*2.5.1. Clinical significance*

Her2/neu (ERBB2) is a well-known receptor tyrosine kinase in breast carcinoma and currently, it is the only established therapeutically important tyrosine kinase in gastric adenocarcinoma. According to the results of the TOGA study, patients show a statistically significant benefit when using the Her2-specific tyrosine kinase inhibitor trastuzumab in Her2/neu positive gastric cancer. About 20% of gastric carcinomas are Her2/neu positive–most of them are located in the proximal part of the stomach and have an intestinal tumour differentiation. The role of the pathologists is the determination of the Her2-status on gastric carcinoma cells using immunohistochemistry or fluorescence-*in situ* (FISH). The criteria of Her2-positivity are different from that of breast carcinoma (compare **Table 2**).


#### **Table 2.** Immunohistochemical Her2/neu criteria.

Gastric carcinomas are highly heterogeneous tumours and Her2/neu is usually not diffusely expressed in most of carcinoma cells (like it is commonly the case in breast carcinoma).

#### *2.5.2. Molecular-based classification systems and prediction of treatment options*

The molecular-based classification systems can be correlated to classical morphology-based divisions. The pathologist can use both to predict treatment options. The chromosomal instable/microsatellite stable subtype is more likely to belong to the intestinal type of adenocarcinoma or to the tubuloacinar-subtype and these tumours are more often correlated with a Her2/neu overexpression/amplification. The genomic stable/microsatellite stable with pithelial-mesenchymal-transposition (EMT) subtype is typically related to the diffuse type of adenocarcinoma or to the poorly cohesive adenocarcinoma including signet-ring cell carcinoma nearly never show Her2/neu positivity.

On the other hand, the microsatellite unstable or EBV-related subtypes can show different morphological patterns (sometimes associated with prominent lymphatic stroma) and are probably associated with better prognosis (Cristescu et al. described a better outcome in patients with microsatellite-instable tumours) and good treatment response to checkpointinhibitors (currently subject of clinical trials). In view of the above, pathologists should consider both traditional morphology-based and molecular-based classifications to find out the most reliable statement about prognosis and treatment options.

Cost-effective molecular-based classifications are possible using traditional morphology, immunohistochemistry (using antibodies against TP53, Her2/neu and MLH1) and *in-situ* technics (like EBER) [7, 8].

In surgical specimens, the determination of tumour stage is the most important prognostic factor in gastric carcinoma. In Western countries, the UICC-based TNM-classification system is well established (compare **Table 3**).



**Table 3.** TNM classification.

Gastric carcinomas are highly heterogeneous tumours and Her2/neu is usually not diffusely expressed in most of carcinoma cells (like it is commonly the case in breast carcinoma).

Pattern of expression (Baso-)lateral expression sufficient Circular expression required

**Gastric carcinoma Breast carcinoma**

Positive tumour cells

≥10%

The molecular-based classification systems can be correlated to classical morphology-based divisions. The pathologist can use both to predict treatment options. The chromosomal instable/microsatellite stable subtype is more likely to belong to the intestinal type of adenocarcinoma or to the tubuloacinar-subtype and these tumours are more often correlated with a Her2/neu overexpression/amplification. The genomic stable/microsatellite stable with pithelial-mesenchymal-transposition (EMT) subtype is typically related to the diffuse type of adenocarcinoma or to the poorly cohesive adenocarcinoma including signet-ring cell carcinoma

On the other hand, the microsatellite unstable or EBV-related subtypes can show different morphological patterns (sometimes associated with prominent lymphatic stroma) and are probably associated with better prognosis (Cristescu et al. described a better outcome in patients with microsatellite-instable tumours) and good treatment response to checkpointinhibitors (currently subject of clinical trials). In view of the above, pathologists should consider both traditional morphology-based and molecular-based classifications to find out the

Cost-effective molecular-based classifications are possible using traditional morphology, immunohistochemistry (using antibodies against TP53, Her2/neu and MLH1) and *in-situ*

In surgical specimens, the determination of tumour stage is the most important prognostic factor in gastric carcinoma. In Western countries, the UICC-based TNM-classification system

T1 Tumour invades lamina propria, muscularis mucosae or submucosa

T1a Tumour invades lamina propria or muscularis mucosa

T4 Tumour perforates serosa or invades adjacent structures

*2.5.2. Molecular-based classification systems and prediction of treatment options*

biopsy: ≥5 cells resection: ≥10%

most reliable statement about prognosis and treatment options.

nearly never show Her2/neu positivity.

Cut-off Positive tumour cells

*Source*: Modified according to Rüschoff et al. [6].

274 Gastric Cancer

**Table 2.** Immunohistochemical Her2/neu criteria.

technics (like EBER) [7, 8].

is well established (compare **Table 3**).

**T Primary tumour**

T1b Tumour invades submucosa T2 Tumour invades muscularis propria

T3 Tumour invades subserosa

The determination of tumour regression and estimation of the percentage of residual tumour after neoadjuvant chemo or radio-chemotherapy treatment is possible using standardized regression scores. Especially in Western countries, the regression score according to Becker et al. is well established (compare **Table 4**).


**Table 4.** Regression score.
