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Carcinosarcoma of gallbladder: A world review

BACKGROUND Gallbladder carcinosarcoma is a rare hepatobiliary tumor comprising of both carcinomatous and sarcomatous components. Due to its rarity, the literature with regards to the topic is scarce and currently lacking, spanning less than 100 cases. AIM To summarize the current literature on gallbladder carcinosarcoma. METHODS A literature review was performed on the PubMed database using the keywords “Gallbladder” AND “Carcinosarcoma” from 1970 to 2021. Additionally, similar searches were performed on MEDLINE and Web of Science. RESULTS Risk factors noted include female gender, gallstones and chronic cholecystitis. In the absence of any diagnostic biochemical testing or tumor markers, imaging modality serves as the key initial impression tool, which can be histologically confirmed only post-resection. While surgery is the only curative option, the use of adjunctive chemotherapy has been considered on top of excision in recent years, with some success. CONCLUSION While this study has taken steps to bridge the gap in the literature, more cases should be reported to further ascertain the current associations and management potential for gallbladder carcinosarcoma.


INTRODUCTION
Gallbladder carcinosarcoma (GBCS) is defined by the presence of both carcinomatous and sarcomatous components in the tumor, making it a rarity even amongst the uncommon gallbladder cancer family [1]. While its history is deep-rooted, with the first case being reported by Karl[2] in 1907, less than 100 cases have been reported since. In 2008, Zhang et al [3] sought to collectively analyze the 70 cases in the literature at that time. However, Zhang et al [3] noted the need for a larger scale case series to provide more information on the neoplasm for better accuracy and reliability. Since then, there has been a gap in the literature for such an analysis (Figure 1). This study aims to fill this gap by providing a comprehensive overview of GBCS.

MATERIALS AND METHODS
A literature review was performed on the PubMed database using the keywords "Gallbladder" AND "Carcinosarcoma" from 1970 to 2021. Additionally, similar searches were performed on Medline and Web of Science. The last search was performed on January 31, 2021. After removing duplicate results from similar databases, the search yielded 105 articles: 16 non-English and non-Japanese studies and 12 unrelated topics (animal studies, gallbladder carcinoma and non-gallbladder pathology) were excluded. Out of the remaining 77 articles, seven were not case reports or case series on GBCS and thus excluded. The remaining 70 articles including 76 patients were included in the final analysis (Table 1) [1,. Article filtering and exclusion was done according to PRISMA guidelines ( Figure 2). Data extracted included study year, age and gender of the patient, clinical presentation, risk factors, laboratory investigations, tumor markers, the ultrasound imaging findings, location of the lesion within the gallbladder, size of the lesion, initial diagnosis, method of confirming the diagnosis, immunohistochemical results (vimentin, cytokeratin, Ki-67), management and prognosis of the patient. Kaplan-Meier survival curves were compared between lesions larger than 5 cm and those smaller than 5 cm as data by Zhang et al [3] suggested that tumors smaller than 5 cm had better survival. For all statistical tests, a P value of 0.05 was used to determine statistical significance.

DISCUSSION
Gallbladder cancer is a rare neoplasm, accounting for about 0.5% of all gastrointestinal malignancies [73]. Most common gallbladder cancer is adenocarcinoma. GBCS is a rare form of gallbladder cancer, with only 78 cases reported. GBCS is characterized by carcinomatous and sarcomatous components and is made up of both epithelial and mesenchymal components. Commonly, the epithelial component consists of adenocarcinoma followed by the less common squamous cell carcinoma [74]. While there are multiple theories to justify the mixture of the epithelial and mesenchymal components, there is no consensus on the pathophysiology of the neoplasm. GBCS is considered the most aggressive biliary tract malignancy, usually discovered at late stages, and has poor prognosis[3].

Incidence
In terms of patient demographics, our results are consistent with the report of Zhang et al [3]. In a report including 68 GBCS patients, those authors reported a median age of 68 years (range: 45 to 91 years) with female predominance (female:male = 2.7:1), consistent with our results with a gender ratio of 2.32 and a mean age of 66.0 years (range: 40-91 years). Female preponderance is likely due to increased prevalence of gallstones in females. Zhang et al [3] noted gallstones in 66.7% of their patients. In our study, the incidence of gallstones was high (83%). However, gallstone presence was not specific nor sensitive in the diagnosis of GBCS, as not only are they a common finding in cancers of the gallbladder, only 1%-5% of patients with gallstones develop gallbladder malignancies. In our analysis of the literature, gallstone presence was only noted in 83.3% of patients where the presence of gallstones was assessed.
APBJ is also another risk factor of gallbladder malignancy [12]. Matsubayashi et al [12] reported a 72-year-old female patient with symptoms of abdominal pain. Laboratory investigations revealed raised alkaline phosphatase and gamma-glutamyl transpeptidase. CT scan confirmed a polypoid gallbladder mass. Magnetic resonance cholangiopancreatography scan showed ABPJ, and this was confirmed at subsequent endoscopic retrograde cholangiopancreatography. While APBJ is a well-known risk factor for gallbladder cancers[75], this was the first case of APBJ in GBCS noted in the literature.
Other risk factors mentioned include chronic cholecystitis, which could be both a risk factor and the manifestation of gallbladder malignancy. Unique to the gallbladder is a cycle of gallbladder epithelium damage and repair, enabling a chronic inflammatory environment from chronic cholecystitis [76]. This cycle of inflammation, injury, repair and regeneration increases cell turnover and oxidative stress. Yildiz et al [77] stated biliary tract to be the "consummate example of inflammation-associated carcinoma". Chronic inflammation from gallstone disease can lead to protein damage, genetic mutations, inhibition of apoptosis, promotion of angiogenesis, modulation of cell adhesion and motility as well as immunosuppression. Chronic cholecystitis leads to gallbladder wall thickening, and CT or magnetic resonance imaging (MRI) scans are sensitive to detect wall thickness. However, it is not possible to distinguish if thickening of the gallbladder wall is due to inflammation or malignancy [78]. Thus, multidisciplinary discussion involving experienced radiologists and hepatobiliary surgical team is essential to make management plans for patients with suspicious gallbladder lesions.

Signs and symptoms
Clinical manifestations of GBCS are nonspecific, with symptoms such as abdominal pain localized to the right upper quadrant, constitutional symptoms, nausea, vomiting and fever. The mechanism resulting in constitutional symptoms in patients with cancer is multifactorial and not yet fully understood. It is thought that multiple pathways involving pro-cachectic and pro-inflammatory signals from tumor cells along with systemic inflammation of the host combine with widespread metabolic changes contribute to the manifestations of symptoms like anorexia and cachexia [79]. In particular, cholecystokinin is an integral peptide involved in satiety and regulating diet intake [80]. Given its role in gallbladder contraction, dysregulation of cholecystokinin could be involved in the manifestation of constitutional symptoms of anorexia in patients with GBCS.
Similarly, the pathophysiology of febrile response in malignancies is complex. Released pyrogenic cytokines from tumor cells and tissue macrophages induces a chain of events that result in reset of hypothalamic thermostat due to prostaglandin E2 and related pathways [81]. On physical examination, the presence of a right hypochondria tenderness or mass is not specific, and it does not rule out malignancy. Thus, if a patient is managed for suspected acute or chronic cholecystitis, a follow-up physical examination and imaging needs to be arranged to document resolution of inflammatory process. In this review, 2 asymptomatic patients were diagnosed with GBCS.

Biochemical investigations
Biochemical abnormalities in GBCS are also mostly nonspecific. The most common derangements were transaminitis, hyperbilirubinemia and anemia. This was consistent with Ayoub et al [5] who reported that hepatic and inflammatory markers were often normal.
Presurgical diagnosis of gallbladder malignancies is difficult due to its varying presentations. Differentials to consider for such lesions when calcification is present include calcified gallstones, porcelain gallbladder and GBCS [78]. Our analysis noted cases where GBCS was initially diagnosed with cholelithiasis, acute cholecystitis, gallbladder empyema, diffuse peritonitis, pancreatic cancer and pyogenic liver abscess.

Imaging
As there are no radiological signs identified in the current literature that distinguishes GBCS from other gallbladder malignancies[50,51], the diagnosis is difficult even with imaging. For instance, Appelman et al [72] described a 91-year-old male presenting with yellow sclera, pale stools, dark urine and pruritus. His liver function tests were deranged with obstructive pattern, and a diagnosis of pancreatic cancer with biliary tract obstruction was made. The patient refused surgical intervention and died within 2 wk. Autopsy confirmed the diagnosis of metastatic disease with GBCS primary.
Khurram et al [4] reported a 64-year-old lady presented with right upper quadrant mass, intermittent fever and abdominal distension following a recent travel history to Ghana. CT scan revealed a hepatic lesion with coexisting gallbladder distension consistent with pyogenic liver abscess. Due to failure to respond to intravenous antibiotics, MRI scan was done. MRI scan showed a gallbladder fundus soft tissue lesion with local invasion into the liver [22]. Histopathological diagnosis of GBCS was made after surgical excision. Hence, in the absence of a confirmatory preoperative diagnosis, all suspicious gallbladder lesions must be reviewed at multidisciplinary meetings.
Porcelain gallbladder, gallbladder tuberculosis and xanthogranulomatous cholecystitis are common benign conditions that can be confused with malignancy. Porcelain gallbladder is described as a hyperechoic focus with posterior acoustic shadowing on an ultrasound scan [82]. Ultrasound scan is not sensitive for regional and distant spread of malignancy. CT and MRI scans are more sensitive to detect contiguous spread to liver, regional lymph node involvement and distant metastases. Diffuse nodular thickening without layering, early enhancement, low apparent diffusion coefficient and high lesion to spinal cord ratio are MRI features suggestive of gallbladder cancer [83]. In addition, CT and MRI scans provide details that assist in surgical planning. 18-fluorodeoxyglucose-positron emission tomography-CT can aid in distinguishing between benign and malignant gallbladder lesions. Malignant lesions have high standardized uptake value. In a study reporting 30 patients with a mean age of 48.22 ± 31.33 years and gallbladder wall thickening (focal > 4 mm and diffuse > 7 mm), Gupta et al [84] reported that 18-fluorodeoxyglucose-positron emission tomography had high overall sensitivity (91%), specificity (79%), positive predictive value (77%), negative predictive value (92%) and diagnostic accuracy (84%).

Histological diagnosis
Diagnosis of GBCS is usually made after pathological analysis of a surgical specimen. In patients with unresectable neoplasms, tissue diagnosis can be achieved by percutaneous biopsy. This is essential to plan definitive chemotherapy [85]. In clearly resectable lesions, the role of percutaneous biopsy is debated due to risk of needle-tract seeding [86]. Furthermore, as the gallbladder is a hollow organ, bile spill and peritonitis remain a risk too [87]. As GBCS are rare tumors with poor prognostic outcomes, treatment options are not well defined, with little evidence supporting or refuting any postoperative adjuvant therapy. Okabayashi et al [88] and Mochizuki et al [8] both corroborate that surgical treatment remains the only cure for GBCS. While the histopathological features between GBCS and adenocarcinoma of the gallbladder are different, management is similar.

Surgical management
Currently, the consensus for treatment involves surgical excision of the gallbladder and extrahepatic bile duct, regional lymphadenectomy and even a pancreaticoduodenectomy depending on the extent of the growth [88]. Completion liver resection with or without lymphadenectomy and/or bile duct resection is an accepted standard for post simple cholecystectomy discovered gallbladder cancer with T 1b and higher stage. This approach not only involves two surgeries but also increases the risk of cutting through the tumor with potential for tumor seeding and dissemination. Yip et al[89] in a series of 40 patients with incidental gallbladder cancer reported that the majority of patients were not amenable for further curative resection. A report from Memorial Sloan-Kettering Cancer Centre involving 116 patients showed that survival of patients with residual disease was not different than survival of patients with stage IV disease, and neither group of patients benefit from reoperation [90]. Thus, single surgery may be better.
Radical cholecystectomy has higher morbidity as compared to simple cholecystectomy. Thus, the concept of something intermediate, i.e., extended cholecystectomy, is attractive. Fujisaki et al [91] reported a case describing the concept of laparoscopic extended cholecystectomy with 1 cm liver margin; however, they proposed open conversion when intraoperative histology showed gallbladder cancer invading the subserosal layer. With current advancements, laparoscopic extended cholecystectomy was noted to have lesser intraoperative and postoperative complications than open extended cholecystectomy [92].
The key differences between a 'radical' and 'extended' cholecystectomy are restricting the liver parenchyma transection to the 2 cm wedge of liver tissue and performing regional lymphadenectomy and choledochectomy only in selected patients. Radical cholecystectomy can be done by open, laparoscopic or robot assisted approach, with comparable short-term outcomes [93]. Overall, more data is required to determine the safety and feasibility of minimal access techniques in gallbladder malignancies. Due to the absence of histological diagnosis, management of suspicious gallbladder lesions must be determined by local resources, surgeon experience and access to technology.
In a recent systematic review, Frountzas et al [94] reported that many patients with xanthogranulomatous cholecystitis were managed with complex procedures like wedge hepatic resection and bile duct excision with high open conversion rate (35.0%) at planned cholecystectomy. Intraoperative frozen section analysis is a useful adjunct in surgical planning. While intraoperative frozen tissue diagnosis is relatively reliable to determine whether lesions are benign or malignant, it does not reliably detail the depth of invasion of gallbladder malignancies [95]. Furthermore, the accuracy of intraoperative frozen tissue diagnosis for GBCS has yet to be determined due to paucity of scientific data.

Adjuvant treatment
The adjuvant treatment reduces recurrence risk and improves survival outcomes by eliminating or controlling the micrometastatic disease. A meta-analysis of retrospective studies including 6712 gallbladder cancer patients reported that lymph node positive patients enjoyed the survival benefit [96]. Few reported patients consider the use of UFT: tegafur/uracil, gemcitabine or a combination of tegafur/gimeracil/ oteracil. The median survival of GBCS is 7.8 mo [10], and the addition of such regimes has not shown to improve survival [38]. There is a report by Pu et al [38] of using a combination of 5-FU (commonly used in gallbladder cancer) and oxaliplatin (commonly used in sarcomas). They reported a 59-year-old female coming in with right upper quadrant pain, fever and a raised CA19-9 level of 12000 U/mL, which was confirmed to be GBCS. The patient received oxaliplatin 150 mg and 5-FU 500 mg intravenously every 30 d for 6 cycles. At 6-mo follow-up, she did not reveal any signs of recurrence.
Adjuvant radiotherapy is shown to be of value in reducing local recurrence in selected patients with gallbladder cancer. In a study including 4180 patients with resected gallbladder cancer diagnosed from 1988 to 2003 from the Surveillance, Epidemiology, and End results database, Wang et al [97] reported that adjuvant radiotherapy provides survival benefit in node positive or T2 and higher stage disease. A single arm phase II study conducted by South West Oncology Group reported that gemcitabine plus capecitabine, followed by radiation (45 Gy to regional lymphatics, 54-59.4 Gy to tumor bed) and capecitabine resulted in 56% 2-year survival rate for patients with gallbladder cancer. Based on these results, the American Society of Clinical Oncology guidelines recommend chemotherapy plus radiation in gallbladder cancer patients with R1 resection [98]. There is no data to support neoadjuvant chemotherapy. Due to aggressive biological behavior, rapid progression or recurrence is common, and this is associated with a myriad of constitutional symptoms. For holistic care, management of the patients' subjective symptoms of anorexia and lethargy needs to be considered. Testosterone replacement therapy helps alleviate such symptoms in male patients with advanced cancer [99].

Prognosis
Generally, the prognosis of GBCS is poor. The majority of patients presenting to the hospital are locally advanced, with liver metastasis and peritoneal dissemination. Other metastasis sites reported include adrenal glands, pancreas, diaphragm and the lower thoracic vertebrae. Zhang et al [3] reported a mean survival time of 17.5 mo, with 1-year and 5-year survival rates at (19 ± 5)% and (16 ± 5)%, respectively. While it was previously noted the longest survival time to be reported as 54 mo by Uzun et al [44], our review noted 86 mo to be the longest survival time [10]. Aldossary et al [10] reported a 62-year-old female patient who complained of severe intermittent right upper quadrant pain of 2 mo duration. Laboratory investigations were normal, and ultrasound suggested a gallbladder with large stones and a non-mobile echogenic mass. A stage II (pT2, pN0, M0) moderately differentiated GBCS was noted on histology after laparoscopic cholecystectomy. The patient underwent 14 cycles of adjuvant chemotherapy. She had local recurrence at 2 years. Wide local excision of the mass with wedge resection of the liver, lymphadenectomy and partial gastrectomy was done. The patient remained disease free for 86 mo. Zhang et al [3] also claim that tumors smaller than 5 cm had a more prolonged survival, however we did not observe this. More data is required to confirm this, as only 28 patients detailing both the survival data and size of tumor have been reported.

Role of tumor markers
GBCS is not noted to have association with any tumor markers. Consistent with the current literature, most of the patients did not note any raised tumor markers[5]. However, it is still common practice for physicians to perform tumor marker levels such as CA19-9, carcinoembryonic antigen and alpha-fetoprotein when considering possible differentials for masses in the gallbladder as well as for prognostication. For instance, Hayashi et al [100] propose that alpha-fetoprotein-producing carcinomas of the gallbladder are more likely to metastasize to the liver and have poor prognosis. CA19-9 is typically associated with pancreatobiliary malignancies but has a limited role in clinical practice [101]. Thus, prognostication is relied typically on histological features, pathologic stage as well as immunohistochemistry. Immunohistochemistry for the mesenchymal and epithelial components yield positive staining for vimentin and cytokeratin [45]. Our review shows that the majority of the patients had positive staining for vimentin (81.2%) and cytokeratin (79.2%). Additionally, Ki-67 was suggested by Kubota et al [45] to have prognostic value, whereby its presence signifies a possibly higher malignant proliferative potential for GBCS. However, this claim needs to be further investigated as Kubota et al [45] examined this immunohistochemical marker in only 1 patient with CSGB.

Comparison to gallbladder adenocarcinoma
There is substantial overlap of risk factors, diagnosis and treatment of GBCS with gallbladder adenocarcinoma. Thus, the majority of authors extrapolate the clinical characteristics of gallbladder adenocarcinoma to determine the best approach to diagnosis and management of GBCS. From this review, we can determine three key differences between GBCS and gallbladder adenocarcinoma. First, tumor markers have limited utility in patients with GBCS. In a study of 55 cases by Shukla et al[102], it is noted that the combination of CA-125 and CA19-9 helped detect gallbladder malignancy in patients with gallstones (80.7%). Second, the prognosis of GBCS may be marginally better compared to carcinoma of the gallbladder. In the meta-analysis by Zhang et al [3], it was noted that the survival rate was slightly better (16% ± 5% 5-year survival) compared to carcinoma of the gallbladder (0-10% 5-year survival). Thus, the identification of GBCS will be useful to determine the prognosis for patients albeit with only a small variation between the two. Third, immunohistochemistry markers like vimentin and cytokeratin are associated with diagnosis of GBCS.

CONCLUSION
In conclusion, GBCS is more common in females. Gallstones and chronic cholecystitis are risk factors for GBCS. Serum biochemistry and tumor markers have a limited role in diagnosis. Typical imaging modalities can assist to establish a diagnosis in patients with suspicious gallbladder lesions. Multiple imaging modalities are complementary. Multidisciplinary oncology board discussions are essential to guide management plans. Surgery is currently the only curative option for GBCS, and size of the tumor does not impact prognosis. While most features of GBCS parallel that of carcinomas of the gallbladder clinically, identification of GBCS specifically allows clinicians to determine overall prognosis. Due to paucity of reported cases, more evidence is required before meaningful and valid evidence-based patient-centric recommendations can be made. This review serves to educate and raise awareness among the clinicians dealing with gallbladder malignancies. It is likely that there are more clinical differences between GBCS and common forms of gallbladder cancer; active reporting of cases will help enhance understanding of this rare cancer.

Research background
Literature on gallbladder carcinosarcoma (GBCS) is currently scarce, with less than 100 cases reported since the first case by Karl Lansteiner.

Research motivation
While there has been efforts by Zhang et al in 2008 to consolidate the literature, there has not been a review of the current literature since.

Research objectives
This study aims to fill this gap by providing a comprehensive overview of GBCS.