Carcinoma involving the gallbladder: a retrospective review of 23 cases - pitfalls in diagnosis of gallbladder carcinoma
© Giang et al; licensee BioMed Central Ltd. 2012
Received: 19 December 2011
Accepted: 27 January 2012
Published: 27 January 2012
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.
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.
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.
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.
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1443233938651038.
KeywordsCarcinoma gallbladder neoplasm immunohistochemistry histology misdiagnosis
Gallbladder carcinoma (GBC) is a relatively uncommon neoplasm that shows female predominance (female to male ratio, 3-4: 1), possibly related to the increased incidence 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 gallbladder (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 significantly greater risk of developing carcinoma. Recently, clinical and epidemiological studies have suggested a link between gallstone disease , GBC as well as other hepatobiliary diseases and previous infection with Helicobacter species . Sixty percent of GBC arise in the fundus. Invasion of liver, lymph nodes and other organs are frequent. Histologically, most GBC are pancreatobiliary-type adenocarcinomas, showing variable degrees of differentiation. Some arise in association with a noninvasive 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 gallbladder include adenosquamous carcinoma, squamous cell carcinoma, small cell carcinoma, and undifferentiated carcinoma. The determination of the histological type of the tumor and differential diagnosis from gallbladder adenocarcinoma are often difficult [3, 4]. Failure to detect early disease contributes to a generally poor prognosis. Preliminary observations indicating potentially 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.
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 University 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 hematoxylin 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.
Clinical and pathologic features of patients with gallbladder malignancies
Feature of primary GB carcinoma
(abdominal pain, jaundice, nausea and vomiting, weight loss)
Mass associated with gallstones
Pre-op diagnosis benign diseases
Pre-op diagnosis GB cancer
Pre-op diagnosis bile duct tumor
Malignant postoperative diagnosis
Primary: 10/23 (43%)
Metastasis to GB: 6/23 (26%)
Bile duct carcinoma invasive into GB: 6/23 (26%)
Unidentified origin carcinoma: 1/23 (5%)
Summary of case details in problematic cases:
66 yo male
abdominal pain, 4 years post cholecystectomy for ruptured cholecystitis and cholelithiasis
CT: peritoneal carcinomatosis and free fluid
Peritoneal implants with slight granular thickening of peritoneum
Gallbladder wall 5 mm thick no mass, and gallstones in the lumen
Well differentiated adenocarcinoma of the gallbladder and peritoneal metastasis
49 yo female
On routine examination, pelvic mass and gallbladder polyp were found with no remarkable clinical symptoms
CT: an enhancing 2 cm mass in the GB fundus.
US: heterogeneous mass with associated internal flow worrisome for GB malignancy: cholelithiasis
Polypoid mass protruding from a stalk (4.0 × 2.3 × 1.4 cm) gallstones. On cut section the polyp was white tan, homogeneous throughout
Combined adenocarcinoma and neuroendocrine carcinoma, poorly differentiated
86 yo female
Three days of RUQ pain, nausea, fever. History of breast cancer S/P mastectomy 7 years ago, treated with Tamoxifen, squamous cell carcinoma of nose, ovarian cyst removal
US & CT: gallstones and sludge; pancreatic head mass
BG 9.5 × 6.5 × 6.0 cm. seven firm yellow to black multi-faceted calculi. GB wall thickened to 1.5 cm. Mucosa lined by friable pale tan necrotic tissue extruded into lumen. 3.5 cm maximal tumor size, circumferential at neck and filling up to 30% of the luminal volume
Pancreatic biopsy: adenocarcinoma with abundant lymphocytes. GB: Undifferentiated carcinoma of GB with extensive necrosis and acute/chronic inflammation
53 yo female
Increasing abdominal girth over several months
CT & US: moderate volume ascites, 18.5 cm complex right pelvic mass; GB: 1.8 cm polyp
A 5 cm appendix filled with yellow-tan mucoid material.
Gallbladder was 7.3 × 3 cm in greatest dimensions with a flesh colored lesion presenting in the serosa. The mucosa was unremarkable
Low grade mucinous neoplasm/adenocarcinoma of the appendix with peritoneal spread
45 yo female
Mural thickness 5 mm; no mass; stones up to 2.5 cm
Focally invasive adenocarcinoma; extensive CIS involving RAS
Two of our cases (see Table 2, A and E) illustrate the pitfalls associated with this challenging aspect of gallbladder microanatomy. Surface dysplasia was identified on initial evaluation of case E and subsequently submitted additional sections demonstrated numerous areas in which dysplasia extended into deeply situated RAS, mimicking transmural invasion of carcinoma. However, some lateral intramural growth was also present without typical associated mucosal stroma in which atypical small glands were closely juxtaposed to smooth muscle. In contrast, another case in our series (case A) demonstrated small glands embedded in bundles of smooth muscle and surrounding a deep vessel, but resembling RAS (See Figure 1C, D). The surface mucosa was inflamed and also associated with some atypia, making it difficult to differentiate from reactive atypia involving the surface and RAS. However, the lining cells of deep glands presented cytological and subtle architectural atypia without significant inflammation. The surface epithelium exhibited multiple areas with high grade dysplasia (See Figure 1D, E). Further, the stroma surrounding the deeply situated glands was more desmoplastic than inflammatory in nature. The morphological diagnosis at the time was cholecystitis. Unfortunately, 4 years post-cholecystectomy, the patient presented with abdominal pain and radiographic evidence of disseminated peritoneal implants. Surgical sampling at this point led to a diagnosis of metastatic well differentiated adenocarcinoma. Immunostains showed the tumor cells to be diffusely positive for CK7 and negative for CK20, WT1, D240, calretinin, CK5/6 and TTF1. MUC-1, MUC-5A, MLUC6, P53 were positive in the tumor cells. Subsequent review of the previously removed gallbladder revealed the small primary tumor and associated surface dysplasia.
Adenomyosis can also be confused with adenocarcinoma of gallbladder. It is a hyperplastic condition characterized by excessive proliferation of surface epithelium with deepened invaginations or diverticula extending into the thickened muscular layer of gallbladder wall, again mimicking well-differentiated adenocarcinoma of the gallbladder. However, the glands in adenomyosis are usually bland cytologically; they show cystic dilatation, and they communicate with the main gallbladder lumen [7, 8] (See Figure 1F). Pathologists should be aware of the presence of glandular structures embedded in the gallbladder wall. This condition does not simply suggest RAS or adenomyosis. The precise evaluation of the appearance of the whole lesion may be useful in distinguishing these diseases.
The immunoprofile of GBC is similar to that of bile duct carcinoma (intrahepatic and extrahepatic) and pancreatic carcinoma. Cytokeratin 7 (CK7) is almost always positive, Cytokeratin 20 (CK20) can be positive, more often in extrahepatic bile duct carcinoma than intrahepatic cholangiocarcinoma. In addition, carcinoembryonic antigen-monoclonal (CEA-M), carbohydrate antigen (CA19-9), B72.3, MUC1, and MUC5AC are also positively expressed in bile ducts and GBC but can be focal. MUC overexpression rates are reportedly higher in GBC than in cholecystitis and gallbladder adenoma [7, 8].
The finding of focal high grade glandular dysplasia or intramucosal adenocarcinoma within the gallbladder strongly favoured origin of this carcinoma within the gallbladder, despite the history of two other malignancies. IHC stains showed focal moderate tumor immunoreactivity for synaptophysin consistent with focal neuroendocrine differentiation. In this case, her find needle biopsy of the head of the pancreas revealed findings suggestive of typical adenocarcinoma. Given her history of bilateral breast cancer and a pancreatic tumor, metastatic tumor would have been more likely than a primary GBC. Taking a very careful cancer history and maintaining a high index of suspicion together with comparing her current findings with prior histologic appearances and appropriate IHC study was prerequisite to accurate diagnosis. Necrosis may be present in many diseases. An incorrect diagnosis could be made if primarily based on necrosis.
A diagnosis of mucinous carcinoma should be suspected from gross examination when large amounts of mucus are found in the primary tumor. However, it was easily mistaken for pseudomyxoma peritonei disseminated to gallbladder. Pseudomyxoma peritonei (PMP) is an uncommon disease characterized by abundant extracellular mucin in the peritoneum. It is an older, broad descriptive term embracing a wide spectrum of biological behaviour of neoplasms from the benign and borderline to malignant lesions. PMP is usually associated with a mucinous neoplasm in the appendix that demonstrates fairly bland well differentiated mucinous epithelium often with minimal nuclear features of malignancy and minimal or no invasion [10, 11].
Hence, it can be diagnostically challenging to recognize a primary mucinous tumor of the gallbladder vs. PMP disseminated to gallbladder, especially in cases in which only the gallbladder is removed. Similarly, mucinous metaplasia in the gallbladder may be associated with mucosal ulceration, particularly if stones are present, presenting the appearance of possible pools of surface or submucosal mucin. This circumstance warrants close sectioning to avoid missing a primary mucinous neoplasm of the gallbladder.
This patient's immunohistochemistry staining results were positive for cytokeratin and synaptophysin. These findings were suggestive of mixed endocrine-exocrine carcinoma involving full thickness of the gallbladder wall. In summary, NET of the gallbladder is extremely rare. As a single dominant element, metastasis may be more common than primary origin in the gallbladder.
Carcinoma of the gallbladder is a poor prognosis malignancy since it usually presents at a very advanced stage. Detection of GBC at an earlier stage is very difficult because the symptoms most of the time mimic benign gallbladder diseases like chronic cholecystitis, adenomyosis and because the absence of a gross lesion makes pathologic detection problematic. Further, we have illustrated and identified from our experience other pathologic factors leading to misdiagnosis. Misinterpretation of subtle microscopic abnormalities appears to contribute to improper diagnosis in some of the 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 that may be mimicking RAS are critical. Further, correlation with radiographic and clinical findings can also be important helps to avoid misdiagnosis in this commonly resected organ.
9 carbohydrate antigen
carcinoma in situ
computed tomography scan
carcinoma of the gallbladder
- H&E stain:
hematoxylin and eosin stain
not otherwise specified
right upper quadrant
The authors gratefully acknowledge the support of Dr. Nguyen Sao Trung, Dr. Eric Suba and the faculty of the OU Pathology department who provided encouragement and other resources. Ms. Karen Solodon and Linda Freeman provided significant clerical assistance.
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