乳腺恶性梭形细胞肿瘤的鉴别诊断最常见于恶性叶状肿瘤(MPT)和化生性癌(MBC)之间。由于弥漫性基质过度生长,MPT的诊断可能具有挑战性,角蛋白(CK)和/或p63免疫阳性,CD34表达缺失,可以模仿MBC,尤其是核心活检。MPT与MBC的区别具有临床意义,手术方法不同,化疗,和辐射。在这项研究中,我们评估了MPT(78个肿瘤,64名患者)用于基质CK,p63和CD34表达,并通过靶向下一代DNA测序(NGS)分析了一个子集(n=31),与MBC相比(n=44)。大多数MPT(71%)为CK和/或p63,包括32%CK+(25/77病灶)和65%p63+(32/66病灶,10/66斑驳,1/66扩散)。30%的MPT同时表达CK和p63(20/66),与95%的MBC相比(40/42,p<0.001)。CK和/或p63在CD34+和CD34-MPT中呈阳性。MPT中的反复遗传畸变涉及TERT,TP53,MED12,CDKN2A,染色质修饰剂,生长因子受体/配体,和PI-3K和MAPK通路基因。只有MED12(39%,12/31)和SETD2(13%,4/31)仅在MPT而非MBC中发生突变(分别为p<0.001和p=0.044),而PIK3R1突变仅在MBC中发现(35%,13/35,p<0.001)。比较文献综述还确定了ARID1B,EGFR,FLNA,NRAS,PDGFRB,RAD50和RARA改变富含或仅在MPT和MBC中。MED12在MPT中突变,伴有弥漫性基质过度生长(53%,9/17),CD34-MPT(41%,7/17),和CK+和/或p63+MPT(39%,9/23),包括36%的CD34-MPT与CK和/或p63表达。总的来说,在68%(21/31)MPT中观察到MED12突变和/或CD34表达,包括61%(14/23)的CK+和/或p63+肿瘤。我们的结果强调了CK和p63在MPT中的表达,并证明了NGS的诊断实用性。特别是在MPT中,具有可以模拟MBC的混杂因素。
The differential diagnosis of malignant spindle cell neoplasms in the breast most frequently rests between malignant phyllodes tumor (MPT) and metaplastic carcinoma (MBC). Diagnosis of MPT can be challenging due to diffuse stromal overgrowth, keratin (CK) and/or p63 immunopositivity, and absent CD34 expression, which can mimic MBC, especially in core biopsies. Distinction of MPT from MBC has clinical implications, with differences in surgical approach, chemotherapy, and radiation. In this study, we evaluated MPT (78 tumors, 64 patients) for stromal CK, p63, and CD34 expression and profiled a subset (n=31) by targeted next-generation DNA sequencing (NGS), with comparison to MBC (n=44). Most MPT (71%) were CK+ and/or p63+, including 32% CK+ (25/77 focal) and 65% p63+ (32/66 focal, 10/66 patchy, 1/66 diffuse). Thirty-percent of MPT expressed both CK and p63 (20/66), compared to 95% of MBC (40/42, p<0.001). CK and/or p63 were positive in CD34+ and CD34- MPT. Recurrent genetic aberrations in MPT involved TERT, TP53,
MED12, CDKN2A, chromatin modifiers, growth factor receptors/ligands, and PI-3K and MAPK pathway genes. Only
MED12 (39%, 12/31) and SETD2 (13%, 4/31) were exclusively mutated in MPT and not MBC (p<0.001 and p=0.044, respectively), whereas PIK3R1 mutations were only found in MBC (35%, 13/35, p<0.001). Comparative literature review additionally identified ARID1B, EGFR, FLNA, NRAS, PDGFRB, RAD50, and RARA alterations enriched or exclusively in MPT versus MBC.
MED12 was mutated in MPT with diffuse stromal overgrowth (53%, 9/17), CD34- MPT (41%, 7/17), and CK+ and/or p63+ MPT (39%, 9/23), including 36% of CD34- MPT with CK and/or p63 expression. Overall,
MED12 mutation and/or CD34 expression were observed in 68% (21/31) MPT, including 61% (14/23) of CK+ and/or p63+ tumors. Our results emphasize the prevalence of CK and p63 expression in MPT and demonstrate diagnostic utility of NGS, especially in MPT with confounding factors that can mimic MBC.