Establishing the Diagnosis of Germ Cell Tumors in Patients Presenting With Metastatic Disease

Germ cell tumors (GCTs) are the most common nonhematopoietic malignancies in young men and typically present as primary testicular masses. However, in ∼12% of cases, GCTs manifest as metastatic disease without a known testicular primary, leading to significant diagnostic challenges. We retrospectively reviewed 55 cases of GCTs presenting as metastases, focusing on the morphologic and immunohistochemical pitfalls encountered in core biopsy specimens. Among a total of 55 cases, seminoma was the most common histologic subtype (61%), followed by embryonal carcinoma (14%) and mixed GCTs (13%), with a median age of 44 years (range: 21 to 87 y). The most frequently biopsied metastatic sites were the retroperitoneum (55%) and left neck (22%). Notably, only 7% of cases had an identified testicular mass at diagnosis. Only a third (32%) of cases were submitted with an initial diagnosis of GCT, while 10% were misclassified as non-GCT malignancies. Histologic features such as crush artifact (83%) and necrosis (54%) frequently obscured morphology, leading to extensive IHC panels. Cytokeratin expression (particularly CAM 5.2 and AE1/3) was identified in 51% of cases, often confounding the diagnosis. A greater number of IHC stains were performed at outside institutions compared with intramurally (9 vs. 4, P =0.0001). The use of OCT3/4 and CD30 proved crucial in diagnosing seminomas and embryonal carcinomas, respectively. In rare cases (n=4) with atypical histology, fluorescence in situ hybridization (FISH) for isochromosome 12p provided additional diagnostic support. Diagnosing metastatic germ cell tumors in needle biopsies remains a significant challenge, often compounded by lack of a known testicular mass, cytokeratin expression, and confounding histologic features such as crush artifact and necrosis that could be used as clues rather than impediments to diagnosis. Awareness of these findings, along with careful integration of clinical context, histology, and immunohistochemistry, is critical to avoid misdiagnosis, particularly in light of the exquisite chemosensitivity of GCTs. The use of reliable markers like OCT3/4 and CD30, coupled with a high index of suspicion in men with retroperitoneal or left neck masses, can aid in improving diagnostic accuracy.