Morphological spectrum and molecular features of somatic malignant transformation in germ cell tumours

Abstract

Aims Somatic malignant transformation (SMT) arising in germ cell tumours (GCTs) is an infrequent, but clinically relevant event. There is only limited knowledge on the morphological spectrum of SMT, and the therapeutic management of these patients is poorly defined. In this work we revisit two consecutive case series (n = 756) of GCTs. Clinicopathological data of SMTs arising in GCTs were determined, with a focus on the histopathological spectrum, and molecular aspects were obtained by Fluorescence in situ Hybridization (FISH) and Next Generation Sequencing (NGS). Methods and Results Thirty male patients (28 primary testicular, two primary extragonadal) were included. These patients represent 4% of GCT patients diagnosed at two institutes (University Hospital Zurich and IPO Porto). The most common SMTs were adenocarcinoma (n = 8), embryonic‐type neuroectodermal tumours (ENETs, n = 8), and rhabdomyosarcoma (n = 6), but a wide range of challenging morphologies were depicted, including low‐grade neuroglial tumour, adenosquamous carcinoma, neuroblastoma, and neuroendocrine carcinoma. SMT was found in 15 primary tumour samples and in 27 metastatic samples of these 30 patients, the latter showing poorer overall survival. Adenocarcinoma occurred only in metastasis postchemotherapy and in one primary retroperitoneal GCT with SMT, but not in GCT of the testis. The 12p gains were identified by FISH in all cases. NGS results were available in six patients. Clinical trials and/or targeted treatments based on the molecular profile of SMT were recommended in four patients. Conclusions SMT arising in GCTs represent a diagnostic challenge and should be confirmed by a specialized uropathologist. NGS‐based treatment recommendations may improve the outcome of these patients.

Transformed Testicular Teratoma to Embryonic-Type Neuroectodermal Tumor With Metastasis to Mediastinum

“…9,10 While there is a wide array of possible malignant transformations, adenocarcinoma, neuroectodermal, and rhabdomyosarcoma are more commonly seen (with mesodermal differentiation being the most common). 9,11,12 Histology is essential in making the diagnosis. In ENET, an overgrowth of immature elements is seen, manifesting as neuroepithelium that may form rosette-like tubular structures.…”

“…3 Regarding malignant transformation, it has been suggested that there is a progenitor cell located within initial teratoma which then gives rise to the malignant neoplasm. 9,13 Notably, many of these malignant transformations of these testicular germ cell tumors contain 12p gains and may affect genes on this chromosome, notably the oncogene KRAS. 9,13 While this may provide a molecular target for therapy, the mainstay of treatment remains resection and chemotherapy.…”

“…In germ cell tumors that undergo malignant transformation, tumors with sarcomatous component and those of ENET histology are associated with worse prognosis. 9 In addition, there is a worse prognosis with incomplete resection, later relapse, a greater number of chemotherapy cycles, and when there is an extragonadal primary. 9 Treatment of teratomas transformed to malignant germ cell tumor provides a few challenges.…”

“…9 In addition, there is a worse prognosis with incomplete resection, later relapse, a greater number of chemotherapy cycles, and when there is an extragonadal primary. 9 Treatment of teratomas transformed to malignant germ cell tumor provides a few challenges. As this disease is rare, it is difficult to ascertain the best treatment modality and factors for determining prognosis.…”

“…6,9 Teratoma, or a teratomatous component, is often identified as the tumor type prior to malignant transformation. 9,10 While there is a wide array of possible malignant transformations, adenocarcinoma, neuroectodermal, and rhabdomyosarcoma are more commonly seen (with mesodermal differentiation being the most common). 9,11,12…”