<b>Histology of aberrant crypt foci in the human colon</b>

Gregorio, Carmela Di; Losi, Lorena; Fante, Rossella; Modica, Salvatore; Ghidoni, M; Pedroni, Monica; Tamassia, Maria Grazia; Gafà, Lorenzo; Leòn, Maurizio Ponz de; Roncucci, Luca

doi:10.1046/j.1365-2559.1997.d01-626.x

Cited by 78 publications

(59 citation statements)

References 13 publications

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“…ACFs are monoclonal proliferations considered putative precursors of colorectal cancer in both humans and exp er i m e n t a l a n i m a l s b e c a u s e t h e y s h o w m o l e c u l a r abnormalities that occur in and are characteristic of more advanced lesions (32,33). However, several studies have also documented that ACFs are a heterogeneous population of lesions, the majority of ACFs in CRC patients and carcinogentreated rodents being not dysplastic (8,(28)(29)(30)(31)(34)(35)(36)(37). In line with these last observations, we found that only one ACF among those analyzed in CRC patients was dysplastic, whereas the others were hyperplastic or nonhyperplastic/ nondysplastic lesions.…”

Section: Discussionmentioning

confidence: 99%

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Identification of Mucin Depleted Foci in the Human Colon

Femia

Giannini²,

Fazi³

et al. 2008

Cancer Prevention Research

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Aberrant crypt foci (ACF) originally described in rodents treated with colon-specific carcinogens have been identified also in humans at high risk of colon cancer (CRC) and are extensively used as cancer biomarkers. However, studies documenting the heterogeneity of ACF have questioned their precancerous nature. Recently, we described dysplastic foci depleted of mucins (MDF) in the colon of rats treated with colon-specific carcinogens. Like colon tumors, MDFs show activation of Wnt signaling driven by mutations in the β-catenin gene and Apc, a key gene in colorectal carcinogenesis. Because MDFs have been identified thus far only in rodents, we wanted to search for similar lesions in humans. Familial adenomatous polyposis (FAP) subjects, carrying germ-line mutations in the APC gene, are at high risk of CRC. Therefore, we first searched for MDF-like lesions in unsectioned colon samples from FAP patients and then in patients with sporadic CRC. MDFs were present in the colon of FAP patients (average of 0.0577 lesions/cm 2 ) and at a much lower density in CRC patients (average of 0.0006 lesions/cm 2 ). ACFs were also observed in all patients. Histologic preparations of all the MDFs identified in FAP and CRC consisted of microadenomas at variable grades of dysplasia. The occurrence of MDF-like lesions in high-risk patients provides evidence that these lesions have a counterpart in human pathology and, as observed in rodents, may represent the very early stages of CRC.Foci of aberrant crypts (ACF), microscopically visible in the unsectioned colon of carcinogen-treated mice, were originally described by Ranjana Bird in 1987 as being related to the early steps of colon carcinogenesis (1). The results of many studies characterizing ACF (2-4) and the demonstration that ACF-like lesions are also present in humans (5, 6) have reinforced the hypothesis that ACFs are precursors of colon cancer (CRC) and have led to their widespread use as biomarkers of colon carcinogenesis (7, 8). However, reports documenting the heterogeneity of ACF and their relationship with cancer not always straightforward (9-12) opened a debate on the validity of ACF as surrogate end points, stressing the need for additional biomarkers more robustly correlated with cancer (12-15).Recently, mucin depleted foci (MDF), formed by dysplastic crypts with scant or absent mucin production, were identified by our group in the colon of rodents treated with azoxymethane or 1,2-dimethylhydrazine (16), which induces CRC through histologic and molecular alterations similar to human carcinogenesis (17). Like ACFs, MDFs are easily identified in unsectioned colon. Moreover, studies carried out by us and others indicate that MDFs are correlated with carcinogenesis and can thus serve as cancer biomarkers in chemoprevention studies (18-21). We documented that MDFs share pathologic and molecular alterations with more advanced lesions, such as Wnt pathway activation, caused in part by mutations in the β-catenin gene (19). Moreover, the fact that MDFs carry mutations in...

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Section: Discussionmentioning

confidence: 99%

“…Lesions showing dysplastic features were classified as microadenomas (25,26) with low or moderate grade of dysplasia (27, 28). Lesions showing no dysplasia were classified as hyperplastic lesions (25,26) or nondysplastic/nonhyperplastic lesions according to previously described criteria (28)(29)(30).…”

Section: Histology Of the Observed Lesionsmentioning

confidence: 99%

Identification of Mucin Depleted Foci in the Human Colon

Femia

Giannini²,

Fazi³

et al. 2008

Cancer Prevention Research

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“…For in-depth review of the experimental and human observational evidence on the phenotypes and genetic and epigenetic spectra of ACF, see Pretlow and Pretlow [9] and Alrawi et al [10]. For detailed description of histopathological features of ACF see Hurlstone and Cross [11] and Di Gregorio et al [12].…”

Section: Rationale For This Reviewmentioning

confidence: 99%

Epidemiology of colonic aberrant crypt foci: Review and analysis of existing studies

2007

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Since first described in a rodent model in 1987, aberrant crypt foci (ACF) in the colon have been shown to exhibit many of the molecular features of the more advanced colonic neoplasms including cancer. Therefore, they may be early lesions with potential for progression, and be valuable biomarkers for reduction of risk of colorectal cancer (CRC). For this review, we searched PubMed, and reference lists of recent publications, for studies which reported on associations of features of ACF in humans, such as number or size, with subject characteristics, such as age or family history of CRC. Over 150 papers have reported on ACF in humans. However, the vast majority of these publications are concerned with molecular and morphological features of biopsied lesions, and not their epidemiology. None of the epidemiological studies were of optimum design, primarily due to their absence of a well-defined subject sampling frame or method. Given their 'first-generation' nature, consistent findings were of increased ACF number with age and with synchronous advanced colonic neoplasia. One study reported a higher mean number of ACF in subjects with a family history of CRC than in those without. The strongest evidence on the ability of ACF to predict a diagnosis of CRC will be from prospective studies with baseline ACF assessment in a large sample of diseasefree persons (many thousands) who are followed carefully for many years. In the interim, because ACF are asymptomatic, well-designed cross-sectional studies are feasible and will yield valuable information on the relation of ACF to the known risk factors for CRC. This information can then be used to improve the design of prospective studies, and of clinical intervention trials that use ACF as an intermediate endpoint.

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“…ACF were classified in to three groups according to cytological and histological criteria (Di Gregorio et al, 1997). ACF in the first group (group A) had only mild alterations (referred to as 'hypertrophy'), namely enlarged crypts (at least 1.5 times larger than normal) with only slightly enlarged and elongated nuclei, but no crowding or stratification, and no mucin depletion or dysplasia.…”

Section: Histologymentioning

confidence: 99%

Aberrant crypt foci in patients with colorectal cancer

Roncucci

Modica²,

Pedroni³

et al. 1998

Br J Cancer

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Summary Aberrant crypt foci (ACF) are clusters of abnormally large colonic crypts identified on the mucosal surface of the human colon. They are thought to be preneoplastic lesions. The aim of the present study was to compare density (number of ACF per square cm of mucosal surface), crypt multiplicity (number of crypts per ACF) and histology of ACF in colonic resections of colorectal cancer patients resident in two Italian provinces with a twofold difference in colorectal cancer incidence rates. Thirty-two and 26 colonic resections were collected after operation in Ragusa (Southern Italy) and Modena (Northern Italy), respectively, and fixed in 10% formalin. Mucosal layers were observed under a light microscope at 25x after staining with methylene blue. Density of ACF was significantly higher in Modena (median 0.101 ACF cm-2) than in Ragusa (0.049, P= 0.001), whereas there was no difference in crypt multiplicity. ACF were classified into three groups according to histological features: ACF with mild alterations (hypertrophic ACF, 73%), ACF with hyperplasia (hyperplastic ACF, 17%) and ACF with dysplasia (microadenomas, 10%). The proportions of ACF in the three groups were similar in the two provinces. Density of ACF was higher and crypt multiplicity lower proceeding from proximal to distal large bowel. Microadenomas were observed only in the colon, whereas hyperplastic ACF were more frequent in the rectum. In conclusion, density of ACF correlates with colorectal cancer rates in two Italian provinces, and shows a positive gradient from proximal to distal large bowel. Histology of ACF suggests that they may be precursors of both hyperplastic and adenomatous polyps. These data provide further evidence of the role of ACF in human colorectal carcinogenesis.

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Histology of aberrant crypt foci in the human colon

Cited by 78 publications

References 13 publications

Identification of Mucin Depleted Foci in the Human Colon

Identification of Mucin Depleted Foci in the Human Colon

Epidemiology of colonic aberrant crypt foci: Review and analysis of existing studies

Aberrant crypt foci in patients with colorectal cancer

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