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Original Article

Changes in human epidermal growth factor receptor 2 status between
primary breast/gastric carcinomas and synchronous metastatic lymph
nodes: how can we explain them?

Antonio Ieni, Valeria Barresi, Giovanni Branca, Luana Licata, Rosario Alberto Caruso, Giovanni Tuccari
Department of Human Pathology “Gaetano Barresi”, University of Messina, 98125 Messina, Italy.
Correspondence to: Prof. Giovanni Tuccari, Department of Human Pathology “Gaetano Barresi”, A.O.U. Polyclinic G. Martino Via Consolare
Valeria 1, 98125 Messina, Italy. E-mail: tuccari@unime.it

ABSTRACT
Aim: Previous studies demonstrated discordant expression of human epidermal growth-factor receptor 2 ( HER2) between primary
cancer and their recurrence/metastasis. This study further evaluated HER2 status between primary gastric and breast invasive
carcinomas and paired metastatic disease to lymph nodes. Methods: This study collected formalin-fi xed paraffi n-embedded
representative tissue blocks from 62 gastric and 65 breast primary carcinomas as well as synchronous metastatic lymph
nodes (male:female = 39:88; age ranged between 44 and 95 years with mean age of 69.32 years) for immunohistochemical staining
™
of HER2 expression (DAKO HercepTest kit). If immunohistochemical HER2 score reached to 2+, HER2 amplifi cation was then
assessed using fl uorescence in situ hybridization (PharmDx kit DAKO). Results: The discordant HER2 pooled rate, regardless
™
either negative or positive conversion, was 9.67% in primary gastric carcinoma and corresponding nodal metastasis, while the
changes in HER2 expression were revealed in 4.61% of mammary and lymph node neoplastic samples. A high-level concordance
in HER2 expression between primary carcinoma and synchronous metastatic lymph nodes was confi rmed in both types of cancer;
the observed event of discordant HER2 status should be ascribed to intra-tumor heterogeneity, mostly appreciable in gastric cancer.
Conclusion: In any case, the shift from positive to negative HER2 expression suggests that trastuzumab could be the targeted
treatment choice whereas the opposite shift should be evaluated by a simultaneous HER2 determination in both primary and
metastatic lymph nodes.

Key words: Breast cancer, epidermal growth-factor receptor 2, gastric cancer, lymph node, metastasis

Introduction 7.7% and 25% depending on localization and histology of
the cancer, [17-19] a higher rate of HER2 amplifi cation occurs
Expression or amplifi cation of human epidermal in unusual aggressive histology types, such as the hepatoid
growth-factor receptor 2 (HER2) frequently occur in variant. [20,21] However, until date, there were only a few
primitive neoplastic tissues from patients with breast studies reporting HER2 heterogeneity in paired primary
carcinoma (BC). [1-4] However, in recent years, several and metastatic GC samples, [22-24] and demonstrating a low
studies have demonstrated that HER2 status may vary in rate of discordance in HER2 amplifi cation with either
the metastatic lesions compared to the primary tumor, [5-8] positive and negative conversion. [23,24]
and this discrepancy is more frequently found in distant
metastases than in loco-regional ones. [9-13] Discordance The potential divergence in the HER2 status between
in HER2 status was not only found between primary the primitive BC/GC and their metastasized diseases,
BC and its metastases, but also among the consecutive or among the successive metastases of the same tumor,
relapses of the same tumor, with similar proportions of has a signifi cant clinical relevance since it may modify
[8]
cases turning from negative to positive or vice versa and the patient’s sensitivity to targeted therapies, which
the changes mainly appeared in the second or following might be appropriate for the primitive tumor, but not for
progressions. [13-16] the metastases or vice versa. [12-15] For this reason, some
investigators proposed that detection of HER2 status
HER2 amplifi cation may also be detected in gastric should be re-assessed in the neoplastic tissues from
carcinomas (GCs), with a prevalence ranging between
metastatic BC to establish whether the therapy is actually
appropriate. [1,2,16,17]
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Thus, in this study, we evaluated HER2 status in
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Website: paired samples of BC/GC and synchronous metastatic
www.jcmtjournal.com lymph nodes that were collected during the same
surgical and tissue processing procedures, thus
limiting and avoiding any potential technical bias
DOI:
10.4103/2394-4722.153445 due to external factors. Our aim was to explore the
eventual HER2 discordance rate between primary

Journal of Cancer Metastasis and Treatment ¦ Volume 1 ¦ Issue 1 ¦ April 15, 2015 ¦ 21