J Clin Pathol 1990;43:448-452

Epithelial markers in pancreatic carcinoma:immunoperoxidase localisation ofDD9, CEA,EMA and CAM 5 2

E Heyderman, S E Larkin, P J O'Donnell, A M R Haines, P J Warren, A Northeast,A G Grant

AbstractParaffin wax embedded, formalin fixedsections of 22 adenocarcinomas of theexocrine pancreas were stained with fourmouse monoclonal antibodies: DD9-E7,an antibody raised against a human pan-

creatic tumour xenograft; carcino-embryonic antigen (CEA); epithelialmembrane antigen (EMA); and cyto-keratin (CAM 5 2). An indirect im-munoperoxidase technique withoutenzyme pre-digestion and an affinity-purified sheep anti-mouse peroxidaseconjugate were used. All of the tumourswere positive for DD9-E7, EMA, andCAM 5 2. Twenty out of 22 were focallypositive for CEA and the staining wasoften weak. As all of these adenocarci-nomas were DD9-E7 positive, absence ofstaining for DD9-E7 in a tumour makesthe diagnosis of adenocarcinoma of theexocrine pancreas very unlikely, and thisis of value in distinction from endocrinecarcinomas with a marked acinar pat-tern. The weak CEA staining distingui-shed pancreatic carcinomas from colo-rectal tumours. Because the distributionof staining for EMA and CAM 5 2 was no

different from that previously seen inadenocarcinomas from other sites, thesemarkers are likely to be of limited valuein the differential diagnosis of ab-dominal adenocarcinomas of uncertainorigin.

Department ofHistopathology,UMDS, St Thomas'sHospital SE1 7EHE HeydermanS E LarkinP J O'DonnellAM R HainesP J WarrenDepartment ofSurgeryA NortheastDepartment ofSurgery, St George'sHospital, LondonA G GrantCorrespondence to:E HeydermanAccepted for publication23 January 1990

In England and Wales there has been a sub-stantial increase in adenocarcinomas of theexocrine pancreas over the past 75 years. Themortality trebled from an age standardisedrate for both sexes of 2-9 per 100 000 in thequinquennium 1911-1915 to 10 6 in men and8-3 in women in 1971-1975.' Since 1974 themortality has remained fairly stable, with a

mean of 2971 a year for men and 2857 forwomen.' There were slightly more deathsfrom this cause in men than in women until1986. Since then the mortality in men hasfallen somewhat from 2950 in 1986 to 2905 in1988, and risen in women from 3093 to 3103.'Carcinoma of the pancreas is uncommon

under the age of 40, and the maximum mor-

tality from this cause is at age 65-79.' Theprognosis is dismal, with a three year survivalof the order of 30% and very few long termsurvivors.4 Most patients present late, oftenwith metastatic deposits demonstrable at sur-

gery or laparotomy and a resectability rate of

only 1200".4 The prognosis of cystadenocarci-nomas of the pancreas seems to be better thanthat of solid ductal carcinomas. In a study of1001 patients, which included ail types ofexocrine and endocrine pancreatic carcinomasand ampullary carcinomas, the resectabilityrate of pancreatic cystadenocarcinomas, whichoccurred in patients with a mean age of 45compared with a mean age of 67 for solidtumours, was 67% (six of nine). The threeyear survival was 330/0 (three of nine), thoughall three patients finally died of recurrencethree, nine, and 16 years later.4The diagnosis of the primary tumour

remains difficult for clinicians, while for thehistopathologist there are various areas ofdifficulty. These include (i) determiningwhether metastatic tumour in nodes, liver,bone, or in other sites could have arisen in thepancreas; (ii) deciding whether an adenocar-cinoma in the lung could represent a meta-stasis from an occult pancreatic carcinoma andtherefore be unsuitable for resection; and (iii)distinguishing chronic pancreatitis from welldifferentiated adenocarcinoma, especially inneedle biopsy specimens.The pronounced desmoplastic response

evoked by many pancreatic adenocarcinomasmay be of some help in the distinction fromother tumours, and many are well differen-tiated with a rather angular glandular pattern,rather unlike the smoother more ring-likeglands seen in gastric or colorectal carci-nomas. They are not, however, sufficientlydifferent morphologically from those arisingelsewhere in the gastrointestinal tract for aconfident diagnosis of a metastatic deposit. Inbiopsy material origin from other sites cannotbe excluded unless there is both a mass in thepancreas felt by the surgeon and pancreatictissue in the biopsy specimen.

In an initial study DD9-E7 supernatant,raised by immunisation of nude mouse hairylittermates (nu/ +) with a homogenisedxenograft of GER pancreatic adenocarcinomacells,5 was used. It had been shown to reactstrongly with 12 of 14 adenocarcinomas of theexocrine pancreas and with a variety of othernormal and neoplastic tissues. Staining ofpolymorphs and macrophages suggested thatthe antigen against which DD9-E7 was direc-ted was similar to normal crossreactingantigen, NCA.67 Western blot analysis hasshown that DD9 recognises a protein epitopeon a family of glycoproteins (80-115 kilo-daltons) which are distinct from the sialogan-glioside and mucin-like pancreatic tumourantigens recognised by other monoclonal

448

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449Epithelial markers in pancreatic carcinoma

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Figure I The rather angular acini commonly seen in carcinomas of the exocrinepancreas are seen in this immunostain for DD9.

Figure 2 At higher power the DD9 positive cytoplasmic globules in another malignatacinus are well shown.

antibodies CA 19-9,8 Du Pan-2,9 or Ca-54The epitope to which the antibody bindsnot found in CEA or NCA-2," but is pres

in NCA-1, suggesting that NCA-1 and iDD9 antigen share a common determin;(AG Grant, unpublished data).

MethodsTwenty two surgically resected or biopsiunequivocal primary pancreatic ducadenocarcinomas were selected from the si

gical files of St Thomas's or St GeorgHospitals, including the adenocarcinoma frcwhich the GER cell line had been derivedBlocks from needle biopsy specimens takenlaparotomy and showing tumour infiltratifat or fibrous tissue without evidence of pacreatic invasion were excluded.DD9-E7 used in this study was an asci

preparation produced in beige mice.'2 Tanti-CEA was also an ascites preparati

(Amersham International plc, Buckingham-shire). It does not stain polymorphs or macro-

phages and does not seem to recognise an

NCA determinant. Anti-EMA was a hybri-doma supernatant raised using a preparaton ofhuman milk fat globule membranes"14(Dakopatts Ltd, Buckinghamshire), and CAM

* 52 was also a supernatant, raised by immu-nisation with the human colon carcinoma cellline HT29.'5An indirect immunoperoxidase technique,

without enzyme predigestion, and an affinitypurified sheep anti-mouse peroxidase con-

jugate prepared by periodate oxidation'6 were

used. The method was similar to that alreadypublished,'7 except that incubation with thefirst antibody was carried out overnight in-stead of for one hour.The positive controls used in this study

were a moderately differentiated colorectalcarcinoma for CEA'8 and CAM 5-2,'5 a ductalcarcinoma of the breast for EMA,'9 and ametastatic deposit in the liver of a pancreaticadenocarcinoma for DD9-E7. A monoclonalantibody directed against prostatic acid phos-phatase, PASE/4LJ, was used as an irrelevantnegative control. This antibody stains somepancreatic islet cells in formalin fixed tissue,but not benign or malignant exocrine pan-creatic tissue.20 Prostatic chippings showingbenign hyperplasia were used as a positivecontrol for PASE/4LJ.

ResultsAll of the tumours were positive for DD9-E7,EMA, and cytokeratin, and 20 of 22 werepositive for CEA (figs 1-6). Most of theresidual pancreatic islets were negative withall four antibodies. A few cells in some islets,however, were positive for cytokeratin, Somepositive staining for DD9-E7, EMA, andcytokeratin was found in normal pancreas, aswell as in the areas of chronic pancreatitis so

it frequently found surrounding pancreaticexocrine carcinomas. Although normal pan-creatic tissue was negative for CEA, there was

i. positive staining in foci of chronic pan-iS creatitis.

ent The distribution of staining for DD9 wasthe on the luminal membrane of malignant aciniant and in the luminal contents (fig 1). Positivity

was also often seen as a cytoplasmic globuleabove the nucleus, separated from the luminalmembrane, and corresponding to the positionof mucigen granules (fig 2).21 The two

ied tumours negative with the supernatant used in-tal the previous study'5 were positive in thisir- study when ascitic fluid was used. This wase's likely to be due either to the increase in)m immunoglobulin content or to prolongation of.L2 the first antibody incubation time.Lat Though some of the tumours were stronglyng positive for CEA (fig 3), several were weaklymn- or focally positive. Staining was on the

luminal membrane or in the cytoplasm, ortes both, but the globular staining seen withhe DD9-E7 (fig 2) was not seen with CEA. Theion normal pancreas surrounding the tumour was

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Heyderman, Larkin, O'Donnell, Haines, Warren, Northeast, Grant

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Figure 3 An immunostain for CEA shows malignant acini witi

partly cytoplasmic, Pattern of staining. A residual islet (top righ

Figure 4 In this tumour there is a "pericellular" pattern of sta:

weight cytokeratin (CAM 5-2).

negative for CEA, but ti

positivity in foci of chronic

In some tumours CAPv

just under the plasma

tumour cells, in a "peric(

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plasmic. In some tumour

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Some residual pancreatic

areas of positivity.

The staining for EMAluminal membrane (fig 5),

some cytoplasmic stainirresidual exocrine pancreasliculi similar to those see

glands were positive.22

Discussion

The presence of DD9 inicreatic adenocarcinomas, aito 500 of other adenocar

that its presence in a metastatic tumour,especially with a weak or only focally positive

; CEA, makes the tumour more likely to be ofpancreatic than of gastric or of colorectalorigin. Conversely, a negative stain for DD9makes the exocrine pancreas a highly unlikely

As primary site. This has already proved usefulclinically in distinguishing endocrine pan-creatic carcinomas with pronounced acinardifferentiation from exocrine carcinomas withtheir very much worse prognosis. Bronchialtumours may also be negative for CEA andsome contain DD923 (E Heydermam, unpub-lished data), so DD9 staining does not dis-tinguish primary adenocarcinomas of the lungfrom metastatic pancreatic tumours. As far asother sites are concerned, prostatic depositscan virtually be excluded by the absence ofstainable prostatic acid phosphatase,2024 andmost thyroid carcinomas are positive forthyroglobulin.25 26The presence of endogenous peroxidase

activity in leucocytes, especially eosinophils,makes it essential to inhibit this activityadequately when studying the distribution of

/ ~~~staining with antibodies to NCA relatedepitopes.27 Positive staining for polymorphscan make interpretation difficult in fociheavily infiltrated by acute inflammatory cells.

-*, r ^! This was not a major problem in the pan-creatic tumours studied here, but we havefound staining for DD9 in squamous carcin-omas of the lungs difficult to assess for this

t reason (E Heyderman, unpublished data).- ; DD9 immunostaining, however, could be of

value in determining whether cells in the bonemarrow in proliferative states or in leukaemiaare of myeloid origin, and this antibody, like

- ^ others recognising an NCA epitope, could beof value in immunoscintigraphy of occult ab-scesses.Tsutsumi et al used a rabbit antibody

apartllu, specifically raised against NCA. They showed[t) is negatuie, the presence of NCA in cryostat sections of

pancrea.ic adenocarcinomas, but not in for-iningfor low molecular malin-fixed, paraffin wax embedded blocks

from the same tissues.28 All of their tumours,here were areas of however, were positive with the Dako anti-pancreatitis. CEA before absorption with a spleen extract.

4 5-2 was localised The Dako antibody is well recognised to havemembrane of the NCA activity, and pre-absorption with anellular pattern" (fig NCA preparation is required before it can beand just under the used to show CEA and not NCA.29 Pre-e rest it was cyto- sumably, the rabbit NCA antibody used byrs the staining was Tsutsumi et al recognises a different, moremost it was strong. labile NCA epitope. In another study mono-islets showed focal clonal and polyclonal NCA antibodies stained

most pancreatic carcinomas and foci ofwas mainly on the chronic pancreatis.30 The monoclonalbut there was also antibody 374 which recognises a shared CEA,

ig (fig 6). In the NCA 95, and NCA 55 determinant, staineds intercellular cana- normal ductal cells and 36 of 40 pancreatic!n in eccrine sweat carcinomas.3" The monoclonal antibody

47D10, which was positive in 95% of pan-creatic adenocarcinomas but not in foci ofchronic pancreatitis, also stains granulocytes,and may recognise an NCA-related antigen.

all 22 primary pan- This antibody, however, is different from[nd its absence in up DD9 in that it recognises a carbohydratercinomas, suggests epitope."2

450

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Epithelial markers in pancreatic carcinoma

pancreas led us to hope that its demonstrationcould be of value in the differentiation oftumour from chronic pancreatitis, but, asfound by others,3 35 both adenocarcinomasand foci of chronic pancreatitis were positive,though such foci were found to be negativewith the F6 CEA antibody.30EMA and cytokeratin, while of possible

value for tumour immunolocalisation inpatients where specificity may not be re-quired, do not distinguish pancreatic adeno-carcinomas from those arising elsewhere.

We are very grateful to Ms CA Makin and AmershamInternational plc for their generous gifts of CAM 5-2 and anti-CEA, respectively. The work was supported by St Thomas'sHospital Research Endowment Fund (AMRH) and the CancerResearch Campaign (SEL and AGG).

The photomicrographs were taken using Ektor Gold 25.

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Figure 5 The EMA stain is mainly luminal with the contents of the malignant acinialso positive.

Figure 6 In this tumour there is a patchy cytoplasmic positivity for EMA.

There have been several studies on thelocalisation of CEA in pancreatic carcin-omas.28 30331338 In the two studies undertakenin 1972 and 19783 334 only three out of six andtwo out of seven of the pancreatic carcinomaswere positive, but neither of the antisera usedshowed positivity in normal colonic mucosa,so that sensitivity was low. More recentstudies have shown results very similar toours, with all or nearly all pancreatic adeno-carcinomas showing some CEA.2830 3i 3539

It has been noted in some studies thatstaining for CEA was stronger in betterdifferentiated pancreatic tumours,31 33 35 butthis was not notable in our series, nor in thoseof others.28 The weakness or focal distributionof staining was surprising. In a recent studyserum concentrations of CEA were increasedin 91 00 of patients with pancreatic cancer39and in most cases in earlier studies.93 Theweak staining, compared with that in ourcolon carcinoma control, may reflect lowlevels of storage of CEA, because immuno-cytochemistry can only detect stored materialand does not necessarily accurately reflectsynthesis.'The absence of CEA staining in normal

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doi: 10.1136/jcp.43.6.448 1990 43: 448-452J Clin Pathol

 E Heyderman, S E Larkin, P J O'Donnell, et al. CEA, EMA and CAM 5.2.immunoperoxidase localisation of DD9, Epithelial markers in pancreatic carcinoma:

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