Skip metastasis in nonsmall cell lung carcinoma

Abstract

BACKGROUND Skip metastasis to mediastinal lymph nodes is a prognostic factor for patients with nonsmall cell lung carcinoma (NSCLC). Little is known about the biologic behavior of tumors with noncontinuous spread to the mediastinal lymph nodes. In patients with pN2 skip metastases, micrometastases to N1 lymph nodes, which only mimic skip metastases, have not been investigated. METHODS In a retrospective study, the authors analyzed the primary tumor specimens from 45 patients with pN2 NSCLC (18 patients had squamous cell carcinomas, 23 had adenocarcinomas, and 4 had large cell carcinomas). They immunohistochemically evaluated the expression of p21, p53, MUC‐1, Bcl‐2, c‐ErbB‐2, and E‐cadherin. Survival rates and biomarker expression levels were compared between patients with pN2 disease and infiltration of N1 lymph nodes (without skip metastasis [n = 28]) and patients with pN2 disease without N1 infiltration (with skip metastasis [n = 17]). To evaluate micrometastasis in the pN1 lymph nodes of 17 patients with skip metastases, lymph nodes were stained using the anticytokeratin antibody, AE1/AE3. RESULTS The 5‐year survival rate of patients with skip metastases was 41%, compared with 14% for patients without skip metastases (P = 0.019). In a multivariate analysis, the incidence of skip metastases did not vary significantly according to gender, age, histology, pT status, or cM status. Three skip‐positive patients (17.6%) had micrometastatic tumor involvement of pN1 lymph nodes. After adding these patients to the group of patients without skip metastases, there was still a significant difference in survival between the two groups. p53, MUC‐1, c‐ErbB‐2, and E‐cadherin expression levels in primary tumor specimens were not significantly different in patients with continuous metastasis and patients with skip metastases. Patients with skip metastases expressed lower levels of p21 (P = 0.026), whereas Bcl‐2 expression levels were considerably higher (P = 0.019) compared with the corresponding levels in patients without skip metastases. CONCLUSIONS Patients with NSCLC and pN2 skip metastases have a more favorable prognosis than do patients with pN2 disease without skip metastases. Tumor specimens from these patients exhibit elevated expression of the antiapoptosis gene BCL2 and lower expression levels of p21 relative to patients with pN2 disease without skip metastases. Micrometastases occurred in 3 of 17 (17.6%) patients with pN2 disease and skip metastases diagnosed by routine histopathology. Cancer 2004. © 2004 American Cancer Society.

Results of Initial Operations in Non–Small Cell Lung Cancer Patients With Single-Level N2 Disease

“…In our series, the 5-year survival rate of the patients with skip-N2 disease was 33.4% despite complete resection with systematic lymphadenectomy Consistent with previous reports [1][2][3][4][5][6][7], survival of patients with non-skip-N2 disease was worse than that of patients with skip-N2 disease. The present study also showed that distant metastasis is the dominant cancer [25].…”

“…As the results of immnunohistochemical staining of N1 lymph nodes with anti-cytokeratin antibodies, one previous report indicated that microscopic spread of cancer cells could be detected in 17.6% of patients with skip-N2 disease [4]. Using immunohistochemical staining for cytokeratin in 3,081 lymph node samples obtained from 181 non-small cell lung cancer patients diagnosed as being in stage I by conventional histopathological examination, we previously found nodal micrometastasis in 44 patients [19].…”

“…From the viewpoint of sentinel lymph node mapping, the results of recently launched clinical trials support the anatomical concept. While the percentage of skip metastasis in lung cancer patients with N2 disease has been reported to be around 20-40% [1][2][3][4][5][6][7], sentinel node mapping in non-small cell lung cancer patients in various stages revealed a similar percentage of mediastinal (N2) sentinel nodes of 16.7-31% with a high sensitivity rate of more than 90% [16][17][18]. Arguably, the direct drainage system appears the most plausible main channel of skip mediastinal nodal spread of cancer cells.…”

“…In this situation, in contrast to alternate induction treatment followed by surgery, the use of an initial operation plus postoperative adjuvant chemotherapy in the management of patients with resectable single-level N2 disease has become a matter of debate. Although studies of the molecular events underlying nodal metastasis in lung cancer are not yet conclusive, some investigators have also postulated a subgroup of skip N2 disease with more favorable therapeutic results as compared to those with non-skip N2 disease [1][2][3][4][5][6][7]. In the present study, we reviewed our experience with non-small cell lung cancer patients with single-level N2 disease who underwent initial operation and performed a retrospective analysis of the surgical results.…”

Prognostic Significance of Subcarinal Station in Non-Small Cell Lung Cancer with T1 - 3 N2 Disease

“…Our data suggested that a favorable prognosis might be obtained in spite of N2 disease, if subcarinal lymph node metastasis is not involved. The difference between these groups might be explained by the biological characteristics of the tumor that the node has [17]. In a study by Fujimoto et al, vascular endothelial cell growth factor (VEGF)-C levels were significantly (p < 0.05) increased in 24 of 40 metastatic lymph node lesions of uterine cervical cancers [18].…”