Spermatocytic seminoma of the testis is an entity distinct from the classic seminoma and other germ cell tumors both clinically and pathologically and has not been reported in the normal ovary or at extragonadal sites, although 1 case was recently described in the dysgenetic gonad of a phenotypic female who had an associated gonadoblastoma.9 This confinement to the male gonad is just 1 of a number of differences that set it apart as a distinct entity from other gonadal germ cell tumors. These differences have been established since the late 1960s when the triad of great investigators mentioned in the introduction had put their stamp on this neoplasm by writing their definitive contributions on it.1–3 Additional differences from other neoplasms ever reasonably in the differential diagnosis have been: a good prognosis with the exception of rare tumors that undergo sarcomatous transformation; a significant tendency to occur in the older male; somewhat greater frequency of bilaterality than usual seminoma; typical lack of association with undescended testis; no association with other germ cell tumor elements, including germ cell neoplasia in situ; a more varied cellular morphology type than usual seminoma; and typical lack of a stromal inflammatory reaction. In the discussion that follows we will elaborate on these various features, and remark on their importance in the differential diagnosis by placing the findings in our series in context with observations already in the literature.1–6,10–15 In addition, we investigated the frequency of unusual features.
The first aspect worth comment is the age of the patients. The average, 52 years, is about 15 years older than that of usual seminoma and 25 years older than that of embryonal carcinoma, the other germ cell tumor in the differential diagnosis on occasion. Although it is possible that our cohort was slightly skewed toward a younger age due to the referral nature of the majority, the incidence of spermatocytic seminoma in younger men is higher than many realize, with 30% of our patients being in the fourth decade. The youngest patient in the literature was 19 years old.14 The presentation of the patients does not differ significantly from that of most other patients with a testicular mass; given the indolent nature of the tumor, there is often some appreciable interval from the time of initial recognition of a lesion by the patient to their seeking medical attention. In his comprehensive review, Eble11 remarked that in about a third of the cases a mass had been known about for 12 months or longer and, in 6 papers he cited, for 5 years or more.
The incidence of left-sided and right-sided tumor was essentially similar in our series (51% vs. 44%); this is at variance with 1 report of right-sided predominance.15 Bilateral testicular tumors were seen in 3 patients (5%), 1 of whom had undescended testes. This frequency of bilaterality, which exceeds that of seminoma, is a well-known aspect of this tumor. Cryptorchidism is a known risk factor for testicular germ cell tumors of the usual forms 16,17 but does not appear to be a risk for spermatocytic seminoma and correlates with the absence of germ cell neoplasia in situ in the latter. Ours, to our knowledge, is the second reported case of spermatocytic seminoma in an undescended testis, a finding we view as coincidental. The previously reported case was from a 44-year-old man.18 The patient in our study presented with bilateral testicular tumors at 67 years.
The key diagnostic feature of spermatocytic seminoma is 3 distinctive cell populations. In addition to the nuclear features of intermediate cells as commonly described in the literature, they may infrequently (6%) become crowded, vesicular, and have very prominent nucleoli. Tumors having cells of this type have been referred to as “anaplastic variants” in the literature and represent a diagnostic pitfall due to their resemblance to solid type of embryonal carcinoma.19,20 In a case like this, the presence of conventional spermatocytic seminoma cells elsewhere, the occurrence within the “anaplastic” population of subtle yet discernible variation, and the regular, round nature of the nuclei aid in the diagnosis. Immunohistochemical studies can be helpful in difficult cases. Embryonal carcinoma is positive for CD30 and OCT3/4 (POU5F1) and spermatocytic seminoma is negative for both markers. The experience with the so-called “anaplastic” variant is quite limited and no solid evidence yet exists that it has a different clinical behavior than typical spermatocytic seminoma. For this reason, it was not recognized as a separate entity in the latest World Health Organization monograph dealing with testicular tumors.8
Spermatocytic seminoma tumor cells grow in sheets or nodules often separated by broad and edematous bands of fibrovascular tissue; delicate fibrous septa as seen in classic seminomas are only rarely seen focally (Fig. 5B). An interesting aspect not previously described, to the best of our knowledge, is the absence of residual testicular parenchyma within tissue between tumor nodules. This is not the usual case in multinodular testicular germ cell tumors of the more common types. An additional “new” observation was a distinct rim of fibrin at the periphery of portions of tumor nodules in a minority of cases. This feature, in our experience, is not seen in other forms of testicular germ cell tumor. Although follicle-like spaces are well described and illustrated in some papers on spermatocytic seminoma, we were somewhat surprised by their frequency in our cases and prominence in individual cases. Conspicuous lymphocytic infiltration and granulomatous inflammation are characteristic of classic seminoma and usually absent in spermatocytic seminoma. Although an uncommon finding, prominent lymphocytic infiltration was seen in a small subset of our cases, and they all had a distinct nodular pattern. The lymphocytic infiltration was most striking in the fibrous bands surrounding tumor nodules. Diffuse lymphocytic infiltration along delicate fibrous bands to the extent similar to classic seminomas was not observed. However, small neoplastic cells can mimic lymphocytes under low-power view occasionally. Exuberant granulomatous inflammation was also observed in 1 case. The occasional presence of a lymphocytic infiltrate and rarely granulomatous inflammation enhances difficulty in differential diagnosis with classic seminoma, but recognition of the 3 cell types remains the key to the diagnosis.
Spermatocytic seminoma undergoing sarcomatous transformation is a rare but well-documented event (Table 2).4–6,15,21–27 Two of our 85 cases exhibited this phenomenon, with predominant spindle cell morphology and pleomorphic sarcoma appearance, respectively. The former showed a focus of chondrosarcomatous differentiation, a finding that has been reported, to the best of our knowledge, only 1 time previously in the English language literature (Table 2).27 Although uncommon, this feature highlights the importance of thorough sampling of the tumor and recognition of such a component because the sarcomatous component usually poses a significant risk for metastatic disease, warranting therapy postorchiectomy (Table 2). On the contrary, the usual spermatocytic seminoma is almost always cured by orchiectomy alone, with only 4 reported cases with histologic documentation of metastases showing spermatocytic seminoma.28–31
The majority of spermatocytic seminomas show intratubular spread at the periphery. It is important not to mistake this as germ cell neoplasia in situ, which is associated with other malignant germ cell tumors in the testis. The basement membrane of the tubules in the latter are usually thickened, spermatogenesis is almost always absent and the tubules have a single layer of seminoma-like cells at the basal aspect, occupying what has been termed the “spermatogonial niche.” In spermatocytic seminoma, the tubules are filled by the same types of tumor cells as the main tumor, the basement membranes are usually not thickened and spermatogenesis can still be seen in many of the involved tubules.
The differential diagnosis of spermatocytic seminoma (excluding rare cases complicated by sarcoma) essentially comes down to 3 other processes, seminoma, particularly with microcystic patterns,7 embryonal carcinoma,32 and malignant lymphoma.33 With regard to typical seminoma, it should be noted that although spermatocytic seminoma is more common in older men, it is still less common than conventional seminoma. For example, in an analysis of testicular tumors in patients 60 years of age or older, Abell and Holtz34 had 9 cases of typical seminoma and only 1 spermatocytic seminoma. It should also be noted that, conversely, a sizeable minority of spermatocytic seminomas occur in the classic seminoma age range. In the very rare scenario in which seminomatous tumors are bilateral, that itself would favor slightly the spermatocytic variant. A further soft “clue” before microscopic evaluation is the somewhat edematous-mucoid appearance of some spermatocytic seminomas which is not a feature of usual seminoma. Also, spermatocytic seminoma less likely shows grossly evident necrosis. At the microscopic level there are architectural, cytologic, and immunohistochemical differences between these 2 neoplasms. However, some element of overlap exists as is evident from our results, so a combination of findings should be considered. Often a very good indication of spermatocytic seminoma is obtained at scanning magnification when multiple closely packed, sharply circumscribed nodules are seen, sometimes having partial rims of fibrin deposits. The typical delicate septa with sprinkling of lymphocytes seen in usual seminoma is a rare and focal feature of the spermatocytic entity (Fig. 5B). However, a stromal component may be striking, which is typically in the form of larger loose bands of edematous fibrous tissue. We found granulomas in 1 of our cases of spermatocytic seminoma, they are much more suggestive of usual seminoma. Particular note should be made here of the recent description of microcystic spaces in otherwise typical seminomas,7 as this is a facet of the morphologic spectrum of “typical seminoma” not appreciated, to the best of our knowledge, at the time of prior contributions on spermatocytic seminoma. It is crucial in these cases to find areas of conventional seminoma and the helpful differing immunohistochemical features between seminoma and spermatocytic seminoma are perhaps never more helpful than they are in this instance. It should also be noted that the follicle-like spaces in spermatocytic seminoma are larger and more regular than the microcystic spaces seen in some cases of typical seminoma. In these and more straightforward cases, the lack of staining of spermatocytic seminoma for OCT3/4 and absent to rare staining for PLAP contrast with what is seen with typical seminomas, including those with microspaces. In contrast, increased immunohistochemical reactivity for FGFR3, HRAS, and DMRT1 has been shown in spermatocytic seminoma. Overexpression of these proteins is associated with mutations of FGFR3 and HRAS or amplification of the 9p21.3-pter region, respectively.35,36
Because the spermatocytic seminoma may have microcysts, brief mention of the differential diagnosis with another germ cell tumor often having microcysts, the yolk sac tumor,37 is warranted. The latter in pure form, however, has a markedly different age distribution from spermatocytic seminoma, being exceptionally rare after 20 years of age (although we have seen 1 case in an elderly male). The typical foci of spermatocytic seminoma bear no reasonable resemblance to even the solid foci of yolk sac tumor38 and varied other features of yolk sac tumor are not seen in spermatocytic seminoma.
The most realistic other germ cell tumor in the differential is embryonal carcinoma because of the presence of a relatively uniform population of cells lacking the classic tripartite features in some spermatocytic seminomas. This so-called “anaplastic” morphology19 may mimic the solid pattern of embryonal carcinoma. From the clinical perspective embryonal carcinoma occurs at an even younger age than does the usual case of typical seminoma, on average occurring a decade earlier, peaking between 25 and 35 years of age. In our study there were only 11 patients 35 years of age or younger. Microscopically almost all cases of embryonal carcinoma have papillary and glandular patterns inconsistent with spermatocytic seminoma. Despite the “anaplastic” nature of this uncommon spermatocytic seminoma variant, they still retain the round nuclei characteristic of this tumor, whereas those of embryonal carcinoma are more irregular in almost all instances. Diligent search for foci of “tripartite” morphology, including additional sections, almost always solves this differential diagnosis. If warranted the typical staining of embryonal carcinoma for CD30 and OCT3/4 will be definitive.
A final and important tumor in the differential diagnosis is malignant lymphoma,33 and this issue is of some interest from the historical perspective. It is of note that in 1965 a series of cases of “spermatocytic seminoma” in which 4 of the 5 tumors were clinically malignant was reported.39 However, Dr Juan Rosai subsequently obtained those tumors for review, as noted in his original paper on spermatocytic seminoma,2 and after consultation with Dr Robert E. Scully (J. Rosai, personal communication), concluded that all 4 malignant cases were malignant lymphoma. It is even possible that Dr Masson made a diagnostic error with 2 of his original 6 cases as they had a clinically malignant course. Given the overall good prognosis with the great majority of cases, it is highly unlikely that one third of his cases would have behaved aggressively. Clinical similarities between the 2 tumors, notably the usual older age range of both, can be an initial feature that can potentially lead to a misdiagnosis if microscopic differences are not appreciated. Should the pathologist encounter one of the rare bilateral cases the possibility of confusion with malignant lymphoma (itself often bilateral) may be enhanced. At the microscopic level the common significant intertubular growth of malignant lymphoma of all forms is generally a much less conspicuous feature of spermatocytic seminoma (except at the periphery of the latter), although there are occasional exceptions (Fig. 2C). As in the differential diagnosis of malignant lymphoma with carcinoma and other entities elsewhere in the body, careful scrutiny on high power to appreciate the typical features of malignant lymphoid cells is crucial. A variety of immunohistochemical differences between lymphoma and spermatocytic seminoma exist and should be applied if this differential arises and is a realistic challenge.
A few final comments should be made on the rare cases of spermatocytic seminoma with sarcomatous transformation. Although it may not be crucial from prognostic or management aspects, it is of academic interest to establish the origin of a testicular sarcoma from spermatocytic seminoma. Most primary sarcomas of the testis in adults arise out of a teratoma and those without that association are rare.40 Thorough sampling is required to diagnose an origin from spermatocytic seminoma, particularly paying attention to different gross aspects. The spermatocytic seminoma typically has a more variegated appearance and sarcoma is more uniformly white and fleshy. Not uncommonly there may be a clinical history that goes along with transformation of spermatocytic seminoma to sarcoma (Table 2). We had the opportunity to review a case of this nature (not included in this series) in the consultation files of Dr Fred W. Stewart (kindly facilitated by Dr Juan Rosai). In this case an elderly man had been aware of a testicular mass for decades and only sought medical attention when there was rapid growth of the mass. Microscopic examination showed spermatocytic seminoma of usual type (presumably accounting for the decades-long mass) and sarcoma, the latter presumptively causing the recent rapid growth. The appearance of the sarcomas in cases with sarcomatous transformation has been varied, ranging from nonspecific, most common, to rhabdomyosarcoma, to rarely chondrosarcomatous in nature (Table 2).
In summary, we have reported the largest series of cases of spermatocytic seminoma focusing on its broad morphologic spectrum. Despite its tendency to occur in older patients, the occurrence of some in relatively young patients is highlighted by our results. Our study also highlights a constellation of findings observable on low power, that can be an immediate clue to the likely diagnosis, even when some unusual features are present.
The authors are grateful to Dr Juan Rosai for sharing with 1 of us (R.H.Y.) the story of his obtaining slides of the cases reported in Jackson and Magner39 when Dr Rosai was in the city of the origin of that report, then sharing them with Dr Robert E. Scully.
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Keywords:Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
spermatocytic seminoma; spermatocytic tumor; testis; germ cell tumor; testicular neoplasms