Expert Commentary.

I began this study in 1982 when I was a Senior Registrar on the Central Middlesex Hospital ⁄ Hammersmith Hospital, London rotation. There was no plan to undertake multivariate analysis at that time; I did not learn about the technique until 1984. At this stage I had completed some research on gastric cancer. It seemed to me that the morphology (typing and grading) of gastric neoplasia was excessively complex and if progress were to be made, I would have to work on a ‘simpler’ model – colorectal cancer. It also seemed that St Mark’s Hospital, London would be the best place to undertake such a study and I broached the possibility with Dr Basil Morson who declared it to be ‘a marvellous idea’. With the kind permission of Dr David Lovell (Central Middlesex Hospital) I began to spend one afternoon each week at St Mark’s reading slides. Dr Dick Bussey selected the period 1960–65. I am pretty sure that this was because he had personally dissected the cases and knew that the staging would be highly reliable (to say the least). Since I was at St Mark’s Hospital, the cancers that I studied were exclusively rectal. When this began, I had the idea that gastric dysplasia could be grouped into ‘adenomatous type’ (type 1) and ‘nonadenomatous type’ (type 2). In the adenomatous type there was crowding, stratification and elongation of nuclei and cytoplasm was relatively scant and basophilic. In the ‘nonadenomatous type’, nuclei were vesicular, round to oval and contained a large nucleolus and cytoplasm was pale, eosinophilic and relatively abundant. I thought I could discern similar patterns in rectal cancers and wondered (heretically) if the type 2 pattern cancers could have originated in hyperplastic polyps. These features were scored in a pilot study, but this was not extended when an initial analysis showed no relation with survival. These are some of the ‘details of data not shown or used in the final study’ (p. 441). However the hyperplastic polyp story has not gone away. The study began to move more quickly when I was appointed to the ICRF Colorectal Cancer Unit at St Mark’s Hospital in 1984. Ian Todd was Director of the Unit and John Northover was consultant surgeon. Basil Morson suggested I speak to Jack Cuzick at the ICRF to sort out the statistics. Wendy Atkin, a PhD student jointly supervised by Jack and Basil, eagerly took up the challenge. The prognostic model based on both gradeand stagerelated variables included: 1. number of involved nodes, 2. lymphocytic infiltration, and 3. spread through bowel wall. A subsequent model based on the same material includes a further variable – expanding vs. infiltrating growth – but lumps slight, moderate and extensive spread beyond the bowel wall. The explanation for these differences probably lies in the fact that the study in Histopathology included palliative cases in which extensive spread beyond the rectal wall would be an important predictor of outcome. One of the independent prognostic variables – lymphocytic infiltration – remains topical because of the interest in tumour immunity and because lymphocytic infiltration is a biomarker for colorectal cancer with microsatellite instability. The good prognosis is not explained merely by the association with MSI-high colorectal cancer. Twenty-five percent of the rectal cancers were associated with a marked peritumoral lymphocytic infiltrate. Only a tiny proportion of these would be expected to be HNPCC (which is uncommon and mainly right-sided) or sporadic MSI-high cancer Address for correspondence: Professor Jeremy R. Jass, Department of Pathology, McGill University, Duff Medical Sciences Building, 3775 University Street, Montreal, Quebec, Canada H3A 2B4. e-mail: jeremy.jass@mcgill.ca