Practical Application of Lineage-Specific Immunohistochemistry Markers: Transcription Factors (Sometimes) Behaving Badly

Abstract

Context.— Transcription factors (TFs) are proteins that regulate gene expression and control RNA transcription from DNA. Lineage-specific TFs have increasingly been used by pathologists to determine tumor lineage, especially in the setting of metastatic tumors of unknown primary, among other uses. With experience gathered from its daily application and increasing pitfalls reported from immunohistochemical studies, these often-touted highly specific TFs are not as reliable as once thought. Objectives.— To summarize the established roles of many of the commonly used TFs in clinical practice and to discuss known and potential sources for error (eg, false-positivity from cross-reactivity, aberrant, and overlap “lineage-specific” expression) in their application and interpretation. Data Sources.— Literature review and the authors' personal practice experience were used. Several examples selected from the University Health Network (Toronto, Ontario, Canada) are illustrated. Conclusions.— The application of TF diagnostic immunohistochemistry has enabled pathologists to better assess the lineage/origin of primary and metastatic tumors. However, the awareness of potential pitfalls is essential to avoid misdiagnosis.

Immunocytochemistry for diagnostic cytopathology—A practical guide

“…Among the carcinoma markers, claudin 4 has been found to be superior to others for distinguishing carcinoma from MM 158–160 . Lineage specific markers can be used to identify the origin of a metastasis; the selection of the ICC panel should be guided by the clinical history, including the age and gender of the patient, imaging features, and location of the effusion 154–157,161–163 (Table 9).…”

“…Metastasis from neuroendocrine carcinomas, mainly SmCC, can be confirmed with neuroendocrine markers. Although the primary site in the majority of these cases is the lung (TTF1+), neuroendocrine carcinomas from other sites are also often positive for this marker 162,167 . The differential diagnosis includes Merkel cell carcinoma and small round blue cell tumours 168–174 …”

“…Use of different keratins can narrow down the differential diagnosis 246,247 (Table 12). Additional ICC may be needed; the most commonly used first‐line markers for identification of the primary site are listed in Table 13 162,244,245,248 …”