Naples, Italy

Stepwise approach and surgery for gallbladder adenomyomatosis: a mini-review

Gianluca Pellino, Guido Sciaudone, Giuseppe Candilio, Giuseppe Perna, Antonio Santoriello, Silvestro Canonico and Francesco Selvaggi

Naples, Italy

BACKGROUND:Gallbladder adenomyomatosis (GBA) is a hyperplastic disease affecting the wall of the gallbladder, with some typical features. It has historically been considered a benign condition, nevertheless recent reports highlighted a potential role of GBA in predisposing to malignancies of the gallbladder.

DATA SOURCES:We reviewed the literature concerning GBA from its identif i cation until July 2012. Owing to the relative rarity of the disease, studies often are case reports or case series. Thus we herein report a summary of the key-points concerning diagnosis and treatment of GBA, easily applicable in everyday practice, rather than a systematic review. Also, results are integrated with our recent experience.

RESULTS:In our experience, we observed a trend toward an increase of GBA during the last years, probably due to enhanced ultrasonographic technical advancements and physician's expertise. GBA has distinctive imaging features. Several recent reports highlight the potential risk of cancer associated with GBA; however the disease is still classif i ed as a benign condition. Although its correlation with malignancy has not been demonstrated, it is prudent to recommend cholecystectomy in some cases. However, in selected asymptomatic patients, a waitand-see policy is a viable alternative. We propose an algorithm, based on GBA pathological pattern (diffuse, segmental, localized or fundal), suitable for decision-making.

CONCLUSIONS:In symptomatic patients and if the diagnosis is doubtful, cholecystectomy is mandatory. Postponing surgery is an option to be offered to asymptomatic patients with lowrisk GBA pattern who adhere to scheduled follow-ups.

(Hepatobiliary Pancreat Dis Int 2013;12:136-142)

gallbladder adenomyomatosis;gallbladder carcinoma; cholecystectomy; ultrasonography

Introduction

Gallbladder adenomyomatosis (GBA) is found in up to 5% of cholecystectomy specimens.[1]It is considered a benign condition, but several reports suggested that it can be associated with higher risk of developing gallbladder malignancies.[2,3]The present study aims to report the key-points concerning GBA in order to def i ne an algorithm suitable for its management. This study is not intended to be a systematic review, hence all available case reports and case series were not included in authors' intention; they were all reviewed for important content, but included selectively.

Def i nition and burden of disease

Debate existed over def i nition of GBA until 1960, when Jutras[4]identif i ed several clinical-pathological conditions (cholecystitis glandularis proliferans, adenomyoma, cystic cholecystitis, adenof i bromyoma, intramural diverticulosis, hamartoma, diverticular disease of the gallbladder, hyperplastic adenomyosis) as being ascribable to the same disease, namely GBA, "degenerative and proliferative disease of the gallbladder".[4,5]GBA was subsequently better def i ned as a benign hyperplastic lesion characterized by excessiveproliferation of surface epithelium with invagination into the thickened muscular layer or deeper, leading to wall thickening and intramural diverticulosis, known as Rokitansky-Aschoff sinuses (RASs).[6,7]Three pathological patterns are described: diffuse; segmental, which has annular distribution; and localized or fundal, also known as adenomyoma, which is typically localized at the fundus.[8]

Most patients are diagnosed with GBA in their 50s and 60s, while only a few cases of GBA in young patients have been reported, and the rate of incidence determined on the basis of cholecystectomy specimens was 2.8%-5%.[1,8-13]Although GBA incidence has been reported to reduce from 49% (reports before 2000) to 24.5% (reports published between 2006 and 2011) and 6.1% in most recent series, we hypothesize that it could nevertheless show a trend toward an increased preoperative diagnosis (see our recent experience) due to variability found in available series. GBA is being diagnosed more frequently in asymptomatic patients and incidentally because of the advancements in ultrasonography (US) and its extensive application.[1]

Pathogenic and pathological considerations

The pathogenesis of GBA is unknown. However, it is unlikely to be a congenital malformation. It is widely accepted to be a degenerative disease, consisting of gallbladder wall epithelial cell proliferation and smooth muscle hyperplasia, presumably in response to primary increased intrafundal pressure or to excessive mural absorption of bile.[11]This result in invaginations of epithelium creating intramural diverticula known as RASs, which are responsible for the imaging fi ndings.[14]In 25%-75% of cases it occurs with coexisting calcolosis, especially in segmental GBA, while coexisting cholesterolosis, consisting of deposition of triglycerides and cholesterol esters within the lamina propria ("strawberry gallbladder"), is found in 33% of cases.[8,12]In their report on 113 patients found to have histologically diagnosed GBA, Kim et al[15]found that patients with diffuse/segmental GBA were more likely to have gallstones than those with fundal GBA; also, fundal GBA was associated with lower inf l ammation grade. The authors concluded that pathogenesis may be different, with RASs resulting from acquired motility.

Diagnosis

Most patients are asymptomatic or paucisymptomatic. The most common symptom is unspecif i c abdominal pain, often localized at the upper right quadrant and epigastrium. The pain is similar to that of gallstone, and it is typically self-limiting.[16,17]Nausea, dyspepsia, intolerance to fatty foods are also noted in GBA patients; however GBA is often diagnosed incidentally or during autopsy.[8,18,19]It has been suggested that patients with diffuse/segmental GBA may have a higher incidence of gallstones and higher inf l ammation grade, which could result in different pattern of presentation.[15]

Laboratory tests are often normal, and no serological marker is available to detect GBA. These can be altered owing to coexisting gallstones, cholecystitis or coledocolithiasis (leukocytosis, elevated transaminases and conjugated bilirubin); in such an event, they are often accompanied by symptoms and signs (fever, pain, jaundice).

US

US is the fi rst-line investigation to evaluate gallbladder diseases. GBA appears as diffuse or segmental thickening of the gallbladder wall. The different patterns of GBA result in dissimilar, peculiar US appearance: segmental GBA may present with segmental wall thickening, which can sometimes give an "hourglass" appearance to the gallbladder body; localized GBA presents as a single polyp-like thickening often found at the fundus; diffuse GBA presents as diffuse wall thickening. Some very specif i c US signs have been described consisting of anechoic intramural diverticula with or without "comet-tail" artefact.[14,20]RAS can appear as echo-poor intramural cystic structures, becoming echogenic if they contain sludge.[14]RAS are also reported to produce distal sonographic shadowing or ring-down ("comet-tail") artefacts.[1,7,11,20]Such ring-down can be due to small highly ref l ective objections (surgical clips, microcalcif i cations, cholesterol crystals), and manifests as multiple ref l ections between the anterior and posterior wall, in thin parallel echogenic bands, very close to each other, decreasing in width. Come-tail artefact in GBA has been proposed to result from reverberation between the near and far surfaces of the sinuses themselves, closely adjacent to intrasinus papillary projections or contained cholesterol crystals.[1,14]Reverberation artefacts due to cholesterol crystals are V-shaped and smaller than gas artefacts. Several conditions may also cause comet-tail artefacts, namely emphysematous cholecystitis, cholesteatosis, microlithiasis and aerocysts. These can be distinguished from GBA by means of some other variables. Size is increased only in emphysematous cholecystitis, and in GBA gallbladder may also be smaller. Shape is round in emphysematous cholecystitis,while GBA may cause alteration depending on its localization (i.e. hourglass appearance in segmental GBA). The lumen of the gallbladder contains sediment in emphysematous cholecystitis, while stones <5 mm in microlithiasis may appear as sludge; in GBA the lumen is often narrowed. The wall shows hypoechoic thickening in emphysematous cholecystitis, it can be mildly thickened in cholesteatosis, while in GBA the wall is thickened with cystic inclusions. Finally, comettail artefact is due to intramural or endoluminal gas in emphysematous cholecystitis. It is scattered intramural or diffuse in cholesteatosis, fl oating inside the lumen in microlithiasis. It is due to gas on the anterior wall varying with decubitus in aerocysts, while it is localized intramural or diffuse in GBA.

Gallbladder carcinoma is often responsible for wall thickening, which is often irregular. Thus irregular intraluminal lesions and invasion of surrounding tissues can be determined. However, distinguishing between gallbladder carcinoma and benign conditions such as GBA may be diff i cult. Concerning focal GBA, Konstantinidis et al[20]in their retrospective report on over 59 000 US exams and over 9000 cholecystectomies found 213 questionably neoplasms at US (32 GBA), and identif i ed several US features suspicious of a malignant lesion. The features consisted of US size >9 mm, age >52 years, US suggestion of invasion at the liver interface, and wall thickening >5 mm, especially in the presence of gallstones. They also found that an US size of ≤9 mm had a negative predictive value of 100% for malignancy.

US has several limitations. It is operator-dependent, it does not allow panoramic view, and it may cause artifacts with gas and/or fat and coexisting gallstones. Furthermore, if diverticula are not seen, differential diagnosis with other diseases causing wall thickening is diff i cult.[7]US is reported to have an accuracy as high as 66% in diagnosing GBA, which is quite low when compared with CT (75%) and MRI (93%).[1]However its role in managing GBA is important, as it is a noninvasive examination and easily performed. These characteristics make US the ideal tool for the follow-up of GBA patients. Moreover, the recent advances in US techniques will probably increase the accuracy of the method.

Endoscopic US (EUS)

EUS is reported to be the procedure of choice for gallbladder disease, with a sensitivity as high as 97%,[21]although some investigators recently reported a lower sensitivity of 84%, but an excellent specif i city of 100%.[22]Akatsu et al[23]reported that localized, polyplike GBA shows specif i c EUS features, namely multiple microcysts, in 100% of GBA patients; half of the patients were found with calcif i cation, and half showed a heterogeneously hyperechoic internal echoic pattern. Recently Kim et al[22]conf i rmed the usefulness of EUS in the differential diagnosis of gallbladder wall thickening. However, they suggested that some variables could be used to increase the detection rate of malignancies. EUS brings about some limitations. By evaluating 134 consecutive patients with gallbladder wall thickening, Kim et al[22]failed to demonstrate a signif i cant difference between EUS and CT in terms of sensitivity, specif i city, positive and negative predictive value, and accuracy, although the former modality seemed to achieve better results. Moreover, EUS is an expensive procedure, requiring dedicated devices and expertise. Also, it is an invasive examination, requiring sedation in some patients. Hence, albeit it is very useful in the diagnosis and differentiation of gallbladder thickening, it cannot be advocated as a routine examination for the follow-up of patients not meeting surgical criteria.

Other imaging modalities

Though complex work-ups with multimodality evaluation are not commonly required for diagnosis, a diagnostic doubt, gallbladder wall thickening or multiple intramural cystic components and the suspicion of malignancies warrant further imaging investigations.[7]Optimal CT evaluation of the gallbladder which requires administration of intravenous contrast CT scan in GBA may show wall thickening and enhancement, which are unspecif i c fi ndings, and RAS is large enough to be visualized. Also, enhancing epithelium within diverticula in the context of an unenhanced gallbladder muscularis may generate the "rosary sign".[1,24]Asymmetric thickening and intraluminal protrusion are common.[25]RAS can also be observed at MRI scan as are hyperintense on T2-weighted images, hypointense on T1-weighted images, and nonenhancing intramural lesions.[25]If intramural diverticula are patent and of suff i cient size, these could be opacif i ed by intraluminal contrast at MRCP. Multiple round-shaped hyperintense intraluminal cavities may be visualized at T2-weighted MRI and MRCP resulting in the so-called "pearl necklace sign", which is typical of GBA.[7,25]These features are specif i c of GBA, and usually allow diagnosis. Nevertheless, it is not always possible to diagnose GBA with certainty even after CT, MRI and MRCP, as only nonspecif i c fi ndings may be observed, such as gallbladder thickening and enhancement. These are often found in other benign gallbladder conditions, such as polyposis, papillomatosis, adenoma, and cystadenoma, as well as malignancies such as gallbladder adenocarcinoma, cholangiocarcinoma, hepatocellularcarcinoma, and metastatic cancer. Hence, some investigators suggested that functional imaging with18FDG-PET may be of help for radiologic differential diagnosis, particularly for focal GBA.[26,27]The value of this observation should be counterbalanced with some limitations of PET and PET-TC evaluation, as there is no agreement on its role in detecting gallbladder carcinoma, and no comprehensive study has yet been reported. Moreover, GBA is thought by some authors to cause false positive fi ndings on PET or PET-TC,[28]similarly to other benign condition associated with hot gallbladder on PET,[29-31]which may result in an improper clinical decision and unnecessary surgery. Suzuki et al[27]suggested another reason to advocate PET scan in case of GBA, as they found it is useful in detecting a coexisting gallbladder carcinoma. So far, it is diff i cult to def i ne the role of PET in distinguishing GBA from malignancies, though better results are likely to be obtained as long as PET sensitivity can be improved by means of newer PET scan image acquisition modalities.[32]As a matter of fact, PET scan has an important role in detecting distant localization of disease (metastases) which are associated with malignancy and poor prognosis.

GDA and cancer: myth or truth?

The pathogenesis of gallbladder and biliary tract carcinoma is thought to be the result of an evolutionary sequence from metaplasia to dysplasia to carcinoma. Metaplasia tends to occur in a setting of inf l ammation and chronic injury and to be associated with dysplasia or carcinoma.[33,34]Several underlying diseases have been examined which could potentially predispose to biliary tract cancer, including pancreaticobiliary maljunction,[35]primary sclerosing cholangitis,[36,37]chronic cholecystitis,[38]gallstones,[38,39]and adenomyomatosis.[2]It has been hypothesized that chronic inf l ammation could result in pathological changes of the biliary epithelium.

Actually, there is consensus regarding the existence of two models, through which the malignant transformation is produced in gallbladder cancer: dysplasia-carcinoma sequence[40-42]and adenomacarcinoma sequence.[43-45]Experimental and clinical evidence support both models, although they probably correspond to distinct biological pathways. Recently, Roa et al[46]questioned the role of adenoma in predisposing to gallbladder cancer, suggesting that only dysplasia could have a certain malignant potential, as areas of dysplasia/carcinomain situare often found next to gallbladder cancer, concluding that gallbladder cancer represents a singular model in human carcinogenesis. Two types of gallbladder carcinoma can be distinguished in broad terms, a protuberant type and a wall thickness type; the former case distinguishing between benign and malignant tumor is easier, and it is mainly based on the size of the lesion (>10 mm raise suspicion of carcinoma).[20,47,48]Sessility, blood fl ow and fast growth are also predictors of malignity.[19,20,49]Conversely, distinguishing between benign lesions such as GBA and cancers is very diff i cult in case of wall thickening.

GBA has been historically considered a benign condition, included in gallbladder pseudotumors.[50]However, a growing body of evidence has been pointing out a potential role for GBA in carcinogenesis during the last years. Aldridge at al[16]described several cases of GBA complicated by gallbladder malignancies. A correlation between segmental GBA and gallbladder carcinoma was hypothesized by Ootani et al in 1992[51]in a retrospective study on 3197 consecutive patients. Nabatame et al[2]conf i rmed this observation by examining 4560 gallbladders resected for gallbladder cancer, gallstones, or other diseases. The incidence of gallbladder carcinoma was higher in patients with segmental adenomyomatosis (22/334, 6.6%) than in those without (181/4226, 4.3%), and the difference was more marked in patients over 60 years of age. It has also been proposed that a peculiar anatomical alteration, namely anomalous pancreaticobiliary ductal union could be associated both with GBA and gallbladder carcinoma, as if these entities could be interconnected,[3,52]but this hypothesis has to be proved. A well-differentiated gallbladder carcinoma with mucin production can have cystic components that may mimic adenomyomatosis.[53]An association between a dysplastic adenoma and diffuse GBA has also been described.[54]Actually, available data do not allow to draw def i nitive conclusions.

Our recent experience

As an exemplif i cation, we gathered data of patients undergoing US and cholecystectomy in our unit between 2007 and 2012: patients who did not undergo US in our unit, those with negative US exams, those who were not operated on in our unit or refused surgery, and those whose specimens were not examined in our center were ruled out from evaluation. One hundred and four patients were found who fulf i lled criteria and were included in our report. Surgical and pathological data were matched with preoperative US fi ndings. GBA was found in 10 (9.6%) patients at US, of which 7 with diffuse/segmental type and 3 with fundal localization. Although four patients had coexisting cholelithiasis and one had cholecystitis between GBA patients, pathologicalexamination of specimens conf i rmed US fi ndings in 100% of cases. However, gallbladder adenocarcinoma was found during pathological examination of the specimen in one patient with segmental GBA which was not suspected preoperatively. Between patients without GBA, one was preoperatively diagnosed with gallbladder carcinoma, conf i rmed on pathological examination of specimen. Our data suggested an incidence of GBA higher than usually reported; also, in experienced hands, we found US is effective in diagnosing GBA, also in complicated cases. Nevertheless, a carcinoma complicating GBA was missed during US.

How to manage GBA

In the light of our fi ndings and taking into account data obtained from the literature, we propose the following algorithm for the management of GBA (Fig.). First of all, symptomatic patients should undergo surgery. In asymptomatic patients, it is our opinion that GBA pattern should be put into decision-making. We would recommend cholecystectomy to all patients with segmental or diffuse GBA, given the unpredictability of the disease and the presumed diff i cult visualization of coexisting malignancies. Conversely, we would deal with patients presenting with fundal GBA in the same way as with those presenting with gallbladder polypoid lesions,[47,50]thus opting for a wait-and-see careful US follow-up. A conservative approach in patients with GBA with an unlikely cancerous evolution and with distinguishable features is a novel concept, and could be suited to avoid surgery in selected patients. Such approach should include surgery on the basis of lesion size and growth rapidity, provided US is performed by experienced physician and the patient is compliant with follow-ups.

Fig.Proposed algorithm for the management of GBA according to morphological subtype.

Conclusions

Incidence of GBA is likely to remain stable with time or increase (5%-10%), due to enhanced technology and expertise in US and EUS imaging. Therefore, an easy, repeatable management algorithm could be of use to deal with GBA in everyday practice. Selected patients could benef i t from a conservative approach. A better comprehension of the disease is crucial to obtain the ideal, def i nitive treatment of GBA.

Contributors:CS proposed the study. PGia performed research and wrote the fi rst draft under supervision of CS and SF. SG, CG, PGiu and SA collected and analyzed the data. All authors contributed to the design and interpretation of the study and to further drafts. SF is the guarantor.

Funding:None.

Ethical approval:Not needed.

Competing interest:No benef i ts in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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Received September 22, 2012

Accepted after revision November 21, 2012

AuthorAff i liations:Unit of General and Geriatric Surgery, School of Medicine, Second University of Naples, Piazza Miraglia 2, 80138, Naples, Italy (Pellino G, Sciaudone G, Candilio G, Perna G, Santoriello A, Canonico S and Selvaggi F)

Francesco Selvaggi, MD, Associate Professor of Surgery, Unit of General and Geriatric Surgery, School of Medicine, Second University of Naples, Piazza Miraglia 2, 80138, Naples, Italy (Tel: 0039-3358419132; Email: fselvaggi@hotmail.com)

This study was presented by Professor Silvestro Canonico as a short oral communication concerning the topic at the 3rd edition of the "Miniinvasive Surgery Congress" held in Naples on 23-24 March 2012.

? 2013, Hepatobiliary Pancreat Dis Int. All rights reserved.

10.1016/S1499-3872(13)60022-3