The Problematic Testicular Tumor
Robert H. Young, M.D.

In this lecture I will discuss selected issues in the pathologic diagnosis of tumors of the testis and its adnexa emphasizing newly appreciated issues as well as some long known but still occasionally a problem. References will be selective (and only some cited herein others being provided for further reading), a standard text having a more comprehensive listing (32). For the most part well known classic aspects are not presented, being elaborated in the text just noted, the third series fascicle on the testis.

SEMINOMA (USUAL TYPE)

The almost invariable framework of delicate fibrous septa with associated blood vessels and sprinkling of lymphocytes should ideally be present to diagnose seminoma with confidence as other tumors may mimic seminoma on low power but usually lack the septal framework. High power scrutiny to make sure the typical cytologic features of seminoma cells are present is always advisable. A rare seminoma of the usual type has inconspicuous septa and the diagnosis of seminoma should be made cautiously in such cases. Although seminomas usually obliterate the underlying parenchyma, they may have a conspicuous interstitial growth pattern with tubular preservation, particularly peripherally, and rarely the cells are so uniformly widely dispersed in the interstitium that a tumor is grossly inapparent (19).

One aspect of the morphology of seminomas of otherwise typical type that may be confusing is the presence in some cases of solid or hollow tubules or others spaces of various types (Fig. 1) (37). The spaces range from small, closely packed, and relatively regular to dilated, more dispersed, and somewhat irregular. These tumors often lack or have scant lymphocytes. These tumors may have edema and that finding and the paucity of lymphocytes may suggest the erroneous diagnosis of spermatocytic seminoma, but the varied cell types of that neoplasm are absent. A microcystic pattern of seminoma is unassociated with other features, such as hyaline bodies, that would make yolk sac tumor a more realistic consideration and seminomas with tubules (that may be confused with glands) do not have as pleomorphic nuclei as seen in embryonal carcinoma. The lesional cells in these patterns, however, have the typical features of usual seminoma cells which is crucial in the differential diagnosis. Staining for OCT-4 (positive in seminoma but not yolk sac tumor) may help in the differential with a yolk sac tumor. Mistaking a malignant Sertoli cell tumor for a seminoma also occurs (see the section on Sertoli cell tumors). In occasional seminomas with syncytiotrophoblasts giant cells prominent intracytoplasmic lacunae may form small cysts which occasionally may be striking on low power (14). In the differential diagnosis of seminoma with embryonal carcinoma, and for that matter certain other issues, immunohistochemistry may play a role. An excellent discussion of this appeared in 2005 in Seminars in Diagnostic Pathology, and the contribution of Dr. R.E. Emerson and Dr. T. M. Ulbright (9) is strongly recommended. An additional rare feature of seminomas is the presence of signet ring cells (40).

SPERMATOCYTIC SEMINOMA

The spermatocytic seminoma has little or no relation to the typical seminoma except that it is another type of germ cell tumor that almost always lacks the ability to differentiate into other tissue. These tumors are composed mainly of cells resembling spermatogonia, with focal differentiation into larger cells that suggest primary spermatocytes in routine sections. On gross examination spermatocytic seminomas are typically pale and edematous or gelatinous, sometimes with cyst formation. They are more often bilateral than is the usual seminoma but are still infrequently bilateral. Rarely the clinical scenario of a long known testicular mass with sudden rapid enlargement is seen and correlates with the enigmatic phenomenon of sarcomatous differentiation in spermatocytic seminoma (31). Microscopic examination shows features that differ from those of the typical seminoma in a number of regards. The tumor is never associated with another germ cell component, only rarely has lymphocytes or a granulomatous inflammation, is glycogen and PLAP negative, and never has syncytiotrophoblasts. Although there is often a diffuse growth there is in many cases an edematous fluid in the background that can cause irregular aggregates of tumor cells (Fig. 2). The septa of typical seminoma are always absent.

The more varied trilineage, cell population is a crucial cellular distinction from usual seminoma. The most common cell type is about the size of the typical seminoma cell but has denser cytoplasm and more uniform, rounder nuclei (6). Smaller, degenerating cells with dense, homogeneous nuclei are usually present as well and represent the second cell type; it is important not to confuse these cells with lymphocytes. The third form of cell is the largest, they suggest primary spermatocytes, usually occur singly and contain very large nuclei with chromatin that may have a filamentous quality. The entity of "anaplastic" spermatocytic seminoma has recently been described (1). We agree that the morphology in these cases differs from that of typical spermatocytic seminoma but think use of the word anaplastic not indicated as there is no evidence that these tumors have a clinical behavior that one might expect for tumors that are "anaplastic". Additionally, those reported in this category have had foci of conventional neoplasia with the well known three cell types noted above. Seven cases of sarcomatous transformation of spermatocytic seminoma have been reported (31). The sarcomatous component is usually non-specific but may have the features of rhabdomyosarcoma.

TROPHOBLASTIC-TYPE TUMORS

Choriocarcinoma occurs very rarely as a pure neoplasm; much more often it is a component of a mixed germ cell tumor. Microscopic examination shows patterns similar to those encountered in uterine choriocarcinomas but rarely there is a monophasic pattern (36). The tumors stain immunohistochemically for hCG, placental lactogen (hPL) and various placental proteins. One testicular tumor indistinguishable from the placental site trophoblastic tumor of the uterus has been described in the testis of a child (36). It is important that choriocarcinoma be distinguished from seminoma or embryonal carcinoma with syncytiotrophoblast giant cells. In those instances there is not the admixture of cytotrophoblast with syncytiotrophoblast that is usually seen in choriocarcinoma, even allowing for the fact that some examples of the latter have a less classically formed biphasic pattern than some others. In seminomas and embryonal carcinomas the cells adjacent to the giant cells are typical seminoma or embryonal carcinoma cells. A pattern of embryonal carcinoma that may be misinterpreted as choriocarcinoma is that described many years ago as the appliqué pattern in which cells that are probably degenerative at the periphery of better preserved cells and applied against them sometimes may superficially suggest the biphasic pattern of choriocarcinoma.

TERATOMAS

Teratomas of the testis are rare in pure form and there is limited new information on these tumors which have one particularly unusual clinical feature namely, the fact that those occurring in prepubertal boys are invariably benign irrespective of their histology whereas those occurring postpuberty have a malignant potential even when histologically mature. The one exception to the latter comment is the rare entity of a mature cystic teratoma (dermoid cyst) of the testis. Although sporadically reported previously there is only one sizable case of dermoid cysts of the testis recently reported (33). The diagnosis should be reserved for lesions that are grossly typical of a dermoid cyst and are unassociated with adjacent intratubular germ cell neoplasia unclassified. The more common mature teratoma that has a malignant potential has a solid and cystic gross sectioned surface contrasting with the predominantly cystic nature of the sectioned surface of a dermoid cyst.

It has recently been appreciated that primitive neuroectodermal components in testicular germ cell tumors may in some instances be conspicuous, and even dominate the microscopic picture, rarely representing most or the entire neoplasm (26). These foci of neoplasia which typically have a significant component of malignant small cell neoplasia with varyingly prominent differentiation of neuroectodermal type, are usually recognized when there is an associated teratomatous component from which they arise but when the latter are inconspicuous problems in differential diagnosis may result. Foci resembling various forms of central nervous system tumors such as medulloepithelioma or ependymal neoplasms, or neuroblastoma may be encountered. These are aggressive neoplasms and should be distinguished from immature teratoma, something that should not be difficult because they usually form a confluent mass lesion.BURNT-OUT (REGRESSED) GERM CELL TUMORSA most remarkable phenomenon in testicular pathology, and which interestingly has no companion in the female gonad, is that seen when germ cell tumors undergo apparent spontaneous regression, resulting in complete or almost complete hyaline scarring. This phenomenon which is variously referred to as spontaneous regression or "burnt-out" germ cell tumor has been the subject of a recent study by the Indiana University group and that paper (3) is recommended. In these cases the testis typically shows a firm white appearance and on microscopic examination hyaline scarring is seen, sometimes with a minor component of associated viable neoplasia, such as seminoma or teratoma or at least intratubular germ cell neoplasia. The latter may be a subtle clue to the diagnosis that what one is observing is something more specific than just an old infarct. Sometimes the scar shows rather prominent vessels, hemosideri n laden macrophages, and particularly in cases that are presumptively "dead" embryonal carcinoma, intratubular calcifications. Although these regressed tumors may be clinically apparent as testicular abnormalities to inspection, sometimes they only show up on ultrasound, the classic situation being when a patient presents with a retroperitoneal germ cell tumor, which is actually a metastasis from the regressed testicular primary.

SEX CORD-STROMAL TUMORS

1. LEYDIG CELL TUMORS

In two recent papers Ulbright and colleagues have described some unusual morphologic manifestations of Leydig cell tumors. The first of these contributions recorded cystic spaces, usually small, but sometimes large (Fig. 3), resulting in confusion with various neoplasms such as yolk sac tumor (4). It is hard to think of a better example of the importance of thorough sampling in evaluating gonadal tumors because when this results in other slides showing typical Leydig cell tumor, mere awareness of the phenomenon will enable the correct interpretation to be made. Particularly in cases with unusual morphology staining for inhibin may be helpful, as it may in cases of sex cord tumors of other types such as Sertoli cell tumors, granulosa cell tumors and those in the unclassified group.

The second series contained 12 tumors with adipose differentiation, eight with spindle cells and three with calcification and ossification (34). These features had only rarely been described previously. The adipose differentiation is important in that it is also a feature of some cases of the testicular tumor of the adrenal genital syndrome and accordingly does not reliably facilitate the differential diagnosis of these two entities. A spindle cell pattern, if prominent, may obscure the underlying diagnosis of Leydig cell tumor and bring other entities such as sex cord-stromal tumor, unclassified, or even testicular sarcoma into the differential diagnosis but thorough sectioning and awareness of the phenomenon usually resolves the problem. Calcification can potentially erroneously suggest the diagnosis of a large cell calcifying Sertoli cell tumor but the latter entity shows unequivocal tubular differentiation. Ossification is only a pathologic curio. None of these unusual features, including spindle cell, appears to have prognostic importance.

2. SERTOLI CELL TUMORS

In our study of 60 Sertoli cell tumors, not otherwise specified (42), the two morphologic findings which we found most noteworthy in the sense that they had not been emphasized in the prior literature were the presence in many cases of a prominent diffuse growth with rather limited evidence of the tubular component that enables the diagnosis to be rendered with confidence, and in addition, the presence in some instances of cells with copious eosinophilic cytoplasm bringing the differential diagnosis of a Leydig cell tumor into consideration.

A subsequent paper on malignant Sertoli cell tumors (18) further emphasized the problem the above noted diffuse pattern may cause. First of all, not surprisingly, a diffuse growth is particularly likely to be seen in malignant tumors because of the limited differentiation seen in such cases. The 13 cases in this category were usually initially misdiagnosed as seminoma, usually of the classic type but occasionally of the spermatocytic type. In many of them the correct diagnosis was only made retrospectively after failure of the patient to respond to therapy usually successful in cases of seminoma. The problems on microscopic examination were related primarily to the diffuse growth but were compounded by other features common in seminoma: a nested pattern, cells with clear cytoplasm that was positive for glycogen in 3 of 4 tumors tested, prominent nucleoli (5 cases) and lymphoid infiltrate (10 cases). Focal tubular differentiation was crucial diagnostically but was often limited in amount. Other helpful findings were nuclei that were smaller and less pleomorphic than those of seminomas and immunohistochemical staining for inhibin and negative staining for placental-like alkaline phosphatase. As expected the testis adjacent to the tumor did not show any intratubular germ cell neoplasm.

An unusual phenomenon associated with an occasional Sertoli cell tumor and for that matter sex cord stromal tumors of the testis of other types arises when these often slowly growing tumors incorporate non-neoplastic germ cells within them resulting in a mimicry of true mixed germ cell-sex cord stromal tumors. We recently reported 10 cases of this type (35). Although the majority of the tumors were in the unclassified sex cord stromal category I will not be discussing such tumors because of time constraints and consider it briefly at this juncture. The admixed germ cells were usually at the periphery and in clusters but occasionally were in the center of the neoplasm or more diffusely distributed. None of the entrapped germ cells stained with markers for neoplastic germ cells. In our experience, this peculiar phenomenon of entrapment of germ cells within a sex cord tumor is more common than the exceptionally rare mixed germ cell sex cord-stromal tumor unclassified.

3. GRANULOSA CELL TUMORS

Granulosa cell tumors of both adult and juvenile types as seen so much more commonly in the ovary may be seen in the testis. The most interesting and potentially crucial issues are associated with the juvenile form so only a few remarks on it are made here. The distinctive tendency for the tumor to occur in the first six months of life is important to remember. On microscopic examination some neoplasms have conspicuous follicles and should be a relatively straightforward diagnosis but others can have only limited follicular differentiation and a solid-to-nested pattern which can be much more problematic (Fig. 4). In some cases the fluid that is typically present in the follicles may be present in an ill-defined manner in the background in foci without an overt follicular pattern and this may separate the tumor cells and impart a vague resemblance to the reticular pattern of yolk sac tumor. The immature nuclei of the juvenile granulosa cell tumor may further heighten resemblance to yolk sac tumor. Although routine light microscopic differences should enable the differential to be made there is a role for immunohistochemistry in this differential should it be deemed necessary. Finally, in some juvenile granulosa cell tumors the cells do not have the appreciable cytoplasm that is generally present and I have even seen confusion with small cell malignant tumors such as rhabdomyosarcoma. Of course, a basic principle of testicular tumor pathology, namely where the tumor is centered, can be helpful because most rhabdomyosarcomas are paratesticular albeit that they may secondarily involve the testis.

MALIGNANT LYMPHOMA, PLASMACYTOMA, AND LEUKEMIA INCLUDING GRANULOCYTIC SARCOMA

Dr. Judith Ferry has been the senior author of a number of important studies on this topic and her work was the foundation for the coverage of this topic in the fascicle and the reader is referred to her series of papers (10-13). An interesting and important issue in differential diagnosis has also just been emphasized by Dr. Ferry's group (5), namely the potential for viral orchitis to be misdiagnosed as lymphoma or leukemia. This topic will be briefly covered in the lecture and the original paper may be reviewed for detailed consideration.

METASTATIC TUMORS

Metastases to the testis are rare in contrast to the frequency of metastatic tumors in the ovary but several recent papers have highlighted the diverse problems that testicular examples may pose. Two of these papers considered specific neoplasms with a well-known propensity for metastatic spread and resultant diagnostic problems, namely renal cell carcinoma and malignant melanoma (7, 8). In the most recent paper on the topic a review of 26 non-incidental cases of metastasis to the testis from diverse sites were described by Dr. Thomas Ulbright and myself (39). Noteworthy findings in the series just noted included the frequent absence of a known primary tumor, relative rarity of bilateral involvement, the occasional lack of a distinct testicular mass on gross examination, the infrequency of multinodularity either grossly or microscopically (common in metastasis to the ovary), the prominence of intertubular growth and conspicuous intrarete or intratubular growth in some cases. Although clinical findings are obviously helpful in some cases, in many cases it is only astute recognition by the pathologist that the microscopic picture is not typical for primary testicular disease that will lead to the appropriate workup which in some cases, particularly those of metastatic melanoma, will include immunohistochemical investigation.

ADENOMATOID TUMOR

The gross and microscopic features of typical examples of this tumor are well-known and need no elaboration here. However, one challenging aspect, problems caused when these lesions infarct, has been the subject of a recent report in the literature and is the only one I will consider briefly here (29). The extensive necrosis often makes it difficult to recognize that the neoplasm is an adenomatoid tumor. Additionally, the necrotic areas may be surrounded by a florid reactive process characterized by fibroblasts and myofibroblasts with plump nuclei, often with prominent nucleoli and occasional mitoses. Furthermore, this results in blurring of the usual relatively well-delineated periphery of an adenomatoid tumor potentially raising concern for a malignant neoplasm infiltrating the adjacent tissue. Recognition of ghost outlines of the typical formations of an adenomatoid tumor in the necrotic regions, and awareness of the phenomenon, are crucial in recognizing these cases as benign.

Legends

Figure 1. Seminoma. The appearance is unusual because of the presence of numerous pseudoglandular formations and cords. Additionally, the fibrous septa do not have the typical sprinkling of lymphocytes seen in the more typical seminoma.

Figure 2. Spermatocytic seminoma. There is conspicuous edema in the background, a picture that may be a clue to the diagnosis on low-power examination, albeit it is not diagnostic.

Figure 3. Leydig cell tumor. Focal conspicuous cysts are seen at the left and more typical diffuse morphology at the right (courtesy Dr. Thomas M. Ulbright).

Figure 4. Juvenile granulosa cell tumor. This tumor from a young boy shows irregular nests with only limited follicular differentiation seen at the left. The paucity of follicles and the immature appearance of the nuclei typical of these cases may cause diagnostic problems and lead to consideration of a yolk sac tumor. Even minimal follicular differentiation may be diagnostically crucial.

References

1. Albores-Saavedra J, Huffman H, Alvarado-Cabrero I, Ayala AG. Anaplastic variant of spermatocytic seminoma. Hum Pathol 27:650-655, 1996.
2. Berdjis CC, Mostofi FK. Carcinoid tumors of the testis. J Urol 118:777-782, 1977.
3. Balzer BL, Ulbright TM. Spontaneous regression of testicular germ cell tumors: An analysis of 42 cases. Am J Surg Pathol 30:858-865, 2006.
4. Billings SD, Roth LM, Ulbright TM. Microcystic Leydig cell tumors mimicking yolk sac tumor: a report of four cases. Am J Surg Pathol 23:546-551, 2001.
5. Braaten KM, Young RH, Ferry JA. Viral-type Orchitis. A Potential Mimic of Testicular Neoplasia. Am J Surg Pathol 33:1477-1484, 2009.
6. Cheville JC, Sebo TJ, Lager DJ, Bostwick DG, Farrow GM. Leydig cell tumor of the testis: a clinicopathologic, DNA content and MIB-1 comparison of non-metastasizing and metastasizing tumors. Am J Surg Pathol 1998;22:1361-7.
7. Datta MW, Ulbright TM, Young RH. Renal cell carcinoma metastatic to the testis and its adnexa: A report of five cases including three that accounted for the initial clinical presentation. Int J Surg Pathol 9:49-56, 2001.
8. Datta MW, Young RH. Malignant melanoma mestastatic to the testis: A report of three diagnostically challenging cases with clinically significant manifestions. Int J Surg Pathol 8:49-57, 2000.
9. Emerson RE, Ulbright TM. The use of immunohistochemistry in the differential diagnosis of tumors of the testis and paratestis. Semin Diagn Pathol 22:33-50, 2005.
10. Ferry JA, Harris NL, Young RH, Coen J, Zietman A, Scully RE. Malignant lymphoma of the testis, epididymis, and spermatic cord. A clinicopathologic study of 69 cases with immunophenotypic analysis. Am J Surg Pathol 18:376-390, 1994.
11. Ferry JA, Srigley JR, Young RH. Granulocytic sarcoma of the testis: A report of two cases of a neoplasm prone to misinterpretation. Mod Pathol 10:320-325; 1997.
12. Ferry JA, Young RH, Scully RE. Testicular and epididymal plasmacytoma: A report of 7 cases, including 3 that were the initial manifestation of plasma cell myeloma. Am J Surg Pathol 21:590-598; 1997.
13. Ferry JA, Ulbright TM, Young RH. Anaplastic large-cell lymphoma presenting in the testis. A lesion that may be confused with embryonal carcinoma. J Urol Pathol 5:139-147, 1996.
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19. Henley, JD, Young RH, Wade CL, Ulbright TM. Seminomas with exclusive intertubular growth. A report of 12 clinically and grossly inconspicuous tumors. Am J Surg Pathol 28:1163-1168, 20.
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21. Jones MA, Young RH. Sertoliform cystadenoma of the rete testis. A report of two cases. J Urol Pathol 7:47-53, 1997.
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23. Kommoss F, Oliva E, Bittinger F, Kirkpatrick CJ, Amin MB, Bhan AK, Young RH, Scully RE. Inhibin-, CD99, HEA125, PLAP, and chromogranin immunoreactivity in testicular neoplasms and the androgen insensitivity syndrome. Hum Pathol 31:1055-1061, 2000.
24. Kratzer SS, Ulbright TM, Talerman A, Srigley JR, Roth LM, Wahle GR, Moussa M, Stephens JK, Millos A, Young RH. Large cell calcifying Sertoli cell tumor of the testis: Contrasting features of six malignant and six benign tumors and a review of the literature. Am J Surg Pathol 21:1271-1280, 1997.
25. Lawrence WD, Young RH, Scully RE: Juvenile granulosa cell tumor of the infantile testis: a report of fourteen cases. Am J Surg Pathol 9:87-94, 1985.
26. Michael H, Hull MT, Ulbright TA, Foster RS, Miller KD. Primitive neuroectodermal tumors arising in testicular germ cell neoplasms. Am J Surg Pathol 21:896-904, 1997.
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28. Proppe KH, Scully RE: Large-cell calcifying Sertoli cell tumor of the testis. Am J Clin Pathol 74:607-619, 1980.
29. Skinnider BF, Young RH. Infarcted adenomatoid tumor. A report of five case of a facet of a benign neoplasm that may cause diagnostic difficulty. Am J Surg Pathol 28:77-83, 2004.
30. Tickoo SK, Hutchinson B, Bacik J, Mazumdar M, Motzer RJ, Bajorin DR, Bosl GJ, Reuter VE. Testicular seminoma: A clinicopathologic and immunohistochemical study of 105 cases with special reference to seminomas with atypical features. Int J Surg Pathol 10:23-32, 2002.
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32. Ulbright TM, Amin MB, Young RH. Tumors of the testis, adnexa, spermatic cord and scrotum. Armed Forces Institute of Pathology Fascicle, Third Series, No. 25, 1999.
33. Ulbright TM, Srigley JR. Dermoid cyst of the testis. Am J Surg Pathol 25:788-793, 2001.
34. Ulbright TM, Srigley JR, Hatzianastassiou DK, Young RH. Leydig cell tumors with unusual features. Adipose differentiation, calcification and ossification, spindle-shaped tumor cells. Am J Surg Pathol 26:1424-1433, 2002.
35. Ulbright TM, Srigley JR, Reuter VE, Wojno K, Roth LM, Young RH. Sex cord-stromal tumors of the testis with entrapped germ cells. A lesion mimicking unclassified mixed germ cell sex cord-stromal tumors. Am J Surg Pathol 24:535-542, 2000.
36. Ulbright TM, Young RH, Scully RE. Trophoblastic tumors of the testis other than classic choriocarcinoma: "Monophasic" choriocarcinoma and placental site trophoblastic tumor: A report of two cases. Am J Surg Pathol 21:282-288, 1997.
37. Ulbright TM, Young RH. Seminoma with tubular, microcystic, and related patterns. A study of 28 cases of unusual morphologic variants that often cause confusion with yolk sac tumor. Am J Surg Pathol 29:500-505, 2005.
38. Ulbright TM, Amin MB, Young RH. Intratubular large cell hyalinizing Sertoli cell neoplasia of the testis: a report of a distinctive lesion of the Peutz-Jeghers syndrome. Am J Surg Pathol 25:827-835, 2007.
39. Ulbright TM, Young RH. Metastatic Carcinoma to the Testis. A Clinicopathologic Analysis of 26 Nonincidental Cases With Emphasis on Deceptive Features. Am J Surg Pathol 32:1683-1693, 2008.
40. Ulbright TM, Young RH. Seminoma with conspicuous signet ring cells: a rare, previously uncharacterized morphologic variant. Am J Surg Pathol 32:1175-1181, 2008.
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42. Young RH, Koelliker DD, Scully RE. Sertoli cell tumors of the testis, not otherwise specified. A clinicopathologic analysis of 60 cases. Am J Surg Pathol. 22:709-721, 1998.
43. Zukerberg LR, Young RH, Scully RE. Sclerosing Sertoli cell tumor of the testis. A report of 10 cases. Am J Surg Pathol 15:829-834, 1991.

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