—  SPECIALTY CONFERENCE  —

Genitourinary Pathology

Case 4 - Seminoma with Microcystic Pattern

Thomas M. Ulbright
Indiana University
Indianapolis, IN


Click on each slide thumbnail image for an enlarged view
Clinical History
A 27-year-old man presented with a 3-week history of an enlarging right testicular mass. An orchiectomy was performed. On gross examination, there was a 5.5 cm, fleshy, well-circumscribed tumor that bulged above the adjacent parenchyma. A separate 0.6 cm nodule was also noted.


Case 4 - Figure 1 - The tumor forms anastomosing islands with diffuse microcystic change.
Case 4 - Figure 2 - Intermediate magnification shows smaller islands of tumor with microcystic change in a prominently hyalinized stroma.



Case 4 - Figure 3 - The microcysts are mostly round and regular and appear empty.
Case 4 - Figure 4 - A high magnification shows the cytological features of the tumor cells.

Diagnosis Seminoma with microcystic pattern

Discussion
Seminoma is the most common form of testicular tumor, representing 50% of the germ cell tumors, [9] which in turn comprise 95% of all testicular neoplasms. Its accurate diagnosis is especially important, not only because of its relative frequency but also because its treatment is often different compared to other testicular tumors. Patients with early stage seminoma usually receive either adjuvant (clinical stage I) or therapeutic (clinical stages IIA and IIB) radiation, whereas those with non-seminomatous germ cell tumors are typically managed by combinations of surveillance, chemotherapy and surgery, depending on their stage. Although most seminomas are easily recognized based on the characteristic sheet-like arrangement of cells with pale to clear cytoplasm that is further subdivided by lymphocyte-containing fibrovascular septa, uncommon and deceptive patterns can occur that make the diagnosis of seminoma difficult.

In 1964 Thackray, in a monograph derived from the experience of the British Testicular Tumour Panel, mentioned that cystic change could occasionally be identified in seminomas and attributed its occurrence to edema. [17] In 1980, Damjanov et al reported a case of "cribriform and sclerosing seminoma devoid of lymphoid infiltrates". [5] This tumor had multiple nests of seminoma cells in a prominently hyalinized stroma; within the cell nests there were multiple small spaces, yielding a microcystic or cribriform pattern. Similar cases have also been illustrated in chapters for textbooks [19] and in the 3rd series AFIP tumor fascicle, [20] but there has been no formal study of such unusual seminomas in a series of cases. We recently studied 28 cases of seminoma with microcystic change that varied from focal to diffuse. [22] There was nothing unusual about the clinical or gross features of these cases, with the patients being in the usual age range for seminoma (21 – 55 years), most presenting with a testicular mass, and the tumors having the typical solid, cream-colored to tan appearance. On microscopic examination, however, all of the tumors had small to more dilated spaces that varied from irregular in size and shape to relatively uniform, round and regular. The development of such spaces caused concern for microcystic yolk sac tumor, a differential consideration that was made more difficult by the paucity or absence of lymphocytes in many of these tumors, similar to the case reported by Damjanov and coworkers [5] . Granular, eosinophilic edema fluid was present in the spaces of some of the cases, but many cases lacked edema fluid and many spaces in those cases with edema appeared empty, so edema does not appear to provide a uniform explanation for this phenomenon. In addition to microcysts, twelve tumors also had distinct tubular patterns with either hollow or solid profiles, a finding previously reported in seminoma that potentially mimics Sertoli cell tumor. [23, 24]

The most important finding in cases of microcystic seminoma that serves to distinguish them from other diagnostic considerations, especially yolk sac tumor, is the retained cytological features of seminoma. The cells lining the spaces have the usual seminoma features - polygonal cells with nuclei having prominent nucleoli and "squared off" nuclear membranes. On the other hand, the microcysts of yolk sac tumor are lined by cells that often have flattened contours, and the adjacent cells are more pleomorphic rather than showing the more monomorphic appearance of seminoma cells. The microcysts of yolk sac tumor also tend to have more complex, anastomosing patterns rather than the predominance of separate, individual spaces in the seminomas. For those cases with a prominent tubular pattern, where the differential diagnosis includes Sertoli cell tumor, the lower grade nuclei with less prominent nucleoli and lower mitotic rate of the latter contrasts with the features of seminoma, [7] as does the absence of intratubular germ cell neoplasia of the unclassified type (IGCNU) in Sertoli cell tumor, whereas IGCNU occurs with seminoma in excess of 90% of the cases. [4] Immunostains are also helpful in resolving these differentials; seminomas are negative for alpha-fetoprotein and usually negative or only focally reactive for AE1/AE3 cytokeratins. [14] On the other hand they are strongly and diffusely positive for OCT3/4 (POU5F1) protein, which appears currently to be the most sensitive seminoma marker, with very high specificity for seminoma and embryonal carcinoma and with no false negative reports to date. [10, 11] In contrast, yolk sac tumors show opposite reaction patterns with these three markers. The very high specificity of OCT3/4 protein staining for seminoma and embryonal carcinoma, with only focal staining in occasional ovarian clear cell carcinomas and rare clear cell renal cell carcinomas and non-small cell carcinomas of the lung, [2, 11] should be contrasted with the low specificity of two other markers that are commonly employed as a positive stain for seminoma, placental alkaline phosphatase and c-Kit (CD117), both of which stain numerous other tumors of both germ cell and non-germ cell type. The distinction from Sertoli cell tumor is facilitated by immunostains against inhibin, OCT3/4 protein and placental alkaline phosphatase, with inhibin often being positive in Sertoli cell tumor but negative for the latter two markers, and seminoma having opposite reaction patterns.

Seminomas may have other deceptive patterns apart from microcystic and tubular arrangements. Focal intertubular growth is common in seminomas, occurring in over half of unselected cases. [8] It is, however, very uncommon for intertubular growth to be the only pattern in a seminoma; such cases of purely intertubular seminoma typically present with metastases or infertility rather than a testicular mass. [8] Even on gross examination of the orchiectomy specimens in such cases there is usually no distinct mass but areas of firmness or discoloration with respect to the adjacent parenchyma. On microscopic examination, intertubular growth is often inconspicuous, consisting of small clusters and individual tumor cells growing between intact seminiferous tubules. In many examples, there is an associated lymphocytic infiltrate, which can potentially obscure the tumor cells but also serve to call attention to them. Admixture of seminoma cells with clusters of hyperplastic Leydig cells is also common in intertubular seminoma. In some cases the intertubular seminoma cells have a plasmacytoid appearance, with somewhat eccentrically placed nuclei and more densely staining cytoplasm than the usual pale to clear cytoplasm of most seminomas. In conjunction with the intertubular growth, these features may provoke concern for lymphoma or plasmacytoma. The detection of intertubular seminoma cells, however, can be considerably facilitated by utilizing immunostains such as placental alkaline phosphatase, c-Kit and OCT3/4, which also serve to distinguish them from potential hematopoietic mimickers. The possible diagnostic problem, however, must be recognized by routine H&E morphology, with careful attention to areas of lymphocytic infiltrates and Leydig cell clusters.

Atypical features can occur in seminoma where the tumor cells have more densely staining cytoplasm, less well-defined cytoplasmic membranes and greater nuclear pleomorphism. [18] These changes cause concern for solid pattern embryonal carcinoma, a realistic consideration given that seminoma is now recognized as a tumor capable of transforming into many of the non-seminomatous germ cell tumors, including embryonal carcinoma. [12] If such atypical foci show any evidence of epithelial differentiation, including glands or papillary structures, a non-seminomatous component should be diagnosed. In the absence of such distinct epithelial differentiation, immunostains can be helpful in deciding if such cases represent transformation of seminoma to embryonal carcinoma; if there is selective highlighting of such atypical foci by AE1/AE3 cytokeratins and CD30, there is justification for an embryonal carcinoma component since seminoma is usually negative or only focally reactive for these antigens in contrast to embryonal carcinoma, which usually expresses them strongly. [3, 15]

On rare occasions, a diffuse granulomatous reaction in a seminoma makes the tumor cells inconspicuous, thereby mimicking idiopathic granulomatous orchitis. Patients with idiopathic granulomatous orchitis, however, often have a prodromal syndrome suspicious for an infectious process, and many have a history of a pre-existing urinary tract infection. [1, 6, 13] They often have pain and swelling. On the other hand, patients who present with seminoma typically have no prodromal symptoms and characteristically present with a painless mass, although certainly some may have a degree of testicular tenderness. On gross examination, the typical example of idiopathic granulomatous orchitis represents a diffuse involvement of the testicular parenchyma, yielding a tan to yellow, uniform pattern, although exceptionally a distinct nodule may be formed. Although some seminomas, notably those with prominent intertubular patterns, may have a similar appearance, it is much more common for seminomas to show a distinct intratesticular mass. On microscopic examination, idiopathic granulomatous orchitis will often display a prominently tubulocentric granulomatous reaction, with a diffuse lymphoplasmacytic infiltrate in the interstitium, whereas the classic granulomatous reaction in seminomas has a greater interstitial component. In my experience, however, there is too much overlap in patterns for this to be of practical diagnostic utility in an individual case, with some seminomas displaying conspicuous intratubular granulomatous reactions. Extensive sectioning of any testicular specimen with a prominent granulomatous reaction is therefore indicated to evaluate for the presence of residual seminoma cells; use of appropriate immunostains is also very helpful in this circumstance to highlight seminoma cells that are made inconspicuous by the inflammation and granulomatous reaction. Identification of IGCNU in such cases may be crucial in supporting the diagnosis of an underlying seminoma.

There are two additional lesions that may cause confusion of seminoma with a non-seminomatous germ cell tumor. These, however, are not patterns of the tumor but potentially deceptive changes induced by involvement of secondary structures by seminoma or by its precursor. When any neoplasm invades into the rete testis it may induce a secondary hyperplasia of the rete epithelium with the formation of small cystic spaces and hyaline globules within the epithelium. [21] In florid examples this reaction can be mistaken for yolk sac tumor because of the combination of a microcystic pattern and hyaline bodies. The keys to its recognition are the low power arborizing architecture of the rete epithelium and the bland cytological features of the hyperplastic rete epithelium. Additionally, sometimes there is extensive involvement of the rete testis by IGCNU associated with a seminoma. [16] The IGCNU cells undermine the rete epithelium in a pagetoid fashion and continue to proliferate, compressing the rete epithelium into rather inconspicuous flattened cells and greatly expanding the volume of the rete testis. The luminal spaces of the rete testis may resemble the luminal spaces of individual glands, causing concern for embryonal carcinoma or yolk sac tumor. The key in this situation is to identify the typical cytological features of the seminoma-like cells of IGCNU, appreciate the compressed rete epithelial cells, and note the overall architectural pattern of the rete testis.

References

  1. Aitchison M, Mufti GR, Farrell J, et al. Granulomatous orchitis: review of 15 cases. Br J Urol. 1990;66:312-314.
  2. Cheng L, Thomas A, Roth LM, et al. OCT4: a novel biomarker for dysgerminoma of the ovary. Am J Surg Pathol. 2004;28:1341-1346.
  3. Cheville JC, Rao S, Iczkowski KA, et al. Cytokeratin expression in seminoma of the human testis. Am J Clin Pathol. 2000;113:583-588.
  4. Coffin CM, Ewing S, Dehner LP. Frequency of intratubular germ cell neoplasia with invasive testicular germ cell tumors. Histologic and immunocytochemical features. Arch Pathol Lab Med. 1985;109:555-559.
  5. Damjanov I, Niejadlik DC, Rabuffo JV, et al. Cribriform and sclerosing seminoma devoid of lymphoid infiltrates. Arch Pathol Lab Med. 1980;104:527-530.
  6. Fauer RB, Goldstein AMB, Green JC, et al. Clinical aspects of granulomatous orchitis. Urology. 1978;12:416-419.
  7. Henley JD, Young RH, Ulbright TM. Malignant Sertoli cell tumors of the testis: a study of 13 examples of a neoplasm frequently misinterpreted as seminoma. Am J Surg Pathol. 2002;26:541-550.
  8. Henley JD, Young RH, Wade CL, et al. Intertubular pattern of growth in seminoma: a report of 12 clinically and grossly inconspicuous tumors. Am J Surg Pathol. 2004;28:1163-1168.
  9. Jacobsen GK, Barlebo H, Olsen J, et al. Testicular germ cell tumours in Denmark 1976-1980. Pathology of 1058 consecutive cases. Acta Radiol Oncol. 1984;23:239-247.
  10. Jones TD, Ulbright TM, Eble JN, et al. OCT4 staining in testicular tumors: a sensitive and specific marker for seminoma and embryonal carcinoma. Am J Surg Pathol. 2004;28:935-940.
  11. Looijenga LH, Stoop H, de Leeuw HP, et al. POU5F1 (OCT3/4) identifies cells with pluripotent potential in human germ cell tumors. Cancer Res. 2003;63:2244-2250.
  12. Looijenga LHJ, Oosterhuis JW. Pathogenesis of testicular germ cell tumours. Rev Reprod. 1999;4:90-100.
  13. Lynch VP, Eakins D, Morrison E. Granulomatous orchitis. Br J Urol. 1968;40:451-458.
  14. Niehans GA, Manivel JC, Copland GT, et al. Immunohistochemistry of germ cell and trophoblastic neoplasms. Cancer. 1988;62:1113-1123.
  15. Pallesen G, Hamilton-Dutoit SJ. Ki-1 (CD30) antigen is regularly expressed in tumor cells of embryonal carcinoma. Am J Pathol. 1988;133:446-450.
  16. Perry A, Wiley EL, Albores-Saavedra J. Pagetoid spread of intratubular germ cell neoplasia into rete testis: a morphologic and histochemical study of 100 orchiectomy specimens with invasive germ cell tumors. Hum Pathol. 1994;25:235-239.
  17. Thackray AC. Seminoma. Br J Urol. 1964;36 (Suppl):12-27.
  18. Tickoo SK, Hutchinson B, Bacik J, et al. Testicular seminoma: a clinicopathologic and immunohistochemical study of 105 cases with special reference to seminomas with atypical features. Int J Surg Pathol. 2002;10:23-32.
  19. Ulbright TM. Testicular and paratesticular tumors. In: Mills SE, Carter D, Reuter VE et al., eds. Sternberg's Diagnostic Surgical Pathology. Philadelphia: Lippincott Williams & Wilkins, 2004:2167-2232.
  20. Ulbright TM, Amin MB, Young RH. Atlas of Tumor Pathology: Tumors of the testis, adenexa, spermatic cord and scrotum. Third series. Washington, D.C.: Armed Forces Institute of Pathology, 1999.
  21. Ulbright TM, Gersell DJ. Rete testis hyperplasia with hyaline globule formation. A lesion simulating yolk sac tumor. Am J Surg Pathol. 1991;15:66-74.
  22. 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. 2005;in press.
  23. Young RH, Finlayson N, Scully RE. Tubular seminoma. Report of a case. Arch Pathol Lab Med. 1989;113:414-416.
  24. Zavala-Pompa A, Ro JY, El-Naggar AK, et al. Tubular seminoma. An immunohistochemical and DNA flow-cytometric study of four cases. Am J Clin Pathol. 1994;102:397-401.