An understanding of the early morphogenesis of hereditary non-polyposis colorectal cancer is relevant to screening strategies. If most of these cancers were to evolve through the classical adenoma-carcinoma sequence, screening and removal of adenomas at relatively long intervals might be a safe and cost-effective approach. We have reviewed 131 cancers from 117 affected members of 34 such families. One hundred and four cancers were initial symptomatic lesions, eight were cancers detected in asymptomatic screened individuals, one was a synchronous cancer and 18 were metachronous cancers. None of the 131 cancers was a small, superficial type. Residual adenoma (contiguous with cancer) was present in three out of three (100%) in situ cancers, eight out of nine (89%) cancers involving only submucosa, four out of 14 (29%) cancers limited to the muscle coat and 13 of 105 (12%) cancers extending beyond the muscle coat. Twenty-one out of 28 (75%) residual adenomas had a villous component. Only one was flat. Of the eight asymptomatic cancers, seven arose within tubular (two) or tubulovillous adenomas (five). The eighth was not associated with an adenoma but was 35 mm in diameter and extended through the bowel wall. Discrete adenomas (contiguous excluded) were present in 22% of surgical specimens and 31% of specimens from subjects older than 50 years. A relatively high proportion (30%) had a villous component and 43% were at least 10 mm in diameter. Patients with one or more discrete adenomas in their first surgical specimen were more likely to develop multiple cancers.(ABSTRACT TRUNCATED AT 250 WORDS)