180 J Clin Pathol 1993;46:180-183 Neutropenic enterocolitis associated with tertium J Clin Pathol: first published as 10.1136/jcp.46.2.180 on 1 February 1993. Downloaded from

N Coleman, G Speirs, J Khan, V Broadbent, D G D Wight, R E Warren

Abstract Case report A 15 year old boy being treated for A 15 year old boy, who had developed acute relapsed acute lymphoblastic leukaemia lymphoblastic leukaemia at the age of 11 and developed severe diarrhoea and abdomi- had been treated with the UKALL 10 sched- nal pain which worsened despite empiri- ule D protocol developed an isolated testicu- cal antibiotic treatment. A right lar relapse, aged 13. He was reinduced with hemicolectomy was performed. The cae- UKALL 10, with early intensification, testicu- cum and ascending colon showed lar irradiation, and maintenance treatment for changes typical of neutropenic enterocol- two years. At the age of 15 he had an isolated itis. Clostridium tertium was isolated central nervous system relapse. He was rein- from faeces, blood cultures, and from the duced with high dose cytosine and etoposide, resected gut wall, with no evidence of together with intrathecal methotrexate, cyto- other organisms capable of causing such sine, and hydrocortisone. a condition. As far as is known, this is the He developed pancytopenia seven days first reported case in which neutropenic after induction and became pyrexial two days enterocolitis has been associated with later, developing severe watery diarrhoea well documented C tertium infection, an mixed with fresh blood, diffuse abdominal organism previously described as a cause pain, and oral mucositis. His C-reactive pro- ofbacteraemia in neutropenic patients. tein concentration was grossly raised at 212 mg/l and blood cultures subsequently grew Pseudomonas aeroginosa and Escherichia coli. (Y Clin Pathol 1993;46:180-183) Despite initial empirical antibiotic treatment with ceftazidime (100 mg/kg/day), genta- micin (7.5 mg/kg/day), and (30 Neutropenic enterocolitis is a rare but serious mg/kg/day) he continued to deteriorate clini- http://jcp.bmj.com/ clinicopathological syndrome in which char- cally, developing severe abdominal pain with acteristic pathological changes develop in the melaena. Abdominal x ray pictures showed no ileocaecal region of patients with neutropenia, intramural gas but there were distended loops often in association with bacteraemia.' The of bowel in the right iliac fossa. Further blood pathogenesis of the condition is complex, but cultures on day 4 of antibiotic treatment seems to involve initial mucosal ulceration in yielded a pure growth of C tertium. At this the ileocaecal region, with subsequent inva- stage ceftazidime was replaced by cipro- on September 23, 2021 by guest. Protected copyright. sion by and occasionally other gut floxacin (8 mg/kg/day), (40 organisms. The bacteraemia may lead to sep- mg/kg/day), and oral vancomycin (125 mg ticaemia or metastatic gas . The pro- four times a day) but despite this he remained duction within the intestinal wall of diffusing pyrexial with worsening abdominal pain. toxins by the invading organisms is thought to Further abdominal x ray pictures showed a be responsible for the characteristic gut dilated irregular transverse colon compatible pathology, which is essentially that of severe with colitis but no evidence of perforation. An necrotising oedema of the bowel wall, associ- ultrasound scan revealed a thickened trans- but verse colon and free fluid in the pelvis. A Department of ated with focal mucosal necrosis, only Histopathology, scanty infiltration by inflammatory cells. computed tomogram of the abdomen showed Addenbrooke's Clostridium septicum is the usual causal considerable thickening of the colonic wall, Hospital, Cambridge, case affecting the caecum, ascending colon, hepat- CB2 2QQ organism2 with occasional single reports N Coleman of C perfringens, C paraperfringens, C sordellii ic flexure and proximal transverse colon, all of D G D Wight and C sphenoides.1 Other clostridial bacter- which was compatible with neutropenic ente- Department of aemias are described in association with gut rocolitis. The patient continued to deteriorate Clinical Microbiology signs and symptoms in neutropenic patients, clinically, and it was felt that surgical inter- G Speirs vention was indicated despite profound neu- R E Warren but clinical severity is usually less than with C Recently a large number of cases of tropenia and thrombocytopenia. Department of septicum. Paediatrics C tertium bacteraemia have been reported.34 At surgery intraabdominal serous fluid was J Khan We present here the first case of C tertium found, together with an oedematous right V Broadbent bacteraemia in neutropenia for which a surgi- colon. There was no evidence of bowel perfo- Correspondence to: resection was available and ration or necrosis macroscopically, but a small Dr N Coleman cal specimen which showed histological features of neu- area of haemorrhagic necrosis was seen on the Accepted for publication 18 September 1992 tropenic enterocolitis. posterior surface of the mobilised ascending Neutropenic enterocolitis associated with Clostridium tertium 181

colon. A right hemicolectomy was performed bleeding, and necrosis (fig 2). The oedema with the formation of an ileostomy. An opera- extended into the muscularis propria, where tive luminal aspirate of the caecum and a it produced splitting of the muscle fibres. The piece of gut wall were taken to the bacteriolo- mucosa was also oedematous, with foci of J Clin Pathol: first published as 10.1136/jcp.46.2.180 on 1 February 1993. Downloaded from gy department within 30 minutes of surgery. haemorrhagic surface ulceration. There was Within 24 hours the patient's condition had no inflammatory cell infiltration. Gram stain- dramatically improved, and antibiotics were ing showed clusters of Gram positive rods stopped six days after surgery. His ileostomy and cocci on the surface of the mucosal was closed after one month. ulcers, although no organisms were seen He subsequently underwent autologous more deeply within the gut wall. bone marrow transplantation after high dose Immunofluorescence examination was per- cyclophosphamide and total body irradiation formed using a mouse monoclonal antibody with a cranial boost, and was discharged at to C septicum and a rabbit polyclonal anti- six weeks after an uneventful recovery from serum to C tertium, but neither identified transplantation. organisms. However, cultures of the gut wall performed after alcohol shock yielded C ter- tium. Pathology MACROSCOPIC Discussion The resected bowel was composed of the cae- C tertium is an aerotolerant clostridium which cum and ascending colon, which together, has been increasingly identified in recent were about 25 cm in length and 10 cm in years as a cause of bacteraemia in neu- diameter (fig 1). The wall of the bowel was tropenic patients, but which is very rare in thickened and oedematous, producing those without neutropenia.3 In previous mucosal folds which bulged into the luminal reports C tertium bacteraemia in neutropenic space. There was patchy mucosal ulceration, patients has been associated with signs and together with focal intramural haemorrhage symptoms referrable to the gastrointestinal and serosal discoloration. tract or with abdominal cellulitis. The pre- sumed intestinal invasion by C tertium usually MICROSCOPIC causes only relatively mild clinical features, Histological examination showed features which respond to appropriate antibiotics characteristic of neutropenic enterocolitis. without surgery, implying that the local dam- There was severe transmural oedema, which age within the gastrointestinal tract is also rel- particularly affected the submucosa of the atively mild. To our knowledge this is the first bowel, where there was also congestion, reported case in which histologically demon-

Figure 1 Resected bowel http://jcp.bmj.com/ showing bulging, oedematous mucosalfolds, with patchy ukeration. on September 23, 2021 by guest. Protected copyright.

'; tr. I.. ,' f .1. 182 Coleman, Speirs, Khan, Broadbent, Wight, Warren

Figure 2 Nectrotising cultures in neutropenia, and a high index of submucosal oedema with in infective with gut symp- overlying mucosal necrosis suspicion episodes and haemorrhage. toms. C tertium is not thought to cause gas gan- J Clin Pathol: first published as 10.1136/jcp.46.2.180 on 1 February 1993. Downloaded from grene: there is a single case report of its isola- tion as the sole clostridial species with Staphylococcus aureus.7 The organism is nei- ther proteolytic, lipolytic, haemolytic nor fib- rinolytic, nor is it described as producing other toxins or proved virulence factors. The mechanism by which it could produce gas- trointestinal myonecrosis is therefore obscure. It is not described as producing the major lethal virulence factor of C septicum-the a toxin nor the fi toxin of C perfringens, which seems to be the major pathogenic factor in enteritis necroticans and pig-bel.8 These viru- lence factors were not specifically sought in our strain. Various mechanisms of damage to the ileo- caecal mucosa have been described in previ- ous reports of neutropenic enterocolitis, including leukaemic infiltration, intramural haemorrhage, instrumentation related trau- ma, and ischaemic colitis.' The most likely cause of the initial mucosal damage in this case seems to be treatment with combination antineoplastic drugs which were used to treat our patient's leukaemic relapse. High dose cytosine arabinoside is well known to cause a variety of abnormalities in rapidly pro- liferating epithelia which range in severity from cytological atypia to frank mucosal ulceration.9 The period between the start of strated neutropenic enterocolitis with gut the antineoplastic treatment and the isolation necrosis has occurred in association with C of C tertium from blood cultures was 13 days, tertium bacteraemia in the absence of infec- an interval similar to that seen in previous tion with other organisms capable of causing studies of C tertium bacteraemia in neu- http://jcp.bmj.com/ such severe intestinal damage. A previous tropenic patients,4 and consistent with obser- case has been reported in which the patholog- vations on the time period required for the ical changes of neutropenic enterocolitis were induction of loss of mucosal continuity by associated with isolation of C tertium from chemotherapeutic agents.9 caecal material taken at the time of necropsy Once suspected, diagnosis and manage- from a patient with relapsed acute myeloid ment of clostridial caecitis can be difficult.'0 the failure to demon- Plain radiography may show dilated loops of leukaemia.5 However, on September 23, 2021 by guest. Protected copyright. strate C tertium in blood cultures taken before large bowel with pneumatosis intestalis, but death, together with the frequent presence of has a high false negative rate. Characteristic this organism as part of the normal faecal echogenic thickening of the mucosa may be flora,' raises doubts as to the importance of seen in an ultrasound scan and was present in finding the isolate after death. In our patient our patient. Computed tomography shows C tertium was isolated from faeces, from that neutropenic colitis is characterised by blood cultures at the onset of the illness, and caecal wall thickening, with or without pneu- from the resected gut wall. matosis, and intraluminal areas of lower den- C tertium was detected retrospectively by sity, reflecting areas of oedema or alcohol shock from faeces at the onset of haemorrhage. Most would favour this as the pyrexia in our patient. The appearance in best method of diagnosis: it confirmed the blood culture on day 4 of antibiotic treatment clinical diagnosis in our patient. reflects the ineffectiveness of the chosen ini- The dramatic clinical improvement after tial antibiotic regimen against this organism. surgery is well reported, and early surgical Ceftazidime, gentamicin, and metronidazole intervention after close clinical monitoring is are inactive under aerobic conditions against now generally regarded as the treatment of this aerotolerant species.' C septicum is rela- choice for a condition which otherwise has an 0 tively more, if not absolutely, sensitive to extremely poor prognosis. The reason for third generation .6 Although the rarity of a requirement for surgery in C we considered that C septicum might have tertium bacteraemial compared with C sep- been responsible for the initial illness, we did ticum may relate to intrinsic pathogenicity of not grow it from the initial faecal sample. The the species, but the virulence factors responsi- resistance of C tertium to standard empirical ble for invasion in neutropenic patients by antibiotic regimens emphasises the need for only certain clostridial species remain careful speciation of clostridia from blood unknown. Neutropenic enterocolitis associated with Clostridium tertium 183

1 Newbold KM. Neutropenic enterocolitis. Clin Pathol Rev 6 Gabay EL, Rolfe RD, Finegold SM. Susceptibility, of Dig Dis 1989;7:281-7. Clostridium septicum to 23 antimicrobial agents. Anti- 2 King A, Rampling A, Wight DGD, Warren RE. microb Agents Chemother 1981;20:852-3. Neutropenic enterocolitis due to Clostridium septicum 7 Masella T. A case of gas gangrene due to tertius

infection. J Clin Pathol 1984;37:335-43. associated with Staphylococcus aureus. Riforma Med J Clin Pathol: first published as 10.1136/jcp.46.2.180 on 1 February 1993. Downloaded from 3 Speirs G, Warren RE, Rampling A. Clostridium tertium 1942;58:508. septicaemia in patients with neutropenia. J Infect Dis 8 Lawrence G, Skerman F, Freestone DS, Walker PD. 1988;158: 1336-40. Prevention of necrotising enteritis in Papua New 4 Valtonen M, Sivonen A, Elonen E. A cluster of seven Guinea by active immunisation. Lancet 1979; i:227-9. cases of Clostridium tertium septicaemia in neutropenic 9 Slavin RE, Dias MA, Saral R. Cytosine arabinoside patients. EurJ Clin Microbiol Infect Dis 1990; 1:40-2. induced gastrointestinal toxic alterations in sequential 5 Yates P, MacGowan AP, Potter M, White H, Slade RR. chemotherapeutic protocols. Cancer 1978;42: 1747-59. Clostridia and neutropenic enterocolitis. Lancet 1988; 10 Koea JB, Shaw JHF. Surgical management of neutropenic i: 185. enterocolitis. Bn J Surg 1989;76:821-4.

J Clin Pathol 1993;46:183-185 183 Mixed adenocarcinoma/carcinoid tumour of large bowel in a patient with Crohn's disease

Y L Hock, K W M Scott, R H Grace

Department of Abstract matous It is that Histopathology change. suggested Y L Hock A 50 year old woman with a 20 year Crohn's disease may have played a part K W M Scott history of Crohn's disease underwent in the pathogenesis of the tumour. Department of laparotomy which revealed extensive Surgery disease in the small and large bowel, and (J Clin Pathol 1993;46:183-185) R H Grace this was resected. Gross emination of The Royal Hospital, the resected bowel showed features of It has been that with Cleveland Road, long recognised patients Wolverhampton Crohn's disease as well as a polypoid ulcerative colitis may develop large bowel WV2 1BT tumour in the caecum. Histopathological cancerl; it has more recently also been recog- Correspondence to: examination of the tumour showed it to nised that in Crohn's disease there may be Dr YL Hock, be an infiltrating mixed adenocarcino- Department of malignant change in association with both Histopathology, Dudley ma/carcinoid tumour arising in a small and large bowel disease.2 Carcinoid Road Hospital, Dudley tubulovillous adenoma. Road, Birmingham tumours have been described both in B18 7QH Random sampling of the rest of the ulcerative colitis' and Crohn's disease.2 Mixed

Accepted for publication bowel affected by Crohn's disease also adenocarcinoma/carcinoid tumours have been http://jcp.bmj.com/ 24 September 1992 showed a focus of dysplasia and adeno- described in ulcerative colitis' but not in association with Crohn's disease.

,I Case report A 50 year old woman with a 20 year history of

4, small and large bowel Crohn's disease was on September 23, 2021 by guest. Protected copyright. ya .4.5 p admitted to hospital for laparotomy following Ao~ ~~~~. the failure of medical treatment for increas- , ingly severe right iliac fossa pain. There were

''P A no clinical features suggestive of a carcinoid syndrome and as there was no clinical suspi- cion, biochemical tests for carcinoid syn- drome were not performed. Laparotomy showed Crohn's disease from 15 cm proximal to the ileo-caecal valve to the junction of the descending and sigmoid colon. The region of the appendix was adherent to the anterior abdominal wall. Resection of the affected bowel with ileo-sigmoid anastomosis was performed.

Pathological examination The specimen included 15 cm of terminal ileum and 45 cm of large bowel. A paracaecal abscess encasing the appendix was noted. On opening the bowel, there was a continuous segment of mucosa showing the typical "cob- Figure I A focus showing typicalfeatures ofmoderately differentiated colonic ble stone" appearance of Crohn's disease, adenocarcinoma (haematoxylin and eosin). measuring 32 cm in length and involving the