Carcinosarcoma with chondroid differentiation and neuroendocrine carcinoma: unusual triphasic tumour arising from intracholecystic papillary neoplasm of the gall bladder

Abstract

Herein, we report a man in his 70s with gallbladder mass. Microscopically, the tumour demonstrated moderately differentiated adenocarcinoma, sarcoma with focal chondroid differentiation and high-grade neuroendocrine tumour component arising in an intracholecystic papillary neoplasm. The patient did not receive adjuvant chemotherapy in the setting of complete surgical resection. Patient presented with extensive metastasis after 47 months and died 3 months later. Due to the low incidence and poor prognosis of this tumour, it is essential to gather all the individual experience-based information. To our knowledge, this is the first reported case of carcinosarcoma arising from intracholecystic papillary–tubular neoplasm.

Background

Gallbladder cancer, while still the most common malignant neoplasm of the biliary tract, remains rare and has a worldwide incidence of less than 2/100 000 individuals. These malignancies are found with the highest frequencies in Eastern Europe, Latin America and Southeast Asia. Major independent risk factors for gallbladder cancer are advanced age, female gender, gallstones, chronic cholecystitis, porcelain gall bladder, chronic Salmonella infection, gallbladder polyps and obesity. Gallbladder adenocarcinoma is by far the most common histological diagnosis, occurring in about 90% of gallbladder cancer cases.^{1 2} Adenosquamous and squamous cell carcinomas together constitute approximately 4%–7% of gallbladder malignancies.^1–3 Less common histological types include neuroendocrine tumours and sarcomas, accounting for 3% and 2% of cases, respectively.² To date, 110 cases of gallbladder carcinosarcoma have been published in English written literature.⁴

Case presentation

A man in his 70s presented with right upper quadrant abdominal pain and distension. His medical history consisted of type 2 diabetes mellitus, hypertension and hyperlipidaemia. He had previously undergone wide local resection of a right upper extremity sarcoma 4 months earlier. Physical examination was remarkable for moderate abdominal tenderness and significant distension. The laboratory evaluation revealed an elevated carbohydrate antigen 19–9 of 64 units/mL (normal 0–35 units/mL), normal carcinoembryonic antigen and normal serum transaminases/bilirubin.

Ultrasound demonstrated lobular gallbladder wall thickening suggestive of a mass with no evidence of biliary ductal dilatation. CT (figure 1A) scan revealed a 3.5×2.9 cm exophytic mass in the fundus of the gall bladder. No lymphadenopathy was noted on either radiological examination. The liver did not have cirrhosis or other lesions. There was no evidence of metastatic disease. Given the high clinical suspicion of gallbladder adenocarcinoma, the patient underwent en bloc resection of the gall bladder with liver segments IVA and V (radical cholecystectomy) and with regional lymphadenectomy.

Figure 1.

(A) CT scan of the abdomen showing a 3.5×2.9 cm mass in the fundus of the gall bladder with no evidence of metastatic disease. (B, C) Intracholecystic papillary neoplasm.Tthese are papillary/polypoid exophytic lesions showing back-to-back epithelial units with a narrow fibrillar and vascular interstitium (B, C, ×2). The right side (B) shows low magnification of carcinosarcoma component (orange solid line). The lower side (C) shows neuroendocrine carcinoma (black dashed line). (D) Adenocarcinoma (arrowheads), sarcoma area (solid orange line) and neuroendocrine component (black dashed line) (D, ×2). (E) The adenocarcinoma is composed of atypical glands lined by cuboidal to columnar cells, with high Nuclear:Cytoplasmic (N:C) ratio. The nuclei are hyperchromatic with irregular nuclear contours. The cells show marked loss of polarity and increase in mitotic figures (E, ×20). (F) The sarcomatous component is composed of spindle cells with focus of cartilaginous differentiation (black arrows) (F, ×20).

On gross examination, the gall bladder measured 5.2×9.5 cm with a 3.5×3.0×1.6 cm polypoid mass near the gallbladder fundus on the hepatic surface. The lesion showed a tan heterogeneous cut surface with focal necrosis and multiple tiny cysts filled with mucin. Grossly, the tumour was 1 cm from the nearest surgical margin.

Histologically, the tumour demonstrated an epithelial component (adenocarcinoma), a mesenchymal component (sarcoma) and a neuroendocrine component. The invasive components were seen arising in the background polypoidal intracholecystic papillary–tubular neoplasm (ICPN) of biliary type with a focus of cartilaginous differentiation (figure 1B–F). The adenocarcinoma and sarcoma components were immunostained for pan cytokeratin (figure 2B) and vimentin (figure 2A), respectively. The neuroendocrine cells were strongly positive for chromogranin and synaptophysin. The Ki-67 showed a high proliferation index of 50%, compatible with neuroendocrine carcinoma in this portion of the tumour.

Figure 2.

(A) H&E ×10 showing adenocarcinoma (arrowheads), sarcoma (solid orange line) and neuroendocrine component (black dashed line). (B) Vimentin immunostain highlights the sarcoma component. (C) Pancytokeratin immunostain highlights adenocarcinoma component strong and diffuse, while it is weak in neuroendocrine component. (D) Synaptophysin stain is positive only in the neuroendocrine component.

The gallbladder carcinoma was classified as stage II (T2AN0M0) based on the American Joint Committee on Cancer classification system eighth edition.

Outcome and follow-up

The patient tolerated the surgery well with no complications and was discharged to home on postoperative day 3. The case was discussed in our multidisciplinary tumour board, and adjuvant therapy was not recommended in the setting of complete surgical resection. He underwent surveillance CT scans showing no evidence of disease recurrence up to 33 months post resection. Subsequent imaging performed 47 months after surgery demonstrated local adenopathy as well as metastases in the mediastinum and lung, left adrenal gland and pancreatic tail. He also had evidence of malignant ascites. The pancreatic lesions were biopsied with endoscopic ultrasound and consistent with a poorly differentiated carcinoma with neuroendocrine features. After multidisciplinary review, he was started on palliative temozolomide and capecitabine chemotherapy. He received two cycles of therapy and developed worsening disease burden leading to pulmonary thromboembolism. He died 50 months after surgery.

Discussion

Gallbladder cancer is the most common malignancy of the biliary tract,^{1 2} and adenocarcinoma accounts for about 90%–95% of gallbladder malignancies.³ Carcinosarcoma is a rare malignant tumour of the gall bladder.⁴ We herein report the first case of carcinosarcoma with heterologous differentiation admixed with neuroendocrine carcinoma arising in an ICPN.

ICPN is a relatively new entity, first described in the 2010 WHO classification.

Adsay et al defined ICPN as an exophytic intramucosal gallbladder mass (>1.0 cm) composed of dysplastic cells forming a lesion distinct from the adjacent mucosa.⁵ There are several small series and case reports of rare gallbladder malignancies who have reported on squamous, adenosquamous, neuroendocrine and carcinosarcomas of the gall bladder.^6–8 The meta-analysis by Zhang et al and the subsequent reported cases revealed the most common epithelial and mesenchymal components in carcinosarcoma cases are adenocarcinoma and spindle-shaped cells, respectively.⁹ The increased availability of immunostains may have contributed to an increased appreciation for the morphological diversity seen in gallbladder cancers.¹⁰ To our knowledge, our case is the only other reported case of a gallbladder tumour consisting of both carcinosarcoma and neuroendocrine carcinoma and the first case with all the three components arising from ICPN of the gall bladder.

The average age of patients with gallbladder cancers is 72 years. Similarly, patients with gallbladder carcinosarcomas present in the seventh and eighth decades of life—just as the patient described here. However, the vast majority (68%) of gallbladder carcinosarcomas occur in women (in contrast to this case report).^{11 12}

The pathogenesis of complex gallbladder malignancies is a topic of debate with several hypothesised mechanisms. First, some authors have proposed that multi-ineage malignancies may arise as part of the metaplasia–dysplasia–carcinoma pathway.^{11 13} Mixed gallbladder tumours may arise from common multipotent cancer stem cells that have diverged along separate epithelial and mesenchymal pathways. Finally, a process of ‘neometaplasia’ has been used to describe the transdifferentiation of adenocarcinoma to neuroendocrine cells.¹⁴ Minimal neuroendocrine cells are present in the normal gallbladder mucosa; they have also been found in the setting of inflammation.¹² It is possible that neuroendocrine tumours may arise from these neuroendocrine cells. This scenario would require that both epithelial and neuroendocrine components independently generate mutations leading to the tumorous phase.¹⁵

Complete surgical resection remains the only curative treatment for patients with gallbladder cancer. In patients with >T1 lesions, this involves a radical cholecystectomy, including cholecystectomy, hepatic resection of the surrounding parenchyma, and regional lymphadenectomy. The accumulated evidence for adjuvant and neoadjuvant therapy for gallbladder cancer is scarce.¹⁶ The American Society of Clinical Oncology clinical practice guideline described that patients with gallbladder cancer with R1 resection may undergo chemotherapy plus radiation therapy.¹⁷ Many trials have led to the consensus statement that all patients with resected biliary tract cancer should be treated with 6 months of adjuvant oral capecitabine or adjuvant chemoradiotherapy in the setting of R1 margins.¹⁸ Our patient underwent an R0 resection and there were no positive nodes identified. We elected to avoid adjuvant therapy in favour of observation.

The histological subtype and stage of gallbladder cancers greatly impact survival after surgery. For patients with gallbladder adenocarcinoma, curative resection can achieve median survival in excess of 17 months. Patients with neuroendocrine tumours of the gall bladder have a median survival of 25 months.¹⁹ However, Gallbladder carcinosarcomas had a dismal 3-year overall survival and median survival of 31% and 9 months, respectively.²⁰ The longest survivor had survived for 7 years and 2 months postoperatively.²¹ Limited data regarding cancers originating from ICPN show excellent survival.²² Our patient survived over 4 years after surgery, suggesting that the premalignant ICPN of his cancer overcame any survival disadvantage due to its multilineage presentation.

In conclusion, we are reporting for the first time a case of gallbladder tumour containing malignant components of adenocarcinoma, neuroendocrine tumour and sarcoma arising from ICPN. Carcinomas from multiple lineages appear to be associated with poor prognosis. However, limited data suggest that invasive carcinoma arising from a mass forming a preinvasive neoplasm may behave better than ordinary invasive carcinoma that arise from flat intraepithelial neoplasia. Our patient’s outcome suggest that the ICPN origin of his tumour lead to improved survival in spite of the different components of his tumour. Future studies with greater numbers of patients should examine this observation further.

Learning points.

• Although this case has mixed neuroendocrine and non-neuroendocrine components, it should not be confused with the entity mixed neuroendocrine non-neuroendocrine neoplasms, which is a close differential diagnosis.

• The histological subtype impact the survival after surgery. Carcinomas from multiple lineagess appear to be associated with poor prognosis.

Ethics statements

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