Adenocarcinoma arising within a Crohn's‐related anorectal fistula: a form of anal gland carcinoma?

Sir: Crohn's disease is well-recognized to predispose to lower gastrointestinal malignancy.1 An unusual example of the latter are adenocarcinomas associated with anorectal fistulae.1 Even rarer are adenocarcinomas which arise solely from within such tracts and show no evidence of anorectal luminal involvement; we are aware of only a few cases that have been reported with sufficient evidence to allow for such a diagnosis to be made.2–7 The more common adenocarcinomas arising from within non-Crohn's-related anorectal fistulae are thought to originate either from anal gland epithelium or from rectal mucosa lining the fistulae.8 Making this distinction has potential clinical implications as anal gland carcinomas are thought to carry a relatively good prognosis if treated early.9 There has been, as yet, no attempt to determine the tissue origin of adenocarcinomas associated with Crohn's-related anorectal fistulae. The following report describes a case of adenocarcinoma arising within such a fistula with the unique addition of mucin studies performed to help address this issue of histogenesis. A 42-year-old woman underwent an ileo-proctocolectomy for Crohn's ileal, rectal and perianal disease resistant to medical therapy. A clinico-radiological diagnosis of Crohn's disease made at the age of 22 years was confirmed pathologically 3 years later following the resection of her terminal ileum for intractable right iliac fossa pain. Over the 13 years leading up to the current operation, the patient developed perineal disease, which was characterized by recurrent ischiorectal abscesses and anorectal fistulae, and which correlated in activity with exacerbations of her rectal disease. She also demonstrated radiological evidence of persisting distal ileal disease. Examination of the ileo-proctocolectomy specimen showed diffuse thickening of the small bowel wall with extensive mucosal ulceration, while the large bowel appeared normal apart from the distal rectum, which showed mucosal ulceration with focal pseudo-polyp formation. There was no macroscopic evidence of a tumour. Microscopy of the abnormal ileum showed transmural acute inflammation associated with fissuring ulceration and multiple scattered non-caseating granulomas. While sections of the colon and upper rectum were within normal histological limits, the lower rectum and anorectal junction showed the microscopic features of an active chronic proctitis with moderate crypt architectural distortion and transmural granulomas. Several anorectal fistulae were also seen. There was no evidence of surface or crypt epithelial dysplasia in the sections of colon or rectum. However, one block of the lower rectum contained, just deep/exterior to the muscularis propria, a single focus (measuring 4 mm in maximum dimension) of signet-ring cells, which showed nuclear atypia and immunoreactivity for the epithelial marker CAM5.2, and were set amongst pools of extracellular mucin (Figure 1). Sections taken adjacent to the carcinoma showed, in place of the mucinous adenocarcinoma, a fistula lined by inflamed granulation tissue only. The orientation of the blocks sampled prevented a demonstration of direct continuity between the fistula and the carcinoma. However, the proximity of the two pathologies to one another, and their isolation from any other epithelial structures, strongly suggested the carcinoma did communicate with the fistula. . Medium power view (main picture) of a focus of adenocarcinoma lying just deep/exterior to the muscularis propria of the rectal wall (haematoxylin and eosin). A higher power view (inset) shows the adenocarcinoma to comprise signet-ring cells set amongst abundant extracellular mucin (haematoxylin and eosin). The carcinoma cells showed a mixture of sulphomucin and sialomucin production, based on high iron diamine-alcian blue histochemistry, but also loss of O-acetylated sialic acids, based on mild periodic acid–Schiff (mPAS) histochemistry (with saponification), and on absence of immunoreactivity to two different, well-characterized monoclonal antibodies to O-acetyl sialic acid groups (PR.3A5, gift from Sir WF Bodmer, Oxford, UK, and 6G4, in-house antibody)10,11 studied without saponification. Tissue from an anal gland carcinoma retrieved from our archival files showed an identical mucin pattern. Further, aside from focal immunoreactivity for PR.3A5, two separate control blocks of normal anal gland tissue showed the same mucin pattern. By contrast, a low rectal adenocarcinoma studied showed focal retention of O-acetylation detected by mPAS histochemistry (with saponification), and by the 6G4 and PR.3A5 antibodies (without saponification). While the presence of carcinoma was unexpected, there was no evidence of malignant tissue at the radial resection margins and further therapy was therefore withheld. However, over the few months following the ileo-proctocolectomy, clinical examination showed persisting granulation tissue extruding from a sinus at the anus excision site. Further, computed tomography scans showed an inflammatory mass at the rectal excision site. Currettings of the sinus tract and a biopsy taken from a nodule found in the posterior vaginal wall showed fragments of a mucinous adenocarcinoma with features very similar to the carcinoma found in the fistula. Local radiotherapy was deemed inappropriate because of the high risk of small bowel toxicity. After extensive discussions regarding the risks and benefits of pelvic exenteration, the patient opted to undergo such surgery 10 months after the ileo-proctocolectomy. Pathological examination of the resected tissue confirmed the presence and the complete resection of residual carcinoma. At 20 months after this most recent operation, the patient remains well with no evidence of metastases or local recurrence. The macroscopic and microscopic features of this case demonstrate a mucinous adenocarcinoma arising solely from within an anorectal fistula in a patient with Crohn's disease. Review of the literature shows such a diagnosis could only be confidently made in six previous case studies,2–7 their authors having adequately excluded the main differential diagnosis of a low rectal carcinoma extending into a pre-existing fistula. In all six cases, as with the current case, the patient had suffered from long-standing Crohn's perineal disease. This would support the hypothesis that chronic irritation to rectal mucosa lining a chronic fistula predisposes to neoplastic transformation.4 However, anal fistulae may also arise from infected anal glands8 and it may be speculated that chronic inflammation could also induce anal gland epithelium to undergo neoplastic change. Determining the tissue origin of a perianal adenocarcinoma has potential clinical implications. While anal gland carcinomas were traditionally described as carrying a poor prognosis, a more recent series suggests that if detected early, there is a good chance of cure with surgery alone.9 In this series, most of the patients showing a good outcome had undergone an abdomino-perineal resection and no significant contribution to survival was derived from adjuvant therapy.9 Fenger and Filipe were the first to report that anal gland carcinomas contain mucin showing a characteristic scarcity or absence of O-acetylated sialic acid.12 A reduction of these sugar groups has also been described in inflammatory bowel disease and in colorectal adenocarcinomas.13 However, the findings of the current and independent previous studies12 suggest the extent of this reduction is less marked than that seen in normal and malignant anal gland epithelium. Indeed, a previous study of 50 colorectal adenocarcinomas suggests it is uncommon for these cancers not to show any PR.3A5 immunostaining at all.10 In light of this, our mucin studies suggest our case of Crohn's fistula-related adenocarcinoma was more likely to have originated from anal gland epithelium than rectal mucosa. We were unable to consolidate this hypothesis by identifying background dysplastic anal glands, and/or anal duct-type epithelium or residual anal gland tissue in continuity with the carcinoma. However, an inability to demonstrate the latter is well recognized with suspected anal gland carcinoma, the site of origin being destroyed early by the malignant process.9 Further, the mucinous appearance of the carcinoma and the good outcome shown by our patient from surgery alone (albeit more extensive than abdomino-perineal resection) are features of anal gland carcinomas.8,9 Interestingly, of the five reported cases of adenocarcinoma arising within Crohn's-related anorectal fistulae with follow-up data, at least three were described as showing a good outcome following surgery (two without any adjuvant therapy).4,6,7 In summary, the reported case illustrates a rare complication of Crohn's disease and provides some unique evidence suggesting, with potential implications for prognosis, that at least some of these fistula-related adenocarcinomas may represent anal gland carcinomas. The case also demonstrates the importance, even in the absence of macroscopic tumour, of generous block sampling from anorectal specimens resected on a background of long-standing Crohn's perineal disease. We thank Mrs Christina Goodall for assisting with the mucin studies.