Expanding the spectrum of dicer1-associated sarcomas

Abstract

DICER1 syndrome is a hereditary cancer predisposition syndrome caused by deleterious germline DICER1 mutations. Characteristic "hotspot" somatic mutations of DICER1 have been identified in DICER1-associated tumors. With the exception of genitourinary embryonal rhabdomyosarcoma and anaplastic sarcoma of the kidney, sarcomas are rarely reported in DICER1 syndrome. Herein, we report the clinical, histopathologic, and molecular findings of a germline DICER1-associated ovarian sarcoma in a 5-year-old female, a somatic DICER1-associated metastatic peritoneal sarcoma in a 16-year-old female, and a somatic DICER1-associated primary intracranial sarcoma in a 4-year-old male. A comprehensive review of the literature, including 83 DICER1-associated sarcomas, illustrates an unequivocal histologic pattern mimicking pleuropulmonary blastoma, regardless of the site of origin. The features include undifferentiated small round blue cells, poorly differentiated spindle cells, and large bizarre pleomorphic cells (anaplasia), often with rhabdomyoblastic and/or chondroid differentiation, and rare bone/osteoid formation. This unique heterogeneous histologic pattern should raise suspicion for pathogenic DICER1 mutation(s) warranting a detailed review of the family history and DICER1 mutation analysis. In addition to expanding the phenotypic spectrum of DICER1-associated conditions, identification of pathogenic DICER1 variants facilitates optimized genetic counseling, caregiver education and judicious imaging-based surveillance.

Fig. 1

Microphotographs of the DICER1-associated ovarian sarcoma (a Patient 1), peritoneal sarcoma (b Patient 2), and primary intracranial sarcoma (c Patient 3). Hematoxylin and eosin sections, ×40: A5; ×200: A1, A4, B1, B4, B5, B6, and B7; ×400: A2, A3, B2, B3, C1, C2, and C3; ×400, Immunohistochemistry, ×400: A6, A7, C4, C5, and C6. Patient 1 (A1–A7): The tumor was ill-defined and comprised a heterogeneous population of loosely cohesive tumor cells demonstrating areas with undifferentiated small round blue cells (A1, box: high power), spindle cells (A2), large, bizarre pleomorphic cells with frequent mitoses (anaplasia; A3, box: mitoses) and islands of malignant cartilage scattered throughout the tumor (A4). Focal bone formation was present (A5). Immunohistochemistry showed that the undifferentiated small round blue cells and spindle cells were partially, strongly positive for desmin (A6), and a smaller number of cells were positive for myogenin (A7). Patient 2 (B1–B7): Peritoneal mass. The sections from the peritoneal mass contained cystic walls in variable thicknesses (Fig. 1B1–B5), lined by bland ciliated columnar cells (B1). The underlying stroma was expanded (overgrown) and demonstrated a heterogeneous population including undifferentiated small round blue cells (B2), spindle cells (B3), and scattered pleomorphic cells (anaplasia, B2 box). The small round blue cells formed a hypercellular zone, “cambium layer” (B1), immediately beneath the epithelium. Loose myxoid stroma with occasional islands of immature-appearing cartilage (B4) and focal osteoid formation (B5) were identified in the background. Autopsy (post chemotherapy, B6 and B7). The tumor was largely necrotic, but single and clusters of viable tumor cells were present throughout. The tumor cells demonstrated prominent rhabdomyoblastic differentiation with abundant eosinophilic cytoplasm and “strap cells” (B6). Pleomorphic cells were occasionally seen. The tumor also contained multiple broad areas of chondrosarcomatous differentiation with abundant chondroid matrix and occasional pleomorphic cells within the lacunae, which were occasionally multinucleated (B7). Patient 3 (C1–C6): The hematoxylin and eosin sections revealed a cellular, heterogenous population of tumor cells with occasional necrosis demonstrating areas with undifferentiated small round blue cells (C1) with scattered large pleomorphic cells (C1 box) and spindle cells (C2). Some areas show abundant myxoid to chondroid matrix in the background (C3). Immunohistochemistry staining showed that tumor cells were partially strongly positive for desmin (C4), MyoD1 (C5) and myogenin (C6). The immunoprofile is supportive of rhabdomyoblastic differentiation