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CASE REPORT
Year : 2022  |  Volume : 42  |  Issue : 3  |  Page : 145-150

Neuroendocrine tumor gall bladder: A case report and review of literature


Department of Radiotherapy, VMMC and Safdarjung Hospital, New Delhi, India

Date of Submission15-Jan-2021
Date of Acceptance29-Mar-2021
Date of Web Publication15-Oct-2021

Correspondence Address:
Dr. Aashita
Department of Radiotherapy, VMMC and Safdarjung Hospital, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jmedsci.jmedsci_17_21

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  Abstract 


Neuroendocrine tumor (NET) of gallbladder (GB) is very rare, accounting for 0.5% of all neuroendocrine malignancies and 2% of all GB cancers. It is very difficult to differentiate between carcinoma GB and NET GB. Here, we present a case of NET GB diagnosed in a 40-year-old female. The clinical features were nonspecific and the diagnosis was confirmed only on histopathological examination. The management of carcinoma GB and NET GB is discussed in detail.

Keywords: Neuroendocrine tumor, gall bladder, gall bladder cancer


How to cite this article:
Aashita, Yadav V, Kapoor A, Sharma R. Neuroendocrine tumor gall bladder: A case report and review of literature. J Med Sci 2022;42:145-50

How to cite this URL:
Aashita, Yadav V, Kapoor A, Sharma R. Neuroendocrine tumor gall bladder: A case report and review of literature. J Med Sci [serial online] 2022 [cited 2022 Jul 2];42:145-50. Available from: https://www.jmedscindmc.com/text.asp?2022/42/3/145/328363




  Introduction Top


Neuroendocrine tumors (NETs) are heterogeneous group of neoplasm originating from neuroendocrine cells present throughout the body. The most commonly involved sites are the gastrointestinal tract (67%) and lung (31%) followed less frequently by the ovaries, testes, hepatobiliary system, and pancreas.[1],[2] NET gall bladder (GB) is very rare, accounting for only 0.2% of all NETs and 2% of all gall bladder cancers (GBCA).[3] Here, we present a case of NET GB in a 40-year-old female. The natural history and management guidelines of NET GB remain largely undefined due to the relative paucity of cases.


  Case Report Top


A 40-year-old female presented with pain abdomen and multiple episodes of vomiting for 3 months with significant weight loss in the past 2 months and no history of jaundice or altered bowel habits. On physical examination, a firm nontender mass was palpable in the right upper quadrant of the abdomen. Routine blood investigations including hemogram, liver function, and renal function tests were within normal limits.

Ultrasonography revealed a 9.2 cm × 7.3 cm mass in the right lobe of the liver with multiple gall stones, the largest measuring 4.8 mm. Another left adnexal cystic mass of size 4.7 cm × 5 cm was also seen with minimal free fluid in the pouch of Douglas.

Contrast-enhanced computed tomography (CECT) showed a 10 cm × 7.4 cm heterogeneous enhancing mass in GB fossa and segment IV of the liver with necrotic changes, compressing primary biliary confluence suggestive of GB malignancy with hepatic invasion along with multiple gall stones in the lumen. Multiple enhancing lesions were present in both lobes of the liver suggestive of hepatic secondaries along with mildly dilated central intrahepatic biliary radicals. Bilateral adnexal enhancing solid cystic mass was present measuring 4.5 cm × 3.6 cm in right and 6 cm × 5.3 cm in left suggestive of Krukenberg tumor [Figure 1]a and [Figure 1]b. A 10 mm lymph node in the aortocaval region was also seen.
Figure 1: (a) Heterogeneous enhancing mass of size 10 cm × 7.4 cm, with necrotic changes and compressing the primary biliary confluence, in gall bladder fossa and segment IV of the liver suggestive of gall bladder malignancy with hepatic invasion; (b) A 4.5 cm × 3.6 cm size enhancing solid cystic mass seen in right adnexa and another 6 cm × 5.3 cm size complex cystic mass with thin enhancing septations seen in the left adnexa

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Biopsy from liver lesion revealed infiltrating tumor with areas of necrosis. Tumor cells were monomorphic without any pleomorphism, small, round-to-oval with scanty cytoplasm arranged in nest-like pattern [Figure 2]a and [Figure 2]b. On immunohistochemistry, tumor cells were positive for nonspecific enolase [Figure 2]c.
Figure 2: (a) Tumor cells arranged in the form of nests and sheets (×100); (b) The individual tumor cells are monomorphic, round-to-oval with a scant amount of cytoplasm and round nucleus (×400); (c) Tumor cells showing positivity for nonspecific enolase (×400)

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  Discussion Top


NET are rare tumors but better understanding of the natural history of the disease and better imaging modalities have led to increase in their incidence.[3] They vary histologically by tumor differentiation and grade. According to the recent WHO Classification system (2019), neuroendocrine neoplasm is classified according to morphological differentiation, grade, mitotic count, and Ki-67 index[4] [Table 1].
Table 1: Classification and grading criteria for neuroendocrine neoplasms of the gastrointestinal tract and hepatobiliary organs, World Health Organization, 2019[4]

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The most common histology of GBCA is adenocarcinoma (90%) while NET of GB is quite rare contributing to only 2% of all GBCA.[3] Histological examination may reveal both neuroendocrine and adenocarcinoma components simultaneously and when each proportion is more than 30%, it is said to be mixed neuroendocrine-nonneuroendocrine neoplasm.[5]

GBCA occurs more frequently in females and in the 6th and 7th decades of life whereas NET GB has been reported in the age group 38–81 years.[6] The literature on NET GB presentation, age, and gender distribution of NET GB provides variable data. In a retrospective analytical study, 68% of patients with NET GB were women, and age at presentation ranged from 26 to 79 years.[5] This is in contrast to a study which reported that NETs are more commonly found in males and at an earlier age.[7]

The etiology and risk factors are well defined for GBCA that includes chronic inflammation due to cholesterol gallstones which increases the risk of GBCA by manifolds.[8] The other associated risk factors for GBCA are obesity, occupational risks (petroleum and porcelain industry), chemical exposure (pesticides and heavy metals), drugs such as organochlorine pesticides, and isoniazid.[9],[10] The etiology of NET GB is not very clear, though, cholelithiasis and chronic inflammation have been associated with NET.[11],[12] Since neuroendocrine cells are not found in GB, it has been hypothesized that chronic inflammation may result in intestinal metaplasia of multipotent stem cells which may give rise to NET. Many studies have shown incidence of metaplasia in postcholecystectomy specimens with cholelithiasis.[13],[14] Nearly 83.3% and 50% cases of cholelithiasis with metaplasia expressed chromogranin and synaptophysin, respectively, which are diagnostic of NET.[13] This hypothesis is supported by the fact that most of the NET GB are diagnosed incidentally on pathological examination of cholecystectomy specimens.[15],[16]

It is difficult to differentiate GBCA with NET GB clinically as both present with nonspecific symptoms of abdominal pain, jaundice, weight loss, and decreased appetite and hormone-related symptoms in NET GB are rarely seen.[12] In a case series of 12 NET GB patients, all presented with right upper quadrant pain indicating acute cholecystitis with ultrasonographic confirmation of cholelithiasis but none of them had any paraneoplastic symptoms. Like GBCA, NET GB also gets diagnosed in advanced stage either with direct hepatic invasion or with distant metastases.[17] On imaging, both GBCA and NET GB appears as focal or diffuse GB wall thickening along with an intraluminal polypoidal mass that may be present with direct invasion of adjacent liver parenchyma. Advanced disease commonly has lymphadenopathy and hepatic metastases. Thus, it is difficult to differentiate between these two tumors both clinically and radiologically.

Neuroendocrine cells express somatostatin receptors on their cell surface, thus providing a specific and unique molecular target for functional imaging of NETs such as somatostatin receptor scintigraphy and Ga-68-labeled somatostatin analogs positron emission tomography/computed tomography (PET/CT).[18] Octreotide, a long-acting somatostatin analog, has become an important agent for somatostatin receptor scintigraphy which is used for both diagnostic and therapeutic purposes.[19] Short peptide analogs of somatostatin are linked to positron emitter Ga-68 with the aid of chelating agent 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA) and are used in PET imaging of Grade 1 and 2 NETs which overexpress somatostatin receptors. The commonly used radiolabeled DOTA peptides are Ga-68 DOTA-TOC, Ga-68 DOTA-NOC, and Ga-68-DOTA-TATE. In high-grade NETs, somatostatin receptor positivity is variable, thus 18-fluorodeoxyglucose PET performs better than somatostatin analog PET as an imaging study.

The management of nonmetastatic GBCA depends on the resectability of disease. In resectable GBCA, only curative modality is complete en bloc surgical resection but carries a poor prognosis with median survival of 30 months approximately.[20] Surgery is mostly followed by adjuvant treatment with fluoropyrimidine-based chemotherapy except in Tis and T1 lesions.[21],[22] There is sufficient data which showed benefit in overall survival with adjuvant treatment with either chemotherapy or radiotherapy.[23] Both NCCN and ESMO guidelines recommend adjuvant fluoropyrimidine chemoradiation or fluoropyrimidine or gemcitabine chemotherapy in patients with high-risk GBCA following curative surgery whereas patients with unresectable locally advanced GBCA can be challenged with neoadjuvant chemotherapy for downstaging of disease.[24] In metastatic GBCA, systemic chemotherapy has shown modest but significant survival benefit, with both fluoropyrimidine and gemcitabine-based combination regimens but maximum benefit was demonstrated with combined gemcitabine and platinum regimen.[25] Single agent gemcitabine, capecitabine, docetaxel, or irinotecan shows limited benefit.[26],[27]

Prognosis and survival depend on the grade of NET, Grade 1 and 2 NETs are indolent in nature and usually have good prognosis.[28] In localized Grade 1 and 2 NET, surgery is the treatment of choice and does not require adjuvant treatment, whereas advanced Grade 1 and 2 NET various treatment options are present. Somatostatin analogs such as octreotide LAR and lanreotide can be used to control symptoms of carcinoid syndrome with added antitumor effect as reported in various trials, so these agents are indicated in advanced functional or nonfunctional NET. Metastectomy or chemotherapy with alkylating agents, capecitabine + bevacizumab, and gemcitabine + platinum has also shown effect. Targeted therapy with sunitinib, a TKI inhibitor or everolimus, an mammalian target of rapamycin inhibitor, alone or in combination with a somatostatin analog can be used. Peptide receptor radionuclide therapy (PRRT) with Yttrium-90 and Lutetium-177 labeled DOTATOC or DOTATATE have been used in the treatment of NETs with liver metastases with promising results. Other therapies are liver-directed therapy by chemoembolization with doxorubicin, embolization, and radioembolization.[29],[30]

As the WHO recently reclassified NET Grade 3 tumors, not much data are present on treatment, follow-up and associated prognosis. Chemotherapy and liver-directed therapy as in NET Grade 1 and 2 have been used while somatostatin analogs, metastasectomy, targeted therapy, PRRT, and immunotherapy have to be selected for individual cases.[29]

Neuroendocrine carcinoma (NEC) are aggressive tumors and almost always present with metastasis, in localized NEC surgery followed by four cycles with platinum-based chemotherapy is generally used. Several studies showed benefit of this chemotherapy regimen in small type NEC when compared to large type.[31],[32] Similarly, chemotherapy response rate was studied in association with Ki67 index which showed that patients with Ki-67 <55% had a lower response rate (15%) but better survival (14 months) than patients with Ki-67 >55% (response rate 42%, 10 months median survival).[33] Thus, for chemotherapy treatment, both grade and Ki-67 index should be taken into consideration.

In metastatic NEC, platinum and etoposide as first line is preferred and second line includes capecitabine and oxaliplatin or 5-Fluorouracil-based chemo regimes. PRRT has also been used and trials with immunotherapy are ongoing. As the presence of somatostatin receptors on NEC is variable, somatostatin analogs are not recommended for treatment in them.[29],[34],[35]


  Conclusion Top


NET GB is very rare. A case of NET Grade 1 with hepatic and ovarian metastasis is reported here. We have tried to differentiate between carcinoma GB and NET of GB [Table 2] and [Flow Chart 1] Due to scarce literature on NET GB, the management guidelines remain unclear and more trials are needed.
Table 2: Differentiating features of gall bladder cancers and neuroendocrine tumors gall bladder

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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 name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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    Figures

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    Tables

  [Table 1], [Table 2]



 

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