Occult metastases in lymph nodes predict survival in resectable non-small-cell lung cancer: report of the ACOSOG Z0040 trial

Abstract

Purpose: The survival of patients with non-small-cell lung cancer (NSCLC), even when resectable, remains poor. Several small studies suggest that occult metastases (OMs) in pleura, bone marrow (BM), or lymph nodes (LNs) are present in early-stage NSCLC and are associated with a poor outcome. We investigated the prevalence of OMs in resectable NSCLC and their relationship with survival.

Patients and methods: Eligible patients had previously untreated, potentially resectable NSCLC. Saline lavage of the pleural space, performed before and after pulmonary resection, was examined cytologically. Rib BM and all histologically negative LNs (N0) were examined for OM, diagnosed by cytokeratin immunohistochemistry (IHC). Survival probabilities were estimated using the Kaplan-Meier method. The log-rank test and Cox proportional hazards regression model were used to compare survival of groups of patients. P < .05 was considered significant.

Results: From July 1999 to March 2004, 1,047 eligible patients (538 men and 509 women; median age, 67.2 years) were entered onto the study, of whom 50% had adenocarcinoma and 66% had stage I NSCLC. Pleural lavage was cytologically positive in only 29 patients. OMs were identified in 66 (8.0%) of 821 BM specimens and 130 (22.4%) of 580 LN specimens. In univariate and multivariable analyses OMs in LN but not BM were associated with significantly worse disease-free survival (hazard ratio [HR], 1.50; P = .031) and overall survival (HR, 1.58; P = .009).

Conclusion: In early-stage NSCLC, LN OMs detected by IHC identify patients with a worse prognosis. Future clinical trials should test the role of IHC in identifying patients for adjuvant therapy.

Fig 1.

Representative examples of cytokeratin immunohistochemistry in bone marrow (BM) and lymph nodes (LNs). (A) Negative BM with false-positive result. This is an example of two hematopoietic cells showing false-positive staining (red). The cells lack the size and nuclear characteristics of tumor cells. Here the nuclear membranes are smooth and the chromatin is finely granular and evenly distributed. Cells such as these were seen in virtually all samples, as well as in negative controls, and are considered nonspecific background. (B) BM with suspicious cells not defined as cancer. The cells in question (red) are more suggestive of tumor cells than the cells in panel A but lack definitive features of malignancy. The cells are slightly smaller than would be expected for tumor cells, and the nuclear-to-cytoplasmic ratio and nuclear features cannot be clearly seen. (C) BM with occult metastases (OMs). Note the four cells showing strong immunoreactivity (red staining). These cells are larger than the surrounding cells and have a scant amount of cytoplasm with large, irregular nuclei; they were confirmed as OMs by multiple independent reviews. (D) LN with OMs. Note the cluster of about nine cells and the two individual cells with strong cytokeratin immunoreactivity as evidenced by brown-red staining. The cells have the morphologic features of cancer cells, including large size compared with surrounding lymphoid cells, high nuclear-to-cytoplasmic ratio, dense irregular nuclei, and prominent nucleoli, and were confirmed as OM by multiple independent reviews.

Fig 2.

Schema summarizing the results of pleural fluid lavage cytology (before and after resection) and of immunostaining on bone marrow (BM) and lymph node (LN) samples in relationship to pathologic tumor stage according to the (A) sixth and (B) seventh editions of the American Joint Committee on Cancer lung cancer staging system.

Fig 3.

(A) Disease-free survival (P = .009) and (B) overall survival (P = .007) for patients with histologic N0 non–small-cell lung cancer who had occult metastases in lymph nodes by immunohistochemistry versus patients who did not.

Fig A1.

Overall survival for all eligible patients by pathologic stage, according to the (A) sixth and (B) seventh editions of the Joint Committee on Cancer lung cancer staging system.

Fig A2.

(A) Disease-free survival (P = .33) and (B) overall survival (P = .89) for patients who had occult metastases in bone marrow by immunohistochemistry versus patients who did not.