Skip metastasis in nonsmall cell lung carcinoma: predictive markers and isolated tumor cells in N1 lymph nodes.
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.
Prenzel
Klaus L
KL
Department of Visceral and Vascular Surgery, University of Cologne, Cologne, Germany. klausprenzel@hotmail.com
Baldus
Stephan E
SE
Mönig
Stefan P
SP
Tack
Daniela
D
Sinning
Jan M
JM
Gutschow
Christian A
CA
Grass
Guido
G
Schneider
Paul M
PM
Dienes
Hans P
HP
Hölscher
Arnulf H
AH
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D001707:Biopsy, Needle; D002289:Carcinoma, Non-Small-Cell Lung / Q000401:mortality / Q000556:secondary* / Q000601:surgery; D015331:Cohort Studies; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000032:analysis; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000401:mortality / Q000473:pathology* / Q000601:surgery; D008198:Lymph Nodes / Q000473:pathology*; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011336:Probability; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D012189:Retrospective Studies; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
D014408:Biomarkers, Tumor; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53