Lu Zhichun, Zhou Yan, Fan Wei, Choksi Sanket, Sultan Lila, Katz Mark H, Wang David S, Zhao Qing, Yang Shi
Department of Pathology & Laboratory Medicine, Boston Medical Center, Boston University Chobanian & Avedisian School of Medicine, 670 Albany St., Boston, MA, 02118, USA.
Department of Urology, Boston Medical Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
Virchows Arch. 2025 Sep 26. doi: 10.1007/s00428-025-04248-6.
Biphasic (squamoid) papillary renal cell carcinoma (BPRCC) is a recently recognized and rare variant of renal cell carcinoma, defined by biphasic morphology and distinct immunophenotypic features. Previously considered a subtype of classic papillary RCC, its clinicopathologic and molecular characteristics remain underexplored. We analyzed ten BPRCC cases for histologic, immunophenotypic, molecular, and clinical features. The cohort included seven men and three women (median age = 48 years), with tumors measuring 25-45 mm, all staged as pT1. No disease progression or cancer-related deaths were observed over a median follow-up of 55 months. Histologically, all tumors showed biphasic architecture with variable proportions of large eosinophilic squamoid and smaller basophilic cells. One tumor demonstrated focal rhabdoid-like features. Immunostains were diffusely positive for PAX8, CK7, AMACR, and Claudin4. The two cell populations showed differential expression of Cyclin D1, AMACR, HMWCK (K903), E-cadherin, and Ki-67. All tumors were negative for GATA3, p63, and CAIX (focal in 2 cases), and showed intact p53, RB1, and mismatch repair proteins. FISH confirmed trisomy 7 and 17 in all tumors. Targeted NGS revealed MET amplification (2 cases), MET mutation (1 case), NOTCH1 mutations (9 cases), and alterations in MAP2K2, FGFR4, DDR pathway genes (e.g., PMS2, CDK12R44W, RAD51C/D), and chromatin remodeling genes (EZH2, ARID1A). These findings support BPRCC as a distinct subtype of papillary RCC with consistent biphasic morphology, immunophenotypic divergence, and a unique molecular profile enriched for NOTCH, MAPK, and DDR pathway alterations.
双相（鳞状样）乳头状肾细胞癌（BPRCC）是一种最近才被认识到的罕见肾细胞癌变体，其定义为双相形态和独特的免疫表型特征。以前被认为是经典乳头状肾细胞癌的一个亚型，其临床病理和分子特征仍未得到充分研究。我们分析了10例BPRCC病例的组织学、免疫表型、分子和临床特征。该队列包括7名男性和3名女性（中位年龄 = 48岁），肿瘤大小为25 - 45毫米，均为pT1期。在中位随访55个月期间，未观察到疾病进展或癌症相关死亡。组织学上，所有肿瘤均显示双相结构，大嗜酸性鳞状样细胞和较小嗜碱性细胞的比例各不相同。1例肿瘤表现出局灶性横纹肌样特征。免疫组化显示PAX8、CK7、AMACR和Claudin4弥漫性阳性。两种细胞群体显示细胞周期蛋白D1、AMACR、高分子量细胞角蛋白（K903）、E - 钙黏蛋白和Ki - 67的差异表达。所有肿瘤GATA3、p63和CAIX均为阴性（2例局灶阳性），并显示p53、RB1和错配修复蛋白完整。荧光原位杂交证实所有肿瘤均有7号和17号染色体三体。靶向二代测序揭示了MET扩增（2例）、MET突变（1例）、NOTCH1突变（9例），以及MAP2K2、FGFR4、DNA错配修复通路基因（如PMS2、CDK12R44W、RAD51C/D）和染色质重塑基因（EZH2、ARID1A）的改变。这些发现支持BPRCC作为乳头状肾细胞癌的一种独特亚型，具有一致的双相形态、免疫表型差异，以及富含NOTCH、丝裂原活化蛋白激酶（MAPK）和DNA错配修复通路改变的独特分子谱。
