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Adenocarcinoma of the Gallbladder, Proliferative Transformation to Neuroendocrine Tumor: Hypothesis of Molecular and Pathological Etiology

Oncology & Cancer Case Reports

ISSN - 2471-8556

Case Report - (2019) Volume 5, Issue 2

Adenocarcinoma of the Gallbladder, Proliferative Transformation to Neuroendocrine Tumor: Hypothesis of Molecular and Pathological Etiology

Amar S1, Mountjoy L2 and West M3*
1Department of Hematology Oncology, Creighton University, Maricopa, USA
2Department of Hematology Oncology, Mayo Clinic, Phoenix, Arizona, USA
3Department of Internal Medicine, Norwalk Hospital, Yale, USA
*Corresponding Author: West M, M.D., MPH, Department of Internal Medicine, 34 Maple Street, Norwalk Hospital, Norwalk CT 06856-3815, Yale, USA, Tel: 4056148374, Fax: 2038995224 Email:

Abstract

Neuroendocrine tumors (NET) of the gallbladder are extremely rare and coexistence with an adenocarcinoma in the same specimen has only rarely been reported. There is a newly defined entity of mixed adenoneuroendocrine carcinoma (both components should be >30%), but not all cases qualify. It is unclear if the NET dedifferentiates into the adenocarcinoma elements or vice versa. We report the case of a woman who presented with non-specific cholecystitis like symptoms and was found to have elements of a high-grade NET of the gallbladder with an area of adenocarcinoma. The prognosis is determined by the high-grade NET element and the patient was treated with surgery followed by concomitant chemo-radiation. The incidence and prevalence of NET ranges from 1.09 per 100,000 individuals over the past 50 years, with a 6.4-fold increase in incidence since 2012.

Diagnosis of NET are commonly made post-surgically, and thus patients will likely present with symptoms ranging from vague epigastric pain, anorexia, weight loss, and jaundice. A patient who present without carcinoid symptoms, including diarrhea, flushing, and skin rashes, defines a poorer prognosis due to poorly differentiated neuroendocrine cells. This case reports a woman with a long history of epigastric pain and bloating who was found to have a primary adenocarcinoma of the gallbladder with dedifferentiation into high grade NET. Pathology showed poorly differentiated nest of neuroendocrine cells within the high-grade adenocarcinoma. Cases of dedifferentiated neuroendocrine cancer of the gallbladder are extremely rare and this case highlights unique pathologic findings. Currently, it is unclear whether pathological findings of adenocarcinoma with neuroendocrine features, arises from linear plasticity, of which specified DNA alterations induce transformation, or that this is a subtype of mixed tumor types.

Keywords: Neuroendocrine; Gallbladder cancer; Adenocarcinoma carcinoid; Neuroendocrine tumors; Mixed neuroendocrine tumor adenocarcinoma; Cholangiocarcinoma

Introduction

NET are a group of heterogeneous tumors, the cells of origin being stem cells of the endocrine and nervous system. NET occurs in many organs such as pancreas, small intestine, colon, stomach, lung, ovary and testis. Although gastroenteropancreatic NETs are the most common type representing 65-75% of all cases, gallbladder neuroendocrine tumors (GB-NETs) are extremely rare with only 2% of all GB tumors being NET [1-5]. In the GB area the most common sites for NET are distal common bile duct 20%, proximal common bile duct 12%, mid common bile duct 18%, and cystic duct 16% [6]. These are more common in women and average age of presentation is about 64 years. NET can be secretory or non-secretory, the former causing carcinoid like symptoms of diarrhea, wheezing, flushing, and skin rashes [7]. GB-NETs are usually non-secretory and present with symptoms of cholecystitis or cholelithiasis like epigastric pain or bloating [8]. Only about 3.3-3.7% GB-NET present with carcinoid symptoms [5]. The etiology of GB-NET is unclear as neuroendocrine cells do not naturally occur in the GB mucosa. Paniz et al. proposed that metaplastic processes could deviate from stem cells from their original differentiation into neuroendocrine cells [9]. Intestinal metaplasia, cholecystitis and cholelithiasis are commonly found in cases of GB-NET suggesting that these might be related to chronic GB inflammation [10]. There are reports of concurrent NET and adenocarcinoma of the GB [11] and a new entity called mixed adenoneuroendocrine carcinoma has been defined as presence of >30% of both components in a tumor [12]. Our patient had mostly NET (>90%) with only one small focus of adenocarcinoma component (<10%) hence did not meet the definition for mixed adenoneuroendocrine carcinoma [13].

Guidelines still have not been implemented as to whether surgical resection is warranted based on tumor grading, location, and size [14]. In addition, no research has been done to determine whether neuroendocrine tumors are a precursor for proliferative transformation into other tumors, such as adenocarcinoma [15], although scientific research has shown that neuroendocrine tumors upregulate the mTOR and Akt pathways.

Case Presentation

A 50-year-old Hispanic woman, with a past medical history of chronic paroxysmal atrial fibrillation, controlled with amiodarone and diltiazem, diabetes mellitus type 2, controlled on sitagliptan-metformin, osteoarthritis, hyperlipidemia, treated with atorvastatin, major depressive disorder, and hypertension, all well controlled on medications, presents to her primary care physician with a chief complaint of epigastric pain, associated with nausea and bloating, worsening with food intake, associated with bright red blood per rectum, for over a year. Surgical history includes total abdominal hysterectomy, due to history of uterine cancer, and bilateral oophorectomy, with partial liver resection. Family history includes cancer on paternal side of the family, including the father and aunt, and diabetes mellitus in siblings and mother. She denies any history of alcohol, tobacco, or illicit drug usage. She was initially diagnosed with GERD and prescribed protonix. The epigastric pain progressively worsened, with no relief on protonix. She returned back to her primary care physician, and H. pylori stool antigen was completed and was positive. Patient was treated with triple therapy, and she continued the protonix. She returned back to the primary care physician, with no resolution of her symptoms, which were still progressively worsening. Stool antigen for h. pylori was repeated, which returned back negative. An EGD was ordered but could not be completed. Patient was referred for colonoscopy. Subsequently, the patient was referred to the gastroenterologist, for which an abdominal ultrasound was completed. Refer to Figure 1 for results and findings. An ultrasound (Figure 1) of the gallbladder showed gallstones, including a non-mobile stone in the gallbladder neck. There was abnormal, eccentric and mass-like thickening of the medial gallbladder wall raising concerns about a neoplasm. CT with contrast of the abdomen and pelvis (Figure 2) shown below. CT scan (Figure 2) shows multiple contiguous 5-mm axial CT slices of the chest, abdomen, and pelvis obtained after IV omnipaque 350 contrasts, dose 131.3 ml, at 2.52 ml/s, multiplanar reformatted images. Radiation dose CTDlvol 19.0 mGy, DLP 1316 mGy-cm. There is a re-demonstration of irregular mass-like thickening along the anteromedial wall of the gallbladder measuring 2.8 × 2.8 × 3.2 cm. There was clear increase in size since in comparison to CT images completed 2 years prior. Cholelithiasis was additionally demonstrated. No pericholecystic fluid found. There was mild prominence of the common bile duct, without discrete obstructing the lesion. Further evaluation with a non-urgent MRCP was recommended. No evidence of metastasis was found. Patient was also referred to complete a triple-phase CT of abdomen and pelvis (Figure 3). Triple phase CT scan (Figure 3) shows multiple contiguous 5-mm axial CT slices of the chest, abdomen, and pelvis obtained after IV omnipaque 350 contrasts, dose 135.0 ml, at 4.34 ml/s, multiplanar reformatted images. Radiation dose CTDlvol 23.7 mGy, DLP 2045 mGy-cm.

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Figure 1: Doppler wavelength ultrasound gallbladder.

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Figure 2: Gallbladder CT with IV contrast.

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Figure 3: Triple phase CT chest, abdomen and pelvis.

The liver was enlarged, with right hepatic lobe measuring 18 cm in craniocaudal dimension at the midclavicular line. No hepatic mass. The hepatic veins and portal venous system were patent. There was progressive enlargement of the mass the thickening of the medial and fundal gallbladder wall, measuring 7 × 4 × 2.7 cm, with likely invasion into the left hepatic lobe, highly concerning for malignancy [16]. There was mild adjacent fat stranding. There were numerous gallstones including a 2 cm stone in the gallbladder, consistent with cholelithiasis. Surgical consultation was this recommended based on imaging findings.

Patient underwent robotic-assisted laparoscopic cholecystectomy [17]. Pathology revealed large areas of HG NET with a small focus of moderately differentiated adenocarcinoma. Tumor markers, CEA 1.87, CCA 19-9 10, and CA 125,14 were all within normal limits. Surgery was complicated by difficulties with intubation and malignant hyperthermia. Post-operatively, patient experienced nausea and vomiting [18]. Hospital stay was also complicated by atrial fibrillation, with rapid ventricular rate. Frozen section was sent to the laboratory. Refer to Figure 4 pathology results shown below.

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Figure 4: Vascular invasion poorly differentiated neuroendocrine and capsular invasion.

Pathological microscopy showed poorly differentiated neuroendocrine carcinoma with necrosis, solid nests and foci of interanastomosing trabecule composed of neoplastic cells with enlarged irregular nuclei and scattered small nucleoli. There was an area of high-grade epithelial dysplasia/carcinoma in situ with associated small focus of moderately differentiated carcinoma with cribriforming architecture. The surface lesion was positive for CK7 but negative for NSE, chromogranin A and synaptophysin [19]. The associated small invasive component was also CK7 positive and showed rare foci of staining with NSE, chromogranin and synaptophysin. The tumor invaded the thickness of the gallbladder wall into the subperitoneal soft tissue. Vascular tumor emboli were noted, without obvious perineural invasion. Refer to Figure 5 for pathology results shown below. Uninvolved gallbladder showed chronic cholecystitis. Immunoperoxidase stains show that the neoplastic cells of the high-grade carcinoma were positive for CK7, NSE, chromogranin A synaptophysin, but negative for CK20. Ki-67 was >80% [20]. See Figure 6 for pathology results shown below.

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Figure 5: CK 7, Synaptophysin, Ki-67 and Vimentin.

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Figure 6: PAX-8, NSE, chromogranin and CK20.

Patient received six cycles of carboplatin etoposide with concomitant radiation therapy post operatively [21]. At the time of writing she was in remission seven months after her surgery. Table 1 shows the chemotherapy regimen and dosaging schedule.

Chemotherapy 7/13/2018 9/11/2018 9/12/2018
Day, Cycle -- Day 1, Cycle 1 Day 2, Cycle 1
Carboplatin (Paraplatin) IV -- 900 mg --
Ertapenem (Invanz) IV 1 g -- --
Etoposide (Vepesid) IV -- 100 mg/m2 100 mg/m2
Chemotherapy 9/13/2018 10/9/2018 10/10/2018
Day, Cycle Day 3, Cycle 1 Day 1, Cycle 2 Day 2, Cycle 2
Carboplatin (Paraplatin) IV -- 900 mg --
Ertapenem (Invanz) IV -- -- --
Etoposide (Vepesid) IV 100 mg/m2 100 mg/m2 100 mg/m2
Chemotherapy 9/13/2018 10/9/2018 10/10/2018
Day, Cycle Day 3, Cycle 1 Day 1, Cycle 2 Day 2, Cycle 2
Carboplatin (Paraplatin) IV -- 900 mg --
Ertapenem (Invanz) IV -- -- --
Etoposide (Vepesid) IV 100 mg/m2 100 mg/m2 100 mg/m2

Table 1: Chemotherapy regimen and dosage.

Discussion

Neuroendocrine tumors with transformational proliferation to epithelial cell types are rare. Studies have shown that, the presence of stem cells provides opportunity of differentiation to various cell types [3]. Due to the rarity of GB NET [12] specially in combination with adenocarcinoma, no standard treatment guidelines are available [22]. Usually these tumors are found post-surgically, with patients presenting with vague abdominal pain and bloating. Many of these patients, as seen in our case, can present with signs very similar to gastroesophageal reflux or dyspepsia. Imaging studies can be used to determine presence of tumor but cannot delineate tumor types [6]. Poorly differentiated NET arise de novo and those that arise from epithelial carcinoma, arises from a mechanism of lineage plasticity associated with genetic alterations in tumor suppressor genes [23]. These poorly differentiated cells with neuroendocrine differentiation can coexist with other well-differentiated adenocarcinomas and can harbor mixed cellular features, pointing to a single precursor of origin [24].

Conclusion

It has been hypothesized that either NET cells or adenocarcinoma share a single origin, or adenocarcinoma cells follow a lineage transformation into NET cells. Others hypothesized that adenocarcinoma differentiates into NET based on similar DNA phenotypes, or tumors with dual adenocarcinoma and neuroendocrine cells arise from multipotent cells. These mechanisms or classification of mixed adenocarcinoma neuroendocrine properties have not yet been specified.

References

Citation: Amar S, Mountjoy L, West M (2019) Adenocarcinoma of the Gallbladder, Proliferative Transformation to Neuroendocrine Tumor: Hypothesis of Molecular and Pathological Etiology. Oncol Cancer Case Rep 5: 153.

Copyright: © 2019 Amar S, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.