Proton Pump Inhibitors and Cancer Risk: A Comprehensive Review of Epidemiological and Mechanistic Evidence.

Background: Proton pump inhibitors (PPIs) are commonly prescribed long-acting drugs used to treat acid reflux, gastroesophageal reflux disease (GERD), and peptic ulcers. Recently, concerns have been raised about their safety, particularly due to the association between long-term PPI use and cancer development. Multiple comprehensive studies have consistently suggested a noteworthy link between prolonged PPI usage and an increased risk of developing gastric, esophageal, colorectal, and pancreatic cancers, yet the precise underlying mechanism remains elusive. Methods: First, we review the extensive body of research that investigates the intricate relationship between cancer and PPIs. Then, we predict PPI toxicity using the prodrug structures with the ProTox-II webserver. Finally, we predict the relative risk of cancer for each PPI, using PubMed citation counts of each drug and keywords related to cancer. Results: Our review indicates that prolonged PPI use (exceeding three months) is significantly associated with an elevated risk of cancer, while shorter-term usage (less than three months) appears to pose a comparatively lower risk. Our review encompasses various proposed mechanisms, such as pH and microbiome alterations, vitamin and mineral malabsorption, hypergastrinemia, and enterochromaffin-like cell proliferation, while ProTox-II also suggests aryl hydrocarbon receptor binding. Potentially, the PubMed citations count suggests that the PPIs omeprazole and lansoprazole are more associated with cancer than pantoprazole and esomeprazole. In comparison, the H2R blocker, famotidine, is potentially less associated with cancer than PPIs, and may serve as a safer alternative treatment for periods beyond 3 months. Conclusions: Despite the well-established cancer risk associated with PPIs, it is notable that these medications continue to be widely prescribed for periods longer than 3 months. Thus, it is of paramount importance for clinicians and patients to thoughtfully evaluate the potential risks and benefits of long-term PPI usage and explore alternative treatments before making informed decisions regarding their medical management.

Cardiac Metastasis of Neuroendocrine Tumor Without Cardiovascular Symptoms.

A 72-year-old man with a stage IV small intestinal neuroendocrine tumor presented to our cardiology clinic as a referral for an abnormal positron emission tomography-computed tomography scan with an intense gallium uptake in the heart. Follow-up cardiac magnetic resonance was suggestive of myocardium infiltration by the neuroendocrine tumor with late gadolinium enhancement and T1 time elevation. (Level of Difficulty: Intermediate.).

Occult Pulmonary Neuroendocrine Tumor Causing Severe Hyperparathyroidism: Diagnostic Challenges and Clinical Outcomes.

Background/Objective: Ectopic tumoral production of parathyroid hormone (PTH) is rare. The incidence of hyperparathyroidism and osteitis fibrosa cystica (OFC) secondary to ectopic PTH secretion has only been reported in case reports, although infrequent. Case Report: We report a case of a well-differentiated pulmonary neuroendocrine tumor (NET) producing PTH that presented with severe hypercalcemia and OFC. Surgical removal of the pulmonary tumor resulted in resolution of hypercalcemia. Immunocytochemical analysis of the tumor tissue revealed PTH-positive staining. Recovery was complicated by severe hypocalcemia due to hungry bone syndrome. Discussion: To the best of our knowledge, this is the first documented case of a pulmonary NET causing OFC via PTH. We further describe the successful identification and resection of a rare NET and restoration of calcium homeostasis with aggressive calcium and vitamin D repletion. Conclusion: Although a rare cause of severe hypercalcemia and OFC, ectopic tumoral production of PTH must be considered in the differential diagnosis. Furthermore, resection of these tumors secreting PTH can lead to a protracted and severe high risk of hungry bone syndrome, which requires aggressive treatment to maintain calcium homeostasis.

Metastatic Insulinoma Presenting With Postprandial Hypoglycemia.

Background/Objective: Patients with an insulinoma, a type of pancreatic neuroendocrine tumor, typically present with fasting hypoglycemia but can rarely present exclusively with postprandial hypoglycemia. Case Report: A 69-year-old man presented with episodes of postprandial blurry vision, sweating, and confusion for the last 2 years that were becoming more frequent over the last several weeks. Home blood glucose measurements revealed postprandial hypoglycemia (glucose level, 45-70 mg/dL), and symptoms were consistent with the Whipple triad. Continuous glucose monitoring revealed only postprandial hypoglycemia within 2 hours following meals. An outpatient fast was conducted with detectable insulin (6 µIU/mL) and C-peptide (2.0 ng/mL) levels with an elevated proinsulin (20.8 pmol/L) level when the serum blood glucose level dropped to 47 mg/dL (21 hours after the initiation of the fast). A computed tomography scan of the abdomen and pelvis showed a 1.6-cm hyperenhancing lesion in the distal body of the pancreas. He underwent endoscopic ultrasonography with fine-needle aspiration. Pathology revealed a low-grade, well-differentiated, neuroendocrine tumor with lymphovascular invasion and regional lymph node metastases, confirming the diagnosis of a pancreatic neuroendocrine tumor. Discussion: Exclusive postprandial hypoglycemia is estimated to occur in 6% of the insulinomas. Patients with postprandial hypoglycemia may be initially managed as those with reactive hypoglycemia; however, this case highlights the importance of evaluating for an insulinoma in a patient who has failed treatment for reactive hypoglycemia. This case also demonstrates the importance of including proinsulin levels in that evaluation. Conclusion: Pancreatic neuroendocrine tumor should be considered in postprandial hypoglycemia, even in the absence of fasting hypoglycemia. Measuring proinsulin levels is essential in the diagnostic workup of insulinoma causing hypoglycemia.

Endoscopic full-thickness resection of well-differentiated T2 neuroendocrine tumors in the duodenal bulb: a case series.

Background and Aims: Endoscopic therapies have moved to the forefront in the removal of small, well-differentiated duodenal neuroendocrine tumors (NETs). Classic procedures used to address small tumors, especially those less than 1 cm in diameter, are banding without resection, ligation endoscopic mucosal resection, or endoscopic submucosal dissection. Endoscopic full-thickness resection (EFTR) is a procedure developed recently that allows for sealing off of the tissue surrounding the tumor before full-thickness removal. Although surgical resection is typically recommended for NETs measuring 2 cm and larger, this may not always be possible given patients' ages or comorbidities. We present the cases of 3 patients with well-differentiated NETs of the duodenal bulb measuring greater than 2 cm who were poor candidates for surgery and were thus offered EFTR for excision of their tumors. Methods: Three patients with well-differentiated, stage II NETs of the duodenal bulb underwent chromoendoscopy and narrow-band imaging, EUS, prophylactic dilation of the upper esophageal sphincter and pylorus, and EFTR using an over-the-scope clip system. Results: In each case, there was no residual mass seen on endoscopy, Ga-68 Dotatate positron emission tomography-CT imaging, or biopsy up to 1 year after the procedure. Two of the 3 cases had normal chromogranin A levels at all follow-up points, and the third case had chromogranin A levels that trended down to a near-normal level of 145 ng/mL. Conclusions: Three patients with NETs of the duodenal bulb who were poor surgical candidates underwent successful EFTR using a full-thickness resection device. At 1-year follow-up, they have no evidence of disease recurrence on imaging and pathology after EFTR.

EUS-guided ethanol ablation of metastatic functional insulinoma.

Video 1EUS-guided ethanol ablation of metastatic functional insulinoma.

Mixed neuroendocrine-non-neuroendocrine neoplasms of ascending colon: A case report.

INTRODUCTION: Neuroendocrine tumor (NET) that develops in the right-sided colon is relatively rare. Coexistence of adenocarcinoma and NET is extremely rare, and such cases are called mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN). PRESENTATION OF CASE: Colonoscopy in an 85-year-old woman for an anemia examination indicated laterally spreading tumor-nongranular (LST-NG) in the transverse colon. Colonoscopy and endoscopic ultrasonography (EUS) showed that the depth of the tumor invasion was deep submucosal. The tumor localization was diagnosed as transverse colon close to the hepatic curvature by enema. Computed tomography (CT) showed no obvious lymph node or distant metastasis. Based on these findings, laparoscopic transverse colectomy with D2 lymphadenectomy was performed. Pathologically, most of the tumor was well-differentiated tubular adenocarcinoma, but some solid follicles of polygonal tumor cells with poor nuclear atypia were observed. Immunostaining was positive for synaptophysin and diagnosed as NET G1. This tumor consisted of adenocarcinoma and neuroendocrine tumor, so we diagnosed it as MiNEN and classified the tumor as fT1N0M0 fStage I (TNM Classification of Malignant Tumors, 8th Edition). Since it was an early stage cancer, postoperative adjuvant therapy was not performed. No recurrence has yet been noted. DISCUSSION: Although MiNEN is extremely rare, the detailed pathological specimen observation and diagnosis are important because long-term follow-up after surgery is needed, as is the adequate selection of postoperative adjuvant therapy. CONCLUSION: It is important to elucidate the mechanisms involved in the coexistence of NET and adenocarcinoma and to apply these findings to future medical care.

Right and Left-Sided Carcinoid Heart Disease in the Setting of Selective Serotonin Reuptake Inhibitor Use.

Carcinoid heart disease is a complication of carcinoid syndrome. The role of selective serotonin reuptake inhibitors in carcinoid heart disease is unclear. We present a case of refractory heart failure due to right- and left-sided carcinoid heart disease in the setting of selective serotonin reuptake inhibitor use despite remission of carcinoid syndrome. (Level of Difficulty: Beginner.).

A Rare Case of Carcinoid Constrictive Pericarditis.

We describe a case of atypical carcinoid heart disease. A 62-year-old woman with well-differentiated neuroendocrine tumor metastatic to the liver and lymph nodes presented with recurrent unilateral pleural effusions and lower extremity edema. Multimodality imaging and workup resulted in the diagnosis of carcinoid-related constrictive pericarditis, a rare form of carcinoid heart disease. (Level of Difficulty: Intermediate.).

Quadruple Bioprosthetic Valve Replacement in a Patient With Severe Carcinoid Heart Disease.

Carcinoid heart disease typically affects the tricuspid and pulmonary valves, causing severe regurgitation and/or stenosis. Valve surgery has been shown to reduce right heart failure and improve long-term prognosis in these patients. We report a severe case of a patient with all 4 heart valves involved who underwent successful quadruple bioprosthetic valve replacement. (Level of Difficulty: Intermediate.).

Fusion Image-Guided and Ultrasound-Guided Fine Needle Aspiration in Patients With Suspected Hepatic Metastases.

AIM: The aim of this study was to compare the diagnostic adequacy of computed tomography (CT)-ultrasound (US) fusion image-guided fine needle aspiration (FNA) and US-guided FNA in patients with suspected hepatic metastases. METHODS: Thirty consecutive patients of either sex with known or unknown primary malignancy suspected of having liver metastases on both US and CT, whose multiphasic contrast-enhanced computed tomography was performed using a 64-slice or a higher slice CT scanner, and who were referred for percutaneous FNA were included in this prospective study approved by the institutional review board of the study institute. CT-ultrasound fusion image-guided FNA of the largest lesion using electromagnetic tracking and with freehand ultrasound-guided FNA were performed in the same sitting. Value of fitness, which is a rough estimate of how well the fusion has been achieved, was recorded. Diagnostic adequacy of smears was assessed by a scoring system based on cellular material, background blood/clot, degree of cellular degeneration or trauma, and retention of architecture. RESULTS: The size of the lesions ranged from 1 to 10 cm, and the depth of location of the lesions ranged from 1.4 to 9.3 cm. The fusion fitness values ranged from 1.2 to 10 mm. The scores of the smears did not correlate with lesion size, depth of location, and fusion fitness value. Diagnostic adequacy was seen in 90% and 93.3% of lesions sampled by fusion image guidance and ultrasound guidance, respectively (p = 0.655). All the lesions that yielded inadequate smears by fusion guidance were deep-seated lesions (>5 cm). All the lesions that yielded inadequate smears by ultrasound guidance were small lesions (<3 cm). No complications were encountered in any of the patients. CONCLUSION: Fusion image-guided FNA is a safe procedure with a high diagnostic adequacy rate. Fusion image-guided FNA is not better than US-guided FNA for conspicuous hepatic lesions; however, it may be useful in inconspicuous lesions.

The Outcome of Primary Hepatic Neuroendocrine Tumors: A Single-Center Experience.

BACKGROUND: Primary hepatic neuroendocrine tumor is an extremely rare entity. Only case reports are available in the literature. The aim of the study was to analyze the symptoms, diagnosis, management, and the outcome of patients with primary liver neuroendocrine tumors. METHODS: In the study, a total of eight patients were diagnosed with primary liver neuroendocrine tumors between 2001 and 2017 in our center. Data were analyzed from the records available including the presentation, diagnosis, treatment received, and follow-up. RESULTS: Of eight patients, five were males and three were females. The age of presentation was between 35 and 70 years. Two patients had pain in the right side of the abdomen, while it was accidentally detected in two patients in routine checkup. One patient presented with carcinoid syndrome, while two had ascites and one patient presented only with loose motions. Of eight patients, two patients with poorly differentiated neuroendocrine tumor died within 1 month of follow-up. Four patients are still being followed up, while 10-12 years of follow-up data are available for the remaining two patients. Four patients underwent surgery, and three patients received Sandostatin LAR for tumor recurrence after procedure. Transarterial chemoembolization (TACE) of the tumor was performed in two patients for whom resection was not possible. CONCLUSIONS: Our data suggest that the prognosis of the tumor seems favorable. Surgical resection is the curative treatment. TACE is a favorable option in unresectable tumors.

Merkel cell carcinoma of unknown primary site; case presentation and review of the literature.

Merkel cell carcinoma (MCC) is a rare skin malignancy associated with sun exposure and considered as a Neuroendocrine Tumor due to its characteristic histologic features. However there is increasing number of reports of Unknown Primary MCC's (UPMCC). Although initially UPMCC was considered a variant of known primary MCC, there is growing evidence that it could represent a different clinical entity. We present the case of a 60 year-old male patient who was referred to our department for surgical management of lymph node disease for UPMCC. The patient had undergone excisional biopsy of an inguinal lump, which was found to be an infiltrated lymph node by MCC. The patient underwent full imaging staging including a PET/CT, which failed to identify a primary site, and revealed only intra-abdominal lymph node disease. The patient underwent extended retroperitoneal and inguinal lymph node dissection and remains free of recurrence 16 months postoperatively.

Finding a Needle in a Haystack: The Diagnosis of a Rectal Neuroendocrine Tumor by Transrectal Prostate Biopsy.

INTRODUCTION: Prostate biopsy, usually performed by a transrectal approach, is executed when there is a suspicion of prostate cancer. Neuroendocrine tumors (NETs) are epithelial neoplasms with predominant neuroendocrine differentiation and only 19% of them are localized in the rectum. CASE REPORT: The authors describe a 73-year-old man without a significant past medical history that underwent a prostate biopsy because of urinary complaints and elevated serum levels of prostate specific antigen. The histology revealed a well-differentiated NET characterized as a low-grade tumor (G1). A total colonoscopy revealed a 5 mm sessile rectal polyp and in the splenic flexure a sessile lesion with central ulceration with 5 cm with histological features compatible with an adenocarcinoma. CONCLUSION: This is the first case reported in the literature of a rectal NET diagnosed by transrectal prostate biopsy. This case is particularly unique because the diagnosis of the NET lead to the subsequent timely detection of a colonic adenocarcinoma.

INTRODUÇÃO: A biópsia prostática transretal é realizada na suspeita de cancro da próstata. Os tumores neuroendócrinos (TNE) são neoplasias epiteliais com diferenciação predominante neuroendócrina e em 19% dos casos localizam-se no reto. CASO: Os autores descrevem o caso de um homem, 73 anos de idade, sem antecedentes médicos prévios, que por elevação dos níveis séricos de antigénio específico prostático realizou biópsia prostática transretal. A histologia revelou TNE bem diferenciado de baixo grau (G1). Foi realizada posteriormente colonoscopia total onde se observou pólipo séssil de 5 mm no reto distal. No ângulo esplénico observou-se ainda um lesão séssil de 5 cm com ulceração central cujas biopsias foram compatíveis com o diagnóstico de adenocarcinoma. CONCLUSÃO: Este é o primeiro caso relatado na literatura de um TNE retal diagnosticado por biópsia prostática transretal. Este caso é peculiar dado que o diagnóstico do TNE do reto permitiu a deteção de um adenocarcinoma do cólon num estadio inicial.