Occult Metastasis on Immunohistochemistry May Affect Survival in Stage I NSCLC


Key Points

  • Immunohistochemistry-positive N2 nodes were associated with poorer overall survival in patients with clinical stage I NSCLC.
  • No association with survival was found for nodes positive on carcinoembryonic antigen RT-PCR.

Mature results of the Cancer and Leukemia Group B 9761/Alliance study, reported in the Journal of Clinical Oncology by Martin et al, indicate that occult metastases detected by immunohistochemistry in N2 lymph nodes may be associated with poorer overall survival after resection in clinical stage I non–small cell lung cancer (NSCLC).

Study Details

CALGB 9761 enrolled 502 patients with suspected clinical stage I (T1-2N0M0) NSCLC between 1997 and 2002. Primary tumor and lymph nodes were assessed for occult metastases via immunohistochemistry for cytokeratin (AE1/AE3) and real-time reverse transcriptase–polymerase chain reaction (RT-PCR) for carcinoembryonic antigen. Of the 502 patients, 489 underwent complete surgical staging; 304 (61%) had pathologic stage I NSCLC (T1 = 58%, T2 = 42%) and were included in the final analysis. Among them, 56% had adenocarcinomas, 34% had squamous cell carcinomas, and 10% had other histology.

Outcome by Immunohistochemistry, RT-PCR Status

Among 298 patients with lymph nodes analyzed by immunohistochemistry, 41 (14%) were immunohistochemistry-positive; N1 nodes accounted for 42% and N2 nodes accounted for 58% of the positive nodes. On multivariate analysis, there was no significant difference in overall or disease-free survival for immunohistochemistry-positive N1 nodes vs immunohistochemistry-negative status. The presence of immunohistochemistry-positive N2 nodes was associated with poorer overall survival vs immunohistochemistry-negative status (hazard ratio [HR] = 2.04, P = .017); no significant difference in disease-free survival was observed.

Among 256 patients with nodes analyzed by RT-PCR, 176 (69%) were PCR-positive (52% N1 and 48% N2 nodes). PCR positivity was not associated with either overall or disease-free survival.

The investigators concluded: “NSCLC tumor markers can be detected in histologically negative [lymph nodes] by AE1/AE3 immunohistochemistry and carcinoembryonic antigen RT-PCR. In this prospective, multi-institutional trial, the presence of [occult metastases] by immunohistochemistry staining in N2 [lymph nodes] of patients with NSCLC correlated with decreased [overall survival]. The clinical significance of this warrants further investigation.”

The study was supported by the National Cancer Institute and others.

Linda W. Martin, MD, MPH, of the University of Maryland Medical School, is the corresponding author of the Journal of Clinical Oncology article. 

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