By Rodney T. Miller, M.D., Director of Immunohistochemistry
Germ cell neoplasms can show a bewildering array of appearances, and there may be significant morphologic overlap among subtypes. For this reason, Immunohistochemistry is often performed to assist in accurately assessing the types and extent of germ cell elements present within a tumor. This month, we discuss our current approach to analyzing problematic germ cell neoplasms, employing some newer (and better) markers than those available to us in the past.
Low molecular weight cytokeratin (CK-lmw) is performed on all of our germ cell tumors. Embryonal carcinoma, yolk sac tumor, and choriocarcinoma are always positive for CK-lmw. Classical seminoma and spermatocytic seminoma may be negative or sometimes show scattered positive cells, often with a perinuclear dot-like pattern of reactivity.
OCT3/4 is a superb nuclear marker of classical seminoma and embryonal carcinoma and has been previously discussed in the May 2004 issue of our newsletter. It has excellent sensitivity and specificity for these two tumors and can be effectively used as the “screen” for these neoplasms when dealing with a metastatic tumor of unknown origin.
D2-40 (also known as podoplanin) has also been previously discussed in the October 2005 issue of the “Focus”, where we addressed its utility as a marker of lymphatics, mesothelial cells, hemangioblastoma, certain vascular tumors, and cutaneous adnexal tumors. At that time, we noted that it stained cases of classical seminoma strongly, and there have been a number of recent publications attesting to the utility of D2-40 as a marker of classical seminoma. In contrast to the strong diffuse staining observed with D2-40 in classical seminoma, embryonal carcinoma is typically negative or only shows focal weak reactivity. Other germ cell tumors have been found to be negative for D2-40.
CD30 has been used for some time as a marker of embryonal carcinoma since it is typically positive in that tumor but negative in other germ cell tumors.
AFP is useful in identifying foci of yolk sac tumor, as it is negative in other tumors, although some authors report focal reactivity in some embryonal carcinomas.
In the December 2006 issue of the American Journal of Surgical Pathology, Glypican 3 (GPC 3) was reported as a useful marker for the classification of germ cell tumors. Specifically, GPC 3 stained all cases (24/24) of yolk sac tumor, and typically in a strong fashion. Additionally, 7 of 7 cases of choriocarcinoma were GPC 3 positive, where it stained the syncytiotrophoblasts strongly with weaker staining of cytotrophoblasts. Overall, however, the staining was weaker than that noted in yolk sac tumor. Some of the immature elements within teratomas reacted with GPC 3, including primitive stroma, neuroepithelium, fetal-type glands, primitive tubules, and cartilage anlage. 35 of 37 (92%) of cases of embryonal carcinoma were negative for GPC 3, with the positive cases showing only focal staining. All classical seminomas (n=42) and mature teratomas (n=20) were negative for this marker.
HCG is well known as a marker of syncytiotrophoblasts in choriocarcinoma, although it will also stain isolated syncytiotrophoblastic giant cells in classical seminoma.
HLA-G is an excellent marker of intermediate trophoblastic lesions and is very useful in highlighting the intermediate trophoblast component of choriocarcinoma. Parenthetically, p63 can be useful to highlight the cytotrophoblast component of choriocarcinoma.
NOTE: All of the above antibodies are available at ProPath. The table above summarizes the expected findings in germ cell tumors.
Use of these selected markers can assist greatly in accurately characterizing these tumors, providing the basis for optimal therapy.
1. Jones TD, Ulbright TM, Eble JN, Cheng L: OCT4 staining in testicular tumors. A sensitive and specific marker for testicular seminoma and embryonal carcinoma. Am J Surg Pathol 28 (7):935-940, Jul 2004.
2. Badve S, Morimiya A, Agarwal B et al: Podoplanin: A Histological marker for seminoma. Mod Pathol 19 (Supplement 1):page 129A, abstract #589, Jan 2006.
3. Kato Y, Sasagawa I, Kaneko M, et al: Aggrus: a marker that distinguishes seminoma from embryonal carcinoma in testicular germ cell tumors. Oncogene 23(52): 8552-8556, Nov 4, 2004.
4. Sonne SB, Herlithy AS, Hoei-Hansen CE et al: Identity of M2A (D2-40) antigen and gp36 (Aggrus, T1A-2, podoplanin) in human developing testis, testicular carcinoma in situ, and germ cell tumours. Virchows Arch May 31, 2006 (EPub ahead of print, as of 8-7-2006).
5. Zynger DL, Dimov ND, Luan C et al: Glypican 3: A novel marker in testicular germ cell tumors. Amer J Surg Pathol 30 (12):1570-1575, Dec 2006.
6. Singer G, Kurman RJ, McMcaster MT et al: HLA-G immunoreactivity is specific for intermediate trophoblast in gestational trophoblastic disease and can serve as a useful marker in differential diagnosis. Amer J Surg Pathol 26(7): 914-920, Jul 2002.
7. Shih I-M, Kurman RJ: p63 expression is useful in the distinction of epithelioid trophoblastic and placental site trophoblastic tumors by profiling trophoblastic subpopulations. Am J Surg Pathol 28(9): 1177-1183, Sep 2004.