Gallbladder carcinoma (GBC)

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Carcinoma involving the gallbladder: a retrospective review of 23 cases - pitfalls in diagnosis of gallbladder carcinoma

Carcinoma involving the gallbladder: a retrospective review of 23 cases - pitfalls in diagnosis of gallbladder carcinoma

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.

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Prognostic significance of muc4 expression in gallbladder carcinoma

Prognostic significance of muc4 expression in gallbladder carcinoma

MUC4 has been shown to function in cell growth signal- ing through interaction with the ErbB2 family of growth factor receptors and activation of ErbB2 downstream signaling pathways, resulting in cell proliferation and survival [14,26,27]. A recent study by Miyahara et al. showed that MUC4 is upregulated and interacts with ErbB2 in gallbladder carcinoma [28]. MUC4 can also promote tumor progression by repressing apoptosis by means of multiple mechanisms. The effects of MUC4 on conferring resistance to apoptosis have been found to be mediated by both ErbB2-dependent and ErbB2- independent mechanisms, indicating that tumor cells could exploit the versatile anti-apoptotic activities of MUC4 to acquire resistance to therapeutic agents, and aug- ment cell survival [29]. Repression of MUC4 expression might be a therapeutic target for eliminating some of those resistance mechanisms. However, the molecular mechan- isms underlying MUC4 anti-apoptotic activity have not been well characterized and need to be investigated.

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Curcumin induces apoptosis in gallbladder carcinoma cell line GBC-SD cells

Curcumin induces apoptosis in gallbladder carcinoma cell line GBC-SD cells

Curcumin, a phenolic compound present in Zingiberaceae Curcuma longa, rhizoma zedoariae, turmeric, etc., has been shown to have anticarcinogenic [9-11] and anti- inflammatory properties [12], including an inhibitory effect on the production of various cytokines. Curcumin has attracted much attention because of its low price and low toxicity, as well as its wide pharmacological and potential anticancer effects. It is believed that the anticancer mech- anism of curcumin is mainly in inducing the apoptosis of cancer cells [13-15] and suppressing metastasis [16-18]. The apoptosis induced by curcumin is due to the activa- tion of a multi-signal transduction pathway. Curcumin in- duces apoptosis in breast cancer cell lines, and the activation of apoptosis was confirmed by PARP-1 cleavage and by the increased ratio between the pro-apoptotic Bax and the anti-apoptotic Bcl-2 proteins [19]. Moreover, apigenin and curcumin synergistically induced cell death and apoptosis and also blocked cell cycle progression at the G2/M phase of A549 cells [20]. Although curcumin has been found to induce apoptosis in several types of cancers, the molecular apoptotic mechanisms of curcumin in the gallbladder carcinoma cell line GBC-SD have not previously been investigated.

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Guided chemotherapy based on patient-derived mini-xenograft models improves survival of gallbladder carcinoma patients

Guided chemotherapy based on patient-derived mini-xenograft models improves survival of gallbladder carcinoma patients

Currently, gemcitabine, oxaliplatin, 5-fluorouracil, nab-paclitaxel, and irinotecan are the five most poten- tially effective agents for gallbladder carcinoma patients [26]. Single or combination chemotherapies of these drugs have shown improved median survival rates of gallbladder carcinoma patients. However, further clini- cal application of these drugs are often impeded by the uncommon nature of gallbladder carcinoma and efficacy data are mostly based on studies from other biliary tract tumors like intrahepatic or extrahepatic cholangiocar- cinoma, which are now considered to be different from gallbladder carcinoma [12, 27]. In this study, an improved prognosis was observed when the effectiveness of five chemotherapeutic drugs were separately tested using mini-PDX models, after which the two most effective drugs identified were prospectively prescribed to gall- bladder carcinoma patients. This personalized treatment provides a scientific rationale for clinical therapy and avoids the side effects from clinical experience-guided medication. Aside from cytotoxic chemotherapeutic agents, several targeted agents against EGFR, VEGF or MEK have also been reported to be useful in treating gallbladder cancer. Therefore, our mini-PDX model could be suitable for preclinical testing of the effectiveness of these drugs in the coming future.

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Long-term survival of a patient with recurrent gallbladder carcinoma, treated with chemotherapy, immunotherapy, and surgery: a case report

Long-term survival of a patient with recurrent gallbladder carcinoma, treated with chemotherapy, immunotherapy, and surgery: a case report

Case presentation: A 59-year-old man underwent an extended cholecystectomy for GBC (pathological stage II, T2 N0 M0, [per UICC 7th edition]) that was incidentally found during cholelithiasis surgery, and was then treated with adjuvant gemcitabine (GEM). Three months later, when a recurrence-suspected lesion was detected in segment 5 (S5) of his liver, we started adoptive immunotherapies with cytokine-activated killer (CAK) cell infusions, combined with chemotherapy. After a year of adjuvant immunochemotherapy, the S5 lesion disappeared on imaging, but lesions suspected metastatic recurrence again appeared in S7 and S8 at 4 years and 6 months post-surgery, for which GEM and cisplatin (CDDP) were administered as second-line chemotherapy. Immunochemotherapy produced stable disease (per RECIST) for 9 months, when tumor growth was detected; open microwave coagulo-necrotic therapy (MCN) was performed for these lesions. Three years after MCN, a solitary liver metastasis was detected in S4. MCN was conducted again, and peritoneal dissemination was found intraoperatively. A month after the second MCN, the patient ’ s

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Clinicopathological significance of SOX4 expression in primary gallbladder carcinoma

Clinicopathological significance of SOX4 expression in primary gallbladder carcinoma

plays a key role in many aspects of development, includ- ing sex determination, testis formation, neuronal devel- opment, lymphocyte differentiation and chondrogenesis [3]. Members in this family share the highly conserved HMG box, which mediates binding of SOX proteins to a short-target DNA sequence directly [4]. In vertebrates, there have been more than 20 genes identified as mem- bers of SOX family, and they have been categorized into groups A-G according to their sequence similarity. SOX4, one of group-C SOX genes, has been shown to be involved in a range of developmental processes, such as embryonic cardiac development, nervous system development, osteoblastic differentiation, and thymocyte development [5]. The SOX4 gene encodes a protein of 474 amino acids with three distinguishable domains: an HMG box, a glycine-rich region and a serine-rich region. The HMG box serves as a DNA-binding region, whereas the serine-rich domain serves as a transactiva- tion domain [6]. The central domain containing the gly- cine-rich region located between the HMG box and serine-rich domains serves as a novel functional region for promoting apoptotic cell death [7]. Recently, it has been demonstrated that SOX4 is involved in tumorigen- esis of many human malignancies. The up-regulation of SOX4 has been detected in breast cancer, pancreatic cancer, lung cancer, prostate cancer, colon cancer, meduloblastoma, ovarian cancer and hepatocellular car- cinoma [8-12]. In addition, Aaboe et al. [13] found that the strong SOX4 expression was correlated with increased survival of patients with bladder cancer, and it also impaired tumor cell viability and promoted apop- tosis. Hur et al. [14] reported that SOX4 contributes to hepatocarcinogenesis by inhibiting p53-mediated apop- tosis and that its overexpression might be a useful prog- nostic marker for better survival in patients with hepatocellular carcinoma after surgical resection. How- ever, its role in PGC is still largely unknown. To address this problem, the aim of this study was to investigate SOX4 expression in PGC and its prognostic significance.

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Surgical Treatment and Prognosis Analysis of Primary Carcinoma of Gallbladder

Surgical Treatment and Prognosis Analysis of Primary Carcinoma of Gallbladder

Surgery should be given priority in the treatment of gallbladder carcinoma, and different surgical methods should be selected according to the Nevin grading and individual differences. The surgical methods of gallbladder carcinoma include: cholecystectomy, expanded cholecystectomy (cholecystectomy + lymph node dissection), radical surgery of gallbladder carcinoma (cholecystectomy + lymph node dissection + wedge resection of the gallbladder bed), and expanded radical surgery of gallbladder carcinoma (basic radical surgery of gallbladder carcinoma + expanded hepatectomy + resection of adjacent involved organs + biliary tract reconstruction). Generally, the early stage (Nevin I and II) gallbladder carcinoma patients are merely in need of cholecystectomy The advanced stage (Nevin III and IV) patients should be subjected to radical or palliative surgeries according to the status per se. In this study, the 1-, 3- and 5-year survival rates of the radical surgery group were apparently higher than those of the palliative surgery group. Therefore, basic or expanded radical surgeries are preferred. Todoroki et al. [12] reported that the 5-year survival rate of the radical surgery group was 35.5%, and 24 patients even survived for more than 5 years. The 1-year survival rate of the expanded radical surgery group (maximum: 965 days) was 67.1%, but all the patients who did not receive resection surgeries died within only 1 year. Thus, an expanded surgery

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Routine histopathology of gallbladder after elective cholecystectomy for gallstones: waste of resources or a justified act?

Routine histopathology of gallbladder after elective cholecystectomy for gallstones: waste of resources or a justified act?

The practice of discarding gallbladder specimen is standard in most tertiary care hospitals of Pakistan in- cluding the primary investigator’s own institution on the pretext that “surgeon knows best which gallbladder is to be sent to laboratory”. Histopathology is restricted to only those specimens, which show gross abnormalities. This practice is based on the assumption that gallbladder carcinoma is always associated with macroscopic abnor- malities. At the same time, this selective approach is justified by claiming that it reduces patient’s financial li- abilities and pathologist’s workload. This contradicts to the worldwide practice where gallbladder specimen is in- variably sent for histological analysis for the sole purpose of identifying discrete carcinoma in early stage.

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Undifferentiated giant cell type carcinoma of the gallbladder with sarcomatoid dedifferentiation: a case report and review of the literature

Undifferentiated giant cell type carcinoma of the gallbladder with sarcomatoid dedifferentiation: a case report and review of the literature

The patient in this case report presented with a clinical picture of a gallbladder empyema. This clinical diagnosis was furthermore supported by the radiological as well as the intra-operative findings. The diagnosis of gallbladder neoplasm was only made following histopathological evaluation of the resected specimen. The 2 cm solid lesion obstructed the lumen in the neck of the gallbladder, thus leading to the clinical presentation and the imaging and intra-operative findings of gallbladder empyema in our patient. Incidental finding of gallbladder carcinoma follow- ing cholecystectomy for symptomatic cholelithiasis, acute cholecystitis, gallbladder empyema or even asymptomatic cholelithiasis has also been observed by others [3 – 5]. Our case proved difficult to classify. The final histopatho- logical diagnosis resulted from a combination of mor- phology and immunohistochemistry. The morphological characteristics were those of a tumour of epithelial origin. The positive response to CAM5.2, a strong epithelial marker, was an additional characteristic for a carcinoma. According to the World Health Organization (WHO) 2000 classification, undifferentiated carcinoma lacks glandular structures; in the presented case, there was no evidence of such structures, leading to the diagnosis of an undiffer- entiated gallbladder carcinoma. The neoplastic tissue consisted of diffusely arranged giant cells, with scattered multinucleated cells. The multinucleated cells were mor- phologically and immunohistochemically compared to those of primary giant cell tumours as well as to osteoclast- like giant cells and were shown to resemble the latter more closely. The unusual feature of the immunophenotype of

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Risk factors of gallbladder cancer in Karachi a case control study

Risk factors of gallbladder cancer in Karachi a case control study

This study found statistically significance positive corre- lation of gallbladder carcinoma with large sized and soli- tary gall stones. Multi-parity and increase age seems to play an important role in causation of GC. Based on the results of the present study, a case can be made for pro- phylactic cholecystectomy as a preventive strategy in a high risk group of patients with asymptomatic gall- stones. Early elective cholecystectomy for symptomatic gallstones may reduce the chances of gallbladder carci- noma in countries where there is reported high inci- dence of GC including South of Pakistan (Karachi). Table 2 Multivariate regression analysis showing risk factors for gallbladder cancer

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Expression Analysis of Aquaporin 1 (Aqp 1) in Human Biliary Tract Carcinoma

Expression Analysis of Aquaporin 1 (Aqp 1) in Human Biliary Tract Carcinoma

Background: Aquaporins (AQPs) are important in controlling bile water secretion. AQP is related to the invasion and metastasis of cancer. However, the relationship of biliary tract cancer is not clear. The role of AQP-1 in cancer cell is also unknown. Methhods: We analyzed AQP-1 expression using tissue microarray (TMA) in 99 samples immunohistochemically (50 gallbladder carcinoma, 39 bile duct carcinoma and 10 Papilla Vater carcinoma patients who underwent surgery at our department from 1997 to 2011). Gene expressions were evaluated by the combination of the im- munohistological intensity and distribution. The expression level is compared to the clinico-pa- thological data of the patients. Results: In the TMA, depth of tumor invasion and histological type are associated with AQP-1 expression. The group of patients with high AQP-1 expression is asso- ciated with higher rates of disease specific survival (log-rank p = 0.013). Cox’s proportional hazard model reveals that AQP-1 expression is an independent prognostic factor (RR, 0.324; p = 0.001) in multivariate analysis. There is a correlation between AQP-1 expression and tumor invasion. Con- clusions: These observations of this study suggest that AQP-1 expression may be favorable bio- markers associated with prognosis and tumor invasion in biliary tract carcinoma.

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Two Cases of Small Cell Carcinoma of the Gallbladder

Two Cases of Small Cell Carcinoma of the Gallbladder

Approximately 7000 new cases of gallbladder carcinoma are diagnosed every year [1]. It is a disease process characterized by its insidious onset and advanced stage at presentation, often rendering resection impossible and resulting in an overall median survival of six months [2]. First described in 1981, gallbladder neuroendocrine carcinomas make up a small fraction of this already uncommon tumor [3]. These tumors may be secretory with symptoms arising due to the production of biologically active peptides [4]. Conversely, they can be nonsecretory with symptoms presenting due to mass effect and disease progression. The overall five-year survival rate for gallbladder cancer is approximately five percent [5]. The survival rate for neuroendocrine carcinomas is even less due to its high malignant potential and late stage at presentation [6, 7]. Herein, we report two cases of neuroendocrine carcinoma diagnosed and resected in otherwise healthy individuals.

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Chromosomal structural analysis in carcinoma of the gallbladder

Chromosomal structural analysis in carcinoma of the gallbladder

aberrations. The simple aberrations were observed in four patients. These aberrations were confined on chromosome 1’s long arm. Another aberration was a translocation from the long arm of chromosome 4 to the long arm of chromosome 6. An interesting observation is that all the aberrations were present in the male karyotype. The cause of this breakage in chromosomes of gallbladder patients is unknown, but its association with gallbladder carcinoma is suggested. It may be due to environmental effects, infections and inflammation but further work is needed to establish a definite relation between these aberrations and gallbladder cancer. The prevalence of aberrations in our study is quite high, that is, 16.6%. So, we can presume that this will help to find the correlation between such aberrations and gallbladder cancer. Further research will clarify an understanding of the role of chromosomal anomalies in CaGB.

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An Alternative Approach to Sending All Gallbladders for Histology Following Cholecystectomy?

An Alternative Approach to Sending All Gallbladders for Histology Following Cholecystectomy?

Of the 2696 patients that were included in the study, 662 (24.5%) were male and 2034 (75.5%) were female. The minimum age of patient that underwent a cholecystec- tomy was 8 years old and the oldest 90 years old. The median age was 51.2 years old. 738 patients (27%) were ≤40 years old; 1069 patients (40%) were between 41 and 59 years old and 889 patients (33%) were ≥60 years old at the time of their cholecystectomy. 7 patients (0.26%) were found to have carcinoma of the gallbladder, all of which were female. The ages of the patients that were positive for gallbladder carcinoma ranged from 59 to 90 years old with an average of 75.4 years. 5 out of the 7 gallbladder carcinoma patients (71.4%) satisfied the cri- teria for pre-operative suspicion of carcinoma on the ba- sis of radiological investigation. Of the 5 patients that had pre-surgical suspicion of carcinoma all of them had further investigations which also reinforced suspicion of carcinoma. All 7 patients (100%) satisfied the criteria in the study for being referred to histology on suspicion of cancer on the basis of intra-operative macroscopic ab- normalities including patient 4 in which an investigative laparotomy led to a biopsy diagnosing the carcinoma (Carcinoma of the gallbladder was suspected during the operation which led to the biopsy taking place). 1 patient (0.04%) was diagnosed with non-specific adenocarci- noma, 2 patients (0.07%) were diagnosed with poorly differentiated adenocarcinoma and 4 patients (0.15%) were diagnosed with moderately differentiated adenocar- cinoma of the gallbladder (Table 2).

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Clinicopathological features and CCT2 and PDIA2 expression in gallbladder squamous/adenosquamous carcinoma and gallbladder adenocarcinoma

Clinicopathological features and CCT2 and PDIA2 expression in gallbladder squamous/adenosquamous carcinoma and gallbladder adenocarcinoma

For the first time, we found that positive CCT2 expres- sion in both SC/ASC and AC subtypes was significantly associated with clinicopathological features, including large tumor size, high TNM stage, and lymph node metastasis. Moreover, positive expression of CCT2 in AC also correlated with poor differentiation and adjacent tissue invasion. These results, taken together, suggest an important role for CCT2 in GBC progression. Given the critical role of CCT2 in assisting the folding of actin, tubulin, and other cytosolic proteins [14,15], we assumed that the increased CCT2 expression in GBC cells might be critical for these cells to meet the increased levels of protein folding required during fast growth. In line with this hypothesis, overall survival analysis showed that the survival time of patients with positive CCT2 expression was significantly shorter than that of patients with CCT2 negative expression. Moreover, CCT2 is identified as an independent prognostic biomarker for both SC/ASC and

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Mixed neuroendocrine non neuroendocrine carcinoma of gallbladder: case report

Mixed neuroendocrine non neuroendocrine carcinoma of gallbladder: case report

progressing tumor in the gallbladder and liver area. The patient reported several-month right upper quadrant pain and 4-kg weight loss over the past year. There was no la- boratory sign of obstructive jaundice at the day of admis- sion. Preoperative CT and MR scan (Figs. 5 and 6) of the liver was performed, and the patient was diagnosed with a tumor in the gallbladder area with a relatively massive in- filtration of the S5 and S6 liver segments and extensive re- gions of necrosis. Given the potentially resectable lesion according to preoperative imaging, exploratory laparot- omy was indicated to attempt radical resection. During the exploration, a voluminous tumor was found attached to the peritoneum. Intraoperative ultrasound was per- formed and revealed a tumor originating from the gall- bladder bed area and reaching up to the area of the hepatic hilum and extensive involvement of the hepato- duodenal ligament by the tumor through the lymph nodes. The tumor was classified as inoperable due to this finding. But during the exploration, however, a rupture of the fragile tumor occurred with massive eruption of the necrotic mass and the gallbladder content into the ab- dominal cavity, accompanied by bleeding of the liver par- enchyma. We decided that the condition could only be managed by attempting modified resection. We per- formed cholecystectomy and non-anatomical resection of hepatic segments S5 and S6 and partial resection of S4 without lymphadenectomy as a debulking operation (Fig. 7). The course of hospitalization was uncomplicated, and the patient was discharged to home care on postoper- ative day 9. Histologically, the tumor was confirmed as MINEN of gallbladder (Figs. 1, 2, and 3), and its non-neu- roendocrine component had the character of moderately differentiated tubular gall bladder adenocarcinoma, while the neuroendocrine component had the appearance of small cell carcinoma and was dominant, accounting for more than 65% of the viable tumor. The neuroendocrine component contained extensive necrosis, with mitotic

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Handling Inconsistency in Knowledge Bases

Handling Inconsistency in Knowledge Bases

Gallbladder cancer is a rare disease with an overall poor prognosis. Because of its rarity, studies examining important clinicopathologic factors and management strategies for GBC are often limited to single-institution series and small patient cohorts. In this study, we utilized a large, multi-institutional database to investigate the importance of method of diagnosis (incidental versus non-incidental) in relation to other prognostic factors on overall survival. We found that, overall, non-IGBC was associated with more advanced disease than IGBC, yet even accounting for other poor prognostic factors, it was still independently associated with worse OS. On stage-specific analysis, non-IGBC was associated with worse OS only among Stage III patients, but not Stages I, II, and IV. Although not associated with survival among all patients, adjuvant therapy was also associated with improved OS among only Stage III patients. On further analysis, we found that adjuvant therapy was associated with improved OS only among Stage III IGBC patients, but not Stage III non-IGBC patients.

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A dural metastatic small cell carcinoma of the gallbladder as the first manifestation: a case report

A dural metastatic small cell carcinoma of the gallbladder as the first manifestation: a case report

Meningioma is a common benign tumor that accounts for 20% or more of primary brain tumors [1, 2]. A dural metastasis mimics meningioma, although its treatment and prognosis can be different from meningioma. In general, carcinomas of the breast and lung in females and prostate in males have been the most commonly re- ported primary lesions of dural metastases [3, 4]. How- ever, tumors from uncommon primary lesions with dural metastases have increasingly been cited. Gallblad- der carcinoma, which has a high rate of lymph node or liver metastases, is a rare primary lesion of intracranial dural metastases. Small cell carcinoma (SCC) is a rare

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Long noncoding RNAs as potential biomarkers and therapeutic targets in gallbladder cancer: a systematic review and meta-analysis

Long noncoding RNAs as potential biomarkers and therapeutic targets in gallbladder cancer: a systematic review and meta-analysis

Studies from the literature search were included based on the following criteria: (1) LncRNA expression was detected in gallbladder cancer tissues; (2) the diagnosis of gallbladder cancer was confirmed by pathology and his- tology; (3) the relationship between lncRNA expression and gallbladder cancer patient prognosis was investi- gated, including survival and clinicopathological param- eters; and (4) sufficient data were provided for the hazard ratio (HR) and the 95% confidence interval (95% CI) of survival or the odds ratio (OR) and the 95% CI of clin- icopathological parameters. Meanwhile, unsuited studies were excluded by the following criteria: (1) animal stud- ies, reviews, editorials and letters; (2) duplicate records; and (3) studies without sufficient data.

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A gallbladder tumor revealing metastatic clear cell renal carcinoma: report of case and review of literature

A gallbladder tumor revealing metastatic clear cell renal carcinoma: report of case and review of literature

A 55-year-old woman presented with severe right hypo- chondrium pain, with weight loss and alteration of her general condition, lasting for 6 months. She showed no urological signs, especially no hematuria, no pain, and no flank mass. She had no past history in particular. Nei- ther physical examination nor laboratory examination revealed any significant findings. Abdominal ultrasonog- raphy showed a 2.6 cm diameter intraluminal polypoid hyperechoic mass in the gallbladder. Color Doppler ultra- sonography examination demonstrated vessels in the mid-portion of the mass. Computed tomography scan confirmed the presence of a gallbladder tumor that appeared as an enhancing pedunculated tumor within the gallbladder, without thickening of the gallbladder wall. The tumor seemed to be attached to the edge of the liver with no macroscopic extension to the liver parenchyma (Figure 1). Furthermore, TDM scan showed a cortical fleshy nodule of the right kidney, measuring 2.2 cm, with no involvement of the perinephric adipose (Figure 2). The biliary symptoms and pedunculated appearance of the tumor on the TDM scan suggested a possible diagnosis of

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