediate cells have "spiremelike" chromatin distribution.

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Spermatocytic Tumor Pathology. In this field, one can see striking pleomorphism and an atypical mitosis. Mitoses are usually present, but only seldom exceed 20 per 10 high power fields.

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Spermatocytic Tumor Pathology. In this field, the 3-cell population is noted. In contrast to classic seminoma, the cell borders are indistinct.

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The controversial and rare "anaplastic" variants of spermatocytic tumors consist of a relatively monomorphic population of intermediate-sized cells with only foci of typical spermatocytic tumor elsewhere. ^{[20, 21, 22]} Spermatocytic tumors may also present in combination with sarcoma, in which the sarcomatous component, consisting of poorly differentiated spindle cells, is intermingled with the spermatocytic tumor cells. ^{[19, 23]} One report described a case of spermatocytic tumor and undifferentiated sarcoma, with the sarcomatous component recurring and metastasizing to both lungs within a year of diagnosis. ^[24] Seung-Kwon Choi et al described a case of a spermatocytic tumor with brain metastasis; no sarcomatous transformation was noted. ^[25]

Although spermatocytic tumor is not associated with IGCNU, intratubular spread is a common finding. ^[10] In fact, secondary nodules are thought to evolve from invasive cells in foci of intratubular spermatocytic tumor. The tubules are distended by a polymorphous population of cells that lack the characteristic features of IGCNU.

Fine-needle aspiration cytology findings can be diagnostic if the typical triple-cell population is sampled, with a preponderance of medium-sized cells with visible nucleoli. The background should be clean, in contrast to the "tigroid" substance seen in classic seminoma. Absence of lymphocytes can also aid the diagnosis. ^[26]

Table 1. Clinicopathologic Features of Spermatocytic Tumor Versus Seminoma (Open Table in a new window)

Spermatocytic tumors are negative for markers such as placental alkaline phosphatase (PLAP), OCT3/4, AE1/AE3, and CD30, which are usually positive in embryonal carcinomas. Other negative markers include S-100, vimentin, actin, desmin, alpha-fetoprotein (AFP), human chorionic gonadotropin (hCG), leukocyte common antigen (LCA) and cytokeratins, although CAM 5.2 may show focal cytoplasmic positivity. ^[28]

Immunostaining for c-kit is positive in 100% of spermatocytic tumors, although this finding is not useful in the distinction from classic seminoma because it is positive in both. Positive specific markers for spermatocytic tumor include antibodies directed against synovial sarcoma on the X chromosome (SSX) mainly found in spermatogonia, ^[29] xeroderma pigmentosum type A protein (XPA) which is expressed in pachytene spermatocytes, and synaptonemal complex protein 1 (SCP1), a marker for cells undergoing meiosis. ^[14] Spermatocytic tumors have been reportedly positive for OCT2 and SSX2-4 markers, which may suggest a spermatogonia as their cell of origin. ^[13] More recently, positivity for three antibodies has been described to be highly sensitive, but not entirely specific, for spermatocytic tumor: nuclear protein in testis (NUT), GAGE7, and NY-ESO-1. ^[30]

Although classic seminomas originate from an embryonic germ cell, spermatocytic tumors are likely to originate in a cell farther along the developmental pathway capable of differentiating toward the primary pachytene-spermatocyte stage of maturation. Because of the distinctive meiotic-type chromatin in some cells, it has been proposed that spermatocytic tumors develop from meiotic cells.

Although haploid DNA and lectin-binding studies have failed to demonstrate advanced spermatogenic differentiation, ^[31] stage-specific markers for male germ cell development are positive in spermatocytic tumors but not on other testicular germ cell tumors. ^[14] Similarly, proteins expressed in gonocytes and spermatogonia are consistently present in spermatocytic tumor.

In contrast, antigens expressed in embryonic germ cells but not in the normal adult testis are usually undetectable, with the exception of p53 protein, which has been demonstrated in 80% of cases. ^[32] Furthermore, the genomic imprinting in spermatocytic tumor has a paternal pattern in contrast to other testicular germ cell tumors, which generally show an erased pattern of imprinting, supporting the idea of a more differentiated cell of origin in spermatocytic tumor. ^[33]

Whereas classic seminomas show characteristically overrepresentation of the 12p chromosome, it appears that the most common abnormality in spermatocytic tumors is gains in chromosome 9. ^[34] Based on the region of amplification and the associated expression defined on 9p, DMRT1 (a male-specific transcriptional regulator) was identified as a likely candidate gene for involvement in the development of spermatocytic tumors. ^{[3, 35]}

Despite nuclear pleomorphism and the alarming microscopic appearance, spermatocytic tumors have a benign clinical course, with very few reports of metastasis in the literature if there is no sarcomatous component. ^{[36, 37, 38, 25]} However, if associated with sarcoma, the sarcomatous component is likely to progress either to local recurrence or hematogenic metastasis, lung being the preferred site. ^{[3, 37, 38, 24]} Metastatic disease at the time of presentation or histological diagnosis has been reported in at least six cases of spermatocytic tumor with sarcoma association, with two cases developing metastatic disease months or years after orchidectomy. ^[39] There has been one recent report with an association of spermatocytic tumor with lymphoma. ^[40]

The image below depicts spread to the testicular parenchyma.

Spermatocytic Tumor Pathology. In this case, the tumor cells infiltrate around seminiferous tubules and spread to the testicular parenchyma without a capsule or pseudocapsule.

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Unless complicated by sarcoma, spermatocytic tumors follow a benign course and orchiectomy alone is the preferred treatment. ^[7] Therefore, and also limited by the small number of cases in most series, prognostic markers have been secondary in the disease appraisal and management. One series with a 6-year median follow-up did not show any recurrence in cases without sarcoma. ^[41]

It has been hypothesized, however, that apoptosis may play a role in the indolent behavior of spermatocytic tumors in an analogy to indolent behavior in other tumor systems (notably CD30-positive cutaneous lymphoma, another neoplasm where phenotype and behavior do not match). ^[42] Significantly greater numbers of apoptotic cells and activated caspase-3-positive cells were found in spermatocytic seminoma compared with usual seminoma. Furthermore, apoptotic parameters were decreased in sarcomatous transformation of spermatocytic tumor.