GLI1 Coamplification in Well-Differentiated/Dedifferentiated Liposarcomas: Clinicopathologic and Molecular Analysis of 92 Cases

Abstract

GLI1(12q13.3) amplification is identified in a subset of mesenchymal neoplasms with a distinct nested round cell/epithelioid phenotype. MDM2 and CDK4 genes are situated along the oncogenic 12q13-15 segment, amplification of which defines well-differentiated liposarcoma (WDLPS)/dedifferentiated liposarcoma (DDLPS). The 12q amplicon can occasionally include GLI1, a gene in close proximity to CDK4. We hereby describe the first cohort of GLI1/MDM2/CDK4 coamplified WD/DDLPS. The departmental database was queried retrospectively for all cases of WD/DDLPS having undergone next-generation (MSK-IMPACT) sequencing with confirmed MDM2, CDK4, and GLI1 coamplification. Clinicopathologic data was obtained from a review of the medical chart and available histologic material. Four hundred eighty-six WD/DDLPS cases underwent DNA sequencing, 92 (19%) of which harbored amplification of the GLI1 locus in addition to that of MDM2 and CDK4. These included primary tumors (n = 60), local recurrences (n = 29), and metastases (n = 3). Primary tumors were most frequently retroperitoneal (47/60, 78%), mediastinal (4/60, 7%), and paratesticular (3/60, 5%). Average age was 63 years, with a male:female ratio of 3:2. The cohort was comprised of DDLPS (86/92 [93%], 6 of which were WDLPS with early dedifferentiation) and WDLPS without any longitudinal evidence of dedifferentiation (6/92, 7%). One-fifth (13/86, 17%) of DDLPS cases showed no evidence of a well-differentiated component in any of the primary, recurrent, or metastatic specimens. Dedifferentiated areas mostly showed high-grade undifferentiated pleomorphic sarcoma-like (26/86,30%) and high-grade myxofibrosarcoma-like (13/86,16%) morphologies. A disproportionately increased incidence of meningothelial whorls with/without osseous metaplasia was observed as the predominant pattern in 16/86 (19%) cases, and GLI1-altered morphology as described was identified in a total of 10/86 (12%) tumors. JUN (1p32.1), also implicated in the pathogenesis of WD/DDLPS, was coamplified with all 3 of MDM2, CDK4, and GLI1 in 7/91 (8%) cases. Additional loci along chromosomal arms 1p and 6q, including TNFAIP3, LATS1, and ESR1, were also amplified in a subset of cases. In this large-scale cohort of GLI1 coamplified WD/DDLPS, we elucidate uniquely recurrent features including meningothelial whorl-like and GLI-altered morphology in dedifferentiated areas. Assessment of tumor location (retroperitoneal or mediastinal), identification of a well-differentiated liposarcoma component, and coamplification of other spatially discrete genomic segments (1p and 6q) might aid in distinction from tumors with true driver GLI1 alterations.

Keywords: 12q; CDK4; GLI1; MDM2; amplification; dedifferentiated liposarcoma; well-differentiated liposarcoma.

Figure 1.

Histomorphologic features of GLI1-amplified well-differentiated/dedifferentiated liposarcomas. A. Lipoma-like and sclerosing subtypes comprised the most common variants of well-differentiated liposarcoma, identification of which is crucial in the context of a GLI1 co-amplified tumor. B. Area of ‘early dedifferentiation’ showing a predominantly non-lipogenic low-grade myxofibrosarcoma-like expanse. C. Heterogeneous morphology of dedifferentiated liposarcoma with malignant osteocartilaginous differentiation. D. Dedifferentiated liposarcoma with high-grade myxofibrosarcoma-like morphology. E. Dedifferentiated liposarcoma with heterologous rhabdomyoblastic differentiation. F. Immunohistochemical stain for desmin, which is diffusely positive in areas of rhabdomyosarcomatous differentiation.

Figure 2.

Rare morphologic patterns of dedifferentiation observed in a subset of GLI1 co-amplified well-differentiated/dedifferentiated liposarcomas. A. Osseous metaplasia (left) accompanied by a meningothelial-like whorl (right); a rare dyad observed in the context of dedifferentiated liposarcoma. B. Multiple meningothelial-like nodules of swirling spindle cells. C. Dedifferentiated component composed of a low-grade spindle cell sarcoma with sweeping fascicles reminiscent of desmoid-type fibromatosis. D. ‘GLI1-altered morphology’ showing a distinctly nested architecture of monotonous round cells as a morphologic pattern of dedifferentiation. E. Characteristic GLI1-altered morphology of epithelioid cells in a vaguely organoid pattern imparted by a delicate arborizing capillary network. F. A richly vascularized and nested proliferation of monotonous undifferentiated round cells should raise the differential diagnosis of a GLI1-altered tumor or a GLI1 co-amplified dedifferentiated liposarcoma, the latter corroborated by an MDM2 immunostain (inset).

Figure 3.

Kaplan-Meier curves for the core cohort: A. shows recurrence-free survival (RFS). Median RFS was 36 months, with 3-year recurrence-free survival at 48%, and 5-year recurrence-free survival at 30%. B. shows disease-specific survival (DSS). Median DSS was 141 months, with 5-year DSS at 80% and 10-year DSS at 60%.