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Journal of Surgical Oncology 2006;93:650–664

Application of Modern Imaging Methods in Diagnosisof Gallbladder Cancer

ANTONIO RODRIGUEZ-FERNANDEZ, PhD, MD,1* MANUEL GOMEZ-RIO,1 ANTONIO MEDINA-BENITEZ,2

JESUS VILLAR-DEL MORAL,3 CARLOS RAMOS-FONT,1 JOSE MANUEL RAMIA-ANGEL,3

JOSE MANUEL LLAMAS-ELVIRA,1 JOSE ANTONIO FERRON-ORIHUELA,3

AND PABLO LARDELLI-CLARET41Department of Nuclear Medicine, ‘‘Virgen de las Nieves’’ University Hospital, Granada, Spain

2Department of Radiology, ‘‘Virgen de las Nieves’’ University Hospital, Granada, Spain3Department of Surgery, ‘‘Virgen de las Nieves’’ University Hospital, Granada, Spain4Department of Preventive Medicine and Public Health, University of Granada, Spain

The poor prognosis of gallbladder cancer (GBC) is related to its disseminationcapacity and usually late diagnosis due to its non-specific clinical appearance. Recentimprovements in hepatobiliary surgery have underlined the importance of an earlyspecific diagnosis, which requires a multidisciplinary approach and, when possible,specialized equipment. The first step in an early diagnosis is to identify patients in theappropriate epidemiological setting (e.g., incidental finding, chronic cholecystitis) forthe correct interpretation of test results. It is desirable to enhance the sensitivity of theinitial ultrasound (US) examination by use of the appropriate technology in skilledspecialist hands. When GBC is suggested by US findings, FDG-PET can be consideredcomplementary to establish the benign/malignant nature of the lesion and to obtain aprimary staging study. If GBC is confirmed, thin slice spiral CT can contributevaluable information on local spread. In this regard, recent hybrid PET-CT systemsprovide structural and functional information simultaneously and may offer early andaccurate T, N, and M staging with an improved specificity.J. Surg. Oncol. 2006;93:650–664. � 2006 Wiley-Liss, Inc.

KEY WORDS: gallbladder cancer; positron emission tomography; FDG-PET;imaging methods

INTRODUCTION

Gallbladder carcinoma (GBC) has had a sinister repu-tation since its first description by De Stoll in two autopsycases in 778 [1]. This pessimism has derived from theoutcomes of its treatment, leading Blalock [2] to arguein—1924 against surgery for this entity, an attitude thatpersists to this day. Its poor prognosis largely depends on(a) its facility for local invasion of the liver and dissemi-nation of lymph node and hematogenous metastasesand its great capacity to implant peritoneal surfaces,laparotomy or laparoscopy wounds, and biopsy trajec-tories [1–3]; and (b) its late diagnosis, due to the non-specific nature of its symptoms and signs, sometimes onlypresent in advanced disease and common to other dis-eases such as cholelitiasis or chronic cholecystitis [3].Nevertheless, a better understanding of its biologicalbehavior, improvements in preoperative diagnosis and inthe staging of the disease, and advances in hepatic

surgery have allowed an increased role for surgeryin selected cases [3]. This has translated into a smallincrease in long-term survival indices in recently studiedseries [4–8].Despite being a relatively uncommon tumor, GBC is

the fifth most frequent tumor of the digestive systemand the most frequent of those arising in the biliary tree.Its incidence varies widely according to geographicalregion and race, with Chileans showing the highest rates(12/100.000), followed by Northern Europeans, NorthAmerican Indians, Indians, and Jews, with lower rates

*Correspondence to: Antonio Rodrıguez-Fernandez, PhD, MD, NuclearMedicine Department, Virgen de las Nieves University Hospital, Resi-dence: Avda/Fuerzas Armadas, 2 18014 Granada, Spain. Fax:þ34 958 020579. E-mail: [email protected]

DOI 10.1002/jso.20533

Published online in Wiley InterScience (www.interscience.wiley.com).

� 2006 Wiley-Liss, Inc.

among Africans, Afro-Americans, and SouthernEuropeans [1,3,9]. Its incidence increases with higherage, peaking in the seventh decade of life [1,3]. It is morecommon in women, with a female/male ratio of 4:1.Familial grouping has been detected, probably reflectinghereditary and environmental factors [10].

The most important risk factor for GBC is the pre-sence of cholelithiasis, with an incidence of 0.3–3%among gallstone carriers. The risk is highest in patientswith a history of some years of biliary pain, when there isassociated chronic cholecystitis, with a predisposition tomalignization of the biliary epithelium due to chronicinflammatory stimulus. A similar mechanism would alsoexplain the increased incidence of GBC in patients withporcelain gallbladder (incidence of 10–25%), salmonellacarriers, and patients with anomalous union of pancreaticand biliary ducts favoring reflux of pancreatic juices tothe biliary tree [1,3,11].

GBC usually manifests in one of the three followingsituations:

1. Advanced inoperable cancer; the most commonsituation [1,3].

2. Detection of lesion that occupies space in the vesicularwall leading to suspicion of neoplasm, resectable afterextension study [7].

3. Incidental histopathologic finding of GBC aftercholecystectomy for benign disease, the most com-mon presentation in published surgical series[4,8,14,15]. GBC has been reported as an incidentalfinding in 1–3% of laparoscopic cholecystectomies[1,15].

The symptoms of GBC are identical to those of themore prevalent gallstone disease, hampering the pre-operative diagnosis. It should be suspected in patientsover 60 years of age with moderate and constant pain inthe right hypochondrium associated with recent, weightloss. Anorexia and jaundice are indicative of advanceddisease. In the series recently published by Hawkins et al.[16], 34% of the patients presented with jaundice; only7% of these could undergo curative surgery and nonesurvived at two years. Presence of palpable mass in righthypochondrium is also a sign of advanced disease and oflimited resection possibilities [1].

There are no specific biochemical alterations of utilityfor an early diagnosis. Cholestasis and hyperbilirubine-mia are signs of advanced disease. A CEA of >4 ng/mldiagnoses GBC in clinically compatible cases withsensitivity of 50% and specificity of 93% [1]. CA 19-9also offers poor results; a value of >20 IU/ml indicatesGBC with a sensitivity and specificity of 79%, althoughthe specificity is considerably reduced in patients withjaundice [1].

PATHOLOGICAL ASPECTS WITHDIAGNOSTIC AND THERAPEUTIC

IMPLICATIONS STAGING

The different staging systems used have been a sourceof confusion in the assessment of surgical outcomes. TheTNM system is the most widely used and recommendedsystem [13] and was recently modified by the Interna-tional Union against Cancer (UICC), excluding thecentimeters of infiltration of the hepatic parenchyma(which had differentiated between pT3 and pT4) [13].Any therapeutic decision in GBC must be based on itscorrect staging, based on knowledge of the involvementof different layers of the vesicular wall (mucosa, muscle,subserosa, and serosa), infiltration of the liver and/orother neighboring organs, and lymph node and distantdissemination [3].

The invasion by GBC of neighboring organs is favoredby the absence of a submucosal layer and the presence ofa single muscle layer. Furthermore, the perimuscularconnective tissue of the gallbladder is continuous withthe interlobular connective tissue of the liver, allowingthe tumor to spread along portal ducts to the interior ofthe liver [17,18]. For these reasons, tumors of the gall-bladder body and gallbladder fundus frequently infiltratethe hepatic parenchyma. Tumors of the infundibulumoften involve the cystic duct and can infiltrate the neigh-boring common hepatic duct, right hepatic artery, andright portal vein [1].

Moreover, once the tumor has involved the vesicularmuscle layer it has access to lymph ducts and veins,favoring its dissemination, which is more frequent withgreater parietal involvement of the organ. This situationcalls for hepatic resection and simultaneous regionallymphadenectomy during curative surgery for advancedcases. Lymph node dissection must include the mostfrequently involved nodes, cystic and pericholedocalnodes, followed by retroportal and pancreaticoduodenalnodes of the hepatic artery and celiac trunk.

The classic review by Boerma [12] reported that only10% of gallbladder cancers were confined to the organwall at diagnosis, with liver involvement in 59%, lymphnode involvement in 45%, infiltration of common hepaticduct in 35%, perineural involvement in 42%, andinvolvement of other organs in 45% of patients. Hepaticand other hematogenous metastases were detected in34 and 20% of patients, respectively [12].

The above data underline the vital importance of anadequate preoperative staging, especially in the definitionof T, in order to select patients susceptible to aggressivetreatments and avoid futile therapeutic efforts, given thatthe aggressiveness and growth pattern of GBC usuallyrequires extensive surgical resection. Each clinicalscenario imposes a distinct strategy, as follows.

Journal of Surgical Oncology DOI 10.1002/jso

Diagnosis of Cancer Gallbladder 651

INCIDENTAL GBC

When GBC is detected in a cholecystectomy specimenfor benign disease, the rescue surgery depends on the pTof the tumor, the health status of the patient, and theresults of the extension study [3,4,8]. The performanceof cholecystectomy implies no variation in the subse-quent treatment or outcome. In the case of previouslaparoscopy, excision of trocar wounds is recommendedbecause of the risk of tumor implantation at this level[3,4].For pTis and pTla tumors (mucosal involvement), the

cholecystectomy performed is adequate. Radical surgeryis required for pTlb (muscle involvement) and pT2lesions [8,14,15,19], because the dissection plane in asimple cholecystectomy is subserous and makes contactwith the area infiltrated by the tumor. Patients with pT3tumors only benefit from repeat surgery if there is nomacroscopic lymph node involvement [3,4].

LESION DIAGNOSED WITH GBC CONSIDEREDRESECTABLE AFTER EXTENSION STUDY

When the extension study rules out distant metastasesand pathologic adenopathies at celiac trunk, superiormesenteric artery, or interaortocaval artery level, radicalsurgery is recommended unless contraindicated by thegeneral health status of the patient [3]. During surgery,these lymph node areas are intraoperatively sampled,aborting the resection if histopathologic involvement isdetected. In the uncommon case of Tl tumor detection,cholecystectomy with lymphadenectomy of anterior andposterior cystic, pericholedocal, and pancreatoduodenalnodes is adequate [7].For T2 and T3 tumors without involvement of neigh-

boring organs, extended cholecystectomy is recom-mended: bloc resection of gallbladder with IVb and Vhepatic segments associated with regional lymphade-nectomy [1,3,4,6,7,19]. In cases of infundibular localiza-tion, resection of the main bile duct must be associated. Insome selected cases with prominent liver involvement,right hepatectomy extended to segment IV is indicatedgiven the proximity and frequent involvement of thehepatic pedicle [1,3,4].

SYMPTOMATIC PATIENT WITHADVANCED CANCER

A large proportion of these cases are unresectablebecause of the spread of the disease. At any rate, pooroutcomes are obtained in most patients at advanced stageswho undergo resection. The consequences of an inoperabletumor include jaundice and pruritis. In this situation,placement of endoscopic or percutaneous biliary prostheses

may be indicated, although these can often be a source ofbiliary contamination, sepsis, and cholangitis [1,3].

ADJUVANT TREATMENT

Neoadjuvant, coadjuvant, or palliative chemotherapyand complementary radiotherapy have shown poor or ill-defined outcomes. The response rate for regimens basedon 5-fluorouracil is around 10%, while that for the morerecent treatment combination of gemcitabine and cispla-tin is 36% [20].Neoadjuvant radiotherapy has occasionally proved

useful, although its effectiveness is compromised by thelow tolerance to radiation of neighboring structures, sothat it is usually administered intraoperatively or bybrachytherapy. Radiotherapy has shown neither clearpalliative utility in patients with inoperable tumors noreffectiveness to prevent local recurrence after radicalsurgery [21].

IMAGING DIAGNOSIS OF GBC STRUCTURAL

As with the clinical and biochemical manifestations,structural changes induced by GBC can unfortunatelyoverlap with those produced by several other right upperquadrant disease processes.Ultrasound (US), computed tomography (CT), and

magnetic resonance (MR) have all been used in the diag-nosis of GBC and have replaced conventional radiologytechniques, which have very low sensitivity and specificity.Any of these techniques can show the following structuralchanges induced by growth of the tumor: (a) completeoccupation or replacement of the gallbladder lumen by themass (in 40–65% of published cases); (b) focal or diffuseparietal thickening (20–30% of cases), and (c) intraluminalpolyp (15–25%) [17] (Figs. 1–5).

ULTRASOUND IN GBC

US is currently the most widely used technique in thepreoperative study of GBC, largely because of its role inthe initial examination of patients with pain in the righthypochondrium [22,23].US signs of the primary tumor depend on its type of

growth. When it grows as a mass occupying the gall-bladder or gallbladder bed, the lesion is hypo- or iso-echogenic with respect to the liver and is irregularlyshaped, commonly due to infiltration of the neighboringhepatic parenchyma, appearing as a subhepatic mass thatusually masks the gallbladder [24,25]. It may containanechogenic areas corresponding to necrosis or residualbile within the gallbladder [26]. The presence ofgallstones trapped within the tumor during its growth isa very useful sign of possible GBC [17,23].


652 Rodrıguez-Fernandez et al.

The thickness of the vesicular wall does not normallyexceed 3 mm, and the carcinoma may occasionally pre-sent as a parietal thickening of more than 1 cm, usuallyirregular and often asymmetric [26,27]. This findingrequires a differential diagnosis with other more pre-valent diseases that can also produce this thickening, suchas acute or chronic cholecystis and hyperplastic chole-cystoses. On the other hand, the parietal thickness rarelyexceeds 1 cm in patients with chronic cholecystitis, and

the fibrosis usually makes the wall more echogenic thanin cases of acute inflammation or tumor [26].

The presence of a mass or polyp with intraluminalgrowth is the least frequent form of presentation. On US,it appears as an intraluminal mass, usually with a dia-meter of >10 mm. It is not displaced by movements ofthe patient, has a nodular or smooth shape, and casts noposterior acoustic shadow [28]. It also shows a rapidgrowth [29]. However, these US findings do not provide


Fig. 1. Gallbladder carcinoma: intraluminal mass. (A) Coronal ultrasound view of patient with well-delimited mass occupying gallbladderfundus (M) in examination of hepatic parenchyma (arrow). Lithiasis with acoustic shadow artifact (unfilled arrow). (B) Image obtained in samepatient with higher frequency (7.5 Mhz), showing irregularity at interface of mass with liver, suggesting transmural penetration (arrow) and richintralesional vascularization. According to the histologic study, the tumor was T3. (C) CT axial slice in patient with GBC in T4 stage: polypoidmass with wide base on galbladder wall with intense contrast enhancement. Loss of fatty interface between tumor and liver (arrow) suggestssurface spread into adjacent hepatic parenchyma. [Color figure can be viewed in the online issue, available at www.interscience.wiley.com.]


reliable differentiation between a carcinoma and othernon-neoplastic lesions such as cholesterol polyps oradenomyomatosis [28,29].Besides the above findings for the primary lesion, US

can reveal other associated signs such as the presence oflithiasis, present in 70–75% of cases, porcelain gall-

bladder, invasion of neighboring structures or hepaticmetastases, vascular invasion, biliary dilatation, adeno-pathies, and ascites [24–29].In advanced stages of the disease, when most patients

are diagnosed, US has a sensitivity of 85% and globalaccuracy of 80% for the diagnosis of GBC [16 R].


Fig. 2. Gallbladder carcinoma. Mass replacing gallbladder. (A) Ultrasound image of hepatic mass (between cursors) occupying a large part ofsegments 4 and 5. Identification of its gallbladder origin is facilitated by detection of lithiasis in lower part (arrows). L: liver. D: duodenal gas. (B)Oblique intercostal ultrasound view in another patient. The mass extends along hepatoduodenal ligament where it completely surrounds thehepatic artery (unfilled arrow). There is infiltration of subhepatic fat without duodenal involvement (arrow). M: mass; D: duodenum. (C) Axial CTslice at level of gallbladder replaced by hypodense mass with extensive infiltration of neighboring hepatic parenchyma showing heterogeneousuptake, preferentially peripheral. Tumor delimitation could be established by outer uptake ring (arrows). [Color figure can be viewed in the onlineissue, available at www.interscience.wiley.com.]


However, the detection of early lesions is much moreproblematic [23,29–34]. An early carcinoma is definedas one that is confined to the mucosal layer, includingRokitansky-Aschoff sinuses, up to the muscularis propia.Tsuchiya [34] proposed various microscopic classifica-tions for this type of tumor: pedunculated polyps, sessilepolyps with wide or thin base, thickening or surfaceelevation of 1.5–3 mm, and flat lesions at the mucosallevel. In a retrospective series of 71 patients with earlycarcinoma, the surface and flat forms represented 57% ofcases, with the rest corresponding to pedunculated andsessile fonns. Only 20 cases were diagnosed preopera-tively. US showed sensitivity of 75% in cases of pedun-culated tumor and of 53% in sessile cases. None of theflat lesions were preoperatively diagnosed [34]. Onoyama

et al. [32] reported a correct preoperative diagnosis inonly 34% of cases, with an incorrect diagnosis beingespecially common in patients with associated lithiasisand with flat forms.

In an attempt to increase the specificity of transab-dominal US findings, different methodological proposalshave been advanced. Endoscopic ultrasonography (3,600radial probes, 5–12 MHz) can be of special utility incases where vesicular wall anomalies suggestive of GBCcan be observed. This procedure has been shown to besuperior to conventional US for GBC diagnosis with adiagnostic accuracy of 80% [35]. In using this technique,special attention must be paid to the internal echogenicityof the lesion and its contour to guide the definitivediagnosis [29]. Thus, the presence of small internalechogenic spots or their aggregation is characteristic ofcholesterol polyps. The finding of multiple microcystsand posterior comet tail artifact is pathognomonicfor adenomyomatosis. Solid polypoid lesions withoutthese characteristics are suggestive of neoplasm [29].However, other authors [28] have described the contourof the lesion as more important than its internal echo-genic features; non-neoplastic lesions have a granularcontour, which is smooth or nodular in neoplasticpolyps. Following this criterion, none of 46 patients withpolyps of >10 mm were incorrectly diagnosed asneoplastic [28].

Four patterns have been proposed for the USappearance of the primary lesion [35]:

1. Type A: Polypoid lesion with nodular surface but noalteration of wall architecture.

2. Type B: Lesion with wide base and parietal irregula-rities with no alteration in the outer hyperechogenicband corresponding to the gallbladder serosa.


Fig. 3. Gallbladder carcinoma. Parietal thickening. Diffuse gallblad-der wall thickening (arrows). Extension along hepatoduodenalligament (asterisk) obstructing intraheptic bile ducts (unfilled arrow).L: liver.

Fig. 4. Gallbladder carcinoma. Coronal and transaxial views of FDG-PET imaging that show a high uptake in the liver, at gallbladderlocalization.


3. Types C and D: Lesion that produces irregularitiesor rupture, respectively, of the outer hyperechogenictunic layer.

Some researchers described a clear association be-tween these endosonographic patterns and the pT stageof the neoplasm. Sadamoto et al. [36] reported that 100%of Type A lesions corresponded to pTis tumors, 75% ofType B to pTl, 85% of Type C to pT2, and 93% of Type Dto pT3-4 tumors. A further advantage of this technique isthe possibility of differentiating between inflammatoryand tumoral lymph nodes by fine needle cytology duringthe same examination [35].Another approach to improve the specificity of trans-

abdominal US is the use of color Doppler. Several publi-cations [37–39] have underlined its utility in thedifferential diagnosis of carcinoma with other benigninflammatory or polypoid lesions and with tumescentbiliary sludge. Komatsuda et al. [37] suggested thatdetection of flow within the lesion supports the diagnosisof carcinoma versus biliary sludge (Se: 0.84; Sp: 0.80).However, the absence of flow does not completely ruleout a tumor. He also proposed that benign tumors have alower percentage of detectable blood flow comparedwith malignant tumors, as an additional differentiationcriterion between them. Measurement of the flow rate isalso important, with a higher rate for malignant thanbenign tumors [37]. Hayakawa et al. [40] obtained asensitivity of 0 and specificity of 0.96 for diagnosisof malignant tumor using a cutoff point of 30 cm/s.Komatsuda et al. [37] reported a lower sensitivity (0.72)and specificity (0.66) with a cutoff of 20 cm/s.When necessary, US-guided fine needle aspiration can

be of great utility. Good results were obtained by Zargaret al. [41] using this technique (Se: 0.88; Sp: 1.0, PPV:1.0, NPV: 0.52, and global accuracy: 0.89), and Pandey

et al. [33] reported an even higher sensitivity figure(0.94).When color Doppler findings are ambiguous, US with

contrast can be considered as the next line of examina-tion. This approach was used by Sato et al. [42] and wasuseful to determine carcinomas at stage TIb with muscleinvolvement. Although the addition of contrast did notchange the total number of detected cases, it increased theconfidence in the diagnosis. However, this method did notallow detection of small vessels in TIa carcinoma withonly mucosal involvement [40].Once the diagnosis is made, the spread of the neoplasm

must be determined to develop an adequate treatment plan.Few studies have been published on the usefulness ofUS todetermine tumor resectability [30,33,42,43]. Bach et al.[30] compared US with intraoperative findings in 26patients with GBC and found that US had an accuracy of0.63 to determine the non-resectability of the tumor (Se:0.94; Sp: 0.37; PPV: 0.56; NPV: 0.88). US was useful todetect the primary mass and its spread to the liver but didnot completely reflect the extent of the disease, and wasespecially limited in the localization of metastases toperitoneum and lymph nodes [30]. In another prospectivestudy to stage GBC in 26 patients (performed by a singleultrasonographist), Haribhakti et al. [43] obtained evenworse results, with global accuracy of only 0.38; mosterrors corresponded to understaging due to undetectedlocal infiltration or metastatic dissemination [43]. Pandeyet al. [33] retrospectively studied 203 patients and alsoconcluded that US is not the best technique for theextension study in GBC, describing as its main limitationthe inadequate detection of lymph node metastases,especially in pericholedocal and peripancreatic nodes,and of peritoneal metastases [33].Despite the above, US remains the technique of choice

in patients with suspicion of biliary disease and is


Fig. 5. Peritoneal implants. FDG-PET imaging, coronal and transaxial views, showing hypermetabolism at peritoneal surfaces after laparoscopyexploration.


therefore the imaging technique that most commonly firstwarns of the presence of a tumoral mass in the gall-bladder. Besides detecting the primary tumor, it can alsodemonstrate its non-resectability and can reveal infiltra-tion of neighboring organs, distant metastases, orvascular infiltration of the hepatic pedicle, avoiding theneed for other imaging studies or an unnecessarylaparotomy in these patients. However, further examina-tion with other techniques is required when the tumorappears to be resectable.

CT IN GBC

CT has been widely used in the diagnosis of GBC forthe appearance of the primary tumor (mass replacinggallbladder, wall thickening, intraluminal polyp), for theextension study, and for staging the tumor [25,34,44].

When in mass form, the tumor is usually hetero-geneous, containing hyperdense areas due to necrosisand unequal uptake, which is preferentially peripheralwith necrotic (low-uptake) areas [44]. Dual-phase spiralCT studies can even show early uptake in arterial phase,either peripheral or heterogeneous, in the latter casesimulating a hepatocarcinoma [45]. When calculi areseen, they are surrounded by the mass and in mostcases at least part of the uninvolved gallbladder can beobserved [44,45].

As in the case of US, the presentation of the tumor aswall-thickening is problematic because inflammatorydiseases, especially chronic cholecystitis, must beconsidered in the differential diagnosis. Although thethickening tends to be focal, irregular and more pro-nounced in the carcinoma, these entities are sometimesindistinguishable, especially in absence of associatedfindings. Moreover, the tumor can arise from a chroniccholecystitis, further hampering the differentiation [44].A recent study [46] of differences in gallbladder walluptake between carcinoma and chronic cholecystitisduring arterial and portal phase reported two uptakepatterns in GBC: (1) hypercaptation of the inner walllayer during arterial phase, which was isoattenuatingwith the hepatic parenchyma during portal phase; and(2) hypercaptation of the inner wall layer during botharterial and portal phases. The most common uptakepattern in chronic cholecystitis was isoattenuation ofthe thin inner layer during both phases. Therefore,neoplasm is suggested by hypercaptation of a thickinner layer with iso- or hyperattenuation in relationto the hepatic parenchyma during the portal phase[46].

Tumors in the form of polyps or intraluminal massesusually have a diameter of >1 cm and can be associatedor not to a thickening of their implantation base. They aregenerally histologically well-defined tumors and are

associated with a better prognosis, especially when small[17,25,45].

In the extension study by CT, special attention must bepaid to the detection of infiltration of the liver (the mostfrequent), bile duct and other neighboring organs. It canalso reveal the presence of hepatic and peritonealmetastases and lymphatic dissemination [17,46]. Infil-trated lymph nodes usually have an anteroposteriordiameter of >1 cm and are ring-shaped with hetero-geneous uptake after contrast administration [48,49].Using these criteria, the sensitivity for detection of thedifferent lymph node chains ranges from 0.18 forinteraorticocaval nodes to 0.78 for the right celiac chain.On the other hand, the specificity and positive predictivevalues were high, between 0.83 and 1.0. Therefore,although CT does not localize all regional lymph nodesinvolved by the tumor, their size and uptake are veryuseful to indicate possible lymphatic involvement [48].Pericholedocal nodes are usually the most frequentlyinvolved, followed by cystic nodes [47].

Biliary invasion can occur by direct spread of the lesionalong the hepatoduodenal ligament or by compressionfrom infiltrated adenopathies. Abdominal CT detects theinvolvement by presence of biliary dilatation, althoughfalse negatives are possible because of minimal invasionwith no evident dilatation. Invasion of the digestive tubeand pancreas should be established to assist the treatmentplanning, including the possible combined resection ofthese organs. The limitations of CT to diagnose thisinvasion and to detect small peritorieal lesions ormetastases have been reported [44].

There are few published studies on the usefulness of CTfor staging GBC. A retrospective study of 59 patientsby Ohtani et al. [50] correlated surgical and patho-logical findings with pre-surgical CT results, applyingthree different protocols with conventional equipment.The sensitivity of CT to detect lymph node changes(N status) was 0.36 for NI and 0.47 for N2 (PPV: 0.94;NPV: 0.92). They also reported the diagnostic accuracyfor: hepatic infiltration of <2 cm (Se: 0.65; PPV: 0.77)and>2 cm (Se: 1.0; PPV: 1.0); spread to extrahepatic bileduct (Se: 0.50; PPV: 0.90), digestive tube or pancreas (Se:0.57; PPV: 0); and detection of hepatic metastases (Se:0.71; PPV: 1.0) and interaortic lymph node involvement(Se: 0.21; PPV: 0.86). No cases of peritoneal or omentuminfiltration were detected in their series. The authorsconcluded that the sensitivity of CT to detect the extensionof GBC is low-to-moderate, although its high positivepredictive value means that it is useful to determineresectability and assist treatment planning, especially inadvanced cases [50].

In an attempt to improve on the diagnostic accuracy ofconventional CT, the use of spiral CT has been proposedto study both local spread and in-depth invasion by the



tumor for assessing resectability [45,51,52]. The advan-tages of spiral over conventional CT are the lower slicetime, shorter inter-slice interval, and optimal utilizationof contrast medium [51]. In a retrospective study of 21patients with GBC, Yoshimitsu et al. [51] comparedintraoperative observations with helical CT scans of thelesion (3-mm collimation and 3-mm reconstructioninterval). They assessed local spread using the TNM,since there are significant differences in the prognosisaccording to the degree of in-depth infiltration by theneoplasm. The classification used was as follows: Tl,polypoid lesions without focal thickening of gallbladderwall; T2, nodular lesions associated with focal thickeningof wall at insertion site and presence of separation planewith adjacent organs; T3, lesions showing loss of fat fromseparation planes with adjacent organs indicating tumorinvolvement (� 2 cm in liver) or showing apparentnodularity on exposed serous surface of the tumor; andT4, lesions that involve two or more neighboring organsor extend more than 2 cm into the liver. The diagnosticvalidity of helical CTwas relatively low for TI (Se: 0.33)but was considerably higher for T2 and more advancedstages (Se: 0.6–1.0). The overall diagnostic accuracy ofthe T staging for GBC was 0.83–0.86, superior to that ofconventional CT [51].Kumaran et al. [45] studied 15 patients with double-

phase helical CT, arterial and portal (3-mm collimationslices and reconstruction every 2 mm). Their overallassessment was that helical CT is very useful to deter-mine resectability/non-respectability with a global accu-racy of 0.93. They underlined its utility to study invasionof the portal vein and hepatic artery following the samecriteria as for patients with cholangiocarcinoma, that is,intimate contact between mass and artery or vein andabsence of fat separation plane; presence of irregularity invessel walls; stenosis in lumen demonstrated in sequen-tial slices; or presence of mass on both sides of the vessel.One of the series was unresectable with the sole criterionof vascular invasion [52]. Other authors highlighteddifferences in the diagnostic accuracy of CT for stagingaccording to its presentation as a mass occupying thelumen or gallbladder fossa or as a wall thickening. Theglobal accuracy was less in cases of wall thickening(0.54) than in cases of lumen (0.89) or fossa (0.83)occupation, confirming that the staging is influenced bythe form of tumor growth [52].Variation in study results can probably be explained in

part by differences in study populations, in the time pointin the clinic course, and in the protocols and equipmentused. The recently introduced multidetector CT, whichallows a faster examination with lower collimationthickness and more reliable volumetric reconstructions,is a promising development for increasing detection ofsmall perivesicular tumor infiltration and minimizing

partial volume artifacts, thereby improving the T stagingof the tumor [51,52].

MR IN GBC

MR has been little used for the diagnosis of gallbladderdiseases, including the diagnosis and staging of GBC.However, there have been some recent technologicaladvances, using surface antennae and rapid sequenceswith suspended respiration to reduce movement artifacts.Moreover, the introduction of dynamic techniques afteradministration of paramagnetic contrast has improved thesignal/noise ratio and specific sequences of MR-cholan-giopancreatography (MRCP) and MR-angiography(MRA), allowing their use in the study of primary tumorand disease spread.GBC appears on MR as a hypo- or isointense mass or

wall thickening in TI in relation to the liver and is usuallyhyperintense and poorly defined in T2 sequences [53]. Inearly phase, the uptake of contrast is heterogeneous andpreferentially peripheral and tends to slowly progress in acentripetal manner in dynamic studies, which is char-acteristic of adenocarcinomas. The outer uptake margincorrelates well with the extent of the tumor, which isof particular value in assessing complete penetration ofserosa or invasion of liver [54]. The early peripheraluptake may result from an increased revascularizationand prolonged uptake by the abundant fibrous stroma,since the contrast medium remains in the fibrous stromain equilibrium phase [55]. Assessment of the invasionof neighboring organs and adenopathic infiltration isfacilitated by the combination of enhanced sequencesin T2 with fat suppression, dynamic postgadoliniumTl-weighted images in arterial phase and TI with fatsuppression in equilibrium phase, 2 min after contrastadministration [56]. An irregular interface between tumorand parenchyma in TI in early phase assists assessment ofthe extent of the primary tumor. Detection of metastasesis based, as with CT, on a size of >1 cm and ring-shapedor heterogeneous uptake of the involved node [53].Two recent studies evaluated the usefulness of MR and

MRCP in the pre-surgical diagnosis of GBC [57,58].Schwartz et al. [57] retrospectively studied MR findingsin 34 patients with known diagnosis and compared themwith intraoperative observations in 19 of these casesand with histopathologic diagnosis in 15. MR was ableto demonstrate 17 out of 19 cases of hepatic invasionof >2 cm. The drawbacks of MR in the diagnosis oflymph node involvement are similar to those of CT,since the only valid criterion to suspect invasion is a sizeof>1 cm. In the future, the accuracy may be improved bycontrast agents with lymphatic tropism. The sensitivity todemonstrate biliary invasion was low in the Schwartzseries (Se: 0.69) because microscopic invasion could not



be detected. Perhaps biliary involvement should besuspected whenever the tumor is in contact with the bileduct, even in absence of biliary dilatation. Schwartzidentified four out of the six cases with involvementof the omentum or peritoneum. These good resultsmay be biased by the advanced stage of the neoplasmand the absence of surgical correlation in 44% of thepatients. Similar results were obtained by Tseng et al.[58] in 18 patients with GBC; MR correctly detected 11of 12 patients with hepatic invasion, of 13 patients withnode involvement, and 15 of 16 with bile ductinvolvement. However, none of the cases with peritonealinvolvement and only 50% of patients with duodenalinvolvement were diagnosed.

Kim et al. [59] added MRA to MR in Tl-, T2-weightedsequences and MRCP, which facilitated the diagnosis ofvascular infiltration, crucial before attempting curativeresection. Any focal or excentric stenosis, irregularity inthe lumen, or abrupt amputation of a vascular branch isconsidered indicative of vascular invasion. Consideringthe techniques together, the range of diagnostic validityreported by this group were promising for the detection ofbiliary invasion (Se: 1.0; Sp: 0.89), vascular invasion (Se:1.0; Sp: 0.87), hepatic invasion (Se: 0.67; Sp: 0.89), andlymph node involvement (Se: 0.56; Sp: 0.89). Therefore,MR in combination with MRCP and MRA is an attractiveoption for studying GBC patients in a single act and forobtaining accurate information to determine its resect-ability [59].

FUNCTIONAL IMAGING

As in the case of conventional radiology, classic NuclearMedicine procedures base their capacity to diagnose GBCon the detection of indirect signs produced by growthand invasion of the tumor. These signs are usually detectedonly in advanced stages of the disease and are relativelynon-specific with respect to other benign diseases of thegallbladder [66]. From this base, there has been a gradualdevelopment of procedures based on biochemical featuresof the disease, mainly binding widely bioavailable meta-bolic substrates to positron-emitting radionuclides, notablyfluor-18 bound to [18F]-2-deoxy-D-glucose (FDG) [67].

In comparison with non-tumor cells, tumor cellshave been reported to show an increased membraneexpression of glucose transporters (GLUT-1) (greaterincorporation of FDG) and a reduction in glucose6 phosphatase activity, trapping FDG-P within the tumorcell [67]. When this selective accumulation of FDG in thetumor tissue is sufficient, it can be revealed by specifictomographs for the detection of annihilation reactions(PET).

The marked biochemical-metabolic character of theinformation offered by FDG-PET is counterbalanced by

its relative limited spatial resolution, resulting in thefailure to detect lesions smaller than double the equip-ment resolution (usually 4–5 mm): the partial volumeeffect [68]. At any rate this minimum detection size mustbe corrected as a function of the density and metabolicrate (marked avidity for G) of the tumor cells that formit [67]. Hybrid PET (functional imaging) and CT(structural imaging) equipment has recently been devel-oped. Although there are no specific data on its use inGBC, it is hoped that it can provide invaluablecomplementary information in assessing possible tumorinvolvement in non-specific structural changes and indetermining the precise topographic limits of thisinvolvement [69].

The main shortcoming of FDG-PET is that it is not yetwidely available for routine clinical use, leading it to beincorrectly considered an expensive examination [70,71]only for use in relatively restricted clinical situations. Forthis reason, and because of the low prevalence of GBC(0.5–7.4% of autopsies) [72], there is little information todate on the possible contribution of these procedures inthe functional imaging diagnosis of GBC.

After initial reports by Lomis (GBC recurrent laparo-scopy port sites) and Koh et al. [73] in three patients [74],the latter group studied the first specific series [70], whichincluded six patients scheduled for surgery with protu-berant lesions in the gallbladder and suspicion of tumor.These authors described a global diagnostic accuracyusing FDG-PET for GBC detection of 0.81 (Se: 0.75; Sp:0.875). CT offered considerably lower values in the sameseries (Se: 0.625; Sp: 0.75, and GA: 0.688) for a GBCprevalence of 50%. The studies yielded two false nega-tives, in one patient with diabetes and in another with asmall lesion (13 mm), and one false negative, in a patientwith xanthogranulomatous cholecystitis.

Anderson et al. [74] took a different approach, giventhe practical difficulty of studying a patient for pre-surgical staging when the patient is already diagnosed asinoperable or when the diagnosis is an incidental finding.They focused on the detection of residual carcinoma(defined as primary tumor, local gallbladder fossa in-vasion, or hepatic metastases) and distant metastases.

Fourteen patients (11 primaries and 3 possible recur-rences) were studied, taking as reference the histology ofthe surgical specimen and for tumor absence a normalhistology and the clinical evolution at one year. Theseauthors described a sensitivity of 0.78 and specificity of 0.8for FDG-PET in the diagnosis of residual carcinoma and asensitivity of 0.56 in the detection of distant metastases orcarcinomatosis, detecting peritoneal carcinomatosis inthree out of six affected patients. They attributed theseresults for carcinomatosis to the small size of the lesions(below the limits of detection of the equipment). They alsoreported a false positive in a patient studied at one month



after the cholecystectomy (an important fact when theGBC diagnosis is incidental and a post-surgical staging isperformed). The prevalence of tumor activity in thepatients studied for the first time was 64.3%.Results published by our group [75] on the pre-surgical

FDG-PET study of 16 patients with suspected GBC lesionswere similar to the above reports, obtaining a sensitivity of0.80, specificity of 0.82, PPV of 0.67, and NPV of 0.90,with a prevalence of the disease of 31.2%. One examinationwas considered a false negative in a mucinous adenocarci-noma with low metabolic rate and two were false positives,one in a tuberculous granuloma with caseous necrosis andthe other in a polyp with adenomyomatosis.None of the above studies specifically refer to the

diagnostic validity of FDG-PET in the lymph nodestaging of GBC.

PROPOSALS FOR THE DIFFERENTIALDIAGNOSIS

When GBC manifests structurally as a mass thatreplaces the gallbladder, other tumors must be consideredin the differential diagnosis, such as hepatocarcinoma,cholangiocarcinoma, or metastases.In cases of an intraluminal polyp, adenomatous, or

hyperplastic cholesterol polyps must be ruled out, as wellas less common tumors such as carcinoids or melanomametastases. Despite the above-mentioned size limitations[74], FDG-PET can be useful for the differential diag-nosis between malignant and benign polyp.When the presentation is as a parietal thickening, other

more common inflammatory and non-inflammatory dis-eases must be considered, including heart failure, kidneyfailure, hepatitis, and cholecystitis. An acute cholecystitiswith parietal necrosis, perivesicular abscess, or intestinalfistula formation can be confused with an aggressiveneoplastic process. In this case, the presence of asso-ciated signs can be of value to make the diagnosis ofcarcinoma, such as metastases or adenopathies secondaryto the extension of the neoplasm [17]. Although there areno reports that FDG-PET has produced false positives inpatients with a cholecystitis, it appears recommendable toperform the examination after the acute inflammation hasreduced [70].Xanthogranulomatous cholecystitis presents with a

diffuse thickening of the gallbladder wall that can beconfused with a neoplasm. This disease is a type ofchronic cholecystitis characterized by grayish nodules orbands on the gallbladder wall, mainly comprised of lipid-loaded macrophages. A recently reported characteristic isthe presence of nodules on the gallbladder wall, hypo-echogenic on US or hypodense on CT, which are the firstphase of parietal abscesses that subsequently transforminto xanthogranulomas [60–62]. In MR, these nodules

can be demonstrated by chemical displacement techni-ques that show a fall in signal in the opposite phasesequence due to the presence of intracytoplasmatic fat[63]. There has been a report [70] of a false positive FDG-PET scan in a case of xanthogranuloma to us cholecys-titis.Adenomyomatosis is a pseudotumoral lesion that can

involve the gallbladder in a focal, segmental, or diffusemanner and can be confused with GBC. The key to itsdiagnosis is the demonstration of the Rokitansky-Aschoffsinuses, small outpouchings of mucosa within thethickened muscularis layer. On US, adenomyomatosisappears as a diffuse or segmental parietal thickeningwith presence of small intramural diverticles with orwithout presence of posterior comet-tail artifact, char-acteristic of adenomyomatosis. A recent study reportedthe demonstration by MRCP of Rokitansky signs withinthickened gallbladder walls as characteristic of adeno-myomatosis and advocated the utility of this finding inthe differential diagnosis with carcinoma [64,65]. FDG-PET has shown both true negatives (n¼ 2) [70] and falsepositives (polyp with adenomyomatosis) for this clinicalentity [76].There are considerable methodological limitations to a

true assessment of the diagnostic validity of imagingprocedures in the study of GBC, deriving from the lowprevalence of the disease and the difficulty of maintainingthe principle of independence necessary for estimatingthe diagnostic validity and comparing results of differentprocedures.Because the prevalence of the disease is low, most series

have been small. Moreover, GBC is most frequentlypresented in advanced stages of the disease, when thestaging performed by imaging methods has a smallerimpact on therapeutic decision-making and patient survi-val. On the other hand, imaging diagnostic proceduresshould commit less errors at these late stages in thedetection of structural changes compatible with GBC(higher sensitivity) and in differentiating these changesfrom those induced by benign diseases (higher specificity).The low number of GBC cases also means that most studiesare retrospective, analyzing the proportion of each findingin known cases, with the corresponding limitation in theability to estimate the true diagnostic validity of theprocedure under study. This situation is further complicatedby the considerable variability in the clinical diagnosis ofGBC, that is, in the tests included in the diagnosticalgorithms and in the order of their application. This hasconsiderable influence on the pre-test probability of eachindividual procedure (especially in terms of the predictivecapacity of a positive or negative result). This variability isalso found in the surgical approach, which indirectlydetermines the possibility of comparing reference findings(usually histologic) with tumor presence at sites indicated



by the examination and, even more importantly, with theabsence of disease at sites where the image showed nofinding. Thus, there may be no resection of lymph nodechains that were not considered to be involved.

Despite all of the above and regardless of the basicprinciples of each procedure, imaging diagnosis of GBCmust necessarily be interpreted in the context of theclinical history of the patient. The patient usually pre-sents with right hypochondrium pain and non-specificbiochemical alterations and as a candidate for possiblesurgical treatment. At this stage, the role of transabdom-inal US is undeniable. Leaving to one side the issues ofpossible interexaminer variability and skill level of thespecialist [77], it is necessary to obtain the best possibleresolution capacity, which depends on setting the optimalexamination frequency for the volume of the patient.Thus, the best resolution can be obtained at a range of7.5–10 MHz in a slim patient and at a range of 2.5–5 MHz for an overweight patient. This is of specialimportance because relatively recent equipment offersthe possibility of multi-frequency examination and theproduction of a harmonic image, markedly improving theimage quality in B mode.

The consequences of the US findings in the three mainsituations considered herein are described below.

Diagnosis of Advanced GBC

In this situation, the aim of imaging procedures is toestablish N and M staging as part of the treatmentplanning process. The possibility of obtaining a total bodyscreening with a relatively high PPV for the detection ofmetastatic tumor activity makes FDG-PET especiallyuseful for the diagnosis of unsuspected distant metastases.Likewise, and although any imaging procedure can revealchanges suggestive of peritoneal carcinomatosis, thedetection of functional changes by FDG-PET canprobably be achieved earlier than the detection of director indirect structural changes by CT. On the other hand,the structural defmition of spiral CT is superior to that ofFDG-PET or US for establishing possible locoregionalspread, especially involvement of the hepatic hilum.

Structural Changes Suggestive of GBC: Focal

Thickening of Wall, Intramural Polyp or Mass

Occupying Gallbladder Lumen

A high specificity of the diagnostic procedure is requi-red whenever there is a clear overlap between benign andmalignant entities that can induce these changes. US canbe complemented with a color Doppler study to estimatethe presence of high, low, or absent flow within the lesion,which suggest the presence of malignant tumor, benigntumor, or non-tumoral lesion, respectively [37–40]. If theresult of the color Doppler is ambiguous, contrast US can

be used to increase the specificity of transabdominal USand the confidence in the (positive or negative) diagnosisof GBC [42].

The availability of skills and equipment probablydetermines the next diagnostic procedure that can beapplied: endoscopic ultrasonography, US-guided fine-needle aspiration, spiral CT, and/or FDG-PET. In general,conservative procedures should be attempted beforeadopting an aggressive approach, given the facility ofGBC for inducing tumor in invasive trajectories [73].

FDG-PET not only addresses whether a structurallesion is tumoral but also offers a staging of the extension(both N and M) in the same examination. Although it isunlikely that a small polypoid lesion is a GBC [78], falsenegative results have been attributed to small tumor size[74,76]. FDG-PET can also understage tumor dissemina-tion if lymph node involvement is produced in theproximity of the primary tumor, since the spatialresolution of current detector systems do not allowdetection of minimum locoregional spread, as previouslycommented. In this situation, spiral CT (under thin sliceand reconstruction conditions) can contribute valuableinformation. The precise diagnostic value of the size ofadenopathy for lymph node staging is not definedin GBC, unlike lung cancer, where it is known to below [79].

The questions raised above are likely to be answered inthe relatively near future, thanks to the development ofhybrid PET-CT systems, in which simultaneous acquisi-tion of structural and functional data and their projectionon a single image facilitates correct T and N staging, withthe added advantage of a complete body screening.

Examination Not Suggestive of Tumor Lesion

When the examination is normal, the patient receivessymptomatic treatment and is examined using otherprocedures to determine the etiology of the symptoms ina clinical follow-up program.

US can diagnose the presence of benign disease sus-ceptible to surgical treatment (e.g., acute cholecystitis incholelitiasis, chronic cholecystitis, cholesterolosis, amongothers). In this situation a cholecystectomy is performed,and the histologic study of the specimen can show thepresence of an unsuspected GBC (incidental finding). Inthese patients, it is especially important to establish areliable staging, not only for local extension (provided bythe histologic analysis that definitively determines the Tstaging) but also and mainly for N and M. In thissituation, FDG-PET can be of inestimable value.

FINAL COMMENTS

The proportion of patients diagnosed in each situationvaries considerably across social and health settings. The



critical objective is that a diagnosis is obtained for themaximum number of patients with suspicion of GBC(second situation) whenever curative radical surgery canbe contemplated. Recent advances in the hepatobiliarysurgery have further increased the demands madeon complementary diagnostic procedures [7,8]. Consid-ering all of the above from this perspective, the pro-portion of GBC cases diagnosed incidentally in acholecystectomy specimen can only be reduced byincreasing the sensitivity of the initial US examination.Achieving this will depend on the technological qualityof the equipment and the skill of the specialist using it.More importantly, however, the possibility of reducingthe proportion of patients diagnosed when the GBC isalready disseminated is related to the development ofstrategies for early detection. These can include anepidemiological approach and inclusion of the hepato-biliary region in routine abdominal examinations for anyother motive in high-risk patients (women, hypercholes-terolemia, age over 50 years, etc.). Observation ofchanges compatible with early-phase GBC should befollowed by the application of procedures with higherspecificity. Any diagnostic algorithm that is developed byconsensus among working groups may be valid. Ourgroup is in full agreement with the proposal by Koh et al.[70] based on the size of the primary lesion.As with any phenomenon linked to technological

development, continuing advances will modify presentproposals. Novel multi-detector CT equipment, PET-CTequipment that allows fusion of structural and functionalimages and the use of biological probes are likely totransform the imaging diagnosis of GBC in the nearfuture. However, we wish to emphasize that, in ourexperience, the diagnosis and treatment of GBC is highlydependent on the ‘‘human factor’’. In many cases, theopportunity to honestly discuss findings with fellowspecialists is of critical importance, admitting the theore-tical and practical limitations of each procedure.

ACKNOWLEDGMENTS

The authors are grateful to Richard Davies forassistance with the English version.

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