86 Clin Pathol 1992;45:806-81 1

Fungal infections of the small and large intestine

R J Prescott, M Harris, S S Banerjee

AbstractAims: To study the pathological features offungal infections affecting the lower intes-tinal tract (duodenum, small and largebowels).Methods: Between mid-1981 and mid-1991, 14 cases of deep mycotic infectionsaffecting the lower intestinal tract werefound among 890 consecutive necropsieson patients with malignant disease treatedin a regional cancer centre (incidence1.6%). These 14 cases accounted for 54% ofall gastrointestinal fungal infection detec-ted. The relevant clinical, necropsy, histo-logical and microbiological data werereviewed.Results: Candida spp and AspergiUus sppaccounted for all infections. The macro-scopic appearances included ulcers ofvarying configuration, mucosal flecks,sloughed mucous membranes, polypoidmasses and segmental lesions. Eitherorganism could produce this range oflesions, but Candida tended to have amucosal location and Aspergillus wasassociated with transmural invasion.Combined infections showed Candida inthe surface mucosa and Aspergillushyphae in submucosal vessels with spreadinto the bowel wall in a radiating pattern.During the final illness, gastroinestinalsymptoms and signs were often slight andmicrobiological investigations wereunhelpful.Conclusions: Variable gross appearancesare relevant for endoscopists, particularlylesions which resemble pseudomembra-nous colitis. Endoscopic biopsy specimensmay have a role in antemortem dignosis.Failure to diagnose these infections dur-ing life emphasises the importance ofnecropsy in the clinicopathological auditof deaths in this group of patients.

Department ofHistopathology,Christie Hospital andHolt Radium Institute,Manchester M20 9BXR J PrescottM HarrisS S BanerjeeCorrespondence to:Dr M Harris

Accepted for publication24 February 1992

Fungal infections are increasingly reported as

aetiological agents in man, and are associatedwith increased use of immunosuppressivetreatment regimens for malignant diseases andin connection with organ transplantation. Sev-eral reviews have emphasised the importanceof fungal infections in such patients.'`4 Withthe advent of AIDS the incidence of commonand uncommon infective pathogens, includingfimgi which may affect the gastrointestinaltract' has correspondingly risen.

In routine necropsy practice the incidence ofsystemic mycotic infections was reported as

being 1-2%6; however, in studies based onselected "high risk" patients who wereimmunocompromised the incidence was about20%.7 A recent review of invasive aspergillosisrevealed an incidence of 1-4% in 2315 consec-utive necropsies, but in the immunocom-promised group it approached I I%.8 Anecropsy study of 54 immunocompromisedpatients with mycotic infection (as a result ofchemotherapy or bone marrow transplanta-tion) showed either localised upper and lowergastrointestinal tract or respiratory tract infec-tion, or disseminated infections including boththese sites; the principal organisms were Can-dida and Aspergillus species.3

Because histopathological reviews ofmycotic infections of the alimentary tract,particularly the lower intestinal tract, aresparse, we decided to review all the necropsycases between mid-1981 and mid-i 991 at theChristie Hospital and Holt Radium Institute,which specialises in the treatment of malignantneoplasms, to catalogue these lesions.

MethodsBetween mid-1981 and mid-1991, 64 cases ofdeep mycotic infections were found in 890consecutives necropsies (incidence 7 2%).Among these there were 26 gastrointestinalinfections, with 12 cases affecting the uppergastrointestinal tract (mouth, oesophagus, andstomach) alone, seven the lower intestinal tract(duodenum, jejunum, ileum and colon) alone,and seven both sites. These last 14 cases are thesubject of this report.

In the lower intestinal group the followingvariables were assessed from the clinicalrecords: the age and sex of the patient; theunderlying neoplastic condition; and the treat-ment administered. During the final illness anygastrointestinal symptoms and signs, drugintake, including antibiotics and steroids, thewhite cell count, results of fungal serologicaltests and blood and stool cultures were recor-ded. The degree of the clinician's awareness ofan intestinal infection was assessed as well asthe clinically perceived mode of death.The necropsy reports revealed information

about the gross appearance and distribution ofthe lesions together with the extent of otherorgan disease. An assessment of the degree towhich the intestinal disease contributed todeath was made. Necropsy stool cultures weresent in three cases. Microscopic examinationwas undertaken on formalin fixed, paraffin waxembedded sections stained with haematoxylinand eosin, periodic-acid Schiff (PAS) with and

806

on June 7, 2020 by guest. Protected by copyright.

http://jcp.bmj.com

/J C

lin Pathol: first published as 10.1136/jcp.45.9.806 on 1 S

eptember 1992. D

ownloaded from

Fungal infections of the small and large intestine

Table I Clinical details ofpresenting condition and treatment

Case No Age Sex Underlying condition Treatment

1 73 F Breast carcinoma and nodular sclerosing Mastectomy, CVPPHodgkin's disease

2 18 M Seminoma CVPP, e, cis3 15 F Hodgkin's disease mixed cellularity VAP MVPP4 58 F Breast carcinoma Mastectomy, Radiation, VAC, pred5 63 F Myelodysplasia DAT

Refractory anaemia with excess blasts intransformation

6 62 F Myelodysplasia DATAcute myeloid leukaemia

7 43 M Chronic myeloid leukaemia and blast crisis Bone marrow transplant 4 years prior tomethotrexate and 6-mercaptopurine

8 58 F Non-Hodgkin's lymphoma, centroblastic/ e, a, i, h, Predcentrocytic Diabetes mellitus

9 60 M Non-Hodgkin's lymphoma, lymphoblastic CHOP, EVAM, predDiabetes mellitus

10 66 F Signet ring adenocarcinoma of stomach e, a, cis11 67 F Non-Hodgkin's lymphoma, VAP, CVPP

centroblastic/centrocytic Abdominal irradiation12 50 M Non-Hodgkin's lymphoma, CHOP, B

lymphoblastic VAPECB13 69 M Non-Hodgkin's lymphoma, VAPECB

T cell pleomorphic large cell subtype14 69 M Non-Hodgkin's lymphoma, diffuse VAP pred

centroblastic of thyroidDiabetes mellitus

Key:CVPP = chlorambucil, vinblastine, procarbazine, prednisolone; e = etoposide; cis = cisplatin; VAP = vincristine, adriamycin,cisplatin; MVPP = mustine, vinblastine, procarbazine, prednisolone; VAC = vincristine, adriamycin, cyclophosphamide;pred = prednisolone; DAT = daunorubicin, cytosine arabinoside, 6-thioguanine; a = adriamycin; i = ifosfamide;h = hydroxyurea; CHOP = cyclophosphamide, adriamycin, vincristine, prednisolone; EVAM = etoposide, vincristine,adriamycin, methotrexate; B = bleomycin; VAPECB = vincristine, adriamycin, prednisolone, etoposide, cisplatin, belomycin.

without diastase, Grocott's methenamine silverstain, and the Gram stain. The sections wereseen by two pathologists without priorknowledge of the clinical or necropsy data. Thefungi were all classified confidently on

morphological grounds as either Candida orAspergillus sp.

Because of the high degree of agreementbetween the pathologists, it was not felt neces-sary to confirm the findings by immunohis-tochemical or lectin histochemical techniques.Candida organisms were characterised by blas-tospores and pseudohyphae with buddingforms and Aspergillus organisms by regularseptate hyphae which exhibited dichotomousbranching.9

ResultsCLINICAL DATA

Table 1 shows the relevant clinical details. Allpatients had advanced malignant disease; eighthad malignant lymphoma (two Hodgkin's dis-

ease, and six non-Hodgkin's lymphoma), threecases had leukaemia and four cases had non-

haematological malignancies (case 1 had adouble malignancy). The time span fromdiagnosis to death ranged from two months toeight years. All patients had received more thanone course of an appropriate chemoth-erapeutic regimen. Steroids were administeredto 11 patients in high doses during the finalillness. Two patients had received radiotherapy,with abdominal irradiation in one case (case11).Table 2 shows relevant details of the final

illness which took no more than 16 days.Gastrointestinal symptoms and signs werevariable and ranged from non-existent in one

case, mild in seven cases, and severe in sixcases. Oral thrush was seen in four cases andalerted the clinician to the possibility of a moreserious intestinal infection. All the patientswere feverish, although the causes of this weremultifactorial. Various antibiotics were givenand six patients received specific antifungal

Table 2 Clinical details offinal illness

Microbiology cultures

Case No Gastrointestinal sympwmslsigns Antibiotics Lowest WCC Blood Faeces

1 Melaena n, p, v, me 0-5 NG NG2 Tenderness/pain/diarrhoea and vomiting/melaena n, ceft 0 5 Gram negative bacilli NG3 Oral thrush/herpes/abdominal distension cefu, g, co, ac, mi 0.1 S viridans NG4 Slight diarrhoea n, p 0-1 Ps aeruginosa NG5 Melaena n, v 0-1 Ecoli Ps maltophila6 Tenderness/distension/diarrhoea and vomiting me, am 0-2 Coagulase negative NG

Staphylococcus species7 None n, p, v, e, ceft, co, am 0-1 NG NG8 Mild diarrhoea n, ci, k 0-1 E coli NG9 Tenderness/diarrhoea/melaena n, p, ci 0-1 NG Sfaecalis10 Oral thrush n, p, f 0-2 E coli, S aureus, S mitis NG11 Tenderness/distension/melaena/abdominal mass n cefu, ci 0-1 NG Proteus species12 Oral thrush n, v, i, ceft 0-1 NG Klebsiella aerogenes13 Tenderness/mild diarrhoea n, p 0 1 NG NG14 Oral thrush/mild diarrhoea f, g, ny, k 0 5 E coli NG

Key:WCC = white cell count (x 109'/); n = netilmicin; p = piperacillin; v = vancomycin; me = metronidazole; ceft = ceftazidime; cefu = cefuroxime;g = gentamicin; co = cotrimoxazole; ac = acyclovir; mi = miconazole; e = erythromycin; am = amphotericin; ci = ciprofloxacin; k = ketoconazole;f = flucloxacillin; i = itraconazole; ny = nystatin; NG = No growth.

807

on June 7, 2020 by guest. Protected by copyright.

http://jcp.bmj.com

/J C

lin Pathol: first published as 10.1136/jcp.45.9.806 on 1 S

eptember 1992. D

ownloaded from

Prescott, Harris, Baneree

Table 3 Necropsy findings

Macroscopic findings Microscopic findings

Other organs TransmuralCase No affected Small bowel Large bowel infarction Angioinvasion

Candida organisms:1 Lungs Mucosal flecks Mucosal flecks resembling

Oesophagus Irregular ulcers pseudo-membranous colitisIrregular ulcers

2 None Matted ileal loops forming bloody Normal + +mass Peritonitis

3 Stomach Jejunum and ileum Right side colon + +segmental infarction with ulcers and segmental infarction with poly-bloody masses poid masses

4 Lungs Jejunum small ulcers and haemorrhag- Normalic nodules

Ilum 2 segmental lesions (20 and6 cm long) with ulcers and bloodymembranes

Aspergilus organisms:5 Lungs Jejunum multiple segmental Normal + +

Liver lesions with haemorrhagicSpleen ulceration

6 None Distal ileum shallow ulcers of varying Similar lesions with infarction and + +shape and size including linear ul- pelvic peritonitiscers

7 Lungs Jejunum Transverse colonOesphagus mucosal flecks mucosal flecks resembling

pseudo-membranous colitis8 Lungs Proximal ileum Normal + +

necrotic mucosal plaques with mattedileal loops

9 Oesophagus Jejunum extensive mucosal sloughing. Right sided colon mucosal sloughing (No fungi seen in colonic lesions)Ikum oval ulcers in longitudinal axis and oval ulcers

Combined Candida and Aspergillus organisms:10 Lungs Normal Transverse colon + +

Spleen segmental infarction11 Lungs Multiple ulcers of linear and serpigi- Normal + +

nous type Pseudomembranes12 Lungs Jejunum tumour-like Normal + +

Liver ulcerated intraluminalBrain polypoid mass (4 x 5 cm)Oesophagus

13 Oesophagus Scattered oval ulcers in Surface bloody exudate + +Stomach transverse axis, some circumferen- (No fungi in colon)

tial14 Lungs Duodenum multiples small Normal + +

Stomach ulcersJejunum segental lesion (30 cm long)

with ulceration

treatment. The rationale for giving these agentsincluded evidence of a systemic mycosis atother sites, notably the lungs in two cases, ahigh degree of clinical suspicion in two cases,and the use of a standard protocol in febrilepatients with acute leukaemia (two cases).During the final illness all patients had severeneutropenia with leucocyte counts generallybelow 0.1 x I09/l. The clinical impression ofthe mode of death included septicaemia in 12cases of which one was thought to contain afungal component (case 7).

PATHOLOGICAL DATA

Table 3 shows the necropsy details. Otherorgan pathology was seen in 12 cases; five casesinvolved the lungs alone or with other organsexcept the gastrointestinal tract, three casesinvolved the upper gastrointestinal tract alone,and four cases both these sites. Of the 14 lowerintestinal tract infections, nine cases affectedthe small bowel alone, one case involved thecolon alone, and four both sites. In four casesCandida alone was found, in five Aspergillusalone, and in five both organisms were identi-fied in the same lesions.

Macroscopically the lesions comprisedulcers, mucosal flecks, sloughed mucous mem-branes, polypoid masses and segmental lesions(fig 1). The ulcers were of variable configura-

tion including elliptical forms transverse andlongitudinal to the bowel axis, serpiginousulcers, linear ulcers and extensive ulcers withirregular margins (fig 2). Segmental lesionswere found in five cases: of these, four casesshowed transmural infarction, and one casewas due to Candida infection limited to themucosa alone (case 4). In the four cases ofsegmental infarction, two involved the smallbowel alone, one the colon alone, and one bothsites. One case was due to Candida alone, oneto Aspergillus alone, and two to both organismsin the same lesions (fig 3). Mucosal flecks wereseen in two cases; one was associated withCandida and the other with Aspergillus organ-isms admixed with fibrinous exudate.Of the nine cases with Candida infection, five

had coexistent infections in the upper gastro-intestinal tract. Of the four pure Candidalesions, two were limited to the surface mucosaand submucosa, the other two showed exten-sive angioinvasion with transmural infarctionincluding one with peritonitis producing aninflammatory ileal mass (case 2). In the fivecases of combined infection the Candidaorganisms were located only in the surfacenecrotic debris.Of the 10 cases with Aspergillus infection,

seven had coexistent lung lesions. Nine of theAspergillus infections showed transmural

808

on June 7, 2020 by guest. Protected by copyright.

http://jcp.bmj.com

/J C

lin Pathol: first published as 10.1136/jcp.45.9.806 on 1 S

eptember 1992. D

ownloaded from

Fungal infections of the small and large intestine

Figure I Small bowel showing several short segmental necrotic lesions with irregularmargins (case 5).

Figure 2 Large bowel mucosa showing several round/oval shaped ulcers (arrows) and a

linear ulcer (arrowhead) (case 6).

infarction characterised by numerous hyphalelements, admixed with fibrin thrombi locatedin the submucosal vessels, with spread into thesurrounding tissues in a radial manner (fig 4).The remaining case showed hyphal elementslimited to the mucosal surface alone with no

evidence of angioinvasion (case 7).In keeping with the impaired immune com-

petence of the patients, there was a poor, if any,mixed inflammatory cell response. No granu-lomas were seen. The Splendore-Hoeppli phe-nomenon,'0 an immunological reaction, was

seen in two cases ofAspergillus infection (fig 5).It is characterised by the deposition of an

eosinophilic proteinaceous precipitate, be-lieved to be antigen-antibody complexes,outling the hyphal walls. These deposits havebeen described before in Aspergillus infec-tions.

MICROBIOLOGICAL DATA

None of the antemortem blood cultures grewfungi and eight cases grew bacterial organisms,mostly of Gram negative species. Specificserological tests for fungi were performed in

four cases but none showed significant risingtitres. None of the antemortem faecal culturesgrew fungi, but four cases confirmed path-ogenic Gram negative organisms (table 2).Three necropsy faecal samples were submittedfor analysis and two grew fungal organismswhich corresponded with the histological mor-phology (cases 1 and 6).

DiscussionIn 64 immunocompromised patients with deepfungal infections we found that 41% hadgastrointestinal infection, with 22% affectingthe lower part of the tract. Other studies havereported a much lower overall gastrointestinalinfection rate of 9-17% in such patients,12 13

but others have found comparable figuresincluding a similar high proportion of lowergastrointestinal tract disease.8 14 In agreementwith other studies3 8 14 12 of our 14 cases hadfungal infections with similar organisms else-where, either in the upper gastrointestinal tractor lungs. In our study the lower intestinal tractwas affected in 54% of all gastrointestinal tractfungal infections, emphasising how commonlyaffected this site is.The organisms found in our study were

either Aspergillus or Candida. In a review ofalimentary tract mycoses published in 1969,Candida and Mucor were considered the majorpathogens and Aspergillus a minor pathogen,6but a more recent review agrees with ourfindings.3 Infections with Candida and Aspergil-lus organisms at differing anatomical sitesincluding the lungs, brain, liver andgastrointestinal tract are well recognised,'5 16

but combined infections affecting the intestineat the same site in the maner we have describedare only mentioned in one review of thesubject. 14

Intestinal pathology in disseminated asper-gillosis has been reported,8 14 15 17 18 but themorphological descriptions of the lesions arescanty and none describes solitary or multi-focal infarcted bowel segments with the welldemarcated margins that we observed. All ofthe infarcted lesions, irrespective of grossmorphology, were associated with vascularocclusion, mostly by Aspergillus organisms,apart from two cases involving Candida. This isclearly important in the pathogenesis of theinfarction but it is uncertain if the vascularcolonisation is embolic from a distant site(such as the lungs) or is due to local invasionfollowing mucosal infection. The latter mecha-nism most probably applies to Candida infec-tions.

Intestinal Candida infections were mostlylimited to the mucosa/submucosa, particularlyin the combined infections where the organ-isms probably preferentially colonise the pre-viously infarcted bowel. Previous descriptionsof pure intestinal Candida lesions are similar toour own observations'5 19 including bowel wallperforation and peritonitis.'9The macroscopic appearances fell into five

categories: ulcers; mucosal flecks; sloughedmucous membranes; polypoid masses; andsegmental lesions, none of which was specific

809

on June 7, 2020 by guest. Protected by copyright.

http://jcp.bmj.com

/J C

lin Pathol: first published as 10.1136/jcp.45.9.806 on 1 S

eptember 1992. D

ownloaded from

Prescott, Harris, Banerjee

Figure 3 (A-B): Candidaorganisms on the surface ofthe infarcted bowel mucosawith Aspergillus hyphae inthe underlying mucosa andsubmucosa (Grocott'smethenamine silver) (case12). The asterisk showsmuscularis mucosae.

-'S

MI.

.~~~~~~~/~ ~

\a

0~~~~~~~~~~Afor either organism. These findings may bediagnostically important to endoscopists aswell as pathologists. Discrete ulcers mayresemble those described in typhoid fever,tuberculosis, and inflammatory bowel disease.The mucosal flecks could be mistaken forpseudomembranous colitis and could present adiagnostic trap because this group of patients isprone to develop this condition because of thefrequent administration of antibiotics.The diagnosis of deep mycotic infections

during life is notoriously difficult"u and pre-

vious reports quote detection rates of 3 5%21and 25%.22 In our study antemortem micro-biological investigations failed to detect intesti-nal fungal growth in any case. A high index ofclinical suspicion is therefore needed. Endo-scopic examination with biopsy specimens orbrushings of lesions should theoretically yielddiagnostic information. Brushings for cytologycould detect Candida and, in some cases,Aspergillus organisms as both can be super-ficially located in the lesions. However, in thosecases where Aspergillus organisms are present in

1/.:

Figure 4 Aspergillus organisms showing angioinvasion Figure 5 Aspergillus organisms demonstrating the(Grocott's methenamine silver). Splendore-Hoeppli phenomenon. Note thickened hyphal

walls produced by the deposition of immunologicalcomplexes.

810

on June 7, 2020 by guest. Protected by copyright.

http://jcp.bmj.com

/J C

lin Pathol: first published as 10.1136/jcp.45.9.806 on 1 S

eptember 1992. D

ownloaded from

Fungal infections of the small and large intestine

deeper tissues, a biopsy specimen is more likelyto be diagnostic.

In 12 cases the clinical diagnosis of sepsiswas deemed contributory to death, but only inone case was a fungal agent recognised. Thepathologist agreed that sepsis played a majorpart in the cause of death and that fungaemiawas contributory in 10 cases. In case 11 fatalgastrointestinal haemorrhage was caused by an

unsuspected combined Candida and Aspergillusjejunal infection.Our findings emphasise the value of nec-

ropsy in studying such infections, and dissec-tion of the bowel at necropsy, althoughunpleasant, should be carried out routinelyespecially in immunocompromised patients.Submitting specimens for fungal culture insuspected cases is recommended because cor-relation with histology and a more preciseclassification of the organism can be achieved.We found the use of histological special stainsvaluable in demonstrating the presence offungi, particularly in the infarcted zones wherenecrotic debris may obscure the underlyingpathology. Failure to perform these procedureswill result in an underestimation of theincidence of intestinal fungal infections andhamper further study of the pathology of theseinfections.

1 Scroggs MW, Wolfe JA, Bollinger RR, et al. Causes of deathin renal transplant recipients. A review of autopsy findingsfrom 1966 through 1985. Arch Pathol Lab Med1987;111:983-7.

2 Stein DK, SugarAM. Fungal infections in the immunocom-

promised host. Diagn Microbiol Infect Dis 1989;12(Sup-pl):221S-8S.

3 Brocheriou C, Badillet G, Gluckman E, et al. Mycoticinfection in immunosuppressed patients. An anatomo-pathologic study. Ann Pathol 1990;10:99-108.

4 Brown AE. Overview of fungal infections in cancer patients.Semin Oncol 1990;17(Suppl 6):2-5.

5 Rotterdam H, Sommers SC. Alimentary tract biopsy lesionsin the acquired immune deficiency syndome. Pathology1985;17: 181-92.

6 Smith JMB. Mycoses of the alimentary tract. Gut1969;10: 1035-40.

7 Pedraza MA. Mycotic infections at autopsy. A comparativestudy of 162 cases. Am J Clin Pathol 1969;51:470-6.

8 Boon AP, O'Brien DO, Adams DH. Ten year review ofinvasive aspergillosis detected at necropsy. J Clin Pathol1991 ;44:452-4.

9 Anthony PP. A guide to the histological identification offungi in tissues. J Clin Pathol 1973;26:828-31.

10 Smith JH, von Lichtenberg F. The Hoeppli phenomenon inSchistosomiasis: II. Histochemistry. Am J Pathol1967;50:993-1007.

11 Spencer H. Pulmonary aspergillosis. In: Pathology of theLung. 2nd edn. New York: Pergamon Press,1968:280-90.

12 Atkinson JB, Connor DH, Robinowitz M, McAllister HA,Virmani R. Cardiac fungal infections: Review of autopsyfindings in 60 patients. Hum Pathol 1984;15:935-42.

13 Mangham DC, Lucas SB. Abstract: Deep funm,al infectionsin malignant disease. J Pathol 1991;163:158

14 Young RC, Bennett JE, Vogel CL, Carbone PP, DeVita VT.Aspergillosis. The spectrum of the disease in 98 patients.Medicine (Balt) 1970;49:147-73.

15 Rosen PP. Opportunistic fungal infections in patients withneoplastic diseases. Pathol Annu 1976;11:255-315.

16 Hutter RVP, Lieberman PH, Collins HS. Aspergillosis in acancer hospital. Cancer 1964;17:747-56.

17 Case Record of the Massachusetts General Hospital No 37.N EnglJ Med 1976;2939:608-14.

18 Tan KK, Sugai K, LeongTK. Disseminated aspergillosis.Am J Clin Pathol 1966;45:697-703.

19 Eras P, Goldstein MJ, Sherlock P. Candida infection of thegastrointestinal tract. Medicine 1972;51:367-79.

20 Maksymiuk AW, Thongprasert S, Hopfer R, et al. Systemiccandiasis in cancer patients. Am J Med 1984;77:20-7.

21 DeGregorio MW, Lee WM, Linker CA, et al. Fungalinfections in patients with acute leukaemia. Am J Med1982;73:543-8.

22 Myerowitz RL. The pathology of opportunistic infections withpathogenetic, diagnostic and clinical correlations. NewYork:Raven Press, 1983.

811

on June 7, 2020 by guest. Protected by copyright.

http://jcp.bmj.com

/J C

lin Pathol: first published as 10.1136/jcp.45.9.806 on 1 S

eptember 1992. D

ownloaded from