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The third pathway of colorectal carcinogenesis
  1. Carlos A Rubio1,
  2. Giacomo Puppa2,
  3. Giovanni de Petris3,
  4. Lorand Kis1,
  5. Peter T Schmidt4
  1. 1 Department of Pathology, Karolinska Institute and University Hospital, Stockholm, Sweden
  2. 2 Division of Gastroenterology and Hepatology, Geneva University Hospital, Geneva, Switzerland
  3. 3 Department of Gastrointestinal Pathology, Arizona Gastroenterology Associates, Scottsdale, Arizona, USA
  4. 4 Department of Medicine Solna, Karolinska Institute, Center for Digestive Diseases Karolinska University Hospital, Stockholm, Sweden
  1. Correspondence to Professor Carlos A Rubio, Department of Pathology, Karolinska Institute, Stockholm 171 76, Sweden; carlos.rubio{at}


Aims The majority of the colorectal carcinomas (CRC) arise in a vast mucosal area built with columnar cells and mucus-producing goblet cells. These carcinomas evolve via the conventional (tubular/villous) adenoma–carcinoma pathway, or the serrated adenoma–carcinoma pathway. Much less frequently CRC arise in the gut-associated lymphoid tissue (GALT) mucosal domain via the third pathway of colorectal carcinogenesis.

Methods All publications on human colorectal GALT carcinomas in the literature were reviewed.

Results Only 23 GALT-carcinomas found in 20 patients are in record. The GALT carcinomas were detected at surveillance colonoscopic biopsy in 11 patients (four had ulcerative colitis, two were members of a Lynch syndrome family, two of a CRC family, one had familial adenomatous polyposis (FAP), one prior colon adenomas and one a submucosal tumour), or at diagnostic colonoscopic biopsy in the remaining nine patients (three had rectal bleedings, two abdominal pains, one diverticular disease and one protracted constipation. In three, no ground disease or symptoms were provided). In six of the 23 GALT carcinomas, the luminal surface showed tumour cells, ulcerations or no descriptions were given. Ten (66.7%) of the remaining 15 GALT carcinomas showed on top, adenomas (n=8) or high-grade dysplasia (n=2).

Conclusions The low frequency of GALT carcinomas might be explained by the fact that the colorectal mucosal areas occupied by GALT domains are minute. The finding that two-thirds of the 15 remaining GALT carcinomas (vide supra) were covered by high-grade dysplasia or by conventional adenomas strongly suggest that conventional non-invasive neoplasias might have preceded the majority of the GALT carcinomas in record.

  • colon
  • rectum
  • carcinomas
  • gut-associated-lymphoid-tissue
  • GALT
  • carcinogenesis

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  • Handling editor Runjan Chetty.

  • Contributors CAR conceived the review of this communication, reviewed the literature and wrote the paper. GP provided new reported cases, reviewed the manuscript and provided new aspects, including two important reports. GDeP, one of the pioneers in the subject,reviewed the manuscript and had valuable suggestions. LK reviewed the manuscript and had important suggestions. PTS reviewed the manuscript and suggested several changes. All five authors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; internally peer reviewed.

  • Data sharing statement This original review includes all patients with gut-associated lymphoid tissue carcinoma that have so far been reported in the literature.

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