Small Lung Core With a Broad Differential and Predictive-Marker Demand
A 64-year-old man with a 30 pack-year smoking history has a 1.2 cm left upper lobe lung mass and a 1.8 cm adrenal mass. A CT-guided core biopsy of the lung yields four 1-mm cores; two are used for H&E and one for a rapid on-site impression. The pathologist has one unstained slide and one 4-µm section remaining. The differential includes primary lung adenocarcinoma, squamous cell carcinoma, small cell carcinoma, and metastatic adrenal cortical carcinoma. The oncologist wants PD-L1, ALK, ROS1, and EGFR results within 10 working days to start first-line therapy. The lab's immunohistochemistry menu includes TTF-1, napsin A, p40, p63, synaptophysin, chromogranin, CD56, inhibin, melan-A, and a PD-L1 assay; ALK and ROS1 IHC are send-outs with 7-day turnaround.
1. How would you triage the diagnostic immunohistochemical panel with only one unstained slide and one section remaining?
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First review the H&E and on-site impression to narrow the differential. If the morphology suggests adenocarcinoma, prioritize TTF-1 and p40 on the remaining section or unstained slide; if the tissue is sufficient for multiplexing, use a validated multiplex assay to conserve sections. If morphology suggests small cell carcinoma, prioritize synaptophysin, chromogranin, CD56, and TTF-1. If morphology suggests adrenal cortical carcinoma, use inhibin and melan-A. Do not order the entire menu at once. If the first small panel is nondiagnostic, request additional tissue or a repeat biopsy rather than cutting the block to exhaustion. The predictive markers should wait until the lineage is established, because PD-L1, ALK, ROS1, and EGFR are not equally indicated for small cell carcinoma or adrenal cortical carcinoma.
2. What interpretive pitfalls should be considered when the stains return?
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Interpret stains in the context of morphology. TTF-1 supports lung adenocarcinoma but is also positive in small cell carcinoma and can be focal or absent in poorly differentiated adenocarcinoma; napsin A is more specific but less sensitive. p40 is more specific for squamous differentiation than p63, which can stain adenocarcinoma and basal cells. Adrenal cortical carcinoma can express inhibin and melan-A, but metastatic adrenal carcinoma to the lung is uncommon and should not be diagnosed on a single stain. A PD-L1 result is assay-dependent and requires adequate viable tumor cells; it should not be interpreted across different clones or platforms. ALK and ROS1 IHC are screening tests and usually require confirmation by a molecular method. If staining is aberrant or ambiguous, do not force a lineage; state the uncertainty and recommend additional tissue.
3. How should the predictive-marker requests be prioritized to meet the oncologist's 10-day target without compromising diagnosis?
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The 10-day target is achievable only if the diagnosis is established quickly and tissue is allocated deliberately. If the tumor is a lung adenocarcinoma, send PD-L1 on the remaining tissue and order EGFR and ALK/ROS1 testing through the appropriate molecular pathway; ALK and ROS1 IHC are send-outs with a 7-day turnaround, so they must be initiated as soon as the lineage is confirmed. If the diagnosis is squamous cell carcinoma, PD-L1 is relevant but EGFR, ALK, and ROS1 are not routinely indicated. If the diagnosis is small cell carcinoma, predictive testing should focus on the immediate treatment pathway rather than the adenocarcinoma panel. If the tissue is insufficient, arrange a repeat biopsy early rather than submitting an inadequate sample. Communicate the triage decision and expected turnaround to oncology so that treatment planning is not delayed by tests that do not apply.