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.

Urachal mixed adenocarcinoma and small cell neuroendocrine carcinoma with widespread metastasis and resistance to chemotherapy: a case report.

Neuroendocrine carcinoma arising from the urachus is extremely rare. We describe a case of a 33-year-old gentleman who presented with hematuria and diagnosed to have a composite adenocarcinoma and small cell neuroendocrine carcinoma arising from the urachus. The patient also had widespread metastasis at the time of presentation, therefore, he was referred for chemotherapy. However, the disease showed progression despite treatment. Recognition of neuroendocrine carcinoma component in urachal tumors, although rare, is very essential as this histologic type carries poor prognosis with aggressive clinical outcome.

PROX1 drives neuroendocrine plasticity and liver metastases in prostate cancer.

With the widespread use of anti-androgen therapy, such as abiraterone and enzalutamide, the incidence of neuroendocrine prostate cancer (NEPC) is increasing. NEPC is a lethal form of prostate cancer (PCa), with a median overall survival of less than one year after diagnosis. In addition to the common bone metastases seen in PCa, NEPC exhibits characteristics of visceral metastases, notably liver metastasis, which serves as an indicator of a poor prognosis clinically. Key factors driving the neuroendocrine plasticity of PCa have been identified, yet the underlying mechanism behind liver metastasis remains unclear. In this study, we identified PROX1 as a driver of neuroendocrine plasticity in PCa, responsible for promoting liver metastases. Mechanistically, anti-androgen therapy alleviates transcriptional inhibition of PROX1. Subsequently, elevated PROX1 levels drive both neuroendocrine plasticity and liver-specific transcriptional reprogramming, promoting liver metastases. Moreover, liver metastases in PCa induced by PROX1 depend on reprogrammed lipid metabolism, a disruption that effectively reduces the formation of liver metastases.

Management of Parapharyngeal Metastatic Medullary Thyroid Carcinoma Via a Combined Trans-Cervical and Trans-Oral Robotic Approach.

INTRODUCTION: Medullary thyroid carcinoma constitutes 5% to 10% of all thyroid cancers. Metastatic adenopathies may pose challenges in intricate anatomical locations, such as the parapharyngeal space. A rare case of metastatic medullary thyroid carcinoma in the parapharyngeal space has been treated in our unit using combined trans-cervical trans-oral robotic surgery. Our objective was to provide a detailed description of the surgery performed on this patient. METHOD: We reported a singular case report worth of interest. RESULT: A 42-year-old woman was addressed in our unit for the management of a medullary thyroid carcinoma adenopathy located in the right parapharyngeal space. A parapharyngeal 40.0 mm × 25.0 mm × 12.0 mm adenopathy was removed using a combined trans-cervical and trans-oral robotic approach without sacrifice or injury of vascular or nervous structure. Neither the tracheostomy nor the feeding tube was implemented. Feeding was resumed on postoperative day 1 and hospitalization spanned 7 days. CONCLUSION: An innovative combined trans-cervical and trans-oral robotic surgery approach was conducted to address a metastatic medullary thyroid carcinoma in the parapharyngeal space. This surgical technique allowed us to circumvent the need for a trans-mandibular approach, tracheostomy, and feeding tube and enabling successful tumor removal without fragmentation. Postoperative care was significantly eased. The sole complication observed was dysphonia, likely resulting from intra-operative stretching of the vagus nerve during the dissection of the carotid artery.

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.

Paget Disease of Bone Harboring Bone Metastatic Neuroendocrine Cancer: A Case Report.

In this case report, we describe an uncommon case of neuroendocrine cancer of unknown origin began with cauda equina syndrome in a patient affected by Paget disease of bone (PDB). A 76-year-old man with diagnosis of PDB, without history of pain or bone deformity, developed sudden severe low back pain. Bone alkaline phosphatase was increased and MRI and whole-body scintigraphy confirmed the localization of the disease at the third vertebra of the lumbar spine. Treatment with Neridronic Acid was started, but after only 2 weeks of therapy anuria and bowel occlusion occurred together with lower limb weakness and walking impairment. Cauda equina syndrome consequent to spinal stenosis at the level of L2-L3 was diagnosed after admission to Emergency Department and the patient underwent neurosurgery for spinal medulla decompression. The histologic results showed a complete subversion of bone structure in neoplastic tissue, consistent with metastatic neuroendocrine carcinoma of unknown origin. In conclusion, low back pain in the elderly may require deep investigation to individuate rare diseases. In asymptomatic patients with apparently stable PDB, the sudden appearance of pain or neurologic symptoms may alert the clinician for the possibility of other superimposing diseases, like bone metastases.

Multidisciplinary Approach for the Management of Metastatic Poorly Differentiated Neuroendocrine Carcinoma of the Pancreas: A Case Report of an Exceptional Responder.

ABSTRACT: Poorly differentiated pancreatic neuroendocrine carcinomas (pNECs) are rare, highly aggressive neoplasms. Frequently metastatic at diagnosis, prognosis is poor with median overall survival estimated to be less than 1 year. Although multidisciplinary management, including systemic medications and locoregional therapies aimed at reducing and preventing symptoms caused by mass effect, is the mainstay of treatment for patients with metastatic well-differentiated pancreatic neuroendocrine tumors, rapid progression, organ dysfunction, and poor performance status often preclude initiation of even single-modality palliative chemotherapy for patients with metastatic pNEC, limiting the use of and recommendation for multidisciplinary management.We describe the case of a 51-year-old male patient diagnosed with pNEC metastatic to liver and lymph nodes presenting with impending cholestatic liver failure for whom we were able to successfully initiate and dose-escalate cytotoxic chemotherapy with excellent radiographic response. After multidisciplinary review of his case, the patient underwent pancreaticoduodenectomy and hepatic wedge biopsies, with pathology demonstrating a pathologic complete response to chemotherapy in both the pancreas and liver. Surveillance scans at 2 years from initial diagnosis and 1 year from surgery remain without evidence of locoregional or distant recurrence, highlighting the importance and utility of multidisciplinary management in select cases.

[Metastasis of medullary thyroid carcinoma to the endometrium: A case report and review of the literature]. / Metástasis de carcinoma medular de tiroides en endometrio: reporte de un caso y revisión de la literatura.

Uterine metastases from extra pelvic tumors are rare; involvement of the uterus is usually by direct neoplastic extension from adjacent organs. We report the case of a 68-year-old woman with a history of total thyroidectomy. She presented with urinary incontinence associated with episodes of metrorrhagia. Ultrasound showed a thickened endometrium. A legrado was performed and the biopsy revealed a proliferation of neoplastic cells with oval nuclei, «salt and pepper¼ chromatin, evident nucleoli and a moderate amount of eosinophilic cytoplasm. These cells were positive for CKAE1 / AE3, TTF-1, CEA and calcitonin. The histological and immunohistochemical findings corresponded to a metástasis from a medullary thyroid carcinoma. Although metastatic tumors in the uterus are extremely rare, they may give rise to abnormal uterine bleeding and should be considered when the patient's history and the histological findings are not characteristic of a primary lesion.

Systematic review of neuroendocrine carcinomas of the oropharynx.

Data describing features and management of oropharyngeal neuroendocrine carcinomas (NEC) remain sparse. A systematic review was performed. Patients were stratified by treatment modality and examined for disease progression and survival outcomes. Ninety-four patients from 50 publications were included. Average age at diagnosis was 59.7 years (range 14-83). 73.4% were male. Most studies did not document HPV status. Forty patients (85.1%) were p16 positive, and 34 (85.0%) were HPV-ISH positive. Overall survival was 75.4% at 1 year, and 40.0% at 2 years. Of patients with locoregional disease, 33.8% developed distant metastasis. 12.5% of patients developed locoregional recurrence. Patients who developed distant metastases had worse overall survival (p = 0.0004). No significant difference was found between treatment modalities. Human papilloma virus may be associated with oropharyngeal NEC. Current treatments provide locoregional control, but distant metastases are common and confer low overall survival.

Metastatic Patterns of Duodenopancreatic Neuroendocrine Tumors in Patients With Multiple Endocrine Neoplasia Type 1.

Patients with multiple endocrine neoplasia 1 syndrome (MEN1) often develop multifocal duodenopancreatic neuroendocrine tumors (dpNETs). Nonfunctional pancreatic neuroendocrine tumors (PanNETs) and duodenal gastrinomas are the most frequent origins of metastasis. Current guidelines recommend surgery based on tumor functionality, size ≥2 cm, grade or presence of lymph node metastases. However, in case of multiple primary tumors it is often unknown which specific tumor metastasized. This study aims to unravel the relationship between primary dpNETs and metastases in patients with MEN1 by studying endocrine differentiation. First, it was shown that expression of the endocrine differentiation markers ARX and PDX1 was concordant in 18 unifocal sporadic neuroendocrine tumors (NETs) and matched metastases. Thereafter, ARX, PDX1, Ki67 and gastrin expression, and the presence of alternative lengthening of telomeres were determined in 137 microscopic and macroscopic dpNETs and 36 matched metastases in 10 patients with MEN1. ARX and PDX1 H-score clustering was performed to infer relatedness. For patients with multiple metastases, similar intrametastases transcription factor expression suggests that most metastases (29/32) originated from a single NET of origin, while few patients may have multiple metastatic primary NETs. In 6 patients with MEN1 and hypergastrinemia, periduodenopancreatic lymph node metastases expressed gastrin, and clustered with minute duodenal gastrinomas, not with larger PanNETs. PanNET metastases often clustered with high grade or alternative lengthening of telomeres-positive primary tumors. In conclusion, for patients with MEN1-related hypergastrinemia and PanNETs, a duodenal origin of periduodenopancreatic lymph node metastases should be considered, even when current conventional and functional imaging studies do not reveal duodenal tumors preoperatively.

Spinal metastases from thyroid cancer: Some prognostic factors.

BACKGROUND: Spinal metastases (SpMs) from thyroid cancers (TC) significantly reduce quality of life by causing pain, neurological deficits in addition to increasing mortality. Moreover, prognosis factors including surgery remain debated. METHODS: Data were stored in a prospective French national multicenter database of patients treated for SpM between January 2014 and 2017. Fifty-one consecutive patients affected by TC with 173 secondary SpM were included. RESULTS: Mean overall survival (OS) time for all patients from the diagnosis of a thyroid SpM event was 9.1 years (SD 8.7 months). The 1-year, 5-year and 10-year survival estimates were 94% (SD 3.3), 83.8.0% (SD 5.2), and 74.5% (SD 9.9). The median period of time between primary thyroid tumor diagnosis and the SpM event was 31.4 months (SD 71.6). In univariate analysis, good ECOG-PS (status 0 and 1) (p < 0.0001), ambulatory status (Frankel score) (p < 0.0001) and no epidural involvement (p = 0.01), were associated with longer survival, whereas cancer subtype (p = 0.436) and spine surgery showed no association (p = 0.937). Cox multivariate proportional hazard model only identified good ECOG-PS: 0 [HR: 0.3, 95% CI 0.1-0.941; p < 0.0001], 1 [HR: 0.8, 95% CI 0.04-2.124; p = 0.001] and ambulatory neurological status: Frankel E [HR: 0.262, 95% CI 0.048-1.443; p = 0.02] to be independent predictors of better survival. CONCLUSION: For cases presenting SpM from TC, we highlighted that the only prognostic factors were the progression of the cancer (ECOG-PS) and the clinical neurological impact of the SpM (Frankel status). Surgery should be discussed mainly for stabilization and neurological decompression.

Scalp metastasis as initial presentation of neuroendocrine carcinoma.

Neuroendocrine carcinomas are a rare, heterogenous group of malignancies that arise from neuroendocrine cells throughout the body. Cutaneous metastasis of neuroendocrine carcinoma is uncommon and they can be easily misdiagnosed as benign epidermal cysts or Merkel cell carcinoma. Collectively, histopathology, immunochemical profile, biochemical markers, and nuclear imaging can guide the diagnosis of neuroendocrine metastasis and localization of primary tumors.

Pituitary Metastasis of Lung Neuroendocrine Carcinoma Mimicking Pituitary Adenoma:Case Report and Literature Review.

Pituitary metastasis is an unusual situation in clinical practice, while the incidence is increasing with age. Breast cancer for women and lung cancer for men were the most frequent primary origins of pituitary metastasis. Diagnosing asymptomatic patients with unknown primary malignant origin is difficult, thus pituitary metastasis may be diagnosed as primary pituitary adenoma. Here, we report a case of a 65-year-old patient with visual changes and diabetes insipidus, showing an extensive mass in the sellar region which was initially thought to be a primary pituitary adenoma. Patient corticotropic deficits were corrected, and transnasal transsphenoidal surgery was adopted, leading to total tumor resection. Tumor texture during surgical procedure was similar to that of pituitary adenoma. However, the histopathological and immunohistochemistry results suggested it as a pituitary metastasis from lung neuroendocrine tumor. Postoperative chest CT scan confirmed a pulmonary mass consistent with primary neoplasm. Abdominal CT further detected multiple metastases in liver, pancreas, and colon. Despite intensive treatment, the patient continued to show decreased level of consciousness due to cachexia, resulting in death 1 week after surgery. This case highlights the importance of differential diagnosis of invasive lesions of the sellar region, especially in individuals over 60 years of age with diabetes insipidus.

Metastatic Medullary Thyroid Cancer: The Role of 68Gallium-DOTA-Somatostatin Analogue PET/CT and Peptide Receptor Radionuclide Therapy.

CONTEXT: Metastatic medullary thyroid cancer (MTC) is a rare malignancy with minimal treatment options. Many, but not all, MTCs express somatostatin receptors. OBJECTIVE: Our aim was to explore the role of 68Ga-DOTA-somatostatin analogue (SSA) positron emission tomography (PET)/computed tomography (CT) in patients with metastatic MTC and to determine their eligibility for peptide receptor radionuclide therapy (PRRT). METHODS: We retrospectively identified patients with metastatic MTC who had 68Ga-DOTA-SSA PET/CT at 5 centers. We collected characteristics on contrast-enhanced CT, 68Ga-DOTA-SSA and 18F-FDG PET/CT. The efficacy of PRRT was explored in a subgroup of patients. Kaplan-Meier analysis was used to estimate time to treatment failure (TTF) and overall survival (OS). RESULTS: Seventy-one patients were included (10 local recurrence, 61 distant disease). Of the patients with distant disease, 16 (26%) had ≥50% of disease sites with tracer avidity greater than background liver, including 10 (10/61, 16%) with >90%. In 19 patients with contemporaneous contrast-enhanced CT, no disease regions were independently identified on 68Ga-DOTA-SSA PET/CT. Thirty-five patients had an 18F-FDG PET/CT, with 18F-FDG positive/68Ga-DOTA-SSA negative metastases identified in 15 (43%). Twenty-one patients had PRRT with a median TTF of 14 months (95% CI 8-25) and a median OS of 63 months (95% CI 21-not reached). Of the entire cohort, the median OS was 323 months (95% CI 152-not reached). Predictors of poorer OS included a short calcitonin doubling-time (≤24 months), strong 18F-FDG avidity, and age ≥60 years. CONCLUSIONS: The prevalence of high tumor avidity on 68Ga-DOTA-SSA PET/CT is low in the setting of metastatic MTC; nevertheless, PRRT may still be a viable treatment option in select patients.

Neuroendocrine carcinoma of prostate presenting with ascites.

Prostate cancer is a very common cause of morbidity and mortality in India. The commonest type of prostate carcinoma is adenocarcinoma, most of them are confined to prostate at the time of presentation. Bone is the preferred site for metastasis. The following is a case of neuroendocrine carcinoma of prostate arising in a 36 years old male who presented with ascitis and jaundice to the emergency department. The ascitic tap was positive for malignant cells. CECT done to detect primary showed osteoblastic secondaries in the spine along with lesions in the liver. DRE revealed grade 2 prostatomegaly. A TRUS guided biopsy showed neuroendocrine carcinoma of the prostate. Neuroendocrine carcinoma is a very rare type of prostatic carcinoma, with presentation of the same as ascitis is very uncommon. The following case is presented due to its rarity.

PD-L1, PARP1, and MMRs as potential therapeutic biomarkers for neuroendocrine cervical cancer.

OBJECTIVE: Neuroendocrine cervical cancer (NECC) is a rare cervical cancer with high aggressivity that causes poor prognosis even in the early stage. Given other neuroendocrine carcinomas and other types of cervical cancer have been proved to have expression of programmed cell death protein 1 ligand 1(PD-L1) and poly ADP-ribose polymerase-1(PARP1), we would measure and analyze these proteins in this invasive cancer. The purpose of this study is to investigate the application value of PD-1/PD-L1 and PARP1 inhibitors in NECC. METHODS: The NECC cases in our center with formalin-fixed paraffin-embedded tissue blocks were collected, and immunohistochemical (IHC) staining of PD-L1, PARP1, Mismatch repair proteins (MMRs), and P53 was performed. Chi-square test was used to analyze associations between various protein expressions. We analyzed the efficacy of immunotherapy in a recent patient with secondary recurrence after two courses of chemotherapy. RESULTS: After rigorous screening, 20 cases were finally included. Three cases did not undergo surgical treatment because of their advanced stage. Twelve (60%) developed distant metastases or relapsed within five years, and most of them within two years. The positive rate of PD-L1 and PARP1 were 70% and 75% respectively. Among all the cases, microsatellite instability (MSI) was seen in six cases (30%) and abnormal p53 expression was in 15 patients (75%). PD-L1 was associated with PARP1 expression in the MSI subgroup. The patient treated with chemotherapy + VEGF inhibitor (VEGFi) + programmed cell death protein 1(PD-1) inhibitor had an excellent improvement in clinical symptoms, tumor markers, and mass size. CONCLUSION: The IHC results of PD-L1, PARP1, and MMRs suggested that NECC was the target of immunotargeted therapy. Our case confirmed that immune checkpoint therapy was effective in patients with PD-L1 positive and MMRs loss. Considering the clinical practicability, more cases should be collected, and effective biomarkers still need to be further searched.

Efficacy and safety of peptide receptor radionuclide therapy in advanced radioiodine-refractory differentiated thyroid cancer and metastatic medullary thyroid cancer: a systematic review.

BACKGROUND: It has been shown that a subgroup of patients with differentiated thyroid cancer (DTC) and medullary thyroid carcinoma (MTC) would progress to advanced stages of thyroid cancer. Therefore, the present study was done to systematically review available evidence in order to investigate efficacy and safety of peptide receptor radionuclide therapy (PRRT) in the patients with advanced radioiodine refractory differentiated thyroid cancer (RR-DTC) and metastatic MTC. METHODS: For this purpose, relevant studies investigated safety and efficacy of PRRT in the patients with advanced RR-DTC and metastatic MTC were identified by searching Medline (Pubmed, Ovid, and Ebsco), Scopus, Embase, Web of Science, and Cochrane Library databases (from database inception to March 24, 2021). The review was performed according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement. Searching was done independently by two investigators. Two researchers independently extracted the data and any disagreement was adjudicated by consensus. Quality of the studies was assessed using the tool of case reports/series in systematic reviews. RESULTS: Among 2284 related papers, 41 papers met the inclusion criteria. A total of 157 patients with RR-DTC were treated with PPRT. Biochemical and objective responses (partial and complete) were observed in 25.3 and 10.5% of patients, respectively. Among 220 patients with metastatic MTC, biochemical and objective responses were observed in 37.2 and 10.6% of the patients, respectively. Forty-six deaths were reported in 95 patients with advanced RR-DTC. In addition, 63 deaths were observed in 144 patients with metastatic MTC. Major side effects were reported in 124 patients treated with 90Y -based agent. In the patients treated with 177Lu-DOTA-TATE and 111In-Octreotide, mild and transient hematologic or renal complications were reported. CONCLUSION: Findings of the study revealed that in the absence of the established treatment for the patients with RR-DTC and metastatic MTC, PRRT could be effective with few adverse events. TRIAL REGISTRATION: PROSPERO registration number: CRD42019125245 .