Molecular analysis of diminutive, flat, depressed colorectal lesions: are they precursors of polypoid adenoma or early stage carcinoma?
BACKGROUND
The diminutive, flat depressed colorectal lesion is a possible precursor of early stage carcinoma. However, the significance of this lesion in colon carcinogenesis remains unclear.


METHODS
Eighty-one diminutive flat lesions (<5 mm diameter) with a central depression (DPdep) were resected colonoscopically and their molecular characteristics were investigated. In parallel, 68 diminutive polyps (<5 mm diameter) with a polypoid growth pattern but no depression (DPpo) were analyzed as controls. After histopathologic diagnosis, only neoplastic tissues were stained by immunohistochemistry for p53 gene and cyclooxygenase 2 (COX-2) and the proliferation marker, Ki-67. Mutation of the K-ras gene was analyzed with the polymerase chain reaction-restriction fragment length polymorphism method by using DNA from microdissected tissue in paraffin sections.


RESULTS
Seventy-nine of 81 DPdep and 35 of 68 DPpo were diagnosed as neoplastic. Mild, moderate, and severe dysplasia were found in, respectively, 56, 15, and 8 DPdep polyps, and in 34, 1, and 0 DPpo polyps. Thus, DPdep were more likely to be neoplastic and to exhibit moderate and severe dysplasia compared with DPpo (p < 0.0001). No DPdep or DPpo was positive for the p53 protein. The proportion of specimens with K-ras codon 12 mutation was 13.4% in diminutive polyps (DP), and tended to be lower in DPdep (8.6%) than in DPpo (25.0%) (p = 0.073). The median (interquartile range) of the Ki-67 index of DPdep tended to be lower than that of DPpo (respectively, 0.0 [0.0-5.9] vs. 4.5 [0.0-17.1]; p = 0.0281). COX-2 overexpression was observed in 12 of 77 (15.6%) DP and there was no significant difference between DPdep (3 of 23, 13.0%) and DPpo (9 of 54, 16.7%).


CONCLUSIONS
Diminutive, flat, depressed lesions in this study had low rates of the genetic alterations associated with malignant progression. This indicates that either a different neoplastic mechanism is operative or that these lesions have a lower malignant potential than indicated by their histopathologic features.
Morita
Tetsushi
T
Department of Surgery and Clinical Oncology, Graduate school of Medicine, Osaka University, Japan.
Tomita
Naohiro
N
Ohue
Masayuki
M
Sekimoto
Mitsugu
M
Yamamoto
Hirofumi
H
Ohnishi
Tadashi
T
Tada
Masatomo
M
Ikenaga
Masakazu
M
Miyake
Yasuhiro
Y
Sakita
Isao
I
Tamaki
Yasuhiro
Y
Matsuura
Nariaki
N
Ito
Masayu
M
Monden
Morito
M
D003111:Colonic Polyps / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D051546:Cyclooxygenase 2; D016158:Genes, p53; D011905:Genes, ras; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000032:analysis*; D019394:Ki-67 Antigen / Q000032:analysis; D008565:Membrane Proteins; D009154:Mutation; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D011230:Precancerous Conditions / Q000235:genetics* / Q000473:pathology; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis*; D012189:Retrospective Studies
D007527:Isoenzymes; D019394:Ki-67 Antigen; D008565:Membrane Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases