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Immunohistochemical Detection of Occult Lymph Node Metastases in Non-Small Cell Lung Cancer

Anatomical Pathology Results from Cancer and Leukemia Group B Trial 9761

¹ Laboratory Medicine 113, VA Medical Center, Durham, North Carolina;
² Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina;
³ Division of Cardiovascular and Thoracic Surgery, University of Minnesota Medical School, Minneapolis, Minnesota;
⁴ Laboratory Medicine, VA Medical Center, Syracuse, New York;
⁵ Pulmonary and Critical Care Division, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, Ohio;
⁶ Division of Medical Oncology, Medical University of South Carolina, Charleston, South Carolina; and
⁷ Division of Medical Oncology, University of Minnesota Medical School, Minneapolis, Minnesota

Purpose: Our purpose was to study the detection of occult metastases (OM) in regional lymph nodes using immunohistochemical stain for cytokeratin, and for this study we targeted clinical stage I patients with non-small cell lung cancer.

Experimental Design: The study comprised the first 193 patients entered onto Cancer and Leukemia Group B protocol 9761. All had clinically staged T_1–2N₀M₀ non-small cell lung cancer, and all underwent curative resections of their primary tumors. Samples of the primary tumor and lymph nodes were taken from lymph node stations 2–12 and shipped to a central laboratory, where each lymph node was histologically processed and stained with H&E as well as with immunohistochemical stain using antibodies to cytokeratin (AE1/3).

Results: Altogether, we examined 825 lymph nodes. Whereas routine H&E staining allowed us to detect 18 positive lymph nodes, immunohistochemical staining allowed us to detect 45 positive lymph nodes (P < 0.0001). There were 28 OM [i.e., those detectable only by immunohistochemistry (IHC)], and there was 1 metastasis detected only by H&E staining. The OM included 9 OM in N1 stations and 19 OM in N2 stations. Twelve patients with OM had skip metastases. Routine H&E staining upstaged six patients to N1, and IHC added another five. Routine H&E upstaged 9 patients to N2, and IHC added another 11. We also uncovered new details about the way in which H&E detection depends on metastatic tumor burden. Specifically, for the probability of detecting metastases by H&E to exceed 0.50, the maximum diameter of the metastasis must be greater than 0.23 mm.

Conclusions: IHC detects greater than twice as many positive regional lymph nodes as does H&E staining, and the foci of tumor it detects are significantly smaller than those detected by H&E staining.

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