Carcinosarcoma of Gallbladder with Osteosarcomatous Differentiation — a Case Report with Review of Literature

Abstract

A 44-year-old female presented with dull upper abdominal pain. Contrast-enhanced computed tomography (CECT) of the abdomen revealed a well-distended gallbladder with multiple foci of minimally enhancing, intraluminal, soft tissue lesion, and hyperdensity on non-contrast scan measuring 4.3 × 3.5 cm in the fundus with few calculi embedded in it. There was no evidence of extraluminal extension. The patient underwent extended cholecystectomy with liver wedge resection. Histologically, the tumor showed both carcinomatous and sarcomatous components, with prominent osteosarcomatous differentiation. We report this unusual case and present a review of all cases of carcinosarcoma of the gallbladder with sarcomatous differentiation. Despite curative resection, CSGB prognosis remains poor, and thus, the authors recommend to focus their efforts to improve the surgical outcomes.

Introduction

The concept of “carcinosarcoma” came into being late in 1865, and it was first coined by Rudolf Virchow [1]. The credit for the description of the first carcinosarcoma gallbladder (CSGB) case goes to Karl Landsteiner, an Austrian pathologist, in 1907, the discoverer of the ABO blood groups. Carcinosarcoma of gallbladder (CSGB) also referred to as sarcomatoid carcinoma and malignant mixed tumors by few authors is an extremely rare neoplasm accounting for less than 1% of all the malignant tumors of gallbladder [2]. Carcinosarcoma is well known to involve multiple organs including the lung, esophagus, kidney, pancreas, and uterus [3]. However, the gallbladder is a rare site of occurrence, with only 34 cases being reported in the English literature till date [4]. It is a malignant tumor, composed of intermixed carcinomatous and sarcomatous components. Carcinomatous components include glandular, squamous, or both, and sarcomatous components may include homologous elements like undifferentiated spindle cells or heterologous elements including osteosarcomatous, chondrosarcomatous, fibrosarcomatous, or rhabdomyosarcomatous differentiation [1]. Their invasive nature and aggressive biology explains the limited number of cases. In the review by the Surveillance, Epidemiology and End Results (SEER) Program, 3038 gallbladder cancer cases were collected, 11 of which were identified as carcinosarcoma and 9 of which died [5]. Herein, we report a case of a 44-year-old woman with carcinosarcoma of the gallbladder with prominent osteosarcomatous differentiation as a solitary heterologous element, with only single case reported in literature till date.

Case Report

A 44-year-old female was asymptomatic, 1 year back, when she presented in the Gastro Surgery Department of SGPGI, Lucknow, with dull aching and non-radiating pain, in the epigastric and right upper hypochondriac regions. There was no history of nausea, vomiting, jaundice, or fever. There was no family history of cholelithiasis or gallbladder malignancy. No abdominal lump was palpable. Abdominal ultrasonography revealed an intraluminal, ill-defined heterogenous soft tissue lesion measuring 4 × 2.3 cm located at the fundus. Contrast-enhanced computed tomography (CECT) revealed a well-distended gallbladder with multiple hyperdense foci within gallbladder lumen measuring 0.5 to 0.9 cm in size with minimally enhancing intraluminal, soft tissue lesion, measuring 4.3 × 3.5 cm at the fundus, with few calculi embedded in it (Fig. 1a). There was no evidence of extraluminal extension. Laboratory workup showed normal hematological parameters. Liver function tests revealed mildly elevated ALT (136 U/l) and AST (46 U/l) levels with total bilirubin, alkaline phosphatase, and renal function tests within normal limits. The patient underwent laparotomy and extended cholecystectomy with liver wedge resection and excision of CHA, HDL, retrocholedochal, and retroportal lymph nodes. The specimens were sent to the pathology department, for histopathological examination.

Fig. 1.

a CECT (coronal section) showing a minimally enhancing intraluminal, soft tissue lesion, measuring 4.3 × 3.5 cm at the fundus, with few calculi embedded in well-distended gallbladder. b Extended radical cholecystectomy with liver wedge resection specimen showing an intraluminal, polypoidal growth with cut surface showing grayish-brown, fleshy areas

Pathological Findings

Extended radical cholecystectomy specimen received in the pathology department measured 8 cm in length and attached liver wedge measured 7.5 × 7.5 × 5.5 cm on gross examination. The outer surface was unremarkable. The cut surface showed an intraluminal, polypoidal growth measuring 7.5 × 4.3 × 3.5 cm at the fundus. The cut surface was grayish-brown and fleshy, with areas of necrosis. A cystic lymph node measuring 0.8 × 0.6 cm was identified. Representative sections were taken. Histopathological examination (HPE) revealed an infiltrating tumor composed of both malignant epithelial and mesenchymal components along with scattered islands of malignant osteoid or osteosarcomatous differentiation. The epithelial component was composed of atypical, irregular, closely packed glands, lined by dysplastic tall columnar epithelial cells which displayed nuclear stratification, high nucleo-cytoplasmic ratio, moderately pleomorphic nuclei, and scant to moderate amount of cytoplasm. The mesenchymal component was disposed in sheets and was composed of atypical spindle-shaped cells with moderate nuclear pleomorphism, oval to spindle nuclei, coarse chromatin, and prominent nucleoli with scant to moderate amount of cytoplasm. At many places, these tumor cells showed rhabdoid appearance and malignant osteoid formation. Few multinucleated giant cells and osteoclasts were evident. Areas of necrosis were present. The tumor infiltrated the muscularis propria and perimuscular connective tissue; however, the adventitial margin was free from tumor. The neck resection margin was free from tumor. Adjacent liver parenchyma showed several foci of steatosis and cholestasis, but was free from tumor. All the lymph nodes including retro-choledochal, retro-pancreatic, common hepatic artery, and hepato-duodenal lymph nodes were free from metastatic deposits (Fig. 2a-f). On immunohistochemistry (IHC), the malignant epithelial cells were positive for cytokeratin and EMA while the sarcomatous cells were positive for vimentin and showed focal positivity for SMA and S100 (Fig. 3a-d).

Fig. 2.

a Tumor showing perimuscular connective tissue infiltration (H&E; × 100). b Section showing a malignant epithelial component arranged in a glandular pattern displaying moderately pleomorphic nuclei, prominent nucleoli, and a moderate amount of eosinophilic cytoplasm (H&E; × 400). c, d Tumor showing a malignant mesenchymal component, with a few showing rhabdoid appearance and tumor giant cells (H&E; × 400). e, f Tumor showing malignant osteoid formation by tumor cells (H&E; × 200)

Fig. 3.

a Malignant epithelial component (adenocarcinoma) showing diffuse cytoplasmic positivity for CK and EMA in inset (IHC; × 200). b Malignant mesenchymal component (sarcomatous) showing diffuse cytoplasmic positivity for vimentin (IHC; × 200). c Malignant mesenchymal component (sarcomatous) showing diffuse cytoplasmic positivity for SMA (IHC; × 200). d Focal areas of tumor showed S100 positivity (IHC; × 200)

Collaborating the histolopathological and immunohistochemical findings, the diagnosis of gallbladder carcinosarcoma (CSGB) with osteosarcomatous differentiation was established staged as IIb as per the American Joint Committee on Cancer (AJCC) criteria. The postoperative course was uneventful.

Discussion

GB cancers account for 1 to 2% of all gastrointestinal cancers, including adenocarcinoma from the majority of primary malignant neoplasms, and the remainder include squamous cell carcinoma, undifferentiated carcinoma, tumors with choriocarcinoma-like differentiation, and sarcoma [6]. CSGBs constitute only about less than 1% of GB cancers, hence even more rare. Born et al. reported one case of CSGB among 99 primary gallbladder malignancy cases, admitted to St. Luke’s Hospital in New York City of over a period of 18 years from 1964 to 1981 [7].

The mean age of CS cases usually range from 60 to 70 years with a male to female ratio of 1:2 to 1:5 and a female preponderance [8, 9]. It usually presents with abdominal pain, jaundice, nausea, anorexia, and loss of weight with sometimes palpable abdominal mass and non-specific symptoms. Since it is not associated with specific radiological findings or serological data, the preoperative diagnosis of CSGB is troublesome and poses a difficulty to differentiate it from CA GB, based on imaging modalities, such as ultrasonography, CT, and abdominal angiography or tumor markers like carcinoembryonic antigen or Ca 19–9. Often abdominal angiography shows neo-vascularity, whereas computed tomography (CT) shows an enhanced solid mass lesion. The differentials considered are gallbladder carcinoma when there is calcification, calcified gall stones, or a porcelain gallbladder. Carcinosarcoma of the gallbladder is suspected when a calcification is observed within the tumor on CT examination. However, a more detailed imaging data is needed to improve the diagnosis of CSGB.

Regarding its pathogenesis, it is very controversial, as is reflected by the multitude of names designated to it, including malignant mixed tumor [10–12], sarcomatoid carcinoma [13], spindle cell carcinoma [14, 15], and malignant mixed mesodermal tumor [16]. Various theories have been postulated to explain the pathogenesis of carcinosarcoma. One theory proposed that the reactive process leads to development of the mesenchymal component. A second theory considered it as a true sarcoma (the collision tumor or convergence multiclonal theory); a third theory (divergent monoclonal theory) hypothesized it to be carcinoma with metaplastic changes; a fourth theory pointed towards embryonic rest origin; and the last theory was the totipotential stem cell hypothesis [17, 18].

Diagnosis of CSGB requires the admixture of both malignant epithelial and mesenchymal components histologically. The most common epithelial component is adenocarcinoma, but the squamous cell carcinoma component may also be present frequently which grows twice as rapidly as adenocarcinomas and is associated with poorer prognosis [4]. The mesenchymal component could be homologous and composed of malignant spindle cells with fibrosarcoma-like features or may be present in the form of malignant stromal cells admixed with heterologous elements such as malignant osteoid (osteosarcoma), malignant cartilage (chondrosarcoma), or rhabdomyoblasts (rhabdomyosarcoma). Index cases showed both a malignant epithelial component in form of adenocarcinoma and a sarcomatous component with malignant osteoid which is a rare finding.

Zhang et al. [19] in 2008 performed a computerized search in PubMed of the US National Library of Medicine, and the ISI Web of Science database and found 68 cases, which included carcinosarcoma, sarcomatoid carcinoma, and spindle cell carcinoma of the gallbladder. They retrieved forty-five cases with a reliable histopathological diagnosis of carcinosarcoma of the gallbladder and found that the most common epithelial component was adenocarcinoma observed in 79.2% cases while squamous cell carcinoma was found only in 9.4% cases and a mixture of both the components accounted for 11.3% cases. They also categorized these cases into five groups based on the type of mesenchymal component including spindle cell, chondroid, rhabdomyomatous, osteoid, or an admixture of two or more component types. They found that the homologous spindle cell component accounted for 44.6% of 68 cases while osteoid formation was documented in the least number of cases and accounted for about 5.4%. On statistical analysis, the study showed no significant difference in the outcome of patients with various histological types, thus suggesting little prognostic value of the mesenchymal component of CSGB.

Aldovani et al. and Mehrotra et al. [16, 20] observed malignant osseous tissue exclusively in various stages of differentiation. The rhabdomyosarcomatous element was documented by Wang et al. and Ishihara et al. [18, 21] as the only heterologous component, and it was confirmed by immunohistochemistry and electron microscopy. Even after extensive sampling of the tumor, no other accompanying heterologous component could be identified, except malignant osteoid. After thorough search of literature, not even a single case of carcinosarcoma of the gallbladder showed malignant osteoid, as the sole component of the sarcomatous elements of the tumor.

Demonstration of the dual differentiation of this tumor, by IHC or electron microscopy, is mandatory. The epithelial component expresses CK and EMA while sarcomatous areas may coexpress CK and vimentin or only vimentin, desmin, or actin [22, 23]. Ultrastucturally, it shows desmosome-like junctions and aggregates of cytoplasmic intermediate filaments. These findings suggest an epithelial origin of the sarcomatous component.

We collected all such cases of carcinosarcoma gallbladder with malignant osteoid (osteosarcomatous differentiation) or metaplastic osteoid, since 1925, of over a period of 95 years, from the world literature, which accounted to total of fourteen cases [19]. A large cohort study by Taskin et al. reviewed 656 gallbladder carcinoma cases and documented two cases with heterologous elements with one of them showing osteoclasts adjacent to osteoid [24, 25]. Hence, a total number of cases account  to sixteen including the index case [3, 10–12, 15, 19, 25–39] (Table 1).

Table 1.

List of carcinosarcoma gallbladder with osteosarcomatous/malignant osteoid/metaplastic osteoid differentiation from 1925 till date including the index case

S no	Author, country (year)	Age/sex	Microscopy	IHC for carcinoma	IHC for sarcoma	Outcome and prognosis
1	Kritsch, Germany (1925) [40]	59/F	Carcinoma and sarcoma containing cartilage and bone	Not done	Not done	Autopsy diagnosis
2	Higgs et al., USA (1973) [11]	77/M	Neoplastic glandular structures. Mucinocarminophilia was demonstrated. Neoplastic mesenchymal spindle-shaped cells, malignant cartilaginous, and metaplastic osseous tissue	Not done	Not done	Patient had tumor spread within bile duct. He developed infection of the biliary tract by Klebsiella, and died on the 29th postoperative day. Metastatic spread to liver and bile ducts with fibrosarcoma pattern predominated over all other neoplastic elements
3	Von Kuster and Cohen, USA (1982) Case 1 [13]	91/F In fundus	Well to poorly differentiated adenocarcinoma. Cellular stroma with spindle cells in herring bone pattern. Foci of malignant cartilage. One focus of malignant osteoid	Not done	Not done	Exploratory laparotomy showed a mass in the gallbladder, with extensive metastases to the liver. Patient died on the third postoperative day of massive pulmonary embolism. Autopsy showed metastases to liver, left adrenal gland, and para-aortic lymph nodes
4	Hasegawa et al., Japan (1983) [3]	73/F	Solid nests of carcinoma with signet ring cells. Extensive areas of chondro-sarcoma. Osteoid formation is present	Not done	Not done	Patient had adenocarcinoma of sigmoid colon also. Patient had metastases to the liver. She died of peritoneal metastases 3 months postoperatively
5	Miyamoto et al., Japan (1983) [33]	61/F	Adenocarcinoma and squamous cell carcinoma with malignant osteoid and cartilage	Not done	Not done	Patient died 3 months after surgery
6	Inoshita et al., Japan (1986) [35]	53/M In neck	Adenocarcinoma and papillary and cribriform patterns. Sarcomatous component with interlacing bundles of highly atypical spindle cells admixed with malignant cartilage, osteoid, and foci of rhabdomyoblastic cells	Positive for EMA	Rhabdomyoblast cells were positive for myoglobin	Died 17 months postoperative resection. Metastases to liver (carcinomatous and RMS both component), and to the pancreas, diaphragm, and regional lymph nodes (RMS component only)
7	Uesaka et al., Japan (1995) [36]	54/F	Carcinomatous glandular and ductal structures, nests of squamous cell carcinoma. Sarcomatous component with non-calcified osteoid differentiation and a small island of malignant cartilaginous tissue	Positive for CEA, EMA, and cytokeratin	Positive for EMA, CK, and S-100 protein in chondroid foci. Negative for vimentin and CEA	Portal tumor thrombus of sarcomatous elements, and osteoid differentiation. Metastatic adenocarcinoma to one lymph node. Patient died of liver metastases 3 months after surgery
8	Sakurai et al., Japan (2006) [39]	54/F	Poorly differentiated tubular adenocarcinoma and spindle-cell sarcoma with differentiation to cartilage and partly bone	Not detailed	Positive cytokeratin staining in malignant cartilage	Tumor was advanced involving the transverse colon and the duodenum. Patient received chemotherapy. He developed liver metastases and died 15 months following surgery
9	Kohtani et al., Japan (2009)  [33]	84/M	Adenocarcinoma admixed with malignant mesenchymal elements including bone and cartilage	Positive for cytokeratin and EMA but negative for CD68 and desmin	Positive for CD68 but negative for cytokeratin and EMA	Cholecystectomy only was done, followed by low-dose chemotherapy. Patient survived 4 years postoperatively
10	Coetzee et al., South Africa (2011) [34]	38/F	Malignant glands with serrated architecture, focal adenoma in situ. Pleomorphic and atypical stromal cells showed a myxoid background with chondroid appearance, and focal osteoid was present	Positive pan-cytokeratin AE1/3 in dysplastic lining epithelium	FNA specimen: positive MSA in stromal cells	Patient had cholecystectomy. He turned 9 months later with dyspnea and jaundice. Ultrasound-guided FNA of mass under diaphragm: biphasic tumor, stromal component predominated
11	Parreira et al., Brazil (2012) [35]	58/F	Well-differentiated adenocarcinoma and papillary and tubular, with foci of squamous cell carcinoma. Chondrosarcomatous, osteoid, and atypical tissues	Not done	Not done	Patient died 6 months following surgery due to multiple metastases
12	Sadamori et al., Japan (2012)[37]	80/M	Moderately to poorly differentiated adenocarcinoma. Sarcoma with osteosarcomatous and chondrosarcomatous elements	Not done	Not done	Died due to multiple liver metastases 13 months after surgery
13	Kishino et al., Japan (2014)  [38]	70/F	Adenocarcinoma. Sarcomatous element of malignant spindle cells, foci of malignant cartilage and bone	Positive for cytokeratin (AE1/AE3)	Positive for vimentin, myogenin, and SMA	Liver metastasis developed 19 months after cholecystectomy, and partial hepatectomy was performed. No tumor recurrence after 2 years following operation
14	Faujdar et al., India (2015)  [39]	60/F	Carcinomatous element with moderate anaplasia. Sarcomatous elements in the form of spindle cells arranged in bundles and fascicles, and heterologous elements of cartilage and mature bone	Positive for cytokeratin	Positive for vimentin	Not documented. Patient was lost to follow-up
15	Taskin et al., Germany (June 2019) [24, 28] (Studied 656 GB carcinomas; eleven showed sarcomatoid patterns)	One aged 74 years and the other 77 years Both females	Among 11 cases, two had heterologous elements. One showed few osteoclast-like giant cells, only adjacent to osteoid	Keratin positive	Vimentin positive	One died at 5 months and other at 9 months
16	Index case	44/F	Adenocarcinomatous element and osteosarcomatous component	CK	Vimentin	Patient completed four cycles of radiotherapy 50.4 Gy

We observed that there was female preponderance with a male-to-female ratio of 1:2.8 (4 males and 11 females). Their age ranged from 38 to 91 years (mean age 65.1 years). All the cases showed additional cartilaginous differentiation except the case from the cohort which showed solitary osteoid differentiation [10, 12, 27, 29, 31, 35–39], and one showed rhabdomyosarcomatous differentiation [12].

Okabayashi et al., in a review of surgical outcome of 131 cases of carcinosarcoma of the hepatobiliary tract, reported that 59 cases of CSGB documented in the world literature showed female preponderance with a male-to-female ratio of 1:2.2. Two-thirds of the patients (38 out of 59 patients) were 65 years or older [41] . In another review by Okabayashi et al., on 36 patients of CSGB, there were 10 males and 26 females with a male-to-female ratio of 1:2.6, with a mean age of 67.7 years [42]. A meta-analysis study of 68 cases of CSGB showed the mean age of the patients of 68.8 years. There were 16 males and 52 females with a male-to-female ratio of 1:3.3 [19].

Patients present with abdominal mass and nonspecific symptoms including fever, nausea, vomiting, abdominal pain, anorexia, weight loss, and painless jaundice [28, 33]. Our patient presented with epigastric and right upper hypochondriac region dull aching and non-radiating pain. There was no history of abdominal lump, vomiting, jaundice, or fever. Abdominal mass was confirmed by ultrasound and CECT examination.

CSGB are usually polypoidal with sizes varying from 3 to 15 cm and which fill the gallbladder lumen. The index case tumor measured 8 × 4.3 × 3.5 cm at the fundus. In a review by Zhang et al., data on tumor size and survival of 41 patients with CSGB was collected and it was demonstrated that compared to tumors with size < 5 cm, tumors with ≥ 5 cm had a significantly shorter survival [19]. There was a high association between gallstones and CSGB, as was observed in 8 out of 9 cases (88%) of CSGB in one review [28], in 14 out of 18 cases (77%) in another review [25], and in 66.7% cases in the third [19]. There was presence of few calculi associated in our case. Hence, tumor size should be considered as a major parameter in the future staging system for CSGB, although genetic variations, an earlier detection of CSGB (stage I or stage II), and more extensive surgeries could also contribute to a better prognosis. They also indicated that the presence of gallstones, epithelial and mesenchymal component types, age, and sex were of little prognostic value [33].

CSGB may recur as liver metastasis, peritoneal dissemination, or as LN metastasis. The majority of recurrences occur within half a year of surgery. The median time to recurrence is 50 days. We observed that liver metastasis was documented in 9 out of fifteen cases (64%). Survival data was available in twelve of the cases, excluding autopsy cases. One patient died within days following surgery due to massive pulmonary embolism [12] or cardiogenic shock. Ten patients died of metastatic spread of the tumor or sepsis within a period of time ranging from 1 to 17 months with longest survival of 48 months. Four of them died within 3 months. One of the patients was lost to follow-up (Table 1).

Therapeutic interventions have not been well defined, and there is no established optimal postoperative adjuvant therapy, because of the rarity of CSGB and its poor prognosis. The best treatment option for CSGB is cholecystectomy which alone is sufficient for the tumor confined to the lamina propria, whereas the more advanced stages require the resection of a 3- to 5-cm wedge of the liver tissue at the gallbladder bed, combined with a lymph node (LN) dissection in the absence of an evidence of a distant metastasis. Our case underwent extended radical cholecystectomy with liver wedge resection and excision of lymph nodes.

The prognosis of CSGB patients is reported to be poor. The mean survival after diagnosis is only a few months in such cases. The overall 5-year survival rate after surgery is 31.0% [19]. Two factors importantly predict a good prognosis—curative resection and early stage (stage I or stage II) disease—according to the AJCC classification. The 5-year survival rate after curative resection for CSGB is 88.9% when invasion is restricted to the muscularis propria [2, 4, 9, 23].

We compared the data to ours, and observed that survival data was more or less similar. There are some variations in the mean survival in months following surgical intervention, but is not greatly significant. According to Okabayashi et al., in a review of surgical outcome of 131 cases, the survival rate by the end of one year was 42.8% and the 5-year survival rate was 37.6%. One significant finding observed in this meta-analysis was the correlation of the race of the patients with survival. Japanese patients (27 cases) showed a longer survival time with a mean survival of 19.9 months than non-Japanese patients (24 cases), with a mean survival of 11.5 months. In our review, 8 out of 15 patients were Japanese, with an average survival of 25.1 months, compared to the rest who were non-Japanese (7 cases) with an average survival of 4.6 months (excluding an autopsy case and a patient who was lost to follow-up). One of the Japanese patients had a prolonged survival of 48 months (Table 1). Such better prognosis in Japanese could be attributed to multiple factors including genetic variations, early detection, and better surgical techniques [18].

CSGB is a rare tumor, composed of both malignant epithelial and mesenchymal components with a poorer prognosis than conventional gallbladder adenocarcinoma. Curative resection of stage I or II tumors incurs a good prognosis. More clinic-pathological data and further studies are required to identify the prognostic indicators and the histogenesis of gallbladder carcinosarcoma.

Author Contribution

Literature search, collection of data, and manuscript preparation were done by JV who acts as a guarantor also. I reported this case under faculty-in-charge PP during the tenure of my senior residency in SGPGIMS, Lucknow (2017–2020), and PP helped in framing and analysis of the data. The manuscript was written by JV, and the clinical portion was prepared by RKS. Literature search and the preparation of revised images of restained slides along with analysis of data were done by RY. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Declarations

Disclaimer

Patient’s verbal consent was obtained. There are no financial source of support.

Ethics Approval

Our study is a case report which is exempted from the ethical approval in our institution.

Consent for Publication

The participant has given verbal informed consent for the submission of the case report to the journal.

Conflict of Interest

The authors declare no competing interests.