J Clin Pathol 1984;37:293-297

Increased a-fetoprotein concentration in associationwith ileal adenocarcinoma complicating Crohn'sdiseaseM LEADER, JR JASS

From the Department ofHistopathology, Westminster Hospital, London SW1P 2AR

SUMMARY A considerably raised serum a-fetoprotein concentration was found in a patient withan ileal adenocarcinoma. a-fetoprotein was shown in both the primary tumour and the hepaticmetastases by an immunoperoxidase technique. A raised a-fetoprotein concentration in associa-tion with ileal adenocarcinoma has not been described previously, and it is notable that the firstsuch case should occur as a complication of longstanding Crohn's disease.

a-fetoprotein is a normal product of fetal liver andyolk sac. Small amounts may also be found in fetalgut.' A raised serum a-fetoprotein concentrationhas been described in a variety of conditions, butconcentrations above 1000 Ku/l are unusual in allbut primary hepatocellular carcinomas and germ celltumours.2 We have found a considerably increasedconcentration in association with an ileal-adenocar-cinoma. Interestingly, the tumour arose as a compli-cation of longstanding Crohn's disease.

Case report

A 30 year old man with a 15 year history of Crohn'sdisease presented with severe colicky abdominalpain. He had previously had several episodes of sub-acute intestinal obstruction, some of which necessi-tated admission to hospital. Each had responded tomedical management. He had been maintained onlow dosage prednisone for 13 years and intermittentazathioprine over the preceeding four years.On this occasion the clinical findings included

those of small bowel obstruction, which respondedto conservative treatment. But a new finding of grosshepatomegaly was also noted. Liver function testsshowed a serum bilirubin concentration of 70 ,umo1Il,aspartate transferase 69 IU/l, alanine transferase41 IU/l, and alkaline phosphatase 1500 IU/l.Ultrasound confirmed hepatomegaly and showedmultiple echogenic areas consistent with metastases.A computed tomogram confirmed this impression.

Accepted for publication 24 November 1983

A barium enema was essentially normal; a smallbowel meal was not carried out.

a-fetoprotein estimation by radioimmunoassay(using a double antibody technique withpolyethylene glycol assisted precipitation) showedan initial value of 8612 Ku/I which quickly rose to15 540 KuJI (normal less than 10 Ku/l). A diagnosisof a primary hepatocellular carcinoma or a germ celltumour was therefore considered, but the testeswere normal and there was no previous history ofliver impairment. Carcinoembryonic antigen con-centration was also raised at 963 ,ug/l (normal lessthan 10 4g1l) but ,8-human chorionic gonadotrophinwas within the normal range.A liver biopsy showed widespread infiltration by a

moderately differentiated mucin producingadenocarcinoma. As mucin production is not a fea-ture of primary hepatocellular carcinoma, this diag-nosis, despite the high a-fetoprotein concentration,was discounted and a primary tumour of gastrointes-tinal origin was suggested. The patient deterioratedand died one week later.

POSTMORTEM FINDINGSThe salient features at necropsy concerned the liverand small intestine. The liver weighed 7710 g and80% was replaced by white tumour deposits. Theintervening parenchyma showed no evidence of cir-rhosis. The lymph nodes at the porta hepatis werenot enlarged. The large intestine was normal, butboth the jejunum and ileum showed patchyinvolvement of Crohn's disease. The bowel wall wasthickened and rigid and narrowed by multiple stric-tures (Fig. 1). The mucosal surface was roughened

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Leader, Jass

Fig. 1 Segment of distal ileum showing narrowing of the lumen by multiplestrictures. Arrowhead points to the stricture from which the carcinoma is arisingMagnification xO-33.

and granular and several inflammatory polyps pro-jected into the lumen. Arising from one of the stric-tures in the distal ileum was a tumour measuring 5cm in diameter (Fig. 1).

Histology confirmed the diagnosis of Crohn's dis-ease. The mucosa was inflamed and showed patchyulceration with occasional fissure formation. Themucus content of the glands was not depleted. Theinflammatory polyps were composed of granulationtissue. Granulomas were not seen but pyloric typemetaplasia of the glands was evident in the inflamedmucosa, the inflammatory polyps, and in the mucosa

adjacent to the tumour (Fig. 2). The pyloric glandsstained red with alcian blue/periodic acid Schiff-diastase, indicating the secretion of neutral mucins.The submucosa was oedematous and inflamed andshowed an increase in fibrous tissue. It also con-tained rather prominent nerve trunks and collec-tions of ganglion cells.

Histological examination of the tumour showed amoderately to poorly differentiated mucus produc-ing adenocarcinoma, with a well marked glandularpattern in addition to more solid clumps of infiltrat-ing cells (Fig. 3). Large sheets of tumour invaded

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Increased a-fetoprotein concentration in association with ileal adenocarcinoma complicating Crohn'sdisease

Fig. 2 Pyloric metaplasia ofthe glands adjacent to thecarcinoma. The submucosa is also inflamed and fibrosed.Haematoxylin and eosin. Original magnification x16.

through the muscularis propria to reach the serosa.The pattern of infiltration did not resemble the"endometriotic like" invasion which is consideredtypical of Crohn's carcinoma. The tumour secretedneutral mucins only.

Liver histology showed a mucus producingadenocarcinoma similar to that in the ileum, anddespite extensive sampling there was no evidence ofa hepatocellular carcinoma.

ImmunohistochemistryFormalin fixed paraffin embedded tissue from theprimary small bowel carcinoma and from the livermetastases were tested for a-fetoprotein using theunlabelled (peroxidase-antiperoxidase) technique.Rabbit antihuman serum (Dako) was used at a dilu-tion of 1/50. Tumour from both sites showed posi-tive granular staining of the cytoplasm of the tumourcells (Fig. 3). With a similar technique, the primarysmall bowel carcinoma and the liver metastases werepositive for carcinoembryonic antigen. Rabbit anti-human CEA (Dako) was used at a dilution of 1/100.

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Discussion

Abelev et a13 found the alpha globulin a-fetoproteinin mice in 1963. It is found in low concentrations inthe serum of normal adults (5-10 Ku/l) and smallrises occur in pregnancy. a-fetoprotein was initiallythought to be a specific tumour marker of primaryhepatocellular carcinoma, but with the advent ofmore sensitive radioimmunoassay techniques smallrises in a-fetoprotein concentration were discoveredin a variety of non-neoplastic liver diseases andtumours of the gastrointestinal tract,4 lungs,5 andprostate.67 Slightly increased concentrations havebeen described in association with carcinoma of thestomach, pancreas, biliary tree, and less commonlythe colorectum.489 Ruoslahti et aP0 reported a riseof >4000 KuIl in a case of primary gastric car-cinoma, and two papers report increaseda-fetoprotein concentrations in patients with dualprimary carcinomas of the stomach and prostate.89Five cases of gastric carcinoma with liver metastasesare reported in the French published work" 13 butvalues of ai-fetoprotein are not given.

Increases in a-fetoprotein concentration to >100times normal are exceedingly rare in gastrointestinaltract malignancies. McIntire et al4 report four suchcases: one a colorectal carcinoma with a value of50 000 Ku/l, and two cases of gastric carcinoma andone of a pancreatic carcinoma with values less than10 000 Ku/l.The occurrence of small bowel carcinomas in

Crohn's disease was first described by Ginzburg etal. 14 Over 60 such cases have now been reported,'5 16and Weedon et al'7 and Greenstein et al'8 found theincreased incidence of small bowel carcinoma in thisgroup to be significant. None of the reports of smallbowel cancer have given a-fetoprotein values andthe very high level in the case described hereappears unique.

It is interesting to ask why a raised a-fetoproteinconcentration should be associated with ilealadenocarcinoma complicating Crohn' s disease.a-fetoprotein is a normal product of fetal liver andyolk sac, and small amounts may also be found inthe gastrointestinal tract.' It is well known that theprincipal gastrointestinal malignancies associatedwith a raised a-fetoprotein are those of the biliarysystem, stomach, and pancreas.'9 Taken in conjunc-tion with the liver, it would appear that malignanciesof structures derived from the foregut show a par-ticular association with a-fetoprotein production.Crohn's disease is often associated with foregut ormore specifically pyloric metaplasia. This was notedin the present case, and, in addition, the adenocar-cinoma showed certain morphological and his-tochemical similarities to gastric carcinomas of

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a-fetoprotein. Haematoxylin and eosin. Original magnification x 16. Inset: Originalmagnification x40.

pylorocardiac type.2" Foregut metaplasia could poss- Referencesibly be linked to the production of a-fetoprotein bythe present case, but further examples of this 'Gitlin 1D.i8Stes o6f alpha fetoprotein synthesis. N Engi I Medphenomenonmustbe sught and studied. 2Sell S. Diagnostic application of aipha-fetoprotein. Government

regulations prevent full application of a clinically useful test.Hum Pathol 1981-12:959-63.

We thank Miss Michelle Brooks and Miss Teresa 3Abelev GI, Perova SD, Khramkova NI. Production of embryonalGodden for typing this paper. We are grateful to Mr alpha globulin by transplantable mouse hepatomas. Transplan-M Nelson for his photographic assistance. We also tation 1963;1: 174-86.thank~~Dr BinGzadwh lokd ftr this McIntire KR, Waldmann TA, Moertel CG. Serum alpha-thankDrBranGazzard who lookeaalter tnlS fetoprotein in patients with neoplasms of the gastrointestinal

patient. tract. Cancer Res 1975;35: 991-6.

296 Leader, Jass

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Increased a-fetoprotein concentration in association with ileal adenocarcinoma complicating Crohn'sdisease

Tsung S. Alpha-fetoprotein in lung cancer metastatic to the liver.Arch Pathol 1975;99:267-9.

6 Mehlman DJ, Bulkley BH, Wiemik PH. Serum alpha-fetoprotein in gastric and prostatic carcinomas. N Engl J Med1971;285: 1060-1.

' Kozower M, Fawaz KA, Miller H. Positive alpha-fetoprotein in a

case of gastic carcinoma. N Engl J Med 1971;285: 1059-60.Montplaisir S, Rabin B, Pelletier B. Alpha-fetoprotein content of

gastric carcinoma and hepatic metastases. Am J Dig Dis1973: 18:416-8.

Bierfeld J, Scheiner M, Schultz D. Alpha-fetoprotein and car-

cinoembryonic antigen in a case of gastric carcinoma metasta-tic to the liver. Am J Dig Dis 1973:18:517-20.

'° Ruoslahti E, Seppala M, Vuopio P. Radioimmunoassay ofalpha-fetoprotein in primary and secondary cancer of the liver.J Natl Cancer Inst 1972;49:623-8.

Bourreile J, Metayer P, Sauger F. Existence d' alpha-fetoproteineau cours d'un cancer secondaire du foie d'origine gastrique.Presse Med 1970;78: 1277-8.

2 Geoffroy Y, Metayer P, Denis P. Alpha-fetoprotein et cancer

secondaire du foie. Presse Med 1970;78:1896.13 Bernades P, Smadja M, Rueff B, et al. Presence de ralpha-

fetoproteine serique dans quatre cas de cancers digestifsprimitifs autre que rhepatome. Presse Med 1971;7911:1585-7.

'4 Ginzburg L, Schneider KM, Dreizin DH, et al. Carcinoma of thejejunum occurring in a case of regional enteritis. Surgery1956;39:347-51.

5 Lightdale CJ, Sternberg SS, Posner G, et al. Carcinoma com-

plicating Crohn' s Disease Report of seven cases and review ofliterature. Am J Med 1975;59:262-8.

16 Savage RA, Farmer RG, Hawk WA. Carcinoma of the smallintestine associated with transmural ileitis (Crohn's Disease)Am J Clin Pathol 1975;63:168-78.

7 Weedon DD, Shorter RG, Illstrup DM, et al. Crohn's disease andcancer. N Engl J Med 1973;289: 1099-103.

Greenstein AJ, Sachar DB, Smith H, et al. A comparison ofcancer risk in Crohn's disease and ulcerative colitis. Cancer1981;48:2742-5.

Neville AM, Cooper EH. Biochemical monitoring of cancer. Areview. Ann Clin Biochem 1976;13:283-305.

20 Mulligan RM, Rember RR. Histogenesis and biologic behaviourof gastric carcinoma. Arch Pathol 1954;58: 1-25.

Requests for reprints to: Dr Mary Leader, Department ofHistopathology, The Westminster Hospital, London SW1P2AR, England.

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