G. T. Williams

Preoperative assessment of prognostic factors in rectal cancer using high‐resolution magnetic resonance imaging

The aim was to determine the accuracy of preoperative magnetic resonance imaging (MRI) in the evaluation of pathological prognostic factors that influence local recurrence and survival in rectal cancer.

Gastrointestinal manifestations of type 1 neurofibromatosis (von Recklinghausen's disease)

Gastrointestinal involvement in von Recklinghausens disease occurs in three principal forms: hyperplasia of the submucosal and myenteric nerve plexuses and mucosal ganglioneuromatosis which leads to disordered gut motility; gastrointestinal stromal tumours showing varying degrees of neural or smooth muscle differentiation; and a distinctive glandular, somatostatin‐rich carcinoid of the periampullary region of the duodenum that contains psammoma bodies and which may be associated with phaeochromocytoma. This review describes the histopathological leatures of these lesions and discusses potential pitfalls in their differential diagnosis. Their accurate identification has significant implications for clinical management and may even provide the first pointer to the diagnosis of neurofibromatosis.

Effectiveness of preoperative staging in rectal cancer: digital rectal examination, endoluminal ultrasound or magnetic resonance imaging?

In rectal cancer, preoperative staging should identify early tumours suitable for treatment by surgery alone and locally advanced tumours that require therapy to induce tumour regression from the potential resection margin. Currently, local staging can be performed by digital rectal examination (DRE), endoluminal ultrasound (EUS) or magnetic resonance imaging (MRI). Each staging method was compared for clinical benefit and cost-effectiveness. The accuracy of high-resolution MRI, DRE and EUS in identifying favourable, unfavourable and locally advanced rectal carcinomas in 98 patients undergoing total mesorectal excision was compared prospectively against the resection specimen pathological as the gold standard. Agreement between each staging modality with pathology assessment of tumour favourability was calculated with the chance-corrected agreement given as the kappa statistic, based on marginal homogenised data. Differences in effectiveness of the staging modalities were compared with differences in costs of the staging modalities to generate cost effectiveness ratios. Agreement between staging and histologic assessment of tumour favourability was 94% for MRI (κ=0.81, s.e.=0.05; κW=0.83), compared with very poor agreements of 65% for DRE (κ=0.08, s.e.=0.068, κW=0.16) and 69% for EUS (κ=0.17, s.e.=0.065, κW=0.17). The resource benefits resulting from the use of MRI rather than DRE was £67164 and £92244 when MRI was used rather than EUS. Magnetic resonance imaging dominated both DRE and EUS on cost and clinical effectiveness by selecting appropriate patients for neoadjuvant therapy and justifies its use for local staging of rectal cancer patients.

Observer variation in the assessment of dysplasia in ulcerative colitis.

Six histopathologists allocated 100 sections from patients with long‐standing ulcerative colitis into four diagnostic categories, regular hyperplasia, reactive atypia, low‐grade and high‐grade dysplasia. Their allocations were analysed using kappa statistics, including Fleisss multiple kappa for groups of observers, and agreement on specific diagnoses was explored by constructing a conditional probability matrix. The nature of their disagreements was investigated using coefficients for systematic and haphazard errors. Over the four diagnostic categories there was a wide range of pairwise agreement from a low of 49% up to 72% and kappa values were only ‘fair’ or ‘moderate’. As expected, agreement over the two categories ‘dysplasia’vs‘no dysplasia’ was better, ranging from 68% to 84%, and for ‘atypia present’ (reactive atypia, low‐ and high‐grade dysplasia) vs‘no atypia’ two pairings achieved over 90% and 11 pairings over 80% agreement. In view of its clinical importance, conditional agreement on high‐grade dysplasia was examined. Given that a first observer allocates a case as high‐grade dysplasia, pairwise agreement on this diagnosis ranged from 100% down to as low as 33%. However, most of these disagreements fell into the low‐grade dysplasia category so that closer follow‐up and further biopsies would still have been indicated. It is a truism that the basis for safe management is careful co‐operation between clinicians and pathologists who have all the relevant facts and who know and trust one anothers judgement. Thus, several aspects of the ideal diagnostic process cannot be evaluated in inter‐observer studies and the element of artificiality should be borne in mind when applying the findings to diagnostic practice. Nevertheless, the low level of agreement on the diagnosis of high‐grade dysplasia achieved by certain pairings of specialist pathologists is a disturbing outcome of this study. Inaccuracies should be minimized by a concensus approach and we therefore recommend referral of putative cases of dysplasia to interested pathologists for further opinions. We would also advocate that pathologists faced with appearances which are indefinite between reactive atypia and dysplasia, would do better to describe them in terms of ‘atypia, significance uncertain’, so that closer surveillance is undertaken, rather than force them into more precise diagnostic categories which may be incorrect.

Crypt restricted heterogeneity of goblet cell mucus glycoprotein in histologically normal human colonic mucosa: a potential marker of somatic mutation.

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Primary malignant lymphoma of the large intestine complicating chronic inflammatory bowel disease

Ten cases of malignant lymphoma of the colon and rectum complicating chronic inflammatory bowel disease are presented. Seven patients had chronic ulcerative colitis with a history varying from 6 to 20 years. There was extensive colitis in six of these patients and left‐sided colitis in one. All seven lymphomas showed the pathological and immunohistological features of primary B‐cell tumours of the gastrointestinal tract with a predominance of high‐grade tumours. Three patients had Crohns disease of the large intestine complicated by malignant lymphoma of the sigmoid colon or rectum. The history of Crohns disease varied from 30 months to 20 years and in each case there was fissuring and fistulae. There was extensive anal involvement in two cases. Histologically the three lymphomas were heterogeneous: one was of ‘granulomatous’ T‐cell type and the other two were markedly polymorphic and of equivocal phenotype. They were also characterized by numerous multinucleate tumour giant cells. Primary colorectal malignant lymphoma should be regarded as a rare, but significant, complication of ulcerative colitis. Immunosup‐pression may be an additional factor in the genesis of intestinal lymphoma in Crohns disease. The prognosis appears to be dependent on factors already known to be of prognostic significance in primary gut lymphomas: a predominance of high‐grade tumours suggests that the outlook is generally worse than that for idiopathic primary large intestinal lymphoma.

Clonal overexpression of metallothionein is induced by somatic mutation in morphologically normal colonic mucosa

Metallothionein (MT) overexpression occurs frequently in human tumours but the underlying mechanism is unknown. Morphologically normal‐appearing mucosa from human colorectal carcinoma resection specimens and of the colons of ageing laboratory mice contains scattered single crypts whose cells show uniformly increased MT immunostaining, suggesting that MT overexpression arises directly from random crypt stem cell somatic mutation, followed by colonization of the clonal unit by the mutated progeny. This hypothesis has now been tested by quantifying the frequency of immunocytochemically detectable monocryptal colorectal MT overexpression, 5 and 30 days after injection of 8‐week‐old mice with a single dose of the mutagen dimethylhydrazine (DMH, 30 mg/kg subcutaneous). Otherwise normal‐appearing MT‐positive crypts were recorded as either wholly or partially involved by the overexpressing phenotype. Five days after DMH injection, the median frequency of partially involved MT‐positive crypts was 11·7×10declining significantly to 1·8×10−4 at 30 days (Mann–Whitney U, P<0·01). In contrast, the median frequency of wholly involved crypts was 0·2×10−4 at 5 days, increasing significantly (P<0·005) to 12·9×10−4 at 30 days. The frequency of MT‐positive crypts and the time course of evolution of partially involved to wholly involved forms were similar to those described for mutation‐induced crypt‐restricted loss of glucose‐6‐phosphate dehydrogenase activity in mice treated with an identical DMH regimen. The findings indicate that cellular MT overexpression can occur as a direct consequence of somatic mutation, either cis‐activating mutation(s) of the MT gene itself, or trans‐activating mutation(s) of other genes involved in controlling MT expression. This is likely to be an important mechanism underlying MT overexpression in neoplasia. Such mutation‐induced aberrant MT expression may be involved in the acquisition of selective cellular growth or survival advantage during tumour progression.

Transitional mucosa of the large intestine

The term ‘transitional mucosa’ (TM) was coined by Filipe in 1969 to describe alterations in the morphology and mucin histochemistry of large intestinal mucosa immediately adjacent to colorectal adenocarcinomas. TM has two main featureselongation and branching of the mucosal crypts with dilatation of goblet cells, and an alteration in the ratio of sulphomucins to sialomucins as assessed by the high iron-diamine/Alcian blue (HID/AB) technique. Mucin in normal colonic mucosa is predominantly sulphated (brownlblack with HIDIAB), while that in TM is predominantly non-sulphated sialomucin (blue with HID/AB). In recent years the nature of TM has been the source of considerable controversy among pathologists, the debate being centred on its significance as a premalignant lesion.

Synchronous duodenal neuroendocrine tumours in von Recklinghausen's disease—a case report of co‐existing gangliocytic paraganglioma and somatostatin‐rich glandular carcinoid

The co‐existence of a gangliocytic paraganglioma and a glandular psammomatous carcinoid in the duodenum of a patient with von Recklinghausens disease and bilateral phaeochromocytomas is reported. The two lesions were considered to be distinctive by light microscopy, electron microscopy and immunocytochemistry. The cells of the glandular carcinoid showed strong cytoplasmic immunoreactivity for somatostatin and contained only scanty intracytoplasmic microfilaments on electron microscopy. In contrast, the endocrine cells of the gangliocytic paraganglioma were positive for pancreatic polypeptide and serotonin, were negative for somatostatin, and contained conspicuous intracytoplasmic aggregates of filaments. The histogenic relationship between the two tumours is discussed. This case strengthens the known association of glandular duodenal somatostatinoma with von Recklinghausens disease and phaeochromocytoma and, in the light of a previous case report, suggests that von Recklinghausens disease and gangliocytic paraganglioma may co‐exist more commonly than expected.

No difference in stem cell somatic mutation between the background mucosa of right- and left-sided sporadic colorectal carcinomas

Epidemiological, morphological, and molecular differences exist between carcinomas of the right and left sides of the large bowel. To investigate whether this is reflected in differences in somatic mutation frequency in the background mucosa, mutation of the neutral O‐acetyltransferase gene (oat) was quantified in histologically normal resection margins from 20 informative (heterozygous) patients with caecal or ascending colon cancer (11 males, median age 75 years) and 20 with sigmoid colon or rectal cancer (10 males, median age 70 years). Mutant discordant crypts lacking O‐acetyltransferase activity were visualized by mPAS staining and classified as wholly or partially involved by the mutant phenotype; median frequencies (×10−4) were compared (Mann–Whitney U‐test) after assessing a sample of more than 10 000 crypts per case. No significant difference was found between the frequencies of wholly involved mPAS‐positive crypts in background mucosa of left‐ and right‐sided cancers (p=0·4569), indicating that tumours on both sides of the colon are associated with similar levels of lifetime‐accumulated stem cell mutational load. However, partially involved mPAS‐positive crypts were significantly more frequent in mucosa from left‐sided cancers (p<0·04), indicating increased mutational activity during the previous 12 months. Analysis of mucosa proximal and distal to left‐sided cancers showed that this increase was due to a statistically higher frequency of partially involved crypts in proximal mucosa, which probably resulted from the obstructive effects of the tumour causing increased exposure of the proximal mucosa to luminal carcinogens and/or epithelial regeneration in response to low‐grade inflammation or ischaemia. The findings indicate that although left‐sided colonic cancer is commoner than right‐sided cancer in the British population, carcinomas on both sides of the large bowel arise in a background of similar levels of stem cell mutational activity.