The epidermal growth factor receptor family is constituted by four members with similar structures: HER1/erbB1, HER2/erbB2, HER3/erbB3 and HER4/erbB4. These receptors play an important role in the processes of proliferation and differentiation of normal cells [1]. The binding of the ligand to these receptors causes the creation of homodimers and heterodimers as well as the activation of downstream signaling pathways [1]. Hence, any aberrations in their structure or function can cause transformation of normal cells to malignant cells with consequent tumor development and progression [1]. However, on the basis of results from an international randomized controlled trial (ToGA), the patients with advanced gastric adenocarcinoma (GC) positive for HER2 over-expression could be eligible for a target treatment with trastuzumab [2]. A significant reduction in the risk of mortality was appreciable when trastuzumab was added to the chemotherapy regimen [2]. There is general agreement with regard to a higher HER2 positivity in gastroesophageal junction cancer (24–35%) compared with GC (9.5–21%) [3]. The rate of HER2 immunoreactivity seemed to be vary variable in relation to the different neoplastic histotype of the stomach [4]. Generally, all studies have reported a prevalence of HER2 amplification in advanced GC of intestinal type (81.6–91%) in comparison with diffuse or mixed ones (4–7.9%) [4]. In addition, a progressive increase in HER2 overexpression has been appreciated moving from the poorly cohesive WHO histotype to mitochondrion-rich adenocarcinomas (MRC), tubular adenocarcinomas and hepatoid carcinomas (HAS), these latter representing the top rate of HER2 positivity, characterized by an extremely poor prognosis [4]. Furthermore, HER2 overexpression was also significantly associated with a high grade, advanced stage and high Ki67-LI value, becoming thus an additional morphological parameter able to affect the mortality of patients with GC [5]. Finally, some investigations have been recently reported regarding the concordance of HER status in primary gastric cancer and corresponding lymph nodes or distant metastases, with either positive or negative conversion in HER2 overexpression [6] [7].

Generally speaking, chronic atrophic gastritis and intestinal metaplasia of the stomach have been regarded to as pre-neoplastic lesions, even if data from literature points towards the existence of other pathways, in which intestinal metaplasia may not play a role, as described by Japanese authors [8]. However, the true precancerous gastric lesion should be considered dysplasia, which includes cellular and structural atypia, also codified under the term intraepithelial neoplasia (IEN), a pathological condition that lies between atrophic gastritis and GC [9]. It is well known, that IEN may develop in the gastric or intestinal metaplastic epithelium and it can be categorized into four categories: indefinite for intraepithelial neoplasia, low-grade intraepithelial neoplasia (LG-IEN), high-grade intraepithelial neoplasia (HG-IEN) and suspicious for invasive cancer [10]. The IEN histological distinction as low or high-grade depends on the severity of architectural and cytological atypia. In LG-IEN, the mucosal structure is only faintly modified maintaining tubular differentiation with the proliferative zone limited to the outward portion, whereas HG-IEN exhibits increasing distortion of the mucosal architecture, resulting in crowded possibly irregular glands with obvious cellular atypia and proliferative activity distributed throughout the lesion [10]. High-grade intraepithelial neoplasia is associated with a higher risk of developing GC [10]. It has been described, that the genomic copy number aberration of gastric precancerous lesions and carcinoma in situ (CIS) have provided the most prominent 8q gain, which was detected most frequently in both HG-IEN and CIS, but was undetected in LG-IEN using array comparative genomic hybridization [11]. Previous studies with HGIN and LGIN were mostly based on several known genes [11], such as p53, HER2 and E-cadherin [12].

Only few studies have described the overexpression of HER2 in gastric dysplastic lesions [13]. In a series of gastrectomies and gastric biopsies, there was a 12.6% of HER2 positivity in HG-IEN, while 2+/3+ reactivity was not seen in benign mucosa, even if some cases have showed a weak membranous reaction in foveolar gland elements and also a cytoplasmic staining in specialized glands [13]. Interestingly, a series of intriguing cases with a discordant HER2 status between dysplastic lesions and invasive carcinomas has been reported [13]. In detail, three cases showed a HER2 positivity limited only to dysplastic epithelium despite the invasive component; conversely in four cases, HER2 expression was encountered only in invasive areas and finally six cases showed a concordant 3+ HER2 reactivity, either in dysplastic or in equivalent invasive part [13]. In addition, a questionable percentage of HER2 positivity should be related to characteristics of biological samples, since bioptic specimens could overestimate as false positive for HER2 the dysplastic epithelium, being misinterpreted as invasive carcinoma [13].

More recently, HER2 overexpression was observed in gastric LG-IEN and HG-IEN, with a significant increase from LG-IEN to HG-IEN. There was a HER2 positivity of 4–8% in LG-IEN and 16–20% in HG-IEN [14]. These results suggest that HER2 may be a part of early stage of gastric carcinogenesis, although the heterogeneity of HER2 status documented in IEN supports that the molecular dysregulation may only affect a subset of the intraepithelial neoplastic cell populations [14]. Similar results have been noted in high-grade dysplastic lesions, suggesting a potential rate of HER2 in early neoplastic transformation of gastric mucosa [14]. Study showed of a score 2+ or 3+ staining in 12/63 (19%) high-grade dysplastic samples and in 7/75 (9%) low-grade dysplastic samples has been elsewhere, reported [15], although the a validation by FISH procedure should be performed in equivocal 2+ cases. However, by using an histomorphological profile, dysplasia has been also classified in adenomatous/type I (intestinal phenotype) and foveolar or pyloric/type II (gastric phenotype) [16]. This distinction was mainly based by an immunohistochemical analysis. The intestinal/adenomatous type was immunopositive for CD10 and CDX2, while the gastric/foveolar type was characterized by a negative CD10 staining and MUC5AC, MUC6 reactivity [17]. Moreover, cases with hybrid differentiation may also occur as well as null cases in which there is no expression of the aforementioned markers [17]. HER2 amplification was observed in cases immunophenotyped as gastric or hybrid, suggesting that this type of dysplasia may be an important player in gastric carcinogenesis. [17]. Therefore, we retain that an extensive investigation of HER2 status in gastric morphological dysplasia may help to identify patients at high risk of developing a certain cancer, even if the relationship between HER2 overexpression and progression of dysplasia towards GC probably requires further investigations.

It is well known that HER2 gene amplification can be acquired during progression of the neoplastic disease or recurrence, either in patients affected by breast or gastric carcinomas [6] [7]. Indeed, precancerous lesions are constituted by cells with different pathological conditions, which are continuously dividing and acquiring genetic instability; therefore, some different cellular clones may coexist showing a HER2 status, able to be subjected to the possibility of its change into overt carcinomas, either with a positive or negative conversion in comparison to that exhibited in dysplastic elements. Consequently, although at present the determination of HER in pre-neoplastic gastric morphological lesions is not still mandatory, it can be argued that the determination of HER2 status - also in short series or in case reports - could be performed as it may influence the therapeutic treatment and affect the prognosis, furnishing in the meantime additional information to the eligibility for trastuzumab treatment [18].

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