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  • Carcinoma involving the gallbladder: a retrospective review of 23 cases - pitfalls in diagnosis of gallbladder carcinoma Giang et al.

    Giang et al. Diagnostic Pathology 2012, 7:10 http://www.diagnosticpathology.org/content/7/1/10 (27 January 2012)

  • RESEARCH Open Access

    Carcinoma involving the gallbladder: a retrospective review of 23 cases - pitfalls in diagnosis of gallbladder carcinoma Tran H Giang1†, Tran TB Ngoc1† and Lewis A Hassell2*

    Abstract

    Background: Carcinoma of the gallbladder (GBC) clinically mimics benign gallbladder diseases and often escapes detection until advanced stage. Despite the frequency of cholecystectomy, diagnosis of GBC remains problematic in many situations. We sought to identify pathologic features that contribute to the difficulty in recognition of GBC.

    Methods: We identified 23 patients (ranged from 45 to 86 years, male to female ratio 1:4.5) with carcinoma involving the gallbladder referred to an academic medical center over a period of 10 years for study. This includes 10 cases of primary GBC, 6 cases of metastatic tumor to gallbladder, 6 cases of directly invasive adenocarcinoma arising elsewhere in the biliary tree, and one case of unidentified origin adenocarcinoma. Primary tumors include adenocarcinoma not otherwise specified (NOS) in 6 cases, papillary adenocarcinoma in 2 cases, and single cases of undifferentiated carcinoma and combined adenocarcinoma and neuroendocrine carcinoma (NEC). Metastatic tumors to gallbladder were from a wide range of primary sites, predominantly the gastrointestinal tract.

    Results: These cases illustrate seven potential pitfalls which can be encountered. These include: 1) mistakenly making a diagnosis of adenocarcinoma of gallbladder when only benign lesions such as deeply penetrating Rokitansky-Aschoff sinuses are present (overdiagnosis), 2) misdiagnosing well-differentiated invasive carcinoma with minimal disease as benign disease (underdiagnosis), 3) differentiating between primary NEC of gallbladder and metastasis, 4) confusing primary mucinous adenocarcinoma of gallbladder with pseudomyxoma peritonei from a low grade appendiceal neoplasm disseminated to gallbladder, 5) confusing gangrenous necrosis related to cholecystitis with geographic tumoral necrosis, 6) undersampling early, grossly occult disease, and 7) misinterpreting extracellular mucin pools.

    Conclusions: Clinical history and a high index of suspicion are prerequisite to detecting GBC. Detection of GBC at an early stage is difficult because the symptoms mimic benign gallbladder diseases. Misinterpretation of subtle microscopic abnormalities contributes diagnostic failures in early cases. Careful attention to any evidence of mural thickening, thorough sampling, particularly in older patients, and close examination of any deeply situated glandular structures are critical. Correlations with radiographic and clinical findings are important helps to avoid misdiagnosis in this commonly resected organ.

    Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/ vs/1443233938651038.

    Keywords: Carcinoma, gallbladder neoplasm, immunohistochemistry, histology, misdiagnosis

    * Correspondence: lewis-hassell@ouhsc.edu † Contributed equally 2University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma Full list of author information is available at the end of the article

    Giang et al. Diagnostic Pathology 2012, 7:10 http://www.diagnosticpathology.org/content/7/1/10

    © 2012 Giang et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

    http://www.diagnosticpathology.diagnomx.eu/vs/1443233938651038 http://www.diagnosticpathology.diagnomx.eu/vs/1443233938651038 mailto:lewis-hassell@ouhsc.edu http://creativecommons.org/licenses/by/2.0

  • Background Gallbladder carcinoma (GBC) is a relatively uncommon neoplasm that shows female predominance (female to male ratio, 3-4: 1), possibly related to the increased inci- dence of calculi in women. The mean age of patients is 65 years, compared to a mean age of presentation with cholelithiasis of 49 years. In the United States, Hispanic and Native Americans have a higher rate of gallbladder cancer than other ethnic groups. Gallbladder carcinomas are associated with gallstones (80%), porcelain gallblad- der (10-20%), and abnormal choledochopancreatic duct junction. Size of the gallstones may also be a risk factor, as patients with stones larger than 3 cm have a signifi- cantly greater risk of developing carcinoma. Recently, clinical and epidemiological studies have suggested a link between gallstone disease [1], GBC as well as other hepatobiliary diseases and previous infection with Heli- cobacter species [2]. Sixty percent of GBC arise in the fundus. Invasion of liver, lymph nodes and other organs are frequent. Histologically, most GBC are pancreatobili- ary-type adenocarcinomas, showing variable degrees of differentiation. Some arise in association with a noninva- sive papillary neoplasm. Additional, several histologic variants of adenocarcinoma are recognized: papillary, intestinal, mucinous, signet-ring cell and clear cell. Many tumors contain more than one histologic variant. The remaining epithelial cell types occurring in the gall- bladder include adenosquamous carcinoma, squamous cell carcinoma, small cell carcinoma, and undifferen- tiated carcinoma. The determination of the histological type of the tumor and differential diagnosis from gall- bladder adenocarcinoma are often difficult [3,4]. Failure to detect early disease contributes to a generally poor prognosis. Preliminary observations indicating poten- tially frequent under- and over-diagnosis of GBC led us to undertake this study. In the present report, we review our experience with GBC over a 10 year period, noting some of the pitfalls which can be encountered. We also suggest some ways whereby these pitfalls may be avoided.

    Methods This retrospective study was carried out from data on 23 patients with carcinoma of the gallbladder retrieved from the surgical pathology files of an academic medical center between January 2001 and November 2011. Patients with pathologic materials referred to the Uni- versity of Oklahoma Medical Center (OUMC) and a diagnosis of carcinoma involving the gallbladder were eligible for the study. The surgically resected specimens were fixed in 10% neutral-buffered formalin and embedded in paraffin. Sections were used for hematoxy- lin and eosin staining and immunohistochemical

    examinations. Slides from some patients were reviewed as whole slide digital images if the primary materials had been returned to a referring institution after the patient was seen at OUMC.

    Results Of our 23 cases, 18 presented few difficulties in diagno- sis. The most common presenting symptoms of primary GBC were abdominal pain predominantly in the epigas- tric and right upper quadrant, jaundice, nausea, vomit- ing, anorexia, and weight loss (50%). Imaging studies performed in all the patients showed the presence of gallstones in 14 (60%) cases overall, and in 90% of cases of primary GBC. Grossly evident tumor was seen on initial pathologic examination in 12 of 23 cases (52%). Eight (80%) of 10 primary GBC cases had tumor masses, while 2 cases grossly presented no visible tumor. The most common tumor sites were in the body and the neck of gallbladder. Carcinoma was suspected pre- operatively in only 5 patients (22%), while the clinical diagnosis in the remainder was acute cholecystitis, stone disease and bile duct tumor. Surgical specimens from the 10 patients with primary adenocarcinoma showed adenocarcinoma NOS in 6 cases, papillary adenocarci- noma in 2 cases, and single cases of undifferentiated carcinoma and combined adenocarcinoma and NEC (See Table 1). In the adenocarcinoma NOS group, 4 cases were moderately differentiated and 2 cases were well differentiated carcinoma. Five of our cases presented particular challenges in

    diagnosis. These included one patient in whom the diag- nosis was made only after the initial cholecystectomy specimen was reviewed four years later when he pre- sented with bowel obstructive symptoms due to perito- neal carcinomatosis, one patient in whom surface dysplasia involving Rokitansky-Aschoff sinuses (RAS) and adenomyosis was mistaken for deeply invasive carci- noma, one patient in whom geographic tumoral necrosis closely resembled acute gangrenous necrosis more typi- cal in acute cholecystitis, and one patient with isolated mucin pools and only rare tumor cells. One additional patient with a combined adenocarcinoma and NEC pre- sented a challenge in differential diagnosis of primary vs. metastasis as well (See Table 2).

    Discussion Well-differentiated adenocarcinoma of the gallbladder can be difficult to distinguish from RAS, which can be located throughout the gallbladder wall, even extending into perimuscular adipose tissue. RAS are normally con- tinuous, showing a perpendicular orientation to the sur- face, and typically have undulating, smooth contours (See Figure 1A, B). In contrast, adenocarcinomas show

    Giang et al. Diagnostic Pathology 2012, 7:10 http://www.diagnosticpathology.org/content/7/1/10

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  • small and variably sized glands with angulated contours [5]. The malignant glands are usually densely packed and may be oriented parallel to the surface. Desmoplasia favors a diagnosis of carcinoma. However, a stromal desmoplastic-like reaction surrounding RAS is not uncommon, especially when the