Poorly differentiated neuroendocrinecarcinoma of the gallbladder

Chen-Hao Chang; Jiunn-Chang Lin; Johnson Lin; Ching-Wei Chang

doi:10.4103/JCRP.JCRP_4_22

CASE REPORT

Year : 2022 | Volume : 9 | Issue : 3 | Page : 101-103

Poorly differentiated neuroendocrinecarcinoma of the gallbladder

Chen-Hao Chang¹, Jiunn-Chang Lin², Johnson Lin³, Ching-Wei Chang⁴
¹ Division of Gastroenterology, Department of Internal Medicine, MacKay Memorial Hospital; MacKay Medicine, Nursing and Management College, Taipei, Taiwan
² MacKay Medicine, Nursing and Management College; Department of Surgery, MacKay Memorial Hospital, Taipei, Taiwan
³ MacKay Medicine, Nursing and Management College; Division of Hematology-Oncology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei; MacKay Medical College, New Taipei, Taiwan
⁴ Division of Gastroenterology, Department of Internal Medicine, MacKay Memorial Hospital; MacKay Medicine, Nursing and Management College, Taipei; MacKay Medical College, New Taipei, Taiwan

Date of Submission	27-Dec-2021
Date of Decision	09-Mar-2022
Date of Acceptance	10-Mar-2022
Date of Web Publication	02-Sep-2022

Correspondence Address:
Dr. Ching-Wei Chang
Division of Gastroenterology, Department of Internal Medicine, MacKay Memorial Hospital, No. 92, Sec. 2, Chungshan North Road, Taipei 104
Taiwan

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/JCRP.JCRP_4_22

Abstract

Poorly differentiated neuroendocrine carcinoma of the gallbladder is an aggressive and extremely rare type of neuroendocrine tumor. The clinical presentations in most cases are nonspecific, resulting in patients being diagnosed at an advanced stage of the disease. Herein, we report our experience with the case of a 63-year-old woman with no comorbidities who underwent radical resection for a diagnosed gallbladder mass. Abdominal computed tomography scans and magnetic resonance cholangiopancreatography indicated intraluminal masses in the gallbladder with liver invasion. Histologically, the mass was composed of solid sheets of poorly differentiated carcinoma cells with hyperchromatic nuclei; a high Ki-67 index of approximately 80%. The cells were positive for chromogranin A and synaptophysin, and small-cell-type neuroendocrine carcinoma was diagnosed. Postoperatively, she underwent adjuvant chemotherapy with four cycles of cisplatin/etoposide chemotherapy and was disease-free 16 months after surgical treatment with normal hormone-specific markers.

Keywords: Chromogranin A, gallbladder cancer, neuroendocrine tumor

How to cite this article:
Chang CH, Lin JC, Lin J, Chang CW. Poorly differentiated neuroendocrinecarcinoma of the gallbladder. J Cancer Res Pract 2022;9:101-3

How to cite this URL:
Chang CH, Lin JC, Lin J, Chang CW. Poorly differentiated neuroendocrinecarcinoma of the gallbladder. J Cancer Res Pract [serial online] 2022 [cited 2023 Jun 6];9:101-3. Available from: https://www.ejcrp.org/text.asp?2022/9/3/101/355304

Introduction

Neuroendocrine neoplasms (NENs) account for 1.2% of all malignancies^[1] and can develop in the gallbladder with unusual lesions. Most cases are diagnosed incidentally after cholecystectomy for cholecystitis or other biliary diseases.^[2] The World Health Organization classifies hepatobiliary NENs into two subgroups: well-differentiated neuroendocrine tumors (NETs), and poorly differentiated neuroendocrine carcinomas (NECs) based on the morphology and proliferative rate.^[3] NEC of the gallbladder (NEC-GB) is a highly malignant tumor with a poor prognosis and survival worse than adenocarcinoma of the gallbladder. We report the case of a 63-year-old woman with small-cell-type NEC-GB characterized by a typical clinical presentation and immunohistochemistry findings and nonspecific imaging findings.

Case Report

A 63-year-old woman with no comorbidities was admitted to our hospital for the examination of a newly found bladder mass. She had no right quadrant pain, fever, jaundice, weight loss, or carcinoid syndrome-related symptoms such as flushing, diarrhea, edema, or wheezing. Abdominal ultrasonography revealed an ill-defined echogenic tumor with a hypervascular signal located in the thickened gallbladder wall of the fundus. One mixed echogenic tumor, 5–6 cm in size, was noted in the S5 segment of the liver. No evidence of biliary dilatation was noted. Routine laboratory evaluation and viral hepatitis profile results were normal. Serum levels of tumor markers, including alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), and cancer antigen (CA19-9) were normal. Abdominal computed tomography (CT) and magnetic resonance cholangiopancreatography have confirmed the findings of sonography, indicating a high likelihood of a gallbladder tumor with direct liver invasion [Figure 1]. Cholecystectomy and extended right hepatectomy were performed based on the preoperative diagnosis of a gallbladder tumor with direct liver invasion [Figure 2].

Figure 1: (a) Coronal plane of the abdomen on computed tomography, (b) Coronal plane of the abdomen on magnetic resonance imaging: Irregular eccentric wall thickening at the lateral wall of the gallbladder about 2.9 cm in length (white arrow). One 5.0 cm × 5.5 cm, mildly lobulated, faintly hypodense mass at S4b/S5 junction, compatible with direct invasion of a gallbladder tumor

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Figure 2: The gallbladder measured 7.5 cm on the gross inspection with no evidence of stones in the lumen. A soft papillary tumor involving the liver was seen, measuring 5.5 cm × 4.5 cm × 3 cm in size (white arrow)

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Microscopically, sections of the gallbladder tumor showed small-cell NEC composed of solid sheets of poorly differentiated carcinoma cells with hyperchromatic nuclei and brisk mitosis. Immunohistochemical analysis showed the cytoplasm stained focally positive for tCK (AE1/AE3) (dot-like pattern), insulinoma-associated protein 1, chromogranin A (CgA), synaptophysin, and CD56, and retained the expression of RB and ATRX proteins, consistent with the diagnosis. Ki-67 showed a proliferative index of about 80% [Figure 3]. The patient was discharged in good condition after surgery. The serum level of CgA was checked about 10 days after surgery, which was elevated to 661.7 ng/mL. She underwent four cycles of cisplatin and etoposide combination adjuvant chemotherapy. The results of her chest and abdomen CT showed no definite recurrence, and her serum level of CgA gradually declined to normal; she is currently disease-free 16 months after surgical treatment.

Figure 3: Neuroendocrine carcinoma, small-cell type; immunohistochemically, the tumor cells were positive for chromogranin A (a), synaptophysin (b), and CD56 (c). In addition, the Ki-67 (d) proliferation labeling index was very high (>80%)

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Discussion

NENs are uncommon and defined as epithelial neoplasms with predominant neuroendocrine differentiation. The average age at onset is 60 years, and most NENs are found in the gastrointestinal tract (66%), followed by the lungs (31%).^[4] NEC-GB represents 2.1% of all gallbladder cancers and only 0.5% of all NENs,^[5] and is defined as a high-grade carcinoma that resembles small-cell carcinoma or large-cell NEC of the lungs.

Typically, no neuroendocrine cells exist in the gallbladder. NEC-GB is probably derived from neuroendocrine cells in heterotopic gastric or intestinal metaplasia of gallbladder epithelium caused by cholelithiasis.^[6] NEC-GB may also occur clinically mixed with adenocarcinomas, and some researchers have suggested that NEC is transformed from gallbladder adenocarcinoma.^[6]

The early clinical manifestations of NEC-GB are similar to those of other types of gallbladder cancer and thus, the diagnosis of NEC-GB before surgery remains difficult. The serum levels of tumor markers, including AFP, CEA, CA19-9, and CA-125 are often negative. CgA and synaptophysin are commonly used immunohistochemistry biomarkers. Serum CgA levels have been reported to be higher in 60%–80% of patients with NEC of the digestive system than in normal individuals.^[7] Therefore, serum CgA has the highest significance in the diagnosis of NEC-GB. In cases of nonsecretory NEC, urine 5-hydroxyindoleacetic acid and nuclear imaging studies (octreotide scintigraphy or MIBG) may not be useful for the diagnosis or for evaluating the response to therapy. It is almost impossible to differentiate NEC-GB from other subtypes of gallbladder carcinomas preoperatively based solely on radiologic imaging such as ultrasonography, CT, magnetic resonance imaging, and positron emission tomography CT.^[3]

Radical resection is considered to be the most preferred surgical treatment for patients with NEC-GB.^[1] A tumor restricted to the mucosa or submucosa requires cholecystectomy alone. However, there is a high rate of metastatic dissemination even in clinically localized tumors in patients with NEC-GBs. The most common metastasis sites of small-cell NEC-GB are the lymph nodes and liver (88%), followed by lungs and peritoneum.^[8] Locally advanced disease with no evidence of distant metastasis requires lymphadenectomy and hepatic resection to achieve a tumor-free margin in addition to cholecystectomy.^[9] Systemic chemotherapy can be considered when the tumor is unresectable or metastasized. Cisplatin, carboplatin, and etoposide combinations have been used as the first-line chemotherapy for hepatobiliary NEC. Radiation therapy is effective for the palliation of pain, compression of nerves or the spinal cord, and other local symptoms caused by metastatic bone disease. Radiofrequency ablation, transarterial chemoembolization, and transarterial radioablation may be options for palliative treatment in metastatic hepatic disease.^[1] Due to the high malignancy and early lymphatic and liver metastasis, the prognosis is poor compared with all other types of gallbladder cancer. Chiorean et al.^[10] reported that 1-year survival rates were lower than those of other types of gallbladder cancer (20% vs. 38%). The CgA serum level in our patient gradually decreased after surgery, and she is currently disease-free 16 months after surgical treatment. R0 resection for NEC-GB may play a role in increasing the overall long-term survival time of patients.

In conclusion, NEC-GBs are rare and usually present with a subtle clinical picture and lack of symptoms specific to carcinoid syndrome, making an early diagnosis difficult. Pathological and immunohistochemical examinations are needed for a definitive diagnosis. Most patients with NEC-GB diagnosed in the middle or late stages of the disease have a poor prognosis and rapid disease progression. Some studies have shown that multimodal treatment with surgical resection, chemotherapy, and radiotherapy can improve survival. However, further research is needed due to the low incidence of the disease and no generally accepted treatment options and guidelines.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her names and initials will not be published and due efforts will be made to conceal her identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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