Abstracts
1999 Digestive Disease Week

# 4676 ONGOING STUDY ON THE PROGNOSTIC RELEVANCE OF AN IMMUNOHISTOCHEMICALLY DETECTABLE TUMOR CELL DISSEMINATION IN ESOPHAGEAL CANCER
Stefan Hosch, Univ Hosp Hamburg-Eppendorf, Hamburg Germany; A Rehders, S Bull, Univ of Hamburg, Hamburg Germany; K Pantel, Instute for Immunology, Univ of Munich, Munich Germany; J R Izbicki, Univ Hosp Hamburg-Eppendorf, Hamburg Germany

The concept of endoscopic surgery and local therapy of small primary esophageal cancers is based upon the assumption that these patients display no metastatic cells. However, early recurrence even in low stage esophageal cancer patients indicate an early minimal tumor cell spread to secondary organs not detectable by current tumor staging procedures. We therefore performed a prospective study to assess the frequency and the prognostic significance of minimal residual tumor cells in lymph nodes and bone marrow of patients with completely resected esophageal cancer.Methods:Lymph nodes bone marrow and tumor samples of 115 patients who had undergone radical en-bloc esophagectomy (R0 resection) were collected. Lymph nodes were divided into two parts. One part was embedded in paraffin for routine histopathological examination, the other part was snap-frozen. Lymph nodes without evidence of tumor in routine histopathology were screened for the presence of single tumor cells by the antiepithelial monoclonal antibody Ber-Ep-4 (IgG1; Dako, Carpinteria, USA), using the alkaline phosphatase-anti-alkaline phosphatase (APAAP) technique. For the detection of tumor cells in bone marrow, we used mAb A45-B/B3 (IgG1; Micromet Munich, FRG), which detects cytokeratins 8, 18, and 19 Slides were evaluated in a double blinded fashion using light microscopy. Results:In 83 of 115 patients (72,2%), isolated BerEP4+ cells were found. 32 of the 46 patients (69%) staged as pN0 showed Ber-EP4+ cells as compared to 51 of 69 patients (73.9%) at stage pN1 (n.s.). 9 of the Ber-EP4+ patients in the former group displayed a small pT1 primary tumor and one patient had only a carcinoma in situ (pTis). There was no correlation between the detection of Ber-EP4+ cells in lymph nodes and other clinico-pathological factors, such as primary tumor stage (T stage), tumor type or histopathological grade. Following a mean observation time of 21 months (range 6-64 months), the presence of Ber-EP4+ tumor cells in lymph nodes was associated with a significantly reduced disease-free survival (p =o.ooo1) as well as overall survival (p=0.0047). Using the Cox regression model, this minimal tumor cell dissemination was an independent factor for relapse free survival (p=0.0007) and for overall survival (p=0.001). Remarkably, all of the 14 patients who were re-staged as lymph node negative by both histopathologic and immunohistochemical analyses survived the observation period without recurrence. Interestingly, minimal tumor cell dissemination to bone marrow (n=37) had no influence on prognosis. Conclusions: Immunohistochemical examination of excised lymph nodes may improve current tumor staging. Patients with immunostained tumor cells in their lymph nodes require an upstaging since their prognosis is similar to the prognosis of patients with histopathological lymph node involvement. Considering the minimal residual tumor load in these patients, new therapeutic strategies with less severe side effects, such as intravenous application of monoclonal antibodies might be an alternative or an adjunct to systemic chemotherapy.

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