Histopathologic Grading Is of Prognostic Significance in Primary Angiosarcoma of Breast

Abstract

Despite a wide spectrum of clinical presentations, including primary or secondary, most angiosarcomas are considered high grade. One exception is primary breast angiosarcoma, where historically, histologic grading has shown to predict outcome using the Rosen 3-tier system. However, more recent studies have challenged this concept suggesting that even in this specific clinical context angiosarcomas should be considered high grade. This study aimed to critically reevaluate the impact of histologic grade in a clinically uniform cohort managed at a single institution using a newly proposed grading system. Our study included 49 primary breast angiosarcomas diagnosed during 1994 to 2022 (median follow-up: 33 mo), classified as low grade (29%), intermediate grade (20%), and high grade (51%), based on mitotic count, extent of solid components, and necrosis. At last follow-up, 22% patients developed locoregional recurrences, 63% distant metastases, and 47% patients died of disease. As patients with low and intermediate-grade angiosarcomas had relatively similar outcomes, our cohort was further analyzed using a 2-tier system (low grade and high grade). Targeted-DNA next-generation sequencing (505 cancer gene panel) performed in 11 cases found KDR mutations in 78% and PIK3CA mutations in 44% of high-grade lesions. Histologic grade, by either 3-tier or 2-tier grading systems, had a strong impact on survival, with the 2-tier system being an independent predictor of disease-specific survival and overall survival. Based on 2-tier system, the 5-year overall survival was 38% for high-grade angiosarcoma and 74% for low-grade angiosarcoma. PIK3CA mutations alone or concurrent with KDR alterations were identified in angiosarcomas with worse prognosis.

Clinicopathologic and molecular correlates to neoadjuvant chemotherapy‐induced pathologic response in breast angiosarcoma

“…All except one tumor was classified as high grade, which was defined as displaying solid growth (>10% of the tumor) and necrosis. The only lesion classified as low grade was a primary breast AS, which was defined by focal solid areas (≤10% of the tumor), up to 10 mitoses/mm 2 (score 1 or 2), and lack of necrosis 17 . Mitotic figures for the entire group ranged from 1 to 17/mm 2 .…”

“…Although most AS exhibit genetic heterogeneity with complex karyotypes, by gene expression, not surprisingly, an upregulation of endothelial receptors and angiogenic genes is typically found, including TIE1, TEK, KDR , and FLT4 3,4,6 . Large NGS studies have illustrated that RA‐AS are frequently associated with MYC, FLT4, CRKL, PTPRB, PLCG1, HRAS , and KMT2D , 5,6,33,34 whereas primary AS commonly harbor KDR, PIK3CA, TP53, ATM , and ATRX alterations 3,4,17,34 . Other less common mutations, including KRAS, NRAS, BRAF, NOTCH, PTEN, EGFR, AKT, CTNNB1 , and TERT , have also been reported 5,33 .…”

“…The only lesion classified as low grade was a primary breast AS, which was defined by focal solid areas (≤10% of the tumor), up to 10 mitoses/ mm 2 (score 1 or 2), and lack of necrosis. 17 Mitotic figures for the entire group ranged from 1 to 17/mm 2 . Pretreatment (spontaneous) tumor necrosis was identified in five cases (Table S1) (Figure 1A,C,E,G).…”

“Time Shall Unfold…”: The Clinical Value of Grading Mammary Angiosarcoma

“…More than a quarter of a century later, in 2008, Nascimento et al2 in a rather contrarian series of 48 patients, utilizing the Rosen grading system, did not identify any statistically significant differences among the 3 grades—although of 14 patients with grade 1 tumors: 6 were dead of disease, 2 were alive with disease, and 6 had no evidence of disease—in a median follow-up of 23 months. The series of 48 patients by Kuba et al,3 which appears in this issue of the Journal , found the 5-year survival for high-grade (combined grade 2 and 3) mammary angiosarcoma to be 38%, and that for low-grade ones to be 74%.…”

“…More than a quarter of a century later, in 2008, Nascimento et al 2 in a rather contrarian series of 48 patients, utilizing the Rosen grading system, did not identify any statistically significant differences among the 3 grades-although of 14 patients with grade 1 tumors: 6 were dead of disease, 2 were alive with disease, and 6 had no evidence of disease-in a median follow-up of 23 months. The series of 48 patients by Kuba et al, 3 which appears in this issue of the Journal, found the 5-year survival for high-grade (combined grade 2 and 3) mammary angiosarcoma to be 38%, and that for low-grade ones to be 74%.These 3 series, published over a span of 4 decades, are understandably not comparable in every clinicopathologic respect (particularly in terms of management). Nonetheless, the combined data support the view that an effort should be made to grade primary mammary angiosarcomas, with the caveat that grading is not always predictive of outcome.…”