An elderly case of paraneoplastic anti-NMDA receptor encephalitis associated with large cell neuroendocrine carcinoma of the lung.

BACKGROUND: Recent studies have suggested that N-methyl-D-aspartate (NMDA) receptors are involved in the cell proliferation in several tumors. However, there have been no reports demonstrating the expression of NR1 subunit of the NMDA receptor in large cell neuroendocrine carcinoma (LCNEC). CASE PRESENTATION: Here, we report the first elderly case of paraneoplastic anti-NMDA receptor encephalitis associated with LCNEC of the lung with NR1 expression. Of note, NR1 subunit expression in the tumor cells of the present case was confirmed by immunohistochemistry (IHC). Radiation therapy and immunotherapies, such as corticosteroids and intravenous immunoglobulin (IVIG), shrank the tumors and improved neurological symptoms in the present case. Additionally, we also confirmed the expression of NR1 in the tumor cells obtained from three other cases with LCNEC of the lung at our hospital by IHC. CONCLUSION: Our IHC results indicate that LCNEC generally expresses NR1 subunit and NMDA receptor may be involved in the tumor development and growth.

Case report: A challenging case of severe Cushing's syndrome in the course of metastatic thymic neuroendocrine carcinoma with a synchronous adrenal tumor.

Ectopic ACTH syndrome (EAS) remains one of the most demanding diagnostic and therapeutic challenges for endocrinologists. Thymic neuroendocrine tumors account for 5%-10% of all EAS cases. We report a unique case of a 31-year-old woman with severe EAS caused by primary metastatic combined large-cell neuroendocrine carcinoma and atypical carcinoid of the thymus. The patient presented with severe hypercortisolemia, which was successfully controlled with continuous etomidate infusion. Complex imaging initially failed to detect thymic lesion; however, it revealed a large, inhomogeneous, metabolically active left adrenal mass infiltrating the diaphragm, suspected of primary disease origin. The patient underwent unilateral adrenalectomy, which resulted in hypercortisolemia resolve. The pathology report showed an adenoma with adrenal infarction and necrosis. The thymic tumor was eventually revealed a few weeks later on follow-up imaging studies. Due to local invasion and rapid progression, only partial resection of the thymic tumor was possible, and the patient was started on radio- and chemotherapy.

A case of gallbladder neuroendocrine carcinoma complicated by ectopic adrenocorticotropic hormone syndrome and resulting in rapid fetal outcomes due to sepsis.

A 52-year-old woman presented to our hospital with chief complaints of upper abdominal bloating and lower leg edema. Computed tomography (CT) revealed liver metastasis from a gallbladder tumor. This tumor was diagnosed as neuroendocrine carcinoma (NEC) on performing a biopsy. Physical examination revealed a moon face. Blood tests revealed hypokalemia and high levels of adrenocorticotropic hormone (ACTH) and cortisol. Dexamethasone suppression test revealed that cortisol secretion was not suppressed, and the patient was diagnosed with gallbladder NEC and ectopic ACTH syndrome (EAS). Metyrapone was administered to suppress cortisol production; however, she developed septic shock due to cellulitis in the lower leg and died on the 16th day of admission. A pathological autopsy was performed, which revealed disseminated intravascular coagulation and acute respiratory distress syndrome as the cause of death. Only a few cases of EAS due to NEC originating from the gallbladder have been reported. The patient reported here succumbed shortly after diagnosis, thereby highlighting the challenges in treating gallbladder NEC complicated by EAS.

Multiple endocrine neoplasia type 2B diagnosed after small intestinal volvulus with progressive megacolon in an adolescent.

Multiple endocrine neoplasia type 2B is a rare autosomal dominant disease characterized by the presence of medullary thyroid carcinoma, pheochromocytoma, Marfan-like fatigue, a peculiar face with thickening of the lips, mucosal neuromas on the lips and tongue, and gastrointestinal phenomena. Most patients harbor pathological variants of the RET gene. Herein, we present the first case of a 14 year-old boy who experienced small intestinal volvulus along with a megacolon, and he was diagnosed with multiple endocrine neoplasia type 2B. The patient complained of constipation since he was 2 years old and slowly progressive abdominal distension at school age. At 14 years of age, he presented with remarkable megacolon mimicking Hirschsprung's disease and complicated with small intestinal volvulus. The volvulus was successfully repaired, and the particularly dilated transverse colon was resected following a rectal biopsy. Histopathological evaluation of the resected transverse colon revealed to be compatible with ganglioneuromatosis. After emergency surgery, the patient was diagnosed with multiple endocrine neoplasia type 2B with medullary thyroid carcinoma, and a de novo variant of RET was confirmed. Gastroenterologists should consider it when treating patients with constipation, especially those with megacolon. Therefore, timely diagnosis may lead to appropriate treatment of medullary thyroid carcinoma and improve mortality.

A challenging case of ectopic ACTH-dependent Cushing's syndrome due to medullary thyroid carcinoma.

Not required for Clinical Vignette.

The syndrome of inappropriate antidiuretic hormone associated with nasal and paranasal malignant tumors.

PURPOSE: To investigate the clinical characteristics of the syndrome of inappropriate antidiuretic hormone (SIADH) associated with nasal and paranasal malignant tumors. METHODS: Patients with locally advanced or recurrence/metastatic malignant tumors of the nasal and paranasal sinuses were included. The SIADH was diagnosed according to the diagnostic criteria. The clinical characteristics of SIADH patients were retrospectively analyzed. RESULTS: Six patients (6/188, 3.2%) met the diagnostic criteria of SIADH, including four olfactory neuroblastoma (4/26, 15.4%), one neuroendocrine carcinoma (1/9, 11.1%), and one squamous cell carcinoma (1/63, 1.6%). Five patients (83.3%) had severe hyponatremia; however, the hyponatremia could be improved by fluid restriction or tolvaptan. Three patients' SIADH were recovered during the chemotherapy and the other three were recovered after the surgery. CONCLUSION: The incidence of SIADH associated with nasal and paranasal malignant tumors is relatively more common in olfactory neuroblastoma and neuroendocrine carcinoma. The hyponatremia caused by SIADH may be corrected by fluid restriction or tolvaptan, and the SIADH may be recovered through anti-tumor therapy.

Dysphagia secondary to neuroendocrine carcinoma: a rare esophageal tumor.

We present two clinical cases, a 68-year-old male and a 55-year-old female, who are being studied for progressive solid food dysphagia. The initial gastroscopy revealed a polypoid lesion in the first case and a partially stenosing lesion in the second case. Both lesions were located in the mid-esophagus and presented a normal mucosa. Histological diagnosis confirmed an esophageal neuroendocrine carcinoma (NEC) of large cell and small cell types, respectively.

[Neuroendocrine carcinoma of the gallbladder as a rare cause for melena and hematemesis in dogs]. / Neuroendokrines Karzinom der Gallenblase als seltene Ursache für Meläna und Hämatemesis beim Hund.

A 9-year-old male Malinois was presented for further workup of acute melena, hematemesis and chronic weight loss for a duration of one month. Clinically, the patient presented with a mildly reduced general condition. Blood tests revealed mild non-regenerative anemia as well as a mild elevation of alanine aminotransferase (ALT). Ultrasonography showed signs of an early mucocele. Treatment with gastroprotectants failed to lead to clinical improvement and the dog developed progressive anemia. Gastroduodenoscopy was unremarkable. Due to persistent clinical signs, exploratory laparotomy was performed. An ulcerated bleeding mass was detected at the gallbladder neck. Histopathological examination led to the diagnosis of a neuroendocrine carcinoma. There was no evidence of a mucocele on histopathology. Melena and hematemesis subsided postoperatively and 13 months after cholecystectomy, the dog remains without clinical signs. Neuroendocrine carcinomas of the gallbladder should be considered as a rare cause of melena and hematemesis in dogs.

Surgery for Thyroid Disease in Children.

Thyroid surgery in children results from three main etiologies: Medullary thyroid cancer in MEN syndromes, benign disease most often Graves' disease, and thyroid nodules which may harbor differentiated thyroid cancers. I will discuss the evaluation of these etiologies, pre-operative preparation, and operative strategies for each of these pediatric thyroid problems.

A case of neuroendocrine carcinoma with massive invasion to the liver and multiorgan causing acute liver failure.

INTRODUCTION: Acute liver failure (ALF) due to a malignant neoplasm is rare. Here, we present a case of neuroendocrine carcinoma (NEC) with massive invasion to the liver and multi-organ causing ALF that resulted in a poor outcome. A 56-year-old man was referred to our hospital for ALF of unknown cause. Abdominal imaging studies revealed hepatomegaly with multiple intrahepatic lesions. The patient also showed disseminated intravascular coagulation. Despite administration of prednisolone for the ALF, he died suddenly of respiratory failure on day 3 after admission. Autopsy showed a markedly enlarged liver weighing 4,600 g with diffuse nodular lesions. The tumors had metastasized to the lungs, spleen, adrenal glands, and bone marrow. Severe pulmonary hemorrhage was also noted. Histologically, the tumors were poorly differentiated and composed of small-sized and uniform neoplastic cells, positive for chromogranin A, synaptophysin, CD56, and p53 with a Ki-67 labeling index of over 50%. As there was no primary lesion in the gastrointestinal tract, pancreas, or other organs, primary hepatic neuroendocrine carcinoma (PHNEC) was suspected. CONCLUSION: We experienced a case of NEC causing ALF and multi-organ invasion with a rapidly deteriorating course. Liver metastasis from a neuroendocrine tumor/neoplasm is common, while a primary hepatic neuroendocrine tumor/neoplasm is extremely rare. We could not determine PHNEC; however, it was highly suspected. Further studies are needed to elucidate the pathogenesis of this rare disease.

Combined tubular adenocarcinoma, neuroendocrine carcinoma and adenocarcinoma with enteroblastic differentiation arising in Barrett esophagus.

Adenocarcinoma (AC) with neuroendocrine carcinoma (NEC) or enteroblastic (ENT) differentiation rarely develops in Barrett's esophagus (BE). A 76-year-old man was diagnosed with Barrett's AC (cT1bN0M0) and underwent thoracoscopic esophagectomy. A type 0-IIc + 0-Is lesion measuring 26 × 21 mm was macroscopically observed on a background of long segment BE (pT1bN0M0). The tumor comprised three different histological types of carcinoma (NEC, AC with ENT differentiation and moderately differentiated AC). NEC showed positivity for synaptophysin, chromogranin A and insulinoma-associated protein 1 with a Ki-67 index of 60.6%. ENT tumors were immunopositive for AFP and sal-like protein 4, and focally immunopositive for human chorionic gonadotrophin. The amounts of NEC, ENT and AC were 40%, 40% and 20%, respectively. p53 expression was positive throughout the tumor. Rb expression was negative at the NEC, but positive at the ENT and AC. CD4 and CD8 densities were lower in the NEC segment than in the AC and ENT segments, and PD-L1 expression was negative throughout the tumor. Early cancer arising in BE with a combination of tubular AC, ENT tumors and NEC is very rare. Our observations might contribute to understanding the carcinogenetic pathways and tumor microenvironment of NEC and ENT tumors.

A Combination of Preoperative Computed Tomography-Defined Sarcopenia and Systemic Inflammation on Survival in Patients with Poorly Differentiated Neuroendocrine Neoplasms Following Radical Resection.

This retrospective study of 122 patients with gastrointestinal poorly differentiated neuroendocrine neoplasms (GI-PDNEN) who underwent radical resection between January 2010 and December 2020 aimed to investigate the usefulness of combined computed tomography (CT)-defined sarcopenia and systemic inflammation to evaluate long-term prognoses for patients who underwent radical surgical resection. Sarcopenia, based on a pre-defined L3 skeletal muscle index cutoff value, was assessed using preoperative abdominal CT images. Patients (neuroendocrine carcinoma, 86 patients; mixed adenoneuroendocrine carcinoma, 36 patients) were divided into low-, intermediate-, and high-risk groups using sarcopenia scores and neutrophil-to-lymphocyte ratios (SNLRs). Higher SNLRs were significantly associated with higher age (P = 0.004), larger tumor size (P = 0.042), lower body mass index (P = 0.042), and lower hemoglobin (P = 0.001) and albumin (P = 0.031) levels. Multivariate analysis indicated that a higher SNLR was an independent risk factor for poor overall survival (OS, P = 0.01) and relapse-free survival (RFS, P = 0.001) in patients with GI-PDNEN postoperatively. Sarcopenia and a higher NLR were significantly associated with poor RFS and OS following radical resection. The SNLR had a definite predictive prognostic value in preoperatively identifying patients with GI-PDNEN and a probable poor long-term prognosis, especially those with neuroendocrine carcinoma.

Large-cell Neuroendocrine Carcinoma of the Lung with Carcinoid Syndrome.

A 76-year-old woman was admitted to our hospital for refractory diarrhea with a poor antidiarrheal effect. Chest and abdominal computed tomography revealed a 24×22-mm mass in the left upper lobe of lung and multiple masses in the liver. Urine 5-Hydroxy indol acetic acid was markedly elevated. A liver biopsy revealed large-cell neuroendocrine carcinoma with serotonin production, suggestive of a lung origin, and a lung biopsy revealed combined large-cell neuroendocrine carcinoma and squamous cell carcinoma. Therefore, we made a definitive diagnosis of carcinoid syndrome caused by large-cell neuroendocrine carcinoma of the lung. Although chemotherapy was performed after diagnosis, the patient died 50 days postadmission.

Syndrome of inappropriate antidiuretic hormone presenting with recurrent hiccups in a case of small cell neuroendocrine carcinoma of the lung with concomitant pulmonary tuberculosis.

Tuberculosis (TB) and lung cancer are the leading causes of mortality and morbidity in the world. The burden of TB is significantly high in developing countries causing serious public health concern, and the incidence of lung cancer is also increasing all around the world with high mortality. Pulmonary TB coexisting with lung cancer can mask the underlying disorder producing diagnostic dilemma resulting in a delay in diagnosis leading to decreased survival of the patients. Here, we report a rare case of a 66-year-old male diagnosed with microbiologically confirmed TB along with coexisting small cell neuroendocrine carcinoma of the lung presenting with syndrome of inappropriate antidiuretic hormone.

Metastatic rectal neuroendocrine carcinoma presenting with treatment-refractory immune thrombocytopenia: A case report and literature review.

RATIONALE: Colorectal neuroendocrine cancer (CRNEC) accounts for < 1% of all colorectal cancers. It presents in advanced stages and carries a risk of poor survival. CRNEC may be diagnosed incidentally on imaging or routine endoscopy. When symptomatic, it may mimic colorectal adenocarcinoma. Syncope and immune thrombocytopenic purpura (ITP) have not previously been reported as clinical presentations. PATIENT CONCERNS: A 57-year-old man with human immunodeficiency virus infection on treatment, seizure and stroke without residue presented for the evaluation of fall and syncope. DIAGNOSIS: Physical examination revealed tachycardia, swelling, and ecchymosis of his proximal left lower extremity. Laboratory tests showed a new isolated thrombocytopenia of 26,000/mm3. Computed tomography for a trauma survey showed an incidental left posterior rectal wall mass. After hospital admission, his platelet count dropped to 14,000/mm3. A peripheral blood smear revealed low platelet count, no schistocytes or immature cells. ITP at a high risk for bleeding was diagnosed and treated with standard medical therapy but remained refractory. Bone marrow biopsy showed metastatic neuroendocrine carcinoma, likely from the rectum. INTERVENTIONS: Patient received courses of high-dose dexamethasone and intravenous immunoglobulin. He also receive eleven units of platelet transfusion. A course of rituximab was administered. The platelet count response was suboptimal or short lived with drop to a nadir of 4000/mm3. However, after initiation of Eltrombopag, the thrombocytopenia resolved. Patient was started on etoposide, carboplatin, Atezolizumab. His hospital stay was complicated by neutropenia and sepsis, which was successfully treated. OUTCOMES: He was discharged to subacute rehab in stable condition. About 4 months later, he was readmitted for severe thrombocytopenia, septic shock, and acute respiratory failure. Despite appropriate treatment, the patient deteriorated and expired. CONCLUSION: CRNEC is a rare aggressive disease with dismal outcome that lacks standardized treatment. Metastasis to the bone marrow is uncommon and concomitant ITP has not been reported. We report a rare case of rectal neuroendocrine carcinoma metastatic to bone marrow associated with refractory ITP and review the relevant literature.

Medullary Thyroid Cancer with Ectopic Cushing's Syndrome: A Case Report and Systematic Review of Detailed Cases from the Literature.

Background: Medullary thyroid cancer (MTC) is a neuroendocrine tumor arising from parafollicular C-cells of the thyroid gland that, in rare cases, can cause a paraneoplastic ectopic Cushing's syndrome (ECS). The development of Cushing's syndrome (CS) in MTC patients is generally associated with advanced disease and poor prognosis. Summary: We described a case of severe CS due to MTC in a young male. We performed a systematic review to identify cases of ECS due to MTC. We searched PubMed, Scopus, and Web of Science for publications between database inception and February 2022 and we collected the patient characteristics, disease presentation, employed treatment strategies, and disease outcomes. In addition to our patient, we identified 96 cases of ECS due to MTC reported in literature. Mean age at diagnosis was 44.4 years (range 10-84), and there was a male predominance (male:female [M:F] = 1.8:1). Most patients (51%) presented with metastatic disease at diagnosis and showed severe hypercortisolism. Seventeen patients developed distant metastasis and hypercortisolism during follow-up. Interestingly, in 48% of patients, the diagnosis of CS followed the diagnosis of MTC with a median time of 48 months but, among patients in whom the diagnosis was concomitant (38%), symptoms due to hypercortisolism were frequently the reason for seeking medical advice. Pathology results showed evidence of adrenocorticotropic hormone (ACTH) or corticotropin releasing hormone (CRH) positive cells in 76% of patients in whom they were tested. The management of hypercortisolism was challenging in most patients with 48% requiring, eventually, definitive treatment with bilateral adrenalectomy (BLA). Recently, some limited evidence has emerged regarding tyrosine kinase inhibitors (TKIs) treatment for hypercortisolism in patients with ECS due to MTC. Despite limited information on survival, prognosis was generally poor and the main causes of death were either complications of CS or disease progression. Conclusions: Despite its rarity, MTC should be considered in the differential diagnosis of ECS. Management of hypercortisolism is a key factor to improve the patient's symptoms but it is often challenging and BLA is frequently required. Further studies are needed for investigating the role of TKIs in patients with MTC with ECS.

Somatostatin Receptor-negative and Fluorodeoxyglucose-positron Emission Tomography-positive Lung Neuroendocrine Tumor G1 Exhibiting Cyclic Cushing's Syndrome.

Localization of ectopic cyclic Cushing's syndrome, which causes life-threatening complications, is challenging. A 70-year-old woman showed cyclic hypokalemia and hyperglycemia and was diagnosed with cyclic ectopic Cushing's syndrome. Although somatostatin-receptor scintigraphy failed to localize the responsible tumor, fluorodeoxyglucose-positron emission tomography (FDG-PET) showed the uptake of tracer in a lung tumor. Lobectomy resulted in remission. The resected adrenocorticotropic hormone (ACTH)-producing neuroendocrine tumor had Ki-67<2% and negative staining for somatostatin receptors. This is the first case assessed both radiological findings and pathological findings in cyclic ectopic Cushing's syndrome. Subsequent FDG-PET is recommended if somatostatin-receptor scintigraphy is negative.