Undifferentiated round cell sarcoma with BCOR internal tandem duplications (ITD) or YWHAE fusions: a clinicopathologic and molecular study

Abstract

Until recently, undifferentiated round cell sarcomas (URCS) in infants have been considered a wastebasket diagnosis, composed of various pathologic entities and lacking consistent genetic alterations. The recent identification of recurrent BCOR internal tandem duplications (ITD) and less common alternative YWHAE-NUTM2B/E fusions in half of infantile URCS and the majority of so-called primitive myxoid mesenchymal tumors of infancy (PMMTI) suggests a common pathogenesis with clear cell sarcoma of the kidney which also harbors the same genetic alterations. These tumors also share a similar morphology and immunoprofile, including positivity for BCOR, cyclin D1, and SATB2. In this study, we investigate the largest cohort to date of genetically confirmed URCS and PMMTI with BCOR ITD or YWHAE fusions to better define their morphologic spectrum and clinical behavior. Twenty-eight cases harbored BCOR ITD and five YWHAE fusions, occurring in 29 infants and 4 children, 19 males and 14 females. Microscopically, 20 were classified as URCS and 13 as PMMTI. Follow-up was available in 25 patients, with 14 (56%) succumbing to their diseases at a mean duration of 18-months follow-up (range: 2-62). Six patients remained with no evidence of disease at a mean follow-up of 63 months (range: 4-192), four patients were still alive with disease (mean follow-up: 46 months, range: 4-120), and one died of other causes. Local recurrence and distant metastasis were each observed in 11/25 (44%) of the patients. The overall survival was 42% at 3 years and 34% at 5 years (median survival: 26 months). There was no statistically significant survival difference between cases diagnosed as URCS and PMMTI and between those with BCOR ITD and YWHAE fusions.

Figure 1.. Morphologic spectrum of URCS with YWHAE and BCOR ITD genetic alterations.

YWHAE-NUTM2B/E positive congenital tumor composed of primitive round cells arranged in solid sheets and vague nests (A, case 4). BCOR-ITD infantile URCS showing a solid growth of undifferentiated round to ovoid cells with scant eosinophilic cytoplasm and vesicular nuclei with small nucleoli, mitotic activity is brisk (B, case 9). Alternative growth patterns included rosette formation and alveolar growth (C, D, case 12). Two cases occurred in adolescents both showing matrix formation radiographically and focally microscopically, being misinterpreted as small cell osteosarcomas (E-H, cases 19&20). The scapular bone lesion in a 16 year-old male showed a marbled appearance on low power with alternating hyper and hypocellular areas (E, case 19); at high power the primitive round cells showed a vague nesting growth and focal hyalinized stroma which in the context of SATB2 positivity was interpreted as osteoid production (F). Similarly, the paraspinal lesion showing vertebral bone involvement and marked sclerosis on radiology, was composed of primitive round cells embedded in a myxochondroid and fibrotic matrix (G, H, case 20). Strong and diffuse BCOR expression is typically seen in all cases (I).

Figure 2.. Morphologic spectrum of PMMTI with BCOR ITD abnormalities.

A small number of PMMTI cases showed areas of a solid round cell component limited to <30% of the mass (A, case 32). Most tumors however were diffusely myxoid with primitive round, ovoid or spindle cells floating within the extracellular matrix and associated with a delicate capillary network (B-E, cases 22,24,29). Despite low cellularity, the mitotic activity was often increased (B, case 29). Focal areas of spindling within a fibromyxoid stroma was also noted focally in some cases (F, G, cases 28,31). Focal PMMTI-like areas were noted in a subset of URCS (H, case 18). Similar to URCS, PMMTI consistently showed strong immunoreactivity for BCOR (I).

Figure 3.

Kaplan-Meier survival curves showing overall survival for (A) the two histologic types, URCS and PMMTI; and (B) the two genetic abnormalities, YWHAE fusions and BCOR ITD.