HER2 in gastric cancer: a digital image analysis in pre-neoplastic, primary and metastatic lesions.
The assessment of human epidermal growth factor receptor 2 (HER2) status in gastric cancer is crucial in selecting patients who may benefit from targeted therapy, yet heterogeneous expression could represent an important drawback for HER2 testing. We aimed to analyze (i) HER2 heterogeneity in primary gastric cancers, pre-neoplastic and metastatic lesions and (ii) HER2 prognostic role. We studied 292 surgically resected primary gastric carcinomas and constructed 21 tissue microarrays including tumor tissue cores, invasive front, paired lymph node metastasis, low- and high-grade dysplasia. Microarrays were immunohistochemically stained with HER2 antibody and digitally scanned. Novel digital analysis algorithms were developed to score HER2 expression. Fluorescence in situ hybridization was performed on equivocal cases. HER2-positive cases were 13% and heterogeneous HER2 expression was observed in 71% of positive samples. Analysis of HER2 status in tumor and tumor invasive front demonstrate concordance in 177 cases (88%). Comparison of HER2 expression in primary cancer and synchronous lymph node metastasis exhibited discordant status in 14% of cases. Dysplastic epithelium surrounding the tumor showed immunohistochemical score 2 or 3 in 19% of high-grade and in 9% of low-grade dysplastic samples. HER2 status was significantly associated with intestinal-type carcinomas (P=0.018) and prognosis since patients with primary HER2-positive tumor showed decreased overall survival (P=0.006). Intratumoral HER2 expression heterogeneity and variable lymph node metastases status strongly suggest evaluating more than one sample and, if available, metastatic foci for routinely HER2 testing.
Division of Pathology, Department of Pathophysiology and Transplantation, University of Milan, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Nicola
N
Fusco
Elena Guerini
EG
Rocco
Claudia
C
Del Conte
Caterina
C
Pellegrini
Gaetano
G
Bulfamante
Franca
F
Di Nuovo
Solange
S
Romagnoli
Silvano
S
Bosari
D000465:Algorithms; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D002277:Carcinoma / Q000737:chemistry* / Q000235:genetics / Q000556:secondary; D016009:Chi-Square Distribution; D006801:Humans; D007090:Image Interpretation, Computer-Assisted; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D015999:Multivariate Analysis; D060787:Neoplasm Grading; D011230:Precancerous Conditions / Q000737:chemistry* / Q000235:genetics / Q000473:pathology; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis* / Q000235:genetics; D012189:Retrospective Studies; D013274:Stomach Neoplasms / Q000737:chemistry* / Q000235:genetics / Q000473:pathology; D046888:Tissue Array Analysis
D014408:Biomarkers, Tumor; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human