Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
Mod Pathol. 2022 Oct;35(10):1370-1382. doi: 10.1038/s41379-022-01084-w. Epub 2022 Apr 27.
Invasive lobular carcinoma with extracellular mucin (ILCEM) is a rare histologic subtype of breast cancer. Little is known about the pathologic or genomic signatures that distinguish ILCEM from classic invasive lobular carcinoma (ILC) or mucinous carcinoma. We studied 17 breast cancers with lobular morphology and extracellular mucin. Thirteen tumors with sufficient tissue for DNA extraction were analyzed by a next generation sequencing (NGS) assay that interrogates 447 genes for mutations and copy number variations (CNVs). Median patient age was 66 yrs (range: 31-77 yrs). Sixteen patients presented with masses, 7 of which were >2 cm. Seven patients had lymph node metastases. The cases of ILCEM were moderately (n = 13) or poorly differentiated (n = 4), frequently exhibiting variant morphology that has not been previously described or emphasized, including grade 3 nuclei (n = 11), diffuse signet ring cells (n = 10), solid growth (n = 4), tumor necrosis (n = 3) or apocrine features (n = 2). All tumors showed absent or reduced membranous E-cadherin expression. Concurrent lobular carcinoma in situ (LCIS) was seen in 11/17 cases, 1 of which was a striking example of signet ring cell LCIS with extracellular mucin. Receptor profiles were ER+/HER2- (n = 15) and ER+/HER2+ (n = 2). With a median follow-up of 83.5 months (range: 3-171 months) in 12 patients with available information, 8 patients had recurrences resulting in 4 cancer-related deaths. The most common CNVs were 16q loss (n = 11) and 1q gain (n = 9). CDH1 gene-level alterations were detected in all but one case, including frameshift (n = 7), nonsense (n = 2), and donor splice site (n = 1) mutations and indels (n = 2). Recurrent mutations were also seen in PIK3CA (n = 3), POLQ (n = 3), TP53 (n = 3), ERBB3 (n = 3), ERBB2 (n = 2), and RUNX1 (n = 2). Genes with recurrent amplifications included GATA3 (n = 4), FOXA1 (n = 3), CCND1 (n = 2). Our data highlights ILCEM as a distinct variant of ILC that often presents with higher-grade and variant morphologic features and is associated with an aggressive clinical course. NGS data support an overall lobular-type molecular profile and reveal potentially targetable alterations in a subset of cases with recurrence.
伴有细胞外黏蛋白的浸润性小叶癌（ILCEM）是一种罕见的乳腺癌组织学亚型。目前对于能够将其与经典浸润性小叶癌（ILC）或黏液癌区分开来的病理或基因组特征知之甚少。我们研究了 17 例具有小叶形态和细胞外黏蛋白的乳腺癌。对 13 例具有足够组织进行 DNA 提取的肿瘤进行了下一代测序（NGS）检测，该检测对 447 个基因进行了突变和拷贝数变异（CNV）分析。中位患者年龄为 66 岁（范围：31-77 岁）。16 例患者出现肿块，其中 7 例大于 2cm。7 例患者有淋巴结转移。ILCEM 病例的组织学分级为中分化（n=13）或低分化（n=4），常表现出以前未描述或强调的变异形态，包括 3 级核（n=11）、弥漫性印戒细胞（n=10）、实性生长（n=4）、肿瘤坏死（n=3）或大汗腺特征（n=2）。所有肿瘤均表现出缺失或减少的膜 E-钙黏蛋白表达。17 例中有 11 例伴有同时存在的小叶原位癌（LCIS），其中 1 例为伴有细胞外黏蛋白的显著的印戒细胞 LCIS。受体谱为 ER+/HER2-（n=15）和 ER+/HER2+（n=2）。在 12 例有可用信息的患者中，中位随访时间为 83.5 个月（范围：3-171 个月），8 例患者出现复发，导致 4 例癌症相关死亡。最常见的 CNV 是 16q 缺失（n=11）和 1q 获得（n=9）。除 1 例外，所有病例均检测到 CDH1 基因水平改变，包括移码（n=7）、无义（n=2）、供体位点剪接（n=1）突变和插入缺失（n=2）。PIK3CA（n=3）、POLQ（n=3）、TP53（n=3）、ERBB3（n=3）、ERBB2（n=2）和 RUNX1（n=2）也出现了复发性突变。复发性扩增的基因包括 GATA3（n=4）、FOXA1（n=3）、CCND1（n=2）。我们的数据强调了 ILCEM 是 ILC 的一个独特变体，通常表现出更高的分级和变异形态特征，并与侵袭性临床过程相关。NGS 数据支持总体小叶型分子谱，并揭示了具有复发的情况下具有潜在可靶向改变的病例亚组。
