Influence of Site of Origin and Mucin Productionon Survival in Ampullary Carcinoma

PETER J. DAWSON, M.D., F.R.C. PATH.,* and MARK M. CONNOLLY, M.D.t

We studied a series of 26 cases of carcinoma of the ampulla ofVater. There were 24 adenocarcinomas and two neuroendocrinetumors. Histologically the carcinomas could be divided into tu-mors arising from periampullary duodenal mucosa and thosearising within the ampulla. True ampullary tumors had a sig-nificantly better 5-year survival rate (p = 0.028) than periam-pullary tumors. The type of mucin produced was investigatedhistochemically. Patients with true ampullary tumors producingpredominantly sialomucins had a better prognosis than thosewith tumors secreting sulphated mucins (p = 0.045), but thenumbers were small. We hypothesize that the most favorabletype of ampullary carcinoma arises from biliary-type epitheliumwithin the ampulla.

Wx r E HAVE STUDIED CASES OFCARCINOMA oftheampulla ofVater at the University ofChicagoover a 42-year period. We propose a classifi-

cation of these tumors based on the site of origin- and thetype of mucin produced by the tumor cells that appearsto identify those cases that carry the best prognosis.The ampulla that Abraham Vater described in 1720

lies within the wall of the duodenum. It is a flask-shapedstructure formed by fusion of the main pancreatic ductof Wirsung and the common bile duct. There are severalanatomic variations of the termination of these ducts,'and a true ampulla is present in only about one half ofthe population. Histologically, the ampulla is said to belined by bile duct epithelium.2 However, it represents aconfluence of three types of epithelium, biliary, duodenal,and pancreatic, and carcinomas occurring within this re-gion could arise theoretically from any one ofthem. Whilesuch tumors are relatively rare, more people, in both ab-solute and relative terms, survive carcinoma of the am-pulla of Vater than the much more common carcinomaof the pancreas. Nonetheless, the majority of patients die

From the Departments of Pathology* and Surgery,t theUniversity of Chicago Medical Center, Chicago, Illinois

of their disease. Because the region is so complicated an-atomically, it seemed to us that all tumors occurring atthis site might not have the same histogenesis, and thatthis might be the explanation ofthe behavioral differences.Further, because there are differences in mucin productionby the various epithelia that come together at the ampulla,3we used a battery of mucin stains to supplement and ex-pand our histologic observations.

Methods and Materials

We have been comprehensively reviewing cases ofpan-creatic cancer seen at the University of Chicago. For thepresent study we reviewed all cases indexed as carcinomaof the ampulla of Vater in the Laboratory of Surgical Pa-thology and the Registry of Neoplastic Diseases at theUniversity of Chicago Medical Center from 1943 to 1985.We have previously, as part of another study, reviewedcases of carcinoma of the pancreas operated on at ourinstitution between 1946 and 1983.4 The present studywas restricted to cases in which the tumor clearly arosewithin the ampulla or from periampullary duodenal mu-cosa and in which a curative resection had been per-formed. In all cases but two, resection was carried out atour institution.

Follow-up data was obtained in all cases. Survival wasmeasured from the date of operation. Survival curves wereestimated using the Kaplan-Meier method,5 and the sig-nificance of the difference in the two overall survivalcurves, as well the relationship between mucin secretion,tumor size, age, lymphatic invasion, and lymph node me-tastases and survival was tested using the Cox regressionmodel.6A battery of four mucin stains was used to elucidate

the nature of the mucins secreted. These included alde-

173

Correspondence and reprint requests: Peter J. Dawson, M.D., Labo-ratory of Surgical Pathology, Box 274, 5841 S. Maryland Avenue, Chi-cago, IL 60637.

Accepted for publication: January 11, 1989.

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SURVIVAL IN AMPULLARY CARCINOMA

hyde fuchsin-alcian blue,7 which stains sulphated mucinspurple and carboxylated mucins blue. Alcian blue-penr-odic acid Schiff(pH 2.5),8 which stains sulphated mucinsaquamarine and other mucins magenta was also used,although at this pH this stain does not really distinguishbetween sulphated and carboxylated mucins. High irondiamine-alcian blue,9 which stains sulphated mucinsblack and other mucins magenta was used as well. Inaddition we used the KOH-AB 1.0-PAPS technique,'0which en: les the simultaneous demonstration of bothsulphated mucins (not containing sialomucin) and non-sulphated sialomucins. Cells containing the former stainblue, the latter magenta, and cells containing a mixtureof both types of mucin stain purple.

Results

Total University of Chicago experience included 26cases of ampullary carcinoma that met our criteria forinclusion in this study, namely that histology was availableand they had been operated on for cure. An additional20 cases were seen during this period but none of themhad been operated on for cure. The clinical and pathologicdetails of these cases are summarized in Table 1. Menand women were equally affected and ranged from 37 to72 years in age, with a mean age of 57 years. Classicallythere has -usually been a delay in the diagnosis of ampul-lary malignant neoplasms, and none of our cases was di-agnosed early. The majority ofsymptoms were secondaryto obstruction at this strategic location, and therefore, werenot directly related to the size and extent of the tumor.The triad ofjaundice, pain, and weight loss was the mostcommon presentation in our series, as has been the generalexperience. Nausea and vomiting also were commonlyreported among our patients. Physical signs were minimalexcept for jaundice, which was by far the most commonfinding. This was always progressive and in one half ofthe patients was associated with fever and chills. Hepa-tomegaly was recorded, but a palpable gallbladder wasnot reported. In addition, guaiac-positive stools, clay-col-ored stools, and dark urine were noted in several cases.Thrombophlebitis, malabsorption, or diarrhea were notseen.

Pathologically there were 24 adenocarcinomas and twoneuroendocrine tumors. When we reviewed the carci-nomas histologically, it was clear that they could be di-vided into two groups, tumors apparently arising fromperiampullary duodenal surface mucosa (11 cases), andtumors arising within the ampulla proper (11 cases), adivision that has been made by others.""2 In the tworemaining carcinomas, the point of origin could not bedetermined. There was no significant difference in age atoperation between patients with tumors in the two ana-tomic locations. The duodenal tumors were larger with a

FIG. 1. (Case 13) Infiltrating well-differentiated adenocarcinoma devel-oping in the base of a villous adenoma. The tumor is arising from peri-ampullary duodenal mucosa. (H&E X 10.)

mean maximum diameter of 2.6 cm (range, 1.0 to 5.5cm) compared to 1.4 cm (range, 0.8 to 2.5 cm) for intra-ampullary tumors (p = 0.013). The incidence oflymphaticinvasion within the two groups was similar, althoughlymph node metastases were more frequent with duodenaltumors (six versus four cases).

Histologically there were important differences betweenthe two groups. Eight of 11 duodenal tumors resembledwell-differentiated large bowel carcinomas. Six were pap-illary and four were clearly associated with a villous ad-enoma, but all showed invasion, often into the wall oftheampulla (Fig. 1). The remaining duodenal tumors grewas single cells or narrow trabeculae with some attempt atglandular differentiation and they lacked the exophyticcharacter of the other tumors (Fig. 2). The 11 tumorsarising within the ampulla were all well-differentiated ad-enocarcinomas. The majority formed small irregularglands that infiltrated into the wall of the ampulla (Fig.3). Only four of the ampullary lesions were papillary.The two remaining cases were both neuroendocrine

tumors that arose within the ampulla. One exhibited theusual well-developed carcinoid pattern. It showed exten-sive growth within lymphatics and infiltrated through thewall of the duodenum into the head of the pancreas. Thetumor was argyrophilic and was associated focally withan amyloid stroma. The other tumor was poorly differ-entiated and histologically resembled an oat cell carci-noma (Fig. 4). An unusual feature was the presence ofsevere dysplasia in the overlying ampullary epithelium.The 5-year survival rate (± SE) was 18% (± 12%) for

tumors arising from duodenal mucosa compared to 55%(± 15%) for intra-ampullary lesions. Survival curves (Fig.5) showed a statistically significant difference in survival

Vol. 210 - No. 2 175

176 DAWSON AND CONNOLLY

FIG. 2. (Case 16) Carcinoma arising in periampullary duodenal mucosaand infiltrating predominately as single cells. Although intramucosal inthis photograph, elsewhere the tumor extends to the serosal surface. (H&EX48.)

between the two groups (p = 0.028). With our small num-bers we could detect no statistically significant effect onsurvival of age, tumor size, lymphatic invasion, or lymphnode status. Both patients with neuroendocrine tumorsdied within 1 year.

In an attempt to identify more precisely patients whohad a good prognosis, we looked at mucin production bythe tumor cells. It is well known that different types ofmucin are produced by the various regions of the gas-trointestinal tract and that neoplasia may be associatedwith a change in mucin production. In the case of the

Ann. Surg. August 1989

GM_ a Wi.ak-FIG. 4. (Case 26) Small-cell undifferentiated (oat cell) carcinoma arisingin the mucosa of the ampulla of Vater. Note the atypical proliferationof the overlying intestinal epithelium. (H&E X50.)

ampulla there are differences in mucin secretion by thenormal epithelia that come together at this point. Themain pancreatic duct contains predominantly sulphatedmucins,3 as does the epithelium of the gallbladder; buton the other hand the duodenal surface mucosa containssialomucins and Brunner's glands neutral mucins. Thecommon bile duct contains predominantly sialomucins(and a trace of sulphated mucins). The staining of theampulla of Vater varies. Sialomucins predominate in thelining epithelium near the opening into the duodenum.Deeper in the ampulla. the lining epithelium, as well asthe glands lying beneath the epithelium, secrete principallysulphated mucins.

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FIG. 3. (Case 8) Intra-ampullary carcinoma arising from the epitheliallining of the ampulla of Vater. (H&E X 10.)

FIG. 5. A comparison of survival estimates for tumors arising from peri-ampullary duodenal surface mucosa (solid line) and tumors arising withinthe ampulla proper (dotted line). The 5-year survival rate is significantlybetter for intra-ampullary tumors (p = 0.028).

SURVIVAL IN AMPULLARY CARCINOMA 177TABLE 2. Results ofMucin Stains on Tumors Arising Within Ampulla of Vater andfrom Periampullary Duodenal Mucosa

Aldehyde Fuchsin Alcian Blue Potassium HydroxideCase # High-Iron Diamine Alcian Blue Periodic Acid Schiff Alcian Blue

AmpullaryI -Bk ±Aq +Aq/P ++Aq2 -Bk +Aq ++M ++Aq3 +Bk +Aq ++M ++Aq4 -Bk ±Aq +Aq/P +Aq5 ±Bk++Aq +Aq ++Aq+M ++Aq6 ±Bk+++Aq +Aq+P +++Aq+M ++Aq+M7 +++Bk +++P +++P+M +++Aq+P8 +++Bk+Aq +++Aq +++P +++Aq9 +++Bk +++P +++M+++Aq +++Aq10 ++Bk ++Aq+P +++M+P +++Aq+P11 -Bk ±Aq ++M +Aq

Duodenal tumors12 +++Bk+Aq +++Aq +++M+++P +++M13 -Bk ++Aq ++M ++Aq14 -Bk ++Aq +++M ++M+Aq15 +Bk +++Aq±P +++M+P +M16 ++Bk ++Aq ++M+P +++Aq17 Not Mucin Producing18 ++Bk +++P ++P ++Aq19 +++Bk +++Aq ++M +++Aq

Bk, black; Aq, aquamarine; P, purple; M, magenta.

The results of our mucin stains are summarized in Ta-ble 2 in which the dominant staining is recorded. Among7 tumors arising from the duodenal mucosa, 5 containedsulphated mucins and 2 contained predominantly sialo-mucins. Among tumors arising within the ampulla, seven

contained sialomucins and only four were producing sul-phated mucins. This difference in the type of mucin pro-duction correlated with prognosis. The prognosis for pa-tients with intra-ampullary sialomucin-secreting tumorswas significantly better than for those patients whose tu-mors produce sulphated mucins (p = 0.045).

Discussion

The incidence of both carcinoma of the pancreas andcarcinoma of the ampulla of Vater is increasing. Whileetiologic factors probably play a part in both diseases, theincrease in carcinoma of the ampulla reflects, in part, itsrelatively recent accessibility to the fiberoptic endoscopeand the biopsy loop.

In a large series of 2390 patients compiled by Wise etal.'3 from the literature, the 5-year survival rate was 29.3%;more recent results (Table 3), however, show some slightimprovement. Although it has been stated that patientswith tumors larger than 2 cm in diameter or with carci-noma-positive lymph nodes do not survive 5 years,19 thishas not been our experience.

It has been well known that exophytic lesions of the

ampulla tend to do better than infiltrative lesions, but thishas not been well correlated with the site oftumor origin.Forrest and Longmire'2 first clearly distinguished between

TABLE 3. Survival in Ampullary Cancer FollowingPancreaticoduodenectomy

Number of Operative 5-YearAuthor Year Patients Mortality Rate Survival

Wise et al. (13)(collected series) 1976 2390 18.8% 29.3%

Warren et al. (14) 1975 112 7.6% 32%Makipour et al. (15) 1976 23 8% 17%Nakase et al. (16)X 1977 330 16.4% 6%Treadwell et al. (17) 1978 31 16% 32%Schlippert et al. (18) 1978 31 22.6% 10%Forrest and

Longmire (12) 1979 21 14% 24%Williams et al. (19) 1979 27 11% 27%Herter et al. (20)' 1982 44 14.7% 27.8%Kelum et al. (21) 1983 17 11.8% 50%Knox and Kingston

(22) 1986 24 30% 41%Tarazi etal. (23) 1986 105 7.8% 37.2%Yamaguchi and

Enjoji (24)- 1987 109 6% 28%Hayesetal (25) 1987 35 25% 53%Neoptolemos (26) 1988 23 N.A. 52.1%Present series 24 12.5% 29%

* Recently published series some of which include cases previouslyreported and listed in the compilation of Wise et al. (13).

N.A., not available; xx, multiinstitutional series; x, includes cases ofcarcinoma of the pancreas.

Vol.210 -NO. 2

178 DAWSON AND CONNOLLY Ann. Surg. * August 1989

tumors arising in the ampulla and tumors arising fromthe duodenal mucosa in the region ofthe biliary and pan-creatic outflow tracts. Unfortunately they had only fiveduodenal tumors and follow-up did not extend beyond 2years, so that it was difficult to know if the two groupsdiffered in prognosis. Cubilla and Fitzgerald" also madethe distinction between intra-ampullary and periampul-lary lesions and presented data to show that the 5-yearsurvival rate was better in intra-ampullary (5/20 cases)than in periampullary or duodenal tumors (1/8). Theirnumbers were also small and there were more stage I tu-mors among the intra-ampullary tumors. In our seriesthere was a significant difference in survival between thetwo groups that could not be accounted for by differencesin pathologic stage. Only one patient with a duodenaltype tumor is alive and only two patients survived 5 years.Among the same number of true ampullary lesions, thecorresponding figures are four and six patients, respec-tively. Unfortunately no one has a very large experiencewith ampullary carcinoma (see Table 3) and the criteriafor case selection varies with different series.We would suggest, therefore, that the pathologist report

ampullary tumors in terms that indicate their histologicsite of origin so additional data can be gathered to sub-stantiate our impression.

In several parts of the gastrointestinal tract the devel-opment ofneoplasia has been associated with an alterationin the type of mucin produced. For example, in the colonand rectum the development of neoplasia is associatedwith replacement of the normal sulphated epithelial mu-cins by sialomucins.27 We looked for a similar type ofchange associated with neoplastic transformation of theduodenal surface epithelium. For this purpose we foundthe high iron diamine reaction to be helpful in recognizingan alteration from the normal sialomucin to sulphatedmucin. Although the KOH-AB 1.0-PAPS technique hascertain theoretical advantages, in practice there are prob-lems in obtaining a sharp distinction between the twotypes of mucin.28 The fact that five of seven duodenaltumors secreted predominantly sulphomucins suggeststhat a similar type of transition might occur in the duo-denum.The situation in the ampulla is difficult to interpret for

several reasons. First, the anatomy is complex with widevariations among individual patients. Second, the patternofmucin secretion varies in different parts of the ampulla.Third, our numbers are quite small. The data suggest acorrelation between the type of mucin secreted and prog-nosis. While the change could simply be an epipheno-menon, it could also be a reflection of the site of origin.One could speculate, for example, that the one group oftumors arising in the ampulla that stain black with highiron diamine, purple with alcian blue-PAS, and blue or

purple with aldehyde fuchsin-alcian blue are merely ex-pressing the mucins of their epithelium of origin, namelythe pancreatic duct or transformed duodenal mucosa. Theother group of ampullary tumors secrete mucins, thereactivity of which appears to resemble the mucins se-creted by bile duct epithelium. It is this latter group thatappears to have the best prognosis.

Thus, it is tempting to speculate that what have beenclassified hithertofore by most pathologists as carcinomasof the ampulla of Vater, if true pancreatic neoplasms arerigorously excluded, arise from one of three epithelia,namely duodenal surface epithelium, pancreatic duct ep-ithelium from the duct of Wirsung or bile duct-like epi-thelium within the ampulla. Further it is suggested thatthe long- term survivors mostly have tumors arising fromthe latter type of epithelium. Additional work on a largerseries of cases will be necessary to establish this hypothesis,which would certainly have important implications in themanagement of these cases.

Acknowledgments

The authors thank Theodore Karrison for the statistical analysis, andBelinda Berry for secretarial assistance.

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