cytokeratin

**Basics / Cell biology** - Cytokeratins (keratins) are one of the intermediate filament (IF) classes, along with vimentin (mesenchymal), desmin (muscle), GFAP (glia/astrocytes), and neurofilaments (neurons). - Structure: obligate heterodimers of type I (acidic, CK9–20) and type II (basic/neutral, CK1–8) keratins that assemble into filaments. Filaments anchor to desmosomes (cell-cell adhesion) and hemidesmosomes (cell-basement membrane). - Function: mechanical stress resistance and structural integrity of epithelia.

**Clinical significance: Immunohistochemistry (IHC)** - Cytokeratin positivity = epithelial origin (carcinoma). Useful for identifying poorly differentiated or metastatic tumors of unknown primary. - Pan-cytokeratin markers: AE1/AE3, CAM5.2. - Vimentin + / cytokeratin − generally suggests sarcoma, lymphoma, or melanoma (melanoma is S100, HMB-45, and Melan-A positive). - Some exceptions: epithelioid sarcoma, synovial sarcoma, and chordoma can express cytokeratin. Mesothelioma is cytokeratin positive (calretinin, WT1, and D2-40 also positive). Adrenocortical carcinoma is typically cytokeratin negative or weak.

**CK7 / CK20 patterns (high-yield for site of origin)** - CK7+/CK20−: lung adenocarcinoma, breast, ovarian serous, endometrial, cholangiocarcinoma, pancreatic (variable), thyroid, mesothelioma - CK7−/CK20+: colorectal adenocarcinoma (also CDX2+) - CK7+/CK20+: urothelial carcinoma, pancreatic/ovarian mucinous - CK7−/CK20−: hepatocellular carcinoma, renal cell carcinoma, prostate, squamous cell carcinoma of lung (variable), small cell lung (often dot-like pan-CK) - Merkel cell carcinoma: CK20+ with characteristic perinuclear dot-like staining.

**Other associations** - Mallory-Denk bodies (alcoholic hepatitis): eosinophilic cytoplasmic inclusions of damaged, misfolded cytokeratin intermediate filaments (with ubiquitin, p62). - Keratin mutations cause blistering/skin disorders: epidermolysis bullosa simplex (KRT5/KRT14, basal layer cleavage), epidermolytic hyperkeratosis (KRT1/KRT10). - Squamous cell carcinoma shows keratin pearls and intercellular bridges; stains for high-molecular-weight CK (CK5/6) along with p63/p40. - Serum cytokeratin fragments: CYFRA 21-1 (CK19 fragment) is used as a marker for non-small cell lung cancer (esp. squamous) and TPA/TPS markers are used in monitoring. - Mnemonic for IF types: "Vimentin = connective tissue; Desmin = muscle; Cytokeratin = epithelium; GFAP = neuroglia; Neurofilaments = neurons."

**Test-taking pearl:** A metastatic tumor of unknown origin that stains cytokeratin+ is a carcinoma; if vimentin+ only, think sarcoma/lymphoma/melanoma (check S100); if CD45+ (LCA), think lymphoma.