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.

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.

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.

Medullary thyroid cancer with ectopic Cushing's syndrome: A multicentre case series.

OBJECTIVE: Ectopic Cushing's syndrome (ECS) induced by medullary thyroid cancer (MTC) is rare, and data on clinical characteristics, treatment and outcome are limited. DESIGN: Retrospective cohort study in three German and one Swiss referral centres. PATIENTS: Eleven patients with MTC and occurrence of ECS and 22 matched MTC patients without ECS were included. MEASUREMENTS: The primary endpoint of this study was the overall survival (OS) in MTC patients with ECS versus 1:2 matched MTC patients without ECS. RESULTS: The median age at diagnosis of ECS was 59 years (range: 35-81) and the median time between initial diagnosis of MTC and diagnosis of ECS was 29 months (range: 0-193). Median serum morning cortisol was 49 µg/dl (range: 17-141, normal range: 6.2-18). Eight (73%) patients received treatment for ECS. Treatment of ECS consisted of bilateral adrenalectomy (BADX) in four (36%) patients and adrenostatic treatment in eight (73%) patients. One patient received treatment with multityrosine kinase inhibitor (MKI) to control hypercortisolism. All patients experienced complete resolution of symptoms of Cushing's syndrome and biochemical control of hypercortisolism. Patients with ECS showed a shorter median OS of 87 months (95% confidence interval [95% CI]: 64-111) than matched controls (190 months, 95% CI: 95-285). Of the nine deaths, four were related to progressive disease (PD). Four patients showed PD as well as complications and comorbidities of hypercortisolism before death. CONCLUSION: This study shows that ECS occurs in advanced stage MTC and is associated with a poor prognosis. Adrenostatic treatment and BADX were effective systemic treatment options in patients with MTC and ECS to control their hypercortisolism. MKI treatment achieved complete remission of hypercortisolism and sustained tumour control in one treated case.

Germline RET variants underlie a subset of paediatric osteosarcoma.

BACKGROUND: Although considerable effort has been put into decoding of the osteosarcoma genome, very little is known about germline mutations that underlie this primary malignant tumour of bone. METHODS AND RESULTS: We followed here a coincidental finding in a multiple endocrine neoplasia family in which a 32-year-old patient carrying a germline pathogenic RET mutation developed an osteosarcoma 2 years after the resection of a medullary thyroid carcinoma. Sequencing analysis of additional 336 patients with osteosarcoma led to the identification of germline activating mutations in the RET proto-oncogene in three cases and somatic amplifications of the gene locus in five matched tumours (4%, n=5/124 tumours). Functional analysis of the pathogenic variants together with an integrative analysis of osteosarcoma genomes confirmed that the mutant RET proteins couple functional kinase activity to dysfunctional ligand binding. RET mutations further co-operated with alterations in TP53 and RB1, suggesting that osteosarcoma pathogenesis bears reminiscence to the stepwise model of medullary thyroid carcinoma. CONCLUSIONS: After Li-Fraumeni-predisposing mutations in TP53, RET becomes the second most mutated cancer-predisposing gene in the germline of patients with osteosarcoma. Hence, early identification of RET mutation carriers can help to identify at-risk family members and carry out preventive measures.

Neuroendocrine Carcinoma of the Endometrium with Ectopic Secretion of Parathyroid Hormone Presenting as Hypercalcemia- Related Posterior Reversible Encephalopathy syndrome: A Case Report.

PURPOSE: Posterior reversible encephalopathy syndrome (PRES) displayed various acute neurological symptoms. PRES is a rare presentation of hypercalcemia. Here we present a case with ectopic secretion of parathyroid hormone from neuroendocrine carcinoma of the endometrium presenting as hypercalcemia-related PRES. CASE REPORT: A 67-year-old woman presented with acute generalized tonic-clonic seizure followed by post-ictal confusion and neuropsychiatric behaviors. The diagnosis is PRES. Investigations showed uterine cervical region with multiple liver metastasis complicated with hypercalcemia, elevated intact parathyroid hormone. Further pathology concluded as a poorly differentiated adenocarcinoma of the endometrium with neuroendocrine differentiation and immunoreactive for PTH. The patient's neurologic manifestations had resolved. Serum free calcium level and intact-PTH had declined after first course of definitive chemoradiation. CONCLUSION: Immunostaining of the tumor tissue can be used to estimate the ectopic PTH production within the tumor cells. Early detection and appropriate clinical treatment hold the potential to improve the prognosis of refractory hypercalcemia and hypercalcemia related PRES. Keyword: Posterior reversible encephalopathy syndrome; hypercalcemia; intact-parathyroid hormone; parathyroid hormone-related peptide; neuroendocrine carcinoma of endometrium.

[Superior Vena Cava Syndrome due to Large Cell Neuroendocrine Carcinoma Originated in the Mediastinum].

We report a case of a 53-year-old man with superior vena cava( SVC) syndrome due to large cell neuroendocrine carcinoma (LCNEC) in the mediastinum. His chief complaint was general fatigue. On physical examination, both jugular veins were distended and his face and bilateral upper limbs were swollen. Enhanced chest computed tomography (CT) scan demonstrated a heterogenous tumor of approximately 50 mm in diameter in the middle mediastinum, which infiltrated into the SVC and right atrium, and caused SVC syndrome. Since SVC syndrome developed rapidly, the tumor was resected and the occluded SVC was replaced with a ringed polytetrafluoroethylene graft under cardiopulmonary bypass. After surgery, SVC obstruction was resolved with improvement of the initial symptoms. The patient had an uneventful recovery and was discharged from our hospital. The tumor was diagnosed as LCNEC histologically. He received postoperative adjuvant systemic chemotherapy. Unfortunately, he died of extensive brain and bone metastasis 10 months after the operation. However, we believe that surgical relief from SVC syndrome improved quality of the rest of his life.

A rare case of ectopic ACTH syndrome with rhabdomyolysis.

BACKGROUND: Manifestations of hypokalaemia in ectopic adrenocorticotropic hormonesyndrome(EAS) vary from mild muscle weakness to life-threatening arrhythmia. Herein, we present a rare case of EAS with concomitant rhabdomyolysis(RM) as a result of intractable hypokalaemia. CASE PRESENTATION: A 64-year-old man was admitted for limb weakness and facial hyperpigmentation for 2 weeks. Lab tests revealed intractable hypokalaemia (lowest at 1.8 mmol/L) and metabolic alkalosis. The diagnosis of RM was based on a creatine kinase(CK)level of 5 times the upper limit. The elevated CK and myohemoglobin (Mb) levels returned to within the normal range after the alleviation of hypokalaemia. The patient was diagnosed with ACTH-dependent Cushing's syndrome (CS) based on unsuppressed serum cortisol after a low-dose dexamethasone suppression test(LDDST) and remarkably elevated ACTH levels. The diagnosis of EAS was made based on the results of a high-dose dexamethasone suppression test(HDDST) and bilateral inferior petrosal sinus sampling(BIPSS). Multiple lymph nodes in the left supraclavicular fossa, right root of neck, mediastinum and bilateral hili of the lung were found with abnormal uptake of 68Ga-DOTA-NOC. Mediastinoscopic lymph node biopsy was performed. The pathological diagnosis was small-cell and large-cell neuroendocrine carcinoma with positive ACTH staining. The patient was prescribed mifepristone and received one cycle of chemotherapy. The patient could not tolerate subsequent chemotherapy and died of dyscrasia. CONCLUSIONS: RM is a rare complication of EAS with insidious onset and atypical clinical manifestations. Serum potassium levels should be vigilantly monitored to avoid RM in EAS.

Risk of second primary malignancy in adults with pulmonary high-grade neuroendocrine carcinoma (HGNEC).

BACKGROUND: Pulmonary high-grade neuroendocrine carcinoma (HGNEC) has a rising incidence of developing second primary malignancies (SPMs). This study is the first population-based analysis to quantify the SPM risks among survivors of lung HGNEC. METHODS: We used the Surveillance, Epidemiology, and End Results (SEER) database to calculate standardized incidence ratio (SIR) and absolute excess risk (AER) between 2000 and 2016 for patients with pulmonary HGNEC. RESULTS: The data of 1161 patients with SPMs were retrieved from the SEER database. The ratio of observed/expected number of SPMs in pulmonary HGNEC was 1.53. Solid tumours comprised 91% of all second malignancies in lung HGNEC patients, with the most common cancers reported in the oral cavity and pharynx, the urinary and respiratory systems CONCLUSIONS: Our study observed an increased risk of SPMs among patients with pulmongnancies.

Multiple endocrine neoplasia type 2B: Frequency of physical stigmata-Results of the GPOH-MET registry.

BACKGROUND: Multiple endocrine neoplasia (MEN) 2B is characterized by early development of aggressive medullary thyroid carcinoma (MTC), visible physical stigmata, and associated symptoms. In most cases, de novo mutations are revealed. There are premonitory symptoms and stigmata that enable early diagnosis, before an inoperable MTC develops. The German Society for Paediatric Oncology and Haematology (GPOH)-Malignant Endocrine Tumours (MET) registry maintains records of children with MTC in Germany since 1997. METHODS: Children with a diagnosis of MTC in MEN 2B recorded in the GPOH-MET study were analyzed retrospectively. Stigmata and symptoms associated with MEN 2B were examined. RESULTS: From inception through 2017, 24 patients aged 0.2-17.3 years were included. Symptoms affecting the oral/dental (88.0%), musculoskeletal (79.2%), and gastrointestinal (70.8%) systems were recognized most frequently. Gastrointestinal and musculoskeletal symptoms preceded symptoms of MTC. Twelve patients had short stature. Regarding the prevalence of single symptoms, neuromas of the lips and the oral cavity were mentioned most frequently. Five patients died from MTC. Patients diagnosed by tumor symptoms showed more advanced disease than those with disease detected by other means. Children diagnosed via associated stigmata and symptoms or positive family history had significantly improved overall survival (OS) compared to children diagnosed via symptoms of MTC (OS 100% vs 53.3%). CONCLUSIONS: In children with MEN 2B, oral/dental, musculoskeletal, and gastrointestinal symptoms are most common. If children are diagnosed via associated symptoms and stigmata, OS is improved. Most of the children were diagnosed with growth disturbances; this finding requires verification and ranging in other patient cohorts.

Application of contrast-enhanced ultrasonography for large cell neuroendocrine carcinoma in the urinary bladder: a case report.

BACKGROUND: Large cell neuroendocrine carcinoma (LCNEC) of the urinary bladder is an uncommon malignant bladder tumor, and the overall prognosis is poor. Contrast-enhanced ultrasound (CEUS) provides a new effective modality for tumor detection and diagnosis. CASE PRESENTATION: A 30-year-old man complained of repeated painless gross haematuria for half a month. Conventional ultrasound demonstrated a hypoechoic solitary lesion with hyperechoic margins measuring 3.4 × 3.1 cm in the anterior wall of the bladder. Superb microvascular imaging (SMI) showed a strong flow signal in the mass. CEUS revealed that the lesion was characterized by hyper-enhancement in the early phase and hypo-enhancement in the late phase. The entire bladder wall was disrupted by homogeneous hyper-enhanced tumor tissue on CEUS. Time-intensity curves (TICs) showed a rapid wash-in with a high maximum signal intensity (SI) and quick wash-out. Finally, partial cystectomy was performed and the pathological examination confirmed the diagnosis of LCNEC with invasion into the whole layer of the bladder wall. CONCLUSION: This case suggested that CEUS was a valuable imaging method to detect and diagnose LCNEC in the bladder, and that CEUS can provide information related to the depth of wall invasion and the microvasculature.

Calcitonin levels by ECLIA correlate well with RIA values in higher range but are affected by sex, TgAb, and renal function in lower range.

Calcitonin (CT) is a marker for both initial diagnosis and monitoring of patients with residual or recurrent medullary thyroid carcinoma (MTC). In Japan, serum CT had been measured by radioimmunoassay (RIA) until recently. Electrochemiluminescence immunoassay (ECLIA) became commercially available in 2014, and this technique is now the only method used to examine CT concentration. The purposes of this study were to investigate the correlations between the CT concentration measured with ECLIA (ECLIA-CT) and RIA (RIA-CT) and to explore the clinical characteristics of patients with elevated ECLIA-CT. CT concentrations of 348 sera samples from 334 patients with various thyroid disorders including nine MTC were measured using both assays. The correlation analysis revealed an excellent correlation between ECLIA-CT and RIA-CT among the cases with CT level >150 pg/mL by both assays (rs = 0.991, p < 0.001). However, 63% of all samples exhibited undetectable ECLIA-CT, while their RIA-CTs were measured between 15 and 152 pg/mL. The ECLIA-CTs in all patients who underwent total thyroidectomy for non-MTC showed low concentrations. High ECLIA-CT was observed in patients with MTC or pancreas neuroendocrine tumor. ECLIA-CT was also increased in 14 other male patients with non-MTC, including four with renal failure. Multivariate logistic regression analysis showed that male sex, negative TgAb, and lower estimated glomerular filtration rate were independent factors to predict detectable ECLIA-CT (≥0.500 pg/mL). These results indicate that ECLIA-CT correlates well with RIA-CT in higher range and is affected by sex, TgAb, and renal function.

Successful surgery of neuroendocrine carcinoma infiltrating right ventricle and pulmonary artery.

We present the clinical case of a 60-year-old woman complained of dyspnea on exertion. Echocardiogram showed a giant mass in the right ventricle (RV) with obstruction to the outflow tract. Thorax computed tomography confirmed a mass of greater than 60 mm infiltrating RV and causing severe stenosis in the pulmonary artery, with severe pericardial effusion. Cardiac surgery was performed for tumor resection and pulmonary root replacement with a biological valved conduit. Histological analysis diagnosed a poorly differentiated large-cell neuroendocrine carcinoma. The patient had no immediate postoperative complications and has completed radiotherapy at a 9-month follow-up.

Must antidepressants be avoided in patients with neuroendocrine tumors? Results of a systematic review.

OBJECTIVE: Symptoms of depression and anxiety are common in neuroendocrine tumor (NET), yet controversy exists over whether serotonin-mediated antidepressants (SAs) are safe in this population. We sought to address this knowledge gap. METHOD: Following PRISMA guidelines, we conducted a systematic review to identify NET patients who were prescribed SA. RESULTS: We identified 15 articles, reporting on 161 unique patients, 72 with carcinoid syndrome (CS) and 89 without. There was substantial agreement between reviewers at the full-text stage (κ = 0.69). Three of the articles, all with low risk of bias, accounted for most of the cases (149/161; 93%). Among the 72 NET patients with CS prior to antidepressant usage, CS was exacerbated in 6 cases (8%), only 3 (4%) of whom chose to discontinue the antidepressant. The remaining 89 patients had no prior CS symptoms, and none developed CS following antidepressant usage. Overall, no instances of carcinoid crisis or death were reported. CONCLUSIONS: We found no evidence for serious adverse outcomes related to SA usage in NET patients. Previous authors have recommended avoiding antidepressants in NET, but our findings do not support those recommendations. Oncologists should nonetheless monitor for symptom exacerbation when prescribing SA to patients with NET.

Paraneoplastic Cast Nephropathy Associated With Pancreatic Mixed Acinar-Neuroendocrine Carcinoma: A Case Report.

Acute kidney injury is common in patients with cancer and may result from sepsis, obstruction, radiotherapy, chemotherapeutic agents, and nonsteroidal anti-inflammatory drugs. Rare reports of acute kidney injury due to cast nephropathy in patients with pancreatic acinar cell carcinoma have been described, but a pathogenetic link between cast nephropathy and carcinoma was not established. We report a patient with pancreatic mixed acinar-neuroendocrine carcinoma who developed severe acute kidney injury. Kidney biopsy showed cast nephropathy characterized by fractured periodic acid-Schiff-negative casts, associated with mononuclear and giant cell reaction. The patient did not have multiple myeloma and casts did not show immunoglobulin light chain restriction on immunofluorescence. Analysis using liquid chromatography-tandem mass spectrometry and immunohistochemistry identified 2 acinar cell-specific proteins, regenerating islet-derived 1α and carboxypeptidase A1, in both tubular casts and tumor cells. Thus, this case demonstrates that solid tumor-specific proteins can be nephropathic by obstructing renal tubules, resulting in acute kidney injury, a previously proposed but not characterized pathophysiologic mechanism for paraneoplastic nephropathy associated with carcinoma.

Anal canal adenocarcinoma with neuroendocrine features accompanying secondary extramammary Paget disease, successfully treated with modified FOLFOX6: a case report.

BACKGROUND: Anal canal cancer occasionally accompanies extramammary Paget disease. Although most of them are squamous cell carcinoma, anal canal adenocarcinoma with neuroendocrine features accompanying secondary extramammary Paget disease has never been reported. CASE PRESENTATION: Here, we report a 76-year-old man presented with pruritus in the perianal area. Investigation revealed a fist-sized perianal erythema, diffuse liver tumors, and right inguinal lymph node swelling. Pathological examination of biopsies from the erythema suggested secondary extramammary Paget disease with positive cytokeratin-7 and -20 expressions and negative GCDFP-15 expression. The anal canal tumor was confirmed by digital examination and endoscopy. Biopsies from the anal canal tumor, swollen lymph node, and Paget lesion all showed poorly differentiated adenocarcinoma with neuroendocrine features expressing synaptophysin and chromogranin A. Serum CEA and NSE levels were high, 809.4 ng/ml and 85.8 ng/ml, respectively. After chemotherapy with modified FOLFOX6 for 2 months, the Paget lesion disappeared, and the primary anal canal tumor and liver metastases shrunk remarkably. Serum CEA and NSE levels decreased promptly to within normal ranges. CONCLUSIONS: This is a clinically significant case, as it reveals novel pathological features about anal canal cancer with secondary Paget disease and successfully treated with modified FOLFOX6. Careful pathological investigation and appropriate treatment choice are needed for this rare cancer.

No calcitonin change in a person taking dulaglutide diagnosed with pre-existing medullary thyroid cancer.

BACKGROUND: Glucagon-like peptide-1 receptor agonists, such as dulaglutide, exenatide and liraglutide, are approved to treat Type 2 diabetes mellitus. Although these drugs provide substantial glycaemic control, studies in rodents have prompted concerns about the development of medullary thyroid carcinoma. These data are reflected in the US package insert, with boxed warnings and product labelling noting the occurrence of these tumours after clinically relevant exposures in rodents, and contraindicating glucagon-like peptide-1 receptor agonist use in people with a personal or family history of medullary thyroid carcinoma, or in people with multiple endocrine neoplasia type 2. However, there are substantial differences between rodent and human responses to glucagon-like peptide-1 receptor agonists. This report presents the case of a woman with pre-existing medullary thyroid carcinoma who exhibited no significant changes in serum calcitonin levels despite treatment with dulaglutide 2.0 mg for 6 months in the Assessment of Weekly AdministRation of LY2189265 [dulaglutide] in Diabetes-5 clinical study (NCT00734474). CASE REPORT: Elevated serum calcitonin was noted in a 56-year-old woman with Type 2 diabetes mellitus at the 6-month discontinuation visit in a study of long-term dulaglutide therapy. Retroactive assessment of serum collected before study treatment yielded an elevated calcitonin level. At 3 months post-study, calcitonin level remained elevated; ultrasonography revealed multiple bilateral thyroid nodules. Eventually, medullary thyroid carcinoma was diagnosed; the woman was heterozygous positive for a germline RET proto-oncogene mutation. CONCLUSION: The tumour was not considered stimulated by dulaglutide therapy because calcitonin remained stable throughout.