Clinicopathologic and Immunohistochemical Study of Small Apparently ???De Novo??? Colorectal Adenocarcinomas

Abstract

Rarely, adenocarcinomas of the colorectum develop as small (< or =1.0 cm) rapidly invasive tumors without an obvious adenomatous or "in situ" component. These tumors have been termed "de novo" carcinomas. Although it is believed by some that these tumors are more aggressive than conventional large adenocarcinomas with an identifiable in situ component, little is known about the biologic characteristics and natural history of these lesions. The aim of this study was to evaluate and compare the pathologic features, biologic characteristics, and natural history of small apparently de novo invasive colorectal adenocarcinomas with conventional large (>1.0 cm) carcinomas. Routinely processed specimens from 20 patients (M/F ratio: 13/7; mean age: 65 y) with small apparently de novo invasive colorectal adenocarcinomas (all < or =1.0 cm in size) were evaluated for a variety of clinical and pathologic features. In addition, immunostains for p53, beta-catenin, DPC4, hMLH1, hMSH2, and MGMT were evaluated in all cases. The findings in this group of cases were compared with those from 20 control patients (M/F ratio: 8/12; mean age: 60 y) with stage-matched conventional "large" colorectal adenocarcinomas (all >1.0 cm in size). Patients were followed for a mean of 52.6 and 60.6 months, respectively, for the 2 groups. Small apparently de novo invasive adenocarcinomas were present in the left colon, transverse colon, and right colon in 85%, 10%, and 5% of cases, respectively. Their mean size was 7 mm (range: 3 to 10 mm). All cases were stage T1 and the majority were moderately differentiated (75%). Only 1 (5%) patient had lymph node metastases. Two (10%) cases were mucinous and only 1 (5%) showed prominent tumor infiltrating lymphocytes. Upon complete sectioning of the tissue blocks of tumor, residual foci of adenomatous epithelium were present in 16/20 (80%) cases, of which 75% contained foci of high-grade dysplasia. P53 and nuclear beta-catenin staining was present in 70% and 85% of cases, respectively, but only 5 cases (25%) showed loss of DPC4. Loss of MGMT expression was seen in 5 cases (25%), loss of hMSH2 in only 1 case (5%), and none showed loss of hMLH1. Only 2 patients (10%) developed visceral metastases upon follow-up. Control patients had similar demographic features, clinical outcome, anatomic distribution of tumors, degree of differentiation, and prevalence of positivity for the immunostains noted above, to the study cases. In our patient population, true small de novo colorectal adenocarcinomas, tumors that lack an identifiable adenomatous component, are exceedingly rare, because complete tissue sectioning reveals residual adenomatous tissue in the majority of cases. The biologic characteristics and natural history of small carcinomas with a minimal dysplastic component, and those with no identifiable adenomatous component, are similar to conventional large (>1 cm) adenocarcinomas, and, thus, they should probably be treated similarly.

Clinicopathological differences of colorectal cancers according to tumor origin: Identification of possibly de novo lesions

“…We also examined their correlation with particular clinicopathological characteristics (stage, grade and site). The study was conducted in a sample mainly comprising 'advanced' CRC (i.e., tumors invading beyond the submucosa), consistent with certain previous studies (7,12,13,20,23), although in contrast to most Japanese (5,6,10,18,19) and certain Western studies (8,11) focusing on early (T1) lesions. Consistent with the findings reported by Chen et al, the ascertained incidence of potentially de novo tumors in our series was 28.5% (12).…”

“…Therefore, their detection is confined to a minority of CRC (~15-20%) (6,7), mostly those diagnosed in early stages and thought to retain their initial structural characteristics (7,9,10). This objective difficulty may explain the wide variation in the reported frequencies of de novo tumors in the literature (range, 1-80%) (6)(7)(8)(9)(10)(11)(12)(13). It also necessitates the implementation of additional criteria, potentially associated with these lesions, including small size (<1 or 2 cm), the limited invasion of the bowel wall (T1 lesions) and, mostly, the nonpolypoid growth pattern (presenting in various forms: flat, depressed and infiltrative) (6)(7)(8)(9)(10)(11).…”

“…This objective difficulty may explain the wide variation in the reported frequencies of de novo tumors in the literature (range, 1-80%) (6)(7)(8)(9)(10)(11)(12)(13). It also necessitates the implementation of additional criteria, potentially associated with these lesions, including small size (<1 or 2 cm), the limited invasion of the bowel wall (T1 lesions) and, mostly, the nonpolypoid growth pattern (presenting in various forms: flat, depressed and infiltrative) (6)(7)(8)(9)(10)(11). Despite the lack of absolute specificity for any of these criteria (9), their application may be helpful in the identification of de novo tumors (6,7,10,13).…”

“…Moreover, de novo lesions exhibited a predilection for proximal tumor location (7,16), an association strongly suggesting genetic disparity, given the considerable predominance of the microsatellite instability (MSI) and CpG island methylator phenotype (CIMP) tumorigenic pathways among proximal tumors (4). Other genetic and epigenetic alterations correlated with de novo tumors have also been detected (15,(17)(18)(19), although inconsistently (9,11).…”

“…However, the hypothesis of another tumorigenic pathway, that of de novo carcinogenesis, suggesting the development of a tumor from normal (or intact) colonic mucosa, without the intervening step of an adenoma, has been a matter of discussion for decades (5)(6)(7)(8)(9)(10)(11). By definition, de novo lesions are characterized by the lack of any adenomatous remnant (i.e., the only indisputable evidence of the origin of adenoma) (7,9).…”