靶向DNA测序在恶性叶状肿瘤诊断中的应用，重点关注具有角蛋白和p63表达的肿瘤
Targeted DNA Sequencing in Diagnosis of Malignant Phyllodes Tumors With Emphasis on Tumors With Keratin and p63 Expression.
作者信息
Ye Julia, Theparee Talent, Bean Gregory R, Rutland Cooper D, Schwartz Christopher J, Vohra Poonam, Allard Grace, Wang Aihui, Hosfield Elizabeth M, Peng Yan, Chen Yunn-Yi, Krings Gregor
机构信息
Department of Pathology, University of California San Francisco, San Francisco, California.
Department of Pathology, Stanford University, Stanford, California.
出版信息
Mod Pathol. 2024 Dec;37(12):100593. doi: 10.1016/j.modpat.2024.100593. Epub 2024 Aug 21.
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 MPTs (78 tumors, 64 patients) for stromal CK, p63, and CD34 expression and profiled a subset (n = 31) by targeted next-generation DNA sequencing, with comparison to MBC (n = 44). Most MPTs (71%) were CK+ and/or p63+, including 32% CK+ (25/77 focal) and 65% p63+ (32/66 focal, 10/66 patchy, and 1/66 diffuse). Thirty percent of MPTs expressed both CK and p63 (20/66), compared with 95% of MBCs (40/42, P < .001). CK and/or p63 were positive in CD34+ and CD34- MPTs. Recurrent genetic aberrations in MPTs involved TERT, TP53, MED12, CDKN2A, chromatin modifiers, growth factor receptors/ligands, and phosphoinositide-3 kinase (PI-3K) and MAPK pathway genes. Only MED12 (39%, 12/31) and SETD2 (13%, 4/31) were exclusively mutated in MPTs and not MBCs (P < .001 and P = .044, respectively), whereas PIK3R1 mutations were only found in MBCs (37%, 13/35, P < .001). Comparative literature review additionally identified ARID1B, EGFR, FLNA, NRAS, PDGFRB, RAD50, and RARA alterations enriched or exclusively in MPTs vs MBCs. MED12 was mutated in MPTs with diffuse stromal overgrowth (53%, 9/17), CD34- MPTs (41%, 7/17), and CK+ and/or p63+ MPTs (39%, 9/23), including 36% of CD34- MPTs with CK and/or p63 expression. Overall, MED12 mutation and/or CD34 expression were observed in 68% (21/31) MPTs, including 61% (14/23) of CK+ and/or p63+ tumors. Our results emphasize the prevalence of CK and p63 expression in MPTs and demonstrate the diagnostic utility of next-generation DNA sequencing, especially in MPTs with confounding factors that can mimic MBC.
乳腺恶性梭形细胞瘤的鉴别诊断通常主要在于恶性叶状肿瘤（MPT）和化生性癌（MBC）之间。由于间质弥漫性过度生长、角蛋白（CK）和/或p63免疫阳性以及CD34表达缺失，MPT的诊断可能具有挑战性，这些表现可能会与MBC相似，尤其是在粗针活检中。区分MPT和MBC具有临床意义，因为两者在手术方式、化疗和放疗方面存在差异。在本研究中，我们评估了78例MPT肿瘤（64例患者）的间质CK、p63和CD34表达，并通过靶向二代DNA测序对其中31例进行了分析，同时与44例MBC进行了比较。大多数MPT（71%）为CK+和/或p63+，其中32%为CK+（25/77为局灶性），65%为p63+（32/66为局灶性、10/66为斑片状、1/66为弥漫性）。30%的MPT同时表达CK和p63（20/66），而MBC中这一比例为95%（40/42，P <.001）。CK和/或p63在CD34+和CD34-的MPT中均为阳性。MPT中常见的基因变异涉及端粒酶逆转录酶（TERT）、TP53、中介体12（MED12）、细胞周期蛋白依赖性激酶抑制剂2A（CDKN2A）、染色质修饰因子、生长因子受体/配体以及磷脂酰肌醇-3激酶（PI-3K）和丝裂原活化蛋白激酶（MAPK）信号通路基因。只有MED12（39%，即12/31）和SET结构域蛋白2（SETD2，13%，即4/31）仅在MPT中发生突变，而在MBC中未发生突变（分别为P <.001和P =.044），而PIK3R1突变仅在MBC中发现（37%，即13/35，P <.001）。比较文献回顾还发现，AT丰富互作结构域蛋白1B（ARID1B）、表皮生长因子受体（EGFR）、细丝蛋白A（FLNA）、神经母细胞瘤RAS病毒癌基因同源物（NRAS）、血小板衍生生长因子受体β（PDGFRB）、辐射敏感蛋白50（RAD50）和维甲酸受体α（RARA）的改变在MPT和MBC中存在富集或仅在其中一种中出现。MED12在间质弥漫性过度生长的MPT中发生突变的比例为53%（9/17），在CD34-的MPT中为41%（7/17），在CK+和/或p63+的MPT中为39%（9/23），其中包括36%的同时表达CK和/或p63的CD34-的MPT。总体而言，在31例MPT中有68%（21/31）观察到MED12突变和/或CD34表达改变，其中包括61%（14/23）的CK+和/或p63+肿瘤。我们的结果强调了CK和p63在MPT中的普遍表达，并证明了二代DNA测序在诊断中的应用价值，特别是对于具有可能与MBC混淆的混杂因素的MPT。
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