A Mediastinal Mass Aspirate With Necrosis
A 61-year-old former smoker presents with a 4 cm right paratracheal mediastinal mass, a 1.5 cm right hilar node, and a small right pleural effusion. Endobronchial ultrasound-guided fine-needle aspiration of the paratracheal node yields scant cellular material: clusters of atypical epithelioid cells with prominent nucleoli in a background of abundant necrosis and scattered lymphocytes. No keratinization or gland formation is seen. Immunohistochemistry on the cell block shows the atypical cells are positive for cytokeratin 7, TTF-1, and napsin A, and negative for p40 and cytokeratin 20. The sample is small, and the oncologist asks whether it is sufficient to start treatment.
1. Interpret the immunophenotype and give the diagnosis and its differential.
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Cytokeratin 7, TTF-1, and napsin A positivity with p40 negativity in a necrotic mediastinal/hilar node aspirate is characteristic of metastatic lung adenocarcinoma. The differential includes non-small cell carcinoma, not otherwise specified, if the sample were inadequate, and other TTF-1-positive tumors such as thyroid carcinoma, but napsin A and the clinical setting favor lung primary. Squamous cell carcinoma is excluded by p40 negativity and absence of keratinization. Small cell carcinoma is excluded by the epithelioid morphology with prominent nucleoli and by the adenocarcinoma markers. Necrosis in the aspirate can reduce cellularity and cause false-negative staining, so the adequacy of the cell block must be assessed.
2. What adequacy criteria should be applied before accepting this sample for predictive biomarker testing, and what should be done if it fails?
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Predictive testing for advanced lung adenocarcinoma requires sufficient tumor cellularity, typically at least 20% tumor cells for many DNA-based assays and more for some RNA-based or fusion assays, plus an assessment of DNA quantity and quality. The cell block should be reviewed for tumor fraction, necrosis, and background lymphocytes; if tumor content is marginal, macrodissection or a repeat sample is needed. If the sample fails, options include a repeat EBUS-TBNA or core biopsy, a pleural fluid cell block, or a blood-based circulating tumor DNA assay, recognizing that liquid biopsy has lower sensitivity for some alterations. The judgment call is not to report a negative biomarker result from an inadequate sample.
3. The sample passes adequacy and shows an EGFR exon 19 deletion. How does this alter management and what pitfalls remain?
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An EGFR exon 19 deletion is an activating sensitizing mutation that predicts response to EGFR tyrosine kinase inhibitors, so first-line targeted therapy is appropriate rather than chemotherapy or immunotherapy. Pitfalls: the result must be confirmed on a validated assay with adequate coverage; concurrent resistance alterations such as T790M or MET amplification should be considered if the patient has prior TKI exposure; and PD-L1 testing may still be requested but immunotherapy alone is generally avoided in EGFR-mutant disease because of reduced benefit and potential harm. The pathologist should ensure the report states the assay, tumor fraction, and variant allele frequency so the oncologist can judge reliability.