Morphological and immunohistochemical characterization of isolated tumor cells by p53 status in gastrointestinal tumors.
OBJECTIVE
Isolated tumor cells (ITCs) in cancer patients are retrieved mostly using immunohistochemistry with antibodies directed against antiepithelial antigens (for example Ber-EP4), which are supposed not to be present in metastatic-free tissue. To date, there has been ongoing controversy whether those cells have biologic significance and are linked with tumor progression and impaired patient's prognosis. Therefore, the aim of this study was to further characterize Ber-EP4-positive cells in various tissues, with special emphasis on their tumorigenic origin.


METHODS
The frequency and prognostic impact of ITCs in lymph nodes displayed by means of monoclonal antibody Ber-EP4 were evaluated in retrospective (n = 292) and prospective (n = 100) collectives of various gastrointestinal carcinomas free of metastatic disease in conventional histopathology (pN0). Furthermore, the frequency of ITCs in the peritoneal cavity and bone marrow was analyzed in case of absence of overt distant metastasis (pM0) in the prospective collective. Ber-EP4-immunoreactive cells were further characterized for tumorigenic origin using morphological criteria and immunohistochemical double staining for Ber-EP4 and p53.


RESULTS
Ber-EP4-positive cells could be revealed in lymph nodes in 44.3% of pN0-gastrointestinal carcinomas, in the peritoneal cavity in 19%, and in the bone marrow in 10%. In lymph nodes, BerEP4-immunoreactive cells exhibited a metastatic-atypical morphology in 59%; however, it was always typical for true tumor cells in the peritoneal cavity or bone marrow. The cumulative 5-year survival rate was adversely affected by Ber-EP4-immunoreactive cells in uni- and multivariate analysis, irrespective of the underlying cell morphology (68% for Ber-EP4 negative, 41% for Ber-EP4 positive with atypical and typical morphology each). In the case of a p53-positive primary tumor, 70% of the corresponding ITCs also overexpressed p53, while the remainder was deemed p53 negative (p = 0.002).


CONCLUSIONS
ITCs detected by the antiepithelial antibody Ber-EP4 are present in a substantial proportion of apparently tumor-free lymph nodes. These cells impair patients' prognoses, irrespective of the underlying cell morphology. As approximately one third of Ber-EP4-positive cells in p53-positive primary tumors do not overexpress p53; their true tumorigenic origin needs to be further investigated.
Milsmann
C
C
Department of Surgery, University Clinic Göttingen, Robert-Koch-Str.40, 37085 Göttingen, Germany.
Füzesi
L
L
Heinmöller
E
E
Krause
P
P
Werner
C
C
Becker
H
H
Horstmann
O
O
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor / Q000276:immunology; D001853:Bone Marrow / Q000473:pathology; D002648:Child; D003110:Colonic Neoplasms / Q000401:mortality / Q000473:pathology / Q000601:surgery; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000401:mortality / Q000473:pathology* / Q000601:surgery; D006801:Humans; D007124:Immunoenzyme Techniques; D008197:Lymph Node Excision; D008198:Lymph Nodes / Q000473:pathology; D008207:Lymphatic Metastasis / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010190:Pancreatic Neoplasms / Q000401:mortality / Q000473:pathology / Q000601:surgery; D010537:Peritoneum / Q000473:pathology; D011237:Predictive Value of Tests; D011379:Prognosis; D011446:Prospective Studies; D012189:Retrospective Studies; D013274:Stomach Neoplasms / Q000401:mortality / Q000473:pathology / Q000601:surgery; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000032:analysis*; D000951:Antigens, Neoplasm
D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; D016159:Tumor Suppressor Protein p53; C115012:human epithelial antigen-125; D000951:Antigens, Neoplasm