Middleton L P, Palacios D M, Bryant B R, Krebs P, Otis C N, Merino M J
National Cancer Institute, Bethesda, Maryland, USA.
Am J Surg Pathol. 2000 Dec;24(12):1650-6. doi: 10.1097/00000478-200012000-00009.
Infiltrating pleomorphic lobular carcinoma (PLC) is an aggressive variant of infiltrating lobular carcinoma. Recently, in situ changes identical to PLC (PLCIS) have been described. The role of prognostic markers and their correlation with therapeutics, clinical outcome, and genetic changes is not well established in PLC. The authors examined 38 cases of this entity to understand better this tumor's biology. Immunohistochemical (IHC) analysis was performed in 21 specimens for estrogen and progesterone steroid receptors, p53, Her 2 (p185), and GCDFP-15. Genomic deoxyribonucleic acid was obtained from microdissected tumor as well as normal control cells, and loss of heterozygosity was investigated at the ESR (16q24), p53 (TP53 17p), Her 2 (17q 11-12), and BRCA 1 (17q12-25) loci. In this series, the average patient age was 57.5 years (age range, 24-92 years). Twenty-seven women were postmenopausal. Tumor size ranged from 1.2 to 25 cm. Six patients were a pathologic stage I; 19, stage II; 12, stage III; and one, stage IV. Histologically, multifocal nodular aggregates of discohesive pleomorphic tumor cells were seen interspersed in dense and fibrotic breast parenchyma. Twenty-nine percent of the specimens demonstrated associated signet ring cells. The remainder had dishesive, globoid, plasmacytoid cells with high-grade nuclear features. PLCIS was identified in 17 of 38 patients (45%), and lobular carcinoma in situ (LCIS) was noted in 8 patients (21%). IHC analysis showed estrogen immunoreactivity in 81%, progesterone in 67%, GCDFP-15 in 71%, and Her 2 in 81% (2+ to 3+ membranous staining) of specimens. Antibodies to p53 stained the tumor cell nuclei in 48% of the tumors. Loss of heterozygosity was identified in 52% of the specimens at the p53 locus, 18% at the ESR locus, 19% to 24% at the Her 2 loci, and 27% to 32% at the BRCA 1 locus. Follow-up was available in 19 patients and ranged from 12 months to 15 years (mean, 73 months). Seven patients had no evidence of disease at last examination (range, 1-15 years), three patients were alive with disease (range, 2-14 years), and nine patients were dead of disease (range, 2 months-9 years). Six patients had subsequent diagnoses of tumor in the contralateral breast. Analysis shows that PLC tends to appear in older postmenopausal women who present with locally advanced disease. PLCIS was found to be associated with PLC 45% of the time. The aggressive clinical course of patients with PLC is supported by tumor immunoreactivity with unfavorable markers Her 2 and p53. Overexpression of Her 2 in PLC may be therapeutically relevant, enabling the use of novel chemotherapeutic drugs like Herceptin. Interestingly, tumors that were Her 2 immunoreactive also maintained estrogen hormone immunoreactivity.
浸润性多形性小叶癌（PLC）是浸润性小叶癌的一种侵袭性变异型。最近，已描述了与PLC相同的原位改变（PLCIS）。在PLC中，预后标志物的作用及其与治疗、临床结局和基因改变的相关性尚未完全明确。作者检查了38例该实体病例，以更好地了解这种肿瘤的生物学特性。对21个标本进行了免疫组织化学（IHC）分析，检测雌激素和孕激素类固醇受体、p53、Her 2（p185）和GCDFP-15。从显微切割的肿瘤以及正常对照细胞中获取基因组脱氧核糖核酸，并在ESR（16q24）、p53（TP53 17p）、Her 2（17q 11-12）和BRCA 1（17q12-25）位点研究杂合性缺失。在该系列中，患者的平均年龄为57.5岁（年龄范围为24-92岁）。27名女性处于绝经后状态。肿瘤大小范围为1.2至25厘米。6例患者为病理I期；19例为II期；12例为III期；1例为IV期。组织学上，在致密和纤维化的乳腺实质中可见散在的多形性肿瘤细胞形成的多灶性结节状聚集体。29%的标本显示有印戒细胞。其余标本有黏附性、球状、浆细胞样细胞，具有高级别核特征。38例患者中有17例（45%）发现PLCIS，8例（21%）发现小叶原位癌（LCIS）。IHC分析显示，81%的标本雌激素呈免疫反应性，67%的标本孕激素呈免疫反应性，71%的标本GCDFP-15呈免疫反应性，81%的标本Her 2呈免疫反应性（2+至3+膜染色）。p53抗体在48%的肿瘤中对肿瘤细胞核进行了染色。52%的标本在p53位点发现杂合性缺失，18%在ESR位点发现，19%至24%在Her 2位点发现，27%至32%在BRCA 1位点发现。19例患者有随访资料，随访时间从12个月至15年（平均73个月）。7例患者在最后一次检查时无疾病证据（范围为1-15年），3例患者带瘤存活（范围为2-14年），9例患者死于疾病（范围为2个月至9年）。6例患者随后被诊断出对侧乳腺有肿瘤。分析表明，PLC往往出现在患有局部晚期疾病的老年绝经后女性中。发现PLCIS在45%的情况下与PLC相关。PLC患者侵袭性的临床病程得到了肿瘤与不良标志物Her 2和p53免疫反应性的支持。PLC中Her 2的过表达可能具有治疗相关性，使得能够使用像赫赛汀这样的新型化疗药物。有趣的是，Her 2免疫反应性的肿瘤也保持雌激素免疫反应性。
