Gut, 1970, 11, 1029-1034

Acalculous adenomyomatosis of thegallbladder'

G. BEVAN2From the Department of Medicine, UCLA School of Medicine, Center for the Health Sciences,Los Angeles, California, USA

SUMMARY The course of acalculous adenomyomatosis of the gallbladder in six patients isdescribed. It is suggested that, even in the absence of gallstones, cholecystectomy should beadvised when this condition is demonstrated radiographically in symptomatic subjects. Thecause of the pain is unknown but it is probably related to excessive neuromuscular activity ofthe hyperplastic gallbladder wall.One of the patients was found also to have an adenomatous polyp containing areas of

adenocarcinoma. Although this polyp was not situated within an area of adenomyomatosis,it is possible that, as in most other patients with carcinoma of the gallbladder, previous diseasemay have predisposed to malignant change.

Adenomyomatosis is an uncommon abnormalityof the gallbladder characterized by hyperplasiaof the muscle layer and of the mucosa. Branchedtubular projections of the mucosa into the musclelayer, Rokitansky-Aschoff sinuses, produce ahistological appearance simulating gland and cystformation thus giving rise to the earlier name ofcholecystitis glandularis proliferans cystica (Kingand MacCallum, 1931). Aspects oftheanatomical,pathological, and radiological features of adeno-myomatosis have been reviewed on severaloccasions (King and MacCallum, 1931; Le Quesneand Ranger, 1957; Jutras, Longtin, and L6vesque,1960; Jutras and Levesque, 1966).The clinical significance and management of

this condition continue to provoke controversy.Because of the frequency with which some degreeof adenomyomatosis may be found in prospectivenecropsy surveys, as high as 7% in one report(Bricker and Halpert, 1963), it is clear that inmost instances the lesion does not produce symp-toms. The diagnosis is frequently made by theradiologist on the basis of finding a small dimpledfilling defect at the fundus of the gallbladder, oftenReceived for publication 17 June 1970.'This work was supported in part by USPHS grant no. GRSG05354.2Present address: Edgware General Hospital, Edgware,Middlesex.

accompanied by a kinking deformity of the body,or by a more generalized irregularity of the outlineof the gallbladder caused by contrast materialentering the Rokitansky-Aschoff sinuses. Gall-stones commonly coexist with these changes sothat biliary tract symptoms when they occur areusually ascribed to cholelithiasis with or withoutassociated inflammation. In the absence of gall-stones, however, many surgeons find it difficultto accept that symptoms may arise from simpleadenomyomatosis, especially if gallbladder func-tion appears normal radiologically, as it fre-quently does.

It is the purpose of the present report to em-phasize that acalculous adenomyomatosis can beassociated with symptoms which may be cbredby surgery. In addition, the unsuspected pres!enceof a carcinoma in one of these patients providesreason for caution in assuming that this conditionalways follows a benign course.

Case 1

M.E., a 36-year-old woman, had experiencedepisodes of postprandial right upper quadrantpain for 11 years. The pain was typical of

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biliary colic. It reached its maximum intensitysoon after onset, it was constant in character,radiated into the back between the shoulderblades, and was frequently accompaniedbynauseaand vomiting. There was no history of jaundice,fever, or change in colour of stools or urine. Shehad undergone radiological examination of thegallbladder, together with barium studies of thesmall and large intestines, on three occasions overthis period of time. They were all reported asnormal. For the previous year attacks of painhad increased in severity and frequency, becomingalmost a daily occurrence.

Fig. 1 Cholecystogram from patient 1 performed in1968. A filling defect is visible in the fundus (seealso Fig. 2).

Fig. 3 Photomicrograph ofa section of the gall-bladder removedfrom patient 1 showing the pro-liferation of the mucosal and mutscle layers withpseudoglandular formation (see also Figs. 4 and 5).

Fig. 2 Cholecystogram from patient 1 performed in1961.

Physical examination was unremarkable apartfrom slight right upper quadrant tenderness.Liver function tests were all within normal limits.A barium study of the oesophagus, stomach,small and large intestines revealed only a smallsliding hiatus hernia without demonstrable reflux.A cholecystogram (Fig. 1) showed normal con-centration of contrast material but the shape ofthe gallbladder was altered by a narrow area justproximal to the fundus. At the fundus there wasan umbilicated filling defect suggestive of anadenomyoma. No calculi could be seen. Followinga fatty meal there was normal contraction of the

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Acakculous adenomyomatosis ofthe gallbladder

gallbladder but the defect at the fundus remainedvisible.Review of previous cholecystograms performed

12, 11, and seven years earlier (Fig. 2) showedthat a similar filling defect at the fundus of thegallbladder had been present for the whole of thattime but on each occasion the gallbladder hadconcentrated the contrast material well and con-traction after a fatty meal was normal.A cholecystectomy was carried out. The serosal

surface of the gallbladder was normal as were theextrahepatic ducts. The lesion at the fundus wasfound to be an adenomyoma (Fig. 3). Charac-teristic changes of adenomyomatosis consistingof hyperplastic muscle bundles, areas of pro-liferating mucosa forming gland and cyst-likestructures, and a scattered chronic inflammatorycell infiltration extended around the macroscopiclesion for approximately 0.5 cm. The rest of thegallbladder wall was normal and there were nocalculi.

Following cholecystectomy, the patient lost allher symptoms. When seen a year later sheremained asymptomatic.

Case 2

L.P., a man aged 43 years, complained of rightupper quadrant pain for two years always inassociation with meals. The pain was sudden inonset, steady in intensity during its duration, butdid not radiate. There had been no episodes ofjaundice, fever, or change in colour of stools orurine. There was a past history of amoebicdysentery. Physical examination showed noabnormality, and liver function tests were allwithin normal limits. A cholecystogram showed

Fig. 4 Photomicrograph ofa section of the gall-bladder (patient 2).

a dumbbell-shaped gallbladder with multipleRokitansky-Aschoff sinuses filled with contrastmaterial adjacent to the gallbladder lumen. Nocalculi were visualized. After a fatty meal thegallbladder contracted normally.

Cholecystectomy was carried out. On micro-scopy the wall of the gallbladder showed thetypical changes of adenomyomatosis (Fig. 4).There were no calculi. Following cholecystectomythis patient lost all his symptoms. Fifteen monthsafter the operation he reported that there hadbeen no recurrence of his previous trouble.

Case 3

W.S., a man aged 54 years, complained of rightupper quadrant pain after meals over a period offour years. The pain was poorly described but itdid seem to be steady in intensity when presentalthough not radiating. The attacks of pain wereincreasing in severity and frequency, each episodelasting about one hour. There was no history ofjaundice, fever, dark urine, or pale stools. Thepatient was a diabetic. Physical examinationshowed no abnormalities. Liver function testswereall within normal limits. Cholecystogram showeda non-functioning gallbladder.

Cholecystectomy was carried out. The gall-bladder contained a small, firm, brown, ovoidmass, 1-5 cm in diameter, in the ampulla extendinginto the cystic duct. The gallbladder wall immedi-ately surrounding this mass was thickened to4 mm. The rest of the wall appeared normal. Onmicroscopy (Fig. 5), the ampullary mass was com-posedofafibromuscularstromaembedded inwhichwere glandular structure3 lined by columnar cells.The mucosal surface showed prominent papillary

Fig. 5 Photomicrograph ofa section of the gall-bladder (patient 3).

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formations, and numerous Aschoff-Rokitanskysinuses were present in the surrounding gall-bladder wall. The appearances were those ofadenomyomatosis. After operation this patientwas free of symptoms during a follow-up periodof five years.

Case 4

B.W., a woman aged 69 years, had a 15-year his-tory of attacks of vague upper abdominal painusually occurring after meals without jaundice,episodes of fever, dark urine, or pale stools.Cholecystograms on numerous occasions hadshown a filling defect in the gallbladder fundusbut there had been good concentration and thecontraction of the gallbladder after fatty mealsappeared normal. No calculi had been seen. Agastric resection had been performed for a duo-denal ulcer 40 years before.

Physical examination showed no abnormality.

Liver function tests were all within normal limits.Cholecystectomy was carried out. The gallbladderwas found to contain a small button of tissue atthe fundus of the gallbladder which on sectionproved to be an adenomyoma (Fig. 6). At thejunction of the neck and the body there was apedunculated polypoid mass 2.2 cm in diameter(Fig. 7), which on section (Fig. 8) consisted of anelaborate series of compact tubular and glandularstructures. The cuboidal epithelium lining theglands was generally uniform with regular basalnuclei but in some areas there was crowding ofcells with disruption of the basement membrane.Many glands were apposed 'back to back' withoutintervening stroma. Ball-like syncytial clusters ofspindle-shaped cells with occasional mitosescould also be seen. Morphologically the processwas that of a low-grade adenocarcinoma arisingin a polypoid adenoma. Serial sections of the baseof attachment showed no evidence of invasion.

Following the cholecystectomy, the patientbecame symptom-free and four years later showedno evidence of malignant disease.

Fig. 6

Fig. 8

Fig. 6 Photomicrograph ofa section through thearea ofadenomyomatosis in patient 4.

Fig. 7 Low-power view ofa section through theadenoma from patient 4.

Fig. 8 Photomicrograph of the adenoma shown inFig. 7 demonstrating changes ofadenocarcinoma.Fig. 7

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Acalculous adenomyomatosis of the gallbladder

Case 5

B.R., a woman aged 47 years, had a 20-yearhistory of postprandial epigastric discomfort,particularly after drinking milk. Radiologicalinvestigation on several occasions had revealeda small hiatus hernia. A cholecystogram hadshown a probable adenomyoma at the fundus ofthe gallbladder with multiple Rokitansky-Aschoffsinuses. A severe and sudden attack of epigastricpain radiating into the right upper quadrant andof constant intensity accompanied by nausea andvomiting precipitated admission to hospital.

Physical examination on admission revealedonly right upper quadrant tenderness. There wasno fever and liver function tests were all withinnormal limits.A cholangiogram showed prompt visualization

of the gallbladder and common bile duct. Thecontour of the fundus was irregular and, again,contrast-filled Rokitansky-Aschoff sinuses couldbe seen projecting beyond the lumen. Followinga fatty meal the gallbladder contracted normally.No calculi were seen.

Cholecystectomy was carried out. The grossspecimen showed a smooth serosal surface withno adhesions. No calculi were present. There wasa small, button-like thickening, 0.5cm in diameter,at the fundus of the gallbladder, which on sectionproved to be a typical adenomyoma.

After cholecystectomy this patient lost all hersymptoms. She was followed up for four years.

Case 6

J.K., a woman aged 46, had experienced severalattacks of epigastric and substernal pain over atwo-year period, occurring usually after meals.The pain was constant when present, lasting twoto three hours at a time, but not radiating. Therehad been no episodes ofjaundice, fever, or changein colour of stools or urine.

Physical examination revealed tenderness in theright upper quadrant only. There was no feverand liver function tests were all within normallimits. Oral cholecystography demonstrated amarginal irregularity consisting of Rokitansky-Aschoff sinuses without evidence of calculi.Following a fatty meal there was complete empty-ing of the gallbladder.

Cholecystectomy was carried out. Microscopicsection of the wall of the gallbladder showed thecharacteristic appearances of adenomyomatosiswith a localized condensation at the fundus.

Following cholecystectomy, the patient lost allher symptoms. She was followed up for sevenyears.

Comments

The response to cholecystectomy shown by these

patients suggests that the adenomyomatosis wasthe cause of symptoms in each case. The absenceof cholelithiasis and of inflammatory changesmake them unlikely sources of pain although itis possible that these factors were operative at anearlier stage in the disease process.

It is noteworthy that symptoms had been presentin this group of patients for 11, 2, 4, 15, 20, and2 years respectively. Each patient had undergoneradiological investigation of the whole gastro-intestinal tract on more than one occasion inaddition to several cholecystograms. In allinstances the absence of gallstones and the abilityof the gallbladder to concentrate and excrete dyeadequately had delayed surgical treatment. It isnot uncommon for such patients to undergorepeated investigation in an attempt to find analternative explanation for the pain which mayfinally come to be regarded as functional inorigin.On the basis of observations on the courses of

thepatients in the current report, it isrecommendedthat when symptoms suggestive of biliary tractdisease occur in association with the cholecysto-graphic appearances of acalculous adenomyo-matosis, cholecystectomy should be advised ifthere is no other obvious cause for the symptoms.When the condition is discovered incidentally,in the absence of definite symptoms, the problembecomes similar to that of the silent gallstone.Whether or not surgical treatment is advised willthen depend upon such factors as the age of thepatient, the coexistence of other diseases, and theready accessibility of medical care should com-plications arise.The mechanism by which pain is produced is

not entirely clear. It is presumably related togallbladder contraction since patients oftencomment that their symptoms were reproducedduring cholecystography following ingestion ofthe fatty meal. Jutras and Levesque (1966) havemade the observation that films taken when painis experienced show overdistension of the cysticand common bile ducts. They believe that painis produced by excessive neuromuscular activityof the hyperplastic gallbladder wall resulting invigorous contraction and distension of the ducts.In support of this contention it is commonlyobserved that, following a fatty meal, contractionof the gallbladder takes place earlier than usual,frequently within five minutes, and also that itappears to contract to a smaller size than usual.

It has been suggested that excessive motilitymay be related to a proliferation of subepithelialneural elements accompanying the mucosal andmuscular hyperplasia. This type of superficialneuromatosis was first described in conjunctionwith cholesterolosis of the gallbladder (Riopelle,1942) but it has also been demonstrated in adeno-myomatosis (Jutras et al, 1960). Others havedenied the importance of this appearance whichthey attribute to a condensation rather than aproliferation of nerve fibres (Lubera, Climie,and Kling, 1967).

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The presence of a carcinoma in patient 4 againraises the possibility that adenomyomatosis maypredispose to malignant change. Previous dis-cussions of this topic have been obscured bymisinterpretation of the histological features ofadenomyomatosis and by differences in termin-ology. Sutherland (1898) first used the termadenomyoma for the localized form of thecondition. Since that time other writers havereferred to the same lesion as an adenoma or anadenofibroma or an epitheliomyoma. All theseterms are misleading because they imply, quitefalsely, that the tissue changes are neoplastic inorigin. The Rokitansky-Aschoff sinuses are nottrue glands so that the appellation cholecystitisglandularis proliferans is equally unsuitable.

Malignant degeneration within an area ofadenomyomatosis has not been described.Because of the extension of the Rokitansky-Aschoff sinuses into the muscle layer the lesionmay resemble invasion by adenocarcinoma. Themicroscopic picture may also be confusingbecause of the different planes in which the cellsmay be cut. These factors almost certainly accountfor the occasional impression of malignantchange, as in the case reported by Eiserth (1938).True adenomatous polyps, like the one removedfrom patient 4 in the present series, are rare.This lesion has been considered to be precancerousby some authors (Wellbrock, 1934; Kane, Brown,and Hoerr, 1952; Tabah and McNeer, 1953;Ochsner and Carrera, 1956) whilst others havemaintained that such polyps are always benign(Phillips, 1933; Shepard, Walters, and Dockerty,1942; Eelkema, Hodgson, and Stauffer, 1962).This difference in opinion reflects the generaldifficulty in defining malignant change in adeno-matous polyps arising from all mucosal surfaces.The adenoma in the patient in the present seriesshowed many features, described in the casereport, which warranted a diagnosis of adeno-carcinoma.

It is likely that the tumour was a coincidentalfinding. Nevertheless, carcinoma usually arisesin an abnormally functioning gallbladder, mostcommonly in association with gallstones. Itremains possible, therefore, that the disturbancein physiological function resulting from the adeno-myomatosis may also have contributed to analteration in cell growth within the adenoma.

References

Bricker, D. L., and Halpert, B. (1963). Adenomyoma of the gall-bladder. Surgery, 53, 615-620.

Eelkema, H. H., Hodgson, J. R., and Stauffer, M. H. (1962).Fifteen-year follow-up of polypoid lesions of the gallbladder diagnosed by cholecystography. Gastroenterology,42,144-147.

Eiserth, P. (1938). Adenomyome der Gallenblase. Virchows Arch.path. Anat., 302, 717-723.

Jutras,J. A., and Lkvesque, H. P. (1966). Adenomyoma andadeno-myomatosis of the gallbladder. Radiol. Clin. N. Amer.,4,483-500.

Jutras, J. A., Longtin, M., and L6vesque, H. P. (1960). Hyper-plastic cholecystoses. Amer. J. Roentgenol., 83, 795-827.

Kane, C. F., Brown, C. H., and Hoerr, S. 0. (1952). Papilloma ofthe gallbladder; report of eight cases. Amer. J. Surg., 83,161-164.

King, E. S. J., and MacCallum, P. (1931). Cholecystitis glandularisproliferans (cystica). Brit. J. Surg., 19, 310-323.

LeQuesne, L. P., and Ranger, I. (1957).Cholecystitis glandularisproliferans. Brit. J. Surg., 44, 447-458.

Lubera, R. J., Climie, A. R. W., and Kling, G. E. (1967). Chole-cystitis and the hyperplastic cholecystoses: A clinical,radiologic and pathology study. Amer. J. dig. Dis., 12,696-704.

Ochsner, S., and Carrera, G. M. (1956). Benign tumors of thegall bladder. Gastroenterology, 31, 266-273.

Phillips, J. R. (1933). Papilloma of the gallbladder. Amer. J. Surg.,21,38-42.

Riopelle, J. L. (1942). Sur les proliferations nerveuses de Ia vesiculebiliaire (neuromatoses vesiculaires). J. Hotel-Dieu Montrdal,11,3-76.

Sutherland, L. R. (1898). Small adeno-myoma of the gall-bladder.Glasg. med. J., 50, 216-217.

Shepard, V. D., Walters, W., and Dockerty, M. B. (1942). Benignneoplasms of the gallbladder. Arch. Surg., 45, 1-18.

Tabah, E. J., and McNeer, G. (1953). Papilloma of the gallbladderwith in situ carcinoma. Surgery, 34, 57-71.

Wellbrock, W. L. A. (1934). The occurrence and possible signi-ficance of adenoma of the gallbladder. Amer. J. Surg., 23,358-360.

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