The back door: Venous-mediated metastasis into cervical lymph nodes as an alternative metastatic pathway for oropharyngeal squamous cell carcinoma

Circulating lymphocytes may home to lymph nodes (LNs) via paracortical post capillary venules, high-endothelial venules (HEVs) that recognize circulati ng lymphocytes, enabling them to migrate into nodal cortical/paracortical r egions. Our goal was to find any histologic, immunohistochemical, or in vit ro evidence to support the hypothesis that squamous cell carcinoma (SCC) ma y gain access to LNs via an alternative venolymphatic pathway. Slides from 67 neck dissections with SCC were studied. Standard criteria for lymphatic- mediated metastasis were used; criteria for evidence of venolymphatic metas tasis were tumor nests localized to the paracortical regions, directly cont iguous to HEVs but not marginal sinuses. Cases in which LN architecture was obliterated by metastases were excluded. A modified Stamper-Woodruff assay , which assesses HEV binding, incubated cell lines from oral carcinomas and lung adenocarcinomas with fresh frozen LN sections. Double-blinded cell co unts were performed by two observers and analyzed by Student's t test. Immu nohistochemical examination was undertaken on 19 paraffin-embedded cases wi th the monoclonal antibody, MoAb CD44v6, to discover whether expression of this adhesion molecule correlated with metastatic pattern. Twenty-nine case s (66%) revealed evidence only for the LN route of metastasis; 4 cases (9%) were classified as venolymphatic metastasis; 11 cases (25%) showed evidenc e for both pathways. The Stamper-Woodruff assay confirmed that SCC cells pr eferentially bound to HEV within cervical LN sections more than did adenoca rcinoma cells (P = .02). Strong staining to MoAb CD44v6 was seen in 18 (95% ) of 19 SCCs with a membranous pattern. Occasionally, CD44v6 highlighted tu mor emboli adjacent to HEVs, but no overall correlation could be made betwe en CD44v6 expression and pattern of spread. Tumor metastasis via lymphatic channels is the predominant mode of metastatic spread, but the venolymphati c route is a plausible alternative pathway. The preferential attachment of SCC cells to HEVs supports this theory.