Table 5:

Some therapy and prognosis-related immunomarkers*.

Immunomarker	Remark
Estrogen receptor (ER)	The ER and PR status should be tested on the primary tumor and/or metastases for all newly diagnosed invasive breast cancer or recurrence For ductal carcinoma in situ, ER status is required to decide hormone therapy to reduce the risk of future breast cancer. Testing DCIS for PR status is optional
Progesterone receptor (PR)
HER2/neu (ERBB2; c-erbB-2; erb-b2 receptor tyrosine kinase 2; human epidermal growth factor receptor 2)	For application of HER2-targeted therapy Tested in invasive or recurrent breast cancers, both lobular and ductal (Joint ASCO and CAP) Similarly, inoperable, locally advanced, recurrent or metastatic stomach and esophagus cancers (Joint ASCO and CAP) HER2 status tested by: (a) Immunohistochemistry to measures HER2 protein. (b) Fluorescent in situhybridization evaluates amplification (increased number of gene copies)[73]
CD117	Majority of GISTs overexpress CD117 (c-KIT) and PDGFRA. DOG1 (anoctamin-1/ANO1, a voltage-gated calcium-activated anion channel) immunoexpression may be noted even in CD117 non-immunoreactive GISTs. A minority of GISTs only shows PDGFRA immunoreactivity SDHB immunohistochemical staining should be considered for any tumors that lack CD117 or PDGFRA immunoreactivity to identify SDH-deficient GIST
DOG1
PGDFRA
SDHB
EGFR	EGFR is highly expressed in a variety of solid malignant tumors (including non-small cell lung cancer, pancreatic cancer, breast cancer, medullary thyroid cancer, salivary gland carcinoma, squamous cell carcinoma of the head and neck, colorectal cancer, chordoma, and malignant gliomas) and its expression has been correlated with disease progression and poor survival With increasing role of targeted therapies such as Anti-EGFR monoclonal antibody (IMC-C225: Cetuximab) IHC-based EGFR screening methods using FFPE of tumor assists selection of cancer patients eligible for cetuximab treatment
p16	p16 immunohistochemistry for risk stratification in oropharyngeal SCC with significantly better outcome of p16-positive oropharyngeal SCC than for p16 negative tumors[74]
p40	Thyroid transcription factor-1 (TTF1) and p40 (an isoform of p63) are immunomarkers for adenocarcinoma (ADC) and squamous cell carcinoma (SCC) respectively for objective categorization (especially in cases with solid/squamoid morphology which may be misclassified as SCC with therapy (with bevacizumab) related potentially lethal pulmonary hemorrhage[75]
TTF1
p53	p53 is altered gene in human cancers in approximately 50% of all invasive tumors. The most difficult-to-treat cancers (such as high-grade serous ovarian cancers, triple-negative breast cancers, esophageal cancers, small-cell lung cancers and squamous cell lung cancers) show p53 mutation in at least 80% of cases In such cases, mutant p53 protein is a candidate target for the new anticancer therapies[76]
Ki67	For grading of neuroendocrine tumors, GIST, pheochromocytoma, lymphoma As proliferation marker could be important in many other tumors including breast carcinoma[77]
Ber-EP4	Cases with metastasis of Ber-EP4 immunoreactive (epithelial cell adhesion molecule -positive tumors) may be treated with intraperitoneal catumaxomab antibody[17]
MMR proteins (MLH1, MSH2, MSH6, and PMS2)	To identify patients at risk for Lynch syndrome(hereditary non-polyposis colorectal cancer) and patients with sporadic microsatellite instable colorectal cancer Lynch syndrome is associated with increased risk of carcinoma at various sites including: Gastrointestinal: Colon, small intestine, stomach, hepatobiliary, pancreas Genitourinary: Kidney, bladder, prostate Gynecological: Endometrium, ovary
PDL1	Therapeutic monoclonal antibodies that target either PD-1 or PD-L1 have been FDA approved for use in various malignancies (including metastatic melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma, bladder cancer, head and neck cancer, Merkel cell carcinoma, Hodgkin lymphoma, gastric cancer, hepatocellular carcinoma, and microsatellite instability-high cancer regardless of histology). Approval is pending in other diseases However, testing for PD-L1 positivity is required for therapy of NSCLC with pembrolizumab (PD-1/PD-L1 antibody). However, there are four FDA registered PD-L1 IHC assays based on four different PD-L1 antibodies (22C3, 28-8, SP263, and SP142) used on two different IHC platforms (Ventana and Dako) with different scoring systems[78]

^*Qualitative and quantitative integrity of the tumor cells in cell-blocks (and surgical pathology specimens) is more critical than routine application of immunohistochemistry