Mural Intracholecystic Neoplasms Arising in Adenomyomatous Nodules of the Gallbladder: An Analysis of 19 Examples of a Clinicopathologically Distinct Entity.

Intracholecystic neoplasms (ICNs) (pyloric gland adenomas and intracholecystic papillary neoplasms, collectively also called intracholecystic papillary/tubular neoplasms) form multifocal, extensive proliferations on the gallbladder mucosa and have a high propensity for invasion (>50%). In this study, 19 examples of a poorly characterized phenomenon, mural papillary mucinous lesions that arise in adenomyomatous nodules and form localized ICNs, were analyzed. Two of these were identified in 1750 consecutive cholecystectomies reviewed specifically for this purpose, placing its incidence at 0.1%. Median age was 68 years. Unlike other gallbladder lesions, these were slightly more common in men (female/male=0.8), and 55% had documented cholelithiasis. All were characterized by a compact multilocular, demarcated, cystic lesion with papillary proliferations and mucinous epithelial lining. The lesions' architecture, distribution, location, and typical size were suggestive of evolution from an underlying adenomyomatous nodule. All had gastric/endocervical-like mucinous epithelium, but 5 also had a focal intestinal-like epithelium. Cytologic atypia was graded as 1 to 3 and defined as 1A: mucinous, without cytoarchitectural atypia (n=3), 1B: mild (n=7), 2: moderate (n=2), and 3: severe atypia (n=7, 3 of which also had invasive carcinoma, 16%). Background gallbladder mucosal involvement was absent in all but 2 cases, both of which had multifocal papillary mucosal nodules. In conclusion, these cases highlight a distinct clinicopathologic entity, that is, mural ICNs arising in adenomyomatous nodules, which, by essentially sparing the "main" mucosa, not displaying "field-effect/defect" phenomenon, and only rarely (16%) showing carcinomatous transformation, are analogous to pancreatic branch duct intraductal papillary mucinous neoplasms.

Non-neoplastic Polyps of the Gallbladder: A Clinicopathologic Analysis of 447 Cases.

There is no systematic histopathologic analysis of non-neoplastic polyps in the gallbladder. In this study, in addition to a computer search for cases designated as "polyp," a systematic review of 2533 consecutive routinely sampled archival and 203 totally submitted prospective cholecystectomies were analyzed for >2 mm polyps (cut-off was based on radiologic sensitivity). A total of 447 non-neoplastic polyps were identified. The frequency was 3% in archival cases and 5% in totally submitted cases. Only 21 (5%) were ≥1 cm. The average age was 52 years, and the female to male ratio was 3.1. Two distinct categories were delineated: (1) injury-related polyps (n=273): (a) Fibro(myo)glandular polyps (n=214) were small (mean=0.4 cm), broad-based, often multiple (45%), almost always (98%) gallstone-associated, and were composed of a mixture of (myo)fibroblastic tissue/lobular glandular units with chronic cholecystitis. Dysplasia seen in 9% seemed to be secondary involvement. (b) Metaplastic pyloric glands forming polypoid collections (n=42). (c) Inflammatory-type polyps associated with acute/subacute injury (11 granulation tissue, 3 xanthogranulomatous, 3 lymphoid). (2) Cholesterol polyps (n=174) occurred in uninjured gallbladders, revealing a very thin stalk, edematous cores devoid of glands but with cholesterol-laden macrophages in 85%, and cholesterolosis in the uninvolved mucosa in 60%. Focal low-grade dysplasia was seen in 3%, always confined to the polyp, unaccompanied by carcinoma. In conclusion, non-neoplastic polyps are seen in 3% of cholecystectomies and are often small. Injury-related fibromyoglandular polyps are the most common. Cholesterol polyps have distinctive cauliflower architecture, often in a background of uninjured gallbladders with cholesterolosis and may lack the cholesterol-laden macrophages in the polyp itself. Although dysplastic changes can involve non-neoplastic polyps, they do not seem to be the cause of invasive carcinoma by themselves.

Rapamycin and WYE-354 suppress human gallbladder cancer xenografts in mice.

Gallbladder cancer (GBC) is a highly malignant tumor characterized by a poor response to chemotherapy and radiotherapy. We evaluated the in vitro and in vivo antitumor efficacy of mTOR inhibitors, rapamycin and WYE-354. In vitro assays showed WYE-354 significantly reduced cell viability, migration and invasion and phospho-P70S6K expression in GBC cells. Mice harboring subcutaneous gallbladder tumors, treated with WYE-354 or rapamycin, exhibited a significant reduction in tumor mass. A short-term treatment with a higher dose of WYE-354 decreased the tumor size by 68.6% and 52.4%, in mice harboring G-415 or TGBC-2TKB tumors, respectively, compared to the control group. By contrast, treatment with a prolonged-low-dose regime of rapamycin almost abrogated tumor growth, exhibiting 92.7% and 97.1% reduction in tumor size, respectively, compared to control mice. These results were accompanied by a greater decrease in the phosphorylation status of P70S6K and a lower cell proliferation Ki67 index, compared to WYE-354 treated mice, suggesting a more effective mTOR pathway inhibition. These findings provide a proof of concept for the use of rapamycin or WYE-354 as potentially good candidates to be studied in clinical trials in GBC patients.

Preneoplastic lesions in gallbladder cancer.

BACKGROUND: Gallbladder cancer is an uncommon disease except in countries like Chile and areas of India and Japan. The knowledge regarding the etiology and mechanisms through which this neoplasia is developed is significantly less compared to other malignant tumors. RESULTS: The epithelial lesions involved in gallbladder carcinogenesis are dysplasia and adenomas that represent two biologically distinct carcinogenetic models. Dysplasia progresses to carcinoma in situ (CIS) and subsequently becomes invasive. Over 80% of invasive gallbladder cancers present areas adjacent to the CIS and epithelial dysplasia. Other authors have demonstrated adenomatous areas in carcinomas, or malignant transformation in an adenoma. The low incidence of gallbladder adenomas (0.14% of cholecystectomies) and the presence of adenomatous remnants in the neighboring mucosa to early carcinomas in less than 3% of the cases suggest the limited importance of this carcinogenic pathway. Epithelial dysplasia which is not associated with gallbladder cancer is observed in approximately 1% of cholecystectomies for symptomatic lithiasis. Metaplasia, dysplasia, and CIS are present in the mucosa adjacent to the cancer in 66%, 81.3%, and 69%, respectively. The average ages of patients with dysplasia not associated to cancer (51.9 years), early carcinomas (56.8 years), and advanced carcinomas (62.9 years) demonstrate a gradient which suggests the progression of these lesions. CONCLUSIONS: From the morphological point of view, the dysplasia-carcinoma sequence is the most plausible carcinogenic pathway for gallbladder cancer, a process which would require a period of approximately 10 years.

[DNA content and survival in subserous gallbladder carcinoma]. / Contenido de ADN y sobrevida en el carcinoma subseroso de la vesícula biliar.

BACKGROUND: The clinical and morphological characterization of the subserous gallbladder carcinomas is controversial. AIM: To study the prognostic importance of DNA content of subserous gallbladder carcinoma. MATERIAL AND METHODS: We studied 104 females aged 60+/-12 years old and 16 men aged 70+/-13 years old. In all of them diagnosis was established after mapping of cholecystectomy sample and had a complete clinical follow up. DNA content was measured by flow cytometry. RESULTS: All tumors were adenocarcinoma, and only 16% were well differentiated. Aneuploidy was observed in 29 cases (26%) with DNA index fluctuating between 1.1 and 1.8. Lymphatic vessel tumor involvement was present in 16 of 22 cases with aneuploidy and in 22 of 46 diploid tumors (p=0.05). Eighty nine percent of aneuploid tumors were detected macroscopically and 11% were unapparent. Five years survival was non significantly better among patients with diploid tumors than in patients with aneuploid tumors (45 and 28%, respectively, p=0.2). The histological differentiation was the only variable significantly associated with survival. CONCLUSIONS: Aneuploidy is present in 26% of subserous gallbladder carcinoma. It is not related with any of the morphological or clinical variables studied in this series of patients.

[Clinicopathological features of gallbladder polyps and adenomas]. / Pólipos y adenomas de la vesícula biliar: consideraciones clínico-patológicas.

BACKGROUND: Chile has a high frequency of gallbladder cancer. Polyps are common lesions of gallbladder mucosa but there is little information about their morphological features. AIM: To report the clinical and pathological features of 219 gallbladder polyps. MATERIAL AND METHODS: Cholecystectomites samples in which a polypoid lesion was diagnosed microscopically. In all cases, complete clinical information and digitalized images of the complete surgical specimens was reviewed. RESULTS: In a period of 10 years, 21,412 gall-bladders were processed. Among these, 884 carcinomas were diagnosed and in 219 cases (1%) a polyp was found. One hundred and eighty three patients were females (mean age 49.3 years) and 36 males (mean age 53.4 years). The preoperative diagnosis of gallbladder polyp wars done only in 26 cases (12%). Eighty five percent of polyps were non-neoplastic (metaplastic in 32%, cholesterol in 29%, hyperplastic in 22% and inflammatory in 2%). The remaining 15% were adenomas. Seventy five percent of non-neoplastic polyps were located in the proximal half of the gallbladder and 88% of adenomas in the distal half. Ninety five percent of non-neoplastic polyps measured less than 10 mm. Among adenomas, 47% measured less than 5 mm and 28% more than 10 mm. Smaller polyps were of cholesterol and larger polyps were adenomas. Eight adenomas were associated with an adenocarcinoma, two had less than 5 mm length. Mean age of patients with adenomas associated to cancer was higher than patients with pure adenomas (64.6 and 44.3 years respectively, p > 0.001). CONCLUSIONS: There are size and location differences between non neoplastic polyps and adenomas. Adenomas associated to cancer may measure less than 5 mm. Therefore the polyp size criteria to decide surgical behavior in symptomatic gallstone patients may be misleading.

[Detection of bone marrow micrometastases in patients with gallbladder cancer]. / Detección de micrometástasis en médula ósea de pacientes con cáncer de vesícula biliar.

BACKGROUND: There is a very strong documented correlation between the appearance of cancer cells in blood and occurrence of metastasis in gastrointestinal cancer. AIM: To determine MUC1, CK19, CK20 and CEA mRNA expression in bone marrow of patients with gallbladder cancer and evaluate its clinical significance. MATERIAL AND METHODS: Sixty eight samples were analyzed, 38 bone marrow samples of gallbladder cancer patients, 20 healthy donors, and 10 frozen samples of gallbladder cancer. Nested reverse transcriptase-polymerase chain reaction (nested RT-PCR) was used to analyze mRNA expression. RESULTS: All frozen tumors were positive for CEA, CK19, and MUC1 mRNA and 70% were positive for CK20. Seventeen of 20 donor samples were positive for MUC1 and only one sample from donors was positive for both CK20 and CK19 mRNA. Among the 38 blood and bone marrow samples of gallbladder cancer patients, the expression of MUC1, CK19, CK20, and CEA, mRNA was 60.5% (23/38), 31.6% (12/38), 7.9% (3/38), and 7.9% (3/38), respectively. Disregarding the MUC1 results. 37% (14/38), 13% (5/38) and 5% (2/38) were positive for one, two and three markers respectively. Not significant differences were found in survival with a follow up to 12 months. CONCLUSION: Our results indicate that the molecular detection of tumor cells in bone marrow in patients with gallbladder carcinoma is technically possible, being CEA, CK19 and CK20 gene expression the best markers. The MUC1 gene expression marker was highly unspecific and it should not been considered. The detection of bone marrow micrometastasis might be helpful in prognosis and the selection of clinical treatment but a larger series with a longer follow-up should be studied.

[Morphological prognostic elements in gallbladder cancer]. / Elementos morfológicos pronósticos en el cáncer de la vesícula biliar.

BACKGROUND: The exact survival rates and prognostic factors of gallbladder cancer are still incompletely known. AIM: To report the actuarial survival of patients with gallbladder cancer. MATERIAL AND METHODS: Six hundred thirty seven women, aged 59 years old as a mean and 108 men, aged 64 years old as a mean, with gallbladder cancer are reported. Patients were followed for up to 150 months. RESULTS: Two hundred twenty four patients had an early and 521 had an advanced carcinoma. Overall survival was 38% at ten years. Sex or ethnic origin did not influence survival. Early tumors had a 92% survival at 10 years whereas the survival of advanced tumors was 16% at 5 years. Subserous tumors had a 5 years survival of 32% whereas serous tumors had a 5 years survival of 11%. Well-differentiated advanced tumors had a significantly better survival than moderately or poorly differentiated tumors. Vascular or lymphatic infiltration was also associated to a lower survival. All patients with advanced tumors and vascular infiltration died before 5 years. CONCLUSIONS: Tumor infiltration and differentiation degree were the most important prognostic independent factors in gallbladder cancer.

[Is gallbladder cancer a disease with bad prognosis?]. / Es el cáncer de la vesícula biliar una enfermedad de mal pronóstico en Chile?

Gallbladder cancer is frequent in Chile, but it is not uniformly mortal. The diagnosis is usually made after a cholecystectomy, indicated for a symptomatic cholelithiasis. Global survival of gallbladder cancer can be as high as 40% at five years. In 69% of women of less than 30 years old, the tumor is detected in early stages. In these cases, cholecystectomy is the curative procedure, with a 90% survival at five years. According to our experience, cholecystectomies should be performed between 40 and 50 years of age in men and between 30 and 40 years in women. The prognostic factors that should be considered are symptoms associated to lithiasis, age, parity, obesity, size of stones and the size of the gallbladder. If the tumor is detected in early stages, the survival is good. The natural history of the disease would change significantly if all women with symptomatic stones were operated.