PharmacologyTier 1Medical Sciences concept

Immunohistochemical markers in cancer pathology (Ki-67, HER2, hormone receptors)

Core concept

IHC answers three questions
- What lineage is this? (carcinoma vs lymphoma vs melanoma vs sarcoma)
- Where did it come from? (site-of-origin markers in CUP)
- What will it respond to? (predictive - ER, PR, HER2, PD-L1)
Ki-67 - a nuclear protein expressed in G1, S, G2 and M but absent in G0
- A direct proliferation index = % of nuclei staining
- Not lineage-specific; it grades, it does not diagnose

Lineage screen

CK7 / CK20 in carcinoma of unknown primary

	CK20 positive	CK20 negative
CK7 positive	Urothelial, pancreaticobiliary, gastric	Lung, breast, ovary, endometrium, thyroid, mesothelioma
CK7 negative	Colorectal, Merkel cell	Prostate, renal, hepatocellular, squamous, germ cell, adrenal

Confirmatory second-line markers: TTF-1 (lung adeno, thyroid), CDX2 (colorectal), GATA3 (breast, urothelial), PAX8 (renal, thyroid, Mullerian), NKX3.1/PSA (prostate), HepPar-1/arginase (HCC), WT1 (mesothelioma, serous ovarian), p40/p63 (squamous)

Predictive markers in breast

ER/PR - positive at >=1% nuclear staining
HER2 - IHC scored 0, 1+, 2+, 3+
- 3+ = positive (complete intense membrane staining >10% of cells)
- 2+ = equivocal -> reflex ISH/FISH for HER2 gene amplification
- 0/1+ = negative - but 1+ and 2+/ISH-negative is now "HER2-low" and eligible for trastuzumab deruxtecan
Ki-67 - separates luminal A (low, <=20%) from luminal B (high); guides chemotherapy in node-negative ER+ disease
- Poor inter-observer reproducibility - use as one input, not a hard cutoff

Other named indices

CUP work-up: a small IHC panel typically resolves it into a treatable pattern - squamous cervical nodes, peritoneal serous carcinomatosis, isolated axillary adenopathy in a woman (treat as breast), poorly differentiated midline germ cell
Never call a tumour triple-negative without confirming ER, PR and HER2 including reflex ISH - it removes all endocrine and HER2-directed options
Ki-67 rising between primary and recurrence signals biological progression
HER2-low reclassification changed practice - a previously "HER2-negative" archived block may need re-review
IHC is done on a fixed block - poor fixation, decalcified bone and long ischaemic time cause false negatives, especially for ER and HER2

3 more sections, plus exam facts

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