Diagnostic pitfalls in site-of-origin immunohistochemistry for metastatic carcinoma: Aberrant expression and loss of lineage-associated markers.

Site-of-origin immunohistochemistry is widely used in the evaluation of metastatic carcinoma, but lineage-associated markers are neither completely sensitive nor entirely specific. This review examines diagnostically important patterns of immunophenotypic discordance, with emphasis on aberrant marker expression and loss of expected lineage-associated proteins. Biological mechanisms include dedifferentiation, lineage plasticity, metastatic selection, intratumoral heterogeneity, and treatment-associated reprogramming, whereas fixation, decalcification, antibody clone, assay conditions, staining interpretation, and limited sampling may create analytical or interpretive pseudodiscordance. Particular attention is given to PAX8; GATA3, TRPS1, and SOX10; TTF-1 and Napsin A; CDX2 and SATB2; and NKX3.1, PSMA, PSA, and PSAP. The review also outlines a practical approach to conflicting results based on reassessment of morphology, verification of technical credibility, use of limited complementary panels, comparison with prior material, and clinicoradiologic correlation. Molecular tissue-of-origin profiling may provide ancillary diagnostic support when clinicopathologic findings remain unresolved. Comprehensive genomic profiling serves a distinct treatment-oriented role by identifying potentially actionable molecular alterations. Overall, discordant immunophenotypes should modify diagnostic probability rather than determine site of origin in isolation.