Well-differentiated Neuroendocrine Carcinoma Research Articles

NET G3 vs NEC: p53 and Rb1 Immunolabeling in High-grade Gastrointestinal Neuroendocrine Neoplasms - Is It Enough for the Differential Diagnosis?

High-grade gastrointestinal neuroendocrine neoplasms (GI-NENs) are divided into well-differentiated G3 neuroendocrine tumors (NETs G3) and neuroendocrine carcinomas (NECs), having identical cut-offs of proliferation, but different biomolecular origins. This translates in distinct treatment choices. Our aim was to establish if p53/Rb1 immunohistochemical status in GI-NENs with Ki67 index >20% can predict the histopathological diagnosis. p53/Rb1 immunolabelling was performed on 42 cases of high-grade GI-NENs, diagnosed as NET G3, NEC and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) with NEC component. Immunolabeled slides were digitally scanned, with automatic quantification of p53 and Rb1, blind to the diagnosis. The p53 positive percentage was stratified; two cut-offs were selected, naming the intervals as N (null, <1%), T (tumor, 1%-20%) and C (carcinoma, >20%). The Rb1 expression loss in >90% of neoplastic cells was considered mutational. NETs G3 mainly showed the T status (14/16, 87.5%), followed by N (1/16, 6.25%) and C (1/16, 6.25%); NECs and NEC components in MiNENs predominantly expressed the C status (19/26, 73.08%), followed by N (5/26, 19.23%) and T (2/26, 7.69%) (p<0.001, χ 2 =27.017). NET G3s showed positive expression for Rb1; 73.08% of NECs expressed negative Rb1 (p<0.001, χ 2 =21.351). NECs and NEC components in MiNENs showed Rb1 mutational status in 13 C cases (13/19, 68.42%), 4 N cases (4/5, 80%) and in both the T cases (p=0.002, χ 2 =11.187). Our results highlight the correlations between the p53/Rb1 immunostainings and the histopathological diagnosis of high-grade GI-NENs. NECs and NEC components in MiNENs showed a p53 mutational status (0% or 21-100%) and predominantly negative Rb1 expression. NETs G3 showed a p53 wild-type status (1-20%) and retained Rb1 expression. These findings suggest that the differential diagnosis of high-grade GI-NENs may benefit from p53/Rb1 immunohistochemical tests in everyday practice.

An unusual association between Burkitt's lymphoma and a Carcinoid tumor in a Syrian boy: a rare case report.

The authors report a case of a 15-year-old Syrian adolescent who was admitted to our hospital due to a persistent, severe generalized abdomen pain accompanied by nausea, vomiting, loss of appetite, and inability to pass stool or gas. An abdominal radiograph revealed dilated intestinal loops with air-fluid levels. The patient underwent emergency surgery through which a retroperitoneal mass was removed as well as part of the ileum and the appendix. The final diagnosis was consistent with intestinal BL associated with an appendiceal carcinoid tumor. The correlation between gastrointestinal carcinoids and other types of tumors was frequently reported. However, there have been few reports of carcinoid tumors being associated with lymphoreticular system cancers. BLs were classified into three variants: endemic, sporadic, and acquired immunodeficiency-associated BL while appendiceal neuroendocrine tumors were classified as the following: well-differentiated neuroendocrine tumors with benign or uncertain malignant potential; well-differentiated neuroendocrine carcinoma with low malignant potential; and mixed exocrine-neuroendocrine carcinoma. Our article demonstrates an unusual association between BL and an appendiceal carcinoid tumor that highlights the significant role of histological and immunohistochemical staining in confirming the diagnosis, as well as the role of surgery in treating the complications of intestinal BLs.

New WHO classification 2022: urinary bladder cancer

The new World Health Organization (WHO) classification of urogenital tumors is still primarily based on anatomic location, but is also a hierarchical taxonomic classification without separate chapters for tumors of the upper urinary tract and the urethra. It clarifies aspects regarding grading and noninvasive entities. It consolidates the use of the Paris system for urinary cytology as well as various subtypes/special types of neoplasms, and incorporates general concepts of the 5th edition of the WHO blue book. In addition to mesenchymal tumors, well-differentiated neuroendocrine tumors and neuroendocrine carcinomas are addressed in separate chapters. Papillary non-invasive low- and high-grade carcinomas and carcinoma in situ remain, while dysplasia and urothelial proliferation of unknown malignant potential (UPUMP) are no longer treated as separate entities. Former variants of urothelial carcinoma are now called subtypes and aberrant differentiation and special types are more precisely defined.

Exploring Real World Outcomes with Nivolumab Plus Ipilimumab in Patients with Metastatic Extra-Pulmonary Neuroendocrine Carcinoma (EP-NEC).

Simple SummaryExtrapulmonary neuroendocrine carcinomas (EP-NEC) are a group of tumors which are often metastatic and characterized by poor outcomes. Platinum-etoposide chemotherapy is the current front-line therapy for metastatic EP-NEC, and has been adapted from small cell lung cancer. There are limited treatment options for patients with platinum-resistant EP-NEC, with no current established second-line standard of care. Recently, there has been mixed evidence for the role of immunotherapy in EP-NEC, with limited existing prospective data. In this multicenter retrospective analysis, we compared outcomes between patients with refractory EP-NEC who received single, dual immune check point inhibitors (ICPIs) and cytotoxic chemotherapy in the second-line setting. This real world experience suggests that utilizing ipilimumab and nivolumab in patients with second-line pretreated EP-NEC may be more effective than other existing treatment options.Background: Dual utilization of the immune checkpoint inhibitors (ICPIs) nivolumab plus ipilimumab has demonstrated clinical promise in the treatment of patients with refractory high-grade neuroendocrine neo-plasms (NENs) in phase II clinical trials (DART SWOG 1609 and CA209), while single agent ICPIs have largely been ineffective for these types of tumors. While both trials demonstrated promising results in high grade NENs, there was no adequate description of the association between tumor differentiation (high-grade well-differentiated neuroendocrine tumor vs poorly-differentiated extra-pulmonary neuroendocrine carcinoma (EP-NEC) and ICPI outcomes in the DART SWOG 1609 trial. Our study reports on the effectiveness and toxicity profile of dual ICPIs in a real world second-line EP-NEC patient population. Methods: Data on metastatic EP-NEC patients, treated with either ICPIs (single and dual ICPIs) or chemo-therapy in the second-line setting, were retrieved from databases of three comprehensive cancer centers. Associations between treatment characteristics and outcomes, including progression-free survival (PFS) and overall survival (OS), were evaluated. Results: From 2007 to 2020, we identified 70 patients with metastatic EP-NEC (predominantly of gastro-enteropancreatic origin), of whom 42 patients (23 males, 19 females, median age 62 years old) were eligible for the final analysis. All patients were refractory to platinum etoposide doublet chemotherapy in the first-line setting. The median PFS for patients who received dual ICPIs (11 patients), single agent ICPI (8 patients), and cytotoxic chemotherapy (23 patients) was 258 days, 56.5 days, and 47 days, respectively (p = 0.0001). Median overall survival (OS) for those groups was not reached (NR), 18.7 months, and 10.5 months, respectively (p = 0.004). There were no significant differences in treatment outcomes in patients according to tumor mismatch repair (MMR) or tumor mutational burden (TMB) status. Grade 3–4 adverse events (AEs) were reported in 11.1% of the patients who received dual ICPIs; however, none of these AEs led to permanent treatment discontinuation. Conclusions: In the second-line setting, patients with EP-NECs treated with dual ICPIs (nivolumab plus ipilimumab) experienced improved PFS and OS compared to patients treated with single agent ICPI or cytotoxic chemotherapy. These results echo some of the current evidence for ICPIs in grade 3 NENs and need to be validated in future prospective studies.

What Is the Status of Immunotherapy in Neuroendocrine Neoplasms?

Immunotherapy has changed the treatment of patients with advanced cancer, with different phase III trials showing durable responses across different histologies. This review focuses on the preclinical and clinical evidence of potential predictive biomarkers of response and efficacy of immunotherapy in neuroendocrine neoplasms (NENs) of gastro-entero-pancreatic origin. PD-L1 staining by immunohistochemistry has shown heterogeneous results across different studies in both well-differentiated neuroendocrine tumors (NETs) and poorly-differentiated neuroendocrine carcinomas (NECs). Tumor mutational burden in NENs is low, but seems to be higher in NECs. Immune infiltrate (CD3+ lymphocytes) at the tumor microenvironment (TME) is present in NETs and NECs. However, results from clinical trials with immunotherapy as monotherapy o combinations have shown limited efficacy. Further investigation into new strategies aside from anti-CTLA-4/PD-1/PD-L1 antibodies, validation of predictive biomarkers, and better population selection for clinical trials in NENs are more than needed in the near future.

Small Cell Neuroendocrine Carcinoma in Head and Neck

Introduction: Poorly differentiated neuroendocrine carcinomas (NECs) originating from the eye are rare and very highly malignant diseases with a poor prognosis. Small cell NEC of the head and neck is a rare disease and highly aggressive. Early recognition and treatment are crucial for reducing morbidity and mortality. Case Presentation: A 19-year-old male visited our oncology surgery outpatient department due to the progressive neck mass enlargement originating from the eye. The patient was previously diagnosed with invasive choroid malignant melanoma of the left eye which had metastasized to the lymph nodes of the left neck. He underwent a surgical removal/exenteration of the left eye. The result showed that the patient’s survival with poorly differentiated tumors was about 14% while patients with well-differentiated NEC had a survival rate of 34%. It also indicates that the prognosis of these tumors is very poor with a total of over 90% of patients having distant metastatic disease. Histopathological examination showed the tumor tissue and its immunohistochemistry with positive streaks of CD56, NSE, Synaptophysin, and Ki67 suggested small cell NEC.Conclusions: it is crucial to establish an early diagnosis of these tumors to reduce morbidity and mortality. No optimal treatment for such disease has yet been established.

Neuroendocrine Neoplasms of the Larynx: A Clinicopathologic Analysis of 27 Neuroendocrine Tumors and Neuroendocrine Carcinomas.

Laryngeal neuroendocrine neoplasms (NENs) are rare and heterogeneous, encompassing well-differentiated neuroendocrine tumors (NETs; grade 1, 2, and 3), neuroendocrine carcinomas (NECs, small cell and large cell types), and mixed neuroendocrine non-neuroendocrine neoplasms (MiNEN). We aimed to study the clinicopathologic spectrum of these neoplasms. A retrospective review of all primary laryngeal NENs diagnosed from 2005 to 2017 was undertaken. Mitotic index was divided into < 2, ≥ 2-10, and > 10 mitoses/2 mm2, with a Ki-67 labelling index of < 2%, ≥ 2-20%, and > 20% for the NET grade 1, 2 and 3 categories, respectively. A total of 27 patients were included. The median age at presentation was 60years; the male-to-female ratio was 8:1. Supraglottis (n = 22) was the most frequently affected subsite. There were 9 NETs grade 2 (G2), and 18 NECs cases. There were no NET grade 1 or 3 cases in our cohort. Among the NETs G2, the morphology was epithelioid (2), plasmacytoid (3), clear (2), oncocytic (1), and rhabdoid (1). Unique 'glomeruloid structures' (n = 5), calcification (n = 3), lymphoid aggregates (n = 5), intranuclear inclusions (n = 2), hyaline globules (n = 3), and Leisegang rings (n = 2) were identified. NECs comprised 16 small cell neuroendocrine carcinoma and 2 large cell neuroendocrine carcinoma. On immunohistochemistry, tumor cells expressed AE1/AE3 (86%), synaptophysin (100%), chromogranin (100%), INSM1 (100%), calcitonin (33.3%). In the NEC group, p53 aberrant expression (87.5%), Retinoblastoma (Rb) loss (88.2%), and diffuse p16 immunoreactivity (66.7%) were additionally observed. Lymph-node metastasis was detected in 62.5% and 85.7%, while distant metastasis in 55.6% and 76.9%, respectively in NET G2 and NEC. Laryngeal NENs are aggressive neoplasms with a high rate of nodal and distant metastasis. Awareness of the wide pathologic spectrum of laryngeal NENs and appropriate use of IHC is needed to render an accurate diagnosis. Ki67 assessment is strongly recommended for laryngeal NEN prognostication.

Radical surgical treatment of neuroendocrine tumors of the appendix in children - a Polish multicenter study.

IntroductionThe aim of the study was to examine management of pediatric appendiceal neuroendocrine tumors (ANETs) in Poland.MethodsRecords of 27 patients with ANET diagnosed incidentally after appendectomy in the last decade.ResultsWell-differentiated NET G1/G2 was diagnosed in 25 and well-differentiated neuroendocrine carcinoma G3 in 2 patients. Extended surgery was performed primarily in one instance and secondarily in 10 patients (right hemicolectomy in 9, ileocecal resection in 1) without adjuvant chemotherapy. Follow-up range was 1–121 months. Recurrence after secondary surgery was observed in 1 (3.7%) patient.ConclusionsApplying ENETS guidelines resulted in 100% overall survival of patients with NET.

ACTH Producing Mediastinal Tumor - Multidisciplinary Approach

Abstract Introduction: Ectopic ACTH syndrome is rare but is frequently a severe condition because of the intensity of the hypercortisolism. Patient management is complex and demands both strategies: the diagnosis and treatment of Cushing syndrome, and the specific management of neuroendocrine tumors. Therefore, management should be performed ideally by experienced endocrinology teams in collaboration with surgeons, oncologists, nuclear medicine, specialized hormonal laboratory and modern imaging platforms. Clinical Case: Female patient, born in 2000, at the age of 15 was diagnosed with Cushing’s syndrome secondary to ACTH secretion by mediastinal tumor. At diagnosis, ACTH 1152pg/ml was found (reference value &amp;lt;46pg/ml). Turkish seat resonance was normal, and chest tomography described a 4.5x3.6x3.8cm mediastinal lesion. Underwent a mediastinal surgical approach in 2015, with clinical and laboratory remission of hypercortisolism. The analysis of the lesion revealed a well-differentiated neuroendocrine carcinoma, with Ki67 5%. Progression of the mediastinal lesion was observed, without an exuberant clinic or laboratory, and a new surgery was performed in 2017, with a remaining macroscopic tumor, due to technical difficulties in resection due to contact with vascular structures. The immunohistochemistry of the resected lesion in this approach showed Ki67 30%, which reflects loss of differentiation. Octreoscan was performed, with no uptake. She evolved without exuberant Cushing’s syndrome until May 2019, when the clinical condition decompensated due to hypercortisolism, and was submitted to a new hospitalization. She was assisted by the thoracic surgery and oncology teams. From this moment a follow-up with endocrinology team started. Ketoconazole was introduced and PET-DOTATOC was requested. She underwent chemotherapy with Oxaliplatin and Capecitabine. In March 2020, DOTATOC uptake was checked and a somatostatin analogue was started. She showed considerable clinical and laboratory improvement. The patient remains clinically stable, with control of hypercortisolism using Ketoconazole 600mg daily and Octreotide 30mg every 28 days. The patient remains under clinical and laboratory surveillance. Awaiting PET-FDG. Mediastinal radiotherapy, lutetium, new mediastinal surgical approach, and bilateral adrenalectomy are also considered as possible therapeutic alternatives. Clinical Lesson: The reported case shows a rare location of an ACTH-producing tumor, emphasizing the severity of the presentation, the evolution of tumor de-differentiation, the different results identified in octreoscan and PET-DOTATOC, and the importance of multidisciplinary management.

Biliary tree neuroendocrine tumor, an incidental finding.

Introduction and importanceBiliary tree neuroendocrine tumors (NET) are rare, with 100 cases in the literature, and have an excellent prognosis. Although they are rarely diagnosed before surgery, complete surgical excision offers optimal treatment.Case presentationWe report a case of a 36-year-old female patient referred to the surgical team with obstructive jaundice for which she was investigated and found to have a common bile duct tumor showing proximal obstruction. Excision of the tumor with hepaticojejunostomy was done. Later on, the pathology report showed grade-1, well-differentiated neuroendocrine carcinoma, which was completely excised. No further intervention was provided to the patient.Clinical discussionComplete surgical resection with excision of the extrahepatic bile ducts and portal lymphadenectomy in addition to Roux-en-Y hepaticojejunostomy or even pancreaticoduodenectomy for distal CBD neuroendocrine tumors gives sufficient treatment in the majority of cases. No evidence of the advantage of chemo-radiotherapy as part of the treatment for this tumor.ConclusionBiliary tree neuroendocrine tumors are benign tumors, and it is usually difficult to ascertain the diagnosis preoperatively. However, complete surgical excision offers an optimal treatment with no evidence of chemotherapy or radiotherapy's role in the management.

Application of INSM1 in Diagnosis and Grading of Laryngeal Neuroendocrine Carcinoma.

Chromogranin (CHG), synaptophysin (Syn), and CD56 are generally used in a panel to support diagnoses of laryngeal neuroendocrine carcinomas (NECs). However, the absence of expression of these markers does not completely exclude the diagnosis. INSM1 is a novel marker that is considered sufficiently sensitive and specific for NE differentiation. The aim of this study is not only to detect its sensitivity and specificity, but also to evaluate its application in grading for laryngeal NECs. The clinicopathological characteristics of the 25 cases with laryngeal NECs were retrospectively analyzed. The expressions of INSM1, CHG, Syn, and CD56 were detected by immunohistochemistry. Of the 25 laryngeal NECs, INSM1 had higher sensitivity (92%) than Syn (84%), CHG (76%) and CD56 (76%). The average H scores of INSM1, CD56, Syn, and CHG were 160, 37.5, 300, 300 for well-differentiated neuroendocrine carcinoma (WD-NEC); 190, 149, 209, 215 for moderately differentiated neuroendocrine carcinoma (MD-NEC); 251, 208, 104, 25 for poorly differentiated neuroendocrine carcinoma with small cell (SCNEC); 109, 160, 98, 26 for large cell types (LCNEC), respectively. Of these 98 non-neuroendocrine tumors, INSM1 expression was seen in nine (9%) tumors, all were squamous cell carcinoma. And INSM1 staining was generally focal. INSM1 has high sensitivity and specificity in diagnosis of laryngeal NECs. For grading laryngeal NECs, Syn and CHG showed significant advantages in the diagnosis of WD-NEC and MD-NEC, whereas INSM1 and CD56 showed greater diagnostic value in the diagnosis of SCNEC and LCNEC, especially in SCNEC. 4 Laryngoscope, 131:E2662-E2668, 2021.

Neuroendocrine appendiceal tumor and endometriosis of the appendix: a case report

IntroductionEndometriosis of the appendix is very uncommon, accounting for only about 1% of all cases of endometriosis. However, endometriosis is found in the appendix in approximately 8–13% of patients with deep infiltrating endometriosis and is particularly common in patients with severe forms of deep infiltrating endometriosis. Neuroendocrine tumors are the most common neoplasms of the appendix and may be misdiagnosed when there are multiple endometriosis lesions in the pelvis.Case presentationWe describe a case of a Caucasian patient with deep infiltrating endometriosis with rectal involvement, retrocervical lesions, and a right ovarian endometrioma with no suspected lesions in the appendix. She underwent laparoscopy and, after a systematic intraoperative evaluation, suspected involvement of the appendix was observed. The patient underwent ovarian cystectomy, excision of the pelvic endometriosis lesions, appendectomy, and anterior stapler discoid resection. Histopathological analysis of the appendix revealed endometriosis and a well-differentiated neuroendocrine carcinoma at the appendix tip.DiscussionOur patient’s case emphasizes the need to approach these lesions carefully and strengthens the indication for appendectomy when the appendix is affected in the setting of endometriosis. Despite the more likely diagnosis of appendiceal endometriosis, neuroendocrine tumors cannot be ruled out by imaging examinations, and both conditions can occur in the same patient.

Endobronchial ultrasound- guided transbronchial needle aspiration for mediastinal lymph node staging in patients with typical pulmonary carcinoids

BackgroundPulmonary carcinoids, which are well-differentiated lung neuroendocrine carcinomas, account for only 1–2 % of primary lung malignancies. Although fluorodeoxyglucose positron-emission tomography/computed tomography performs poorly in the identification of mediastinal lymph node metastases, particularly for pulmonary carcinoids, endobronchial ultrasound-guided (EBUS) transbronchial needle aspiration (TBNA) may be a useful means of preoperative nodal assessment in patients with these conditions. However, the diagnostic performance of EBUS TBNA is unknown. This study was designed to determine the sensitivity of EBUS for mediastinal staging in patients with typical carcinoid. Study design and methodsA retrospective review of all patients with carcinoids who underwent EBUS TBNA and/or surgical resection with lymphadenectomy at The University of Texas MD Anderson Cancer Center was performed. The sensitivity of EBUS –TBNA in diagnosis of mediastinal lymph node metastases was determined. ResultsOf the 212 patients with pulmonary carcinoids we identified, 137 had surgery with no preoperative EBUS TBNA, 68 had EBUS TBNA followed by surgery, and 7 had EBUS TBNA only. The sensitivity rate for EBUS TBNA in diagnosis of mediastinal lymph node metastases was 77.78 % overall (95 % CI, 57.7−91.3%) and it was 87.5 % (95 % CI, 67.6−97.3%) when we considered only patients with EBUS TBNA-accessible lymph nodes. DiscussionThe sensitivity of EBUS TBNA for diagnosis of mediastinal lymph node metastases of pulmonary carcinoids was slightly lower than that reported previously for non-small cell lung cancer. Preoperative EBUS TBNA identified nodal metastases not previously identified by imaging.

Diagnosis and Clinical Management of Neuroendocrine Tumor of the Breast: Report of Six Cases and Systematic Review of Existing Literature

Introduction: Neuroendocrine neoplasm of the breast (bNENs) are considered a rare disease, even if in WHO data they represent about 2-5 % of all breast cancer. The last WHO classification includes: welldifferentiated neuroendocrine tumor (bNET), neuroendocrine carcinoma (NEC) and invasive carcinoma with neuroendocrine differentiation. The current knowledge on clinical management of bNENs is poor and patients are usually treated according to non-endocrine tumor components guidelines. Materials and Methods: We presented our experience of six cases of bNENs. Moreover, we conducted a systematic review of published data on diagnosis, treatment and outcome of this kind of tumors. Results: bNENS usually presented as palpable breast masses, classically appearing as irregular hypoechoic lesions at US examination and as hyperdense masses at mammography. Usually pre-operative tumor biopsy is not able to recognize the neuroendocrine components and the final diagnosis is performed only on definitive histopathological assessment. The most frequent subtype seems to be neuroendocrine carcinoma and synaptophysin is positive in most specimens. Treatment strategies, including surgical treatment, radiotherapy and medical treatment are nowadays based on current non-endocrine breast cancer guidelines, independently from neuroendocrine components, even if some studies have proposed the use of somatostatin analogues for bNET and cisplatin-etoposide for NEC. Prognosis of all bNENs, especially of poorly differentiated neoplasia, seems worse compared to non-neuroendocrine breast cancer and stage and morphology seem the best predictor of tumor outcome. Conclusions: We provide an algorithm for clinical management of bNETs, basing on available data. More studies are necessary for confirming the best treatment strategy for these patients, in order to improve clinical outcome

Urgent Surgery for Giant Pancreatic Neuroendocrine Tumor: A Case Report

Pancreatic neuroendocrine neoplasms (P-NENs) are a heterogeneus group of tumors with a low frequency of occurrence (<1/100.000 patients per year). Their incidence has been increasing in the past decades mainly due to incidental discovery of asymptomatic lesions. Approximately, 60% of patients present metastases during the diagnostic process and the liver is the most frequent location where the methastases present themselves. Even though in 2010, the World Health Organization (WHO) presented the most accepted classification so far, that divided P-NENs into well-differentiated neuroendocrine tumors (NETs) and less well-differentiated neuroendocrine carcinomas (NECs), a universally standardized classification is still needed. Imaging tests such as CT or MRI are frequently used for diagnosis but Octreoscan and further complex techniques including preoperative biopsy are also needed for a successful diagnosis. Surgery is the only possible curative treatment, however added adyuvant chemoterapy is considered to improve survival rates.

Ciego Neuroendocrine Tumor: Case Report.

Neuroendocrine carcinoma (NEC) of the colon is a rare and very aggressive tumor, generally diagnosticated in an incidental way and during resolution of complications such as perforation or intestinal obstruction. The case of a 58-year-old male patient who was surgically intervened for presenting localized peritonitis pedhora scan to a perforated blind neuroendocrine tumor. Right hemicolectomy whit ganglion D2 resection and ileo – transverse primary anastomosis was performed. Histopathological examination described a well-differentiated neuroendocrine carcinoma of small cells, with no vascular or neuronal infiltration. Now the patient is awaiting chemotherapy without the need for secondary surgical review.

INTRAPULMONARY SHUNTING IN CARCINOID SYNDROME

SESSION TITLE: Pulmonary Manifestations of Systemic Disease SESSION TYPE: Fellow Case Reports PRESENTED ON: 10/21/2019 3:15 PM - 4:15 PM INTRODUCTION: Carcinoid tumors are rare slow-growing neuroendocrine tumors. The biologic behavior of these tumors can be variable and unpredictable which may lead to unusual clinical presentations and delayed diagnosis. Carcinoid tumors release different vasoactive substances, including serotonin, histamine, and bradykinins. Release of 5-hydroxyindoleacetic acid (5-HIAA), a product of serotonin degradation, results in increased gastrointestinal motility (diarrhea), bronchoconstriction (wheezing), and vasodilation (flushing). Intra-pulmonary shunt (hepatopulmonary-like syndrome) due to pulmonary vasodilatation of the microvascular bed is exceedingly rare in carcinoid syndrome. CASE PRESENTATION: A 57-year-old man presented with chronic diarrhea and flushing. Initially, the diarrhea was believed to be related to metformin, however it persisted despite stopping this medication. Later, he developed progressive dyspnea with profound hypoxia. Hypoxemia was poorly responsive to supplemental oxygen, consistent with shunt physiology. Work up for hypoxia included an unremarkable chest radiograph and arterial blood gas with increased alveolar-arterial gradient. Chest CT angiography was negative for pulmonary embolism or parenchymal lung disease. Inhaled oxygen shunt study revealed 23.3% shunt. Agitated saline contrast echocardiography showed no evidence of intracardiac shunt, but demonstrated late bubbles (>5 beats) in the left side after agitated saline administration consistent with intra-pulmonary shunt. CT of the abdomen demonstrated enlarged and markedly heterogeneous liver concerning for metastatic disease, as well as a 2.6 x 3.0 cm mass in the small bowel mesentery, morphologically consistent with carcinoid tumor. Serum serotonin, 24 hour urine 5 HIAA, and serum chromogranin A level were abnormally elevated. Biopsy of a liver lesion confirmed a well-differentiated neuroendocrine carcinoma, classified as low grade with a Ki-67 of less than 2%. He was initiated on first line therapy with Sandostatin LAR with rapid resolution of his diarrhea. While he remains hypoxic and oxygen dependent, his subjective dyspnea has improved. DISCUSSION: Severe hypoxemia has been described in carcinoid syndrome mostly due to right to left cardiac shunts; however, carcinoid-related intrapulmonary shunt is exceedingly rare. To our knowledge, only three cases of intrapulmonary shunt in carcinoid syndrome have been reported (1-3). Similar to our patient, these were associated with metastatic disease. CONCLUSIONS: Possible mechanisms of hypoxemia in carcinoid syndrome warrant further investigation. Reference #1: Hussain A, Young ET, Greaves JD, et al. Intrapulmonary shunting causing hypoxaemia in a case of carcinoid syndrome. Clin Endocrinol (Oxf). 1994;41(4):535-537. Reference #2: Robert R, Matuchansky C, Picker F, Guitton P, Patte D. Severe hypoxemia in a case of midgut carcinoid tumor. Intensive Care Med. 1989;15(8):536-537. Reference #3: Stewart GW, Freegard SP, Keeling DH, Perrett AD. Cyanosis attributable to right to left shunt in carcinoid syndrome. Br Med J (Clin Res Ed). 1986;292(6520):589-590. DISCLOSURES: No relevant relationships by Mazen Al-Qadi, source=Web Response Consultant relationship with United Therapeutics Please note: $5001 - $20000 Added 02/14/2019 by Hubert Ford, source=Web Response, value=Travel also Consultant relationship with Actelion Please note: $1001 - $5000 Added 03/14/2019 by Hubert Ford, source=Web Response, value=Honoraria Consultant relationship with Liquidia Please note: $1-$1000 Added 03/14/2019 by Hubert Ford, source=Web Response, value=Honoraria Research Grant relationship with United Therapeutics Please note: $5001 - $20000 Added 03/14/2019 by Hubert Ford, source=Web Response, value=Grant/Research Support No relevant relationships by Amanda Kovacich, source=Web Response No relevant relationships by Autumn McRee, source=Web Response

Well-differentiated Neuroendocrine Carcinoma of the Larynx: Confusion of Terminology and Uncertainty of Early Studies.

Well-differentiated neuroendocrine carcinoma (also known as "carcinoid") of the larynx is an exceedingly rare tumor that has an epithelial origin. These tumors are malignant and have a low, but definite, risk of metastasis. Although it can be challenging, this tumor should be differentiated from moderately differentiated neuroendocrine carcinoma (also known as "atypical carcinoid"). The clinical and pathologic features of this tumor, as well as treatment and prognosis, are reviewed in detail.

Non-urothelial carcinomas of the bladder.

Non-urothelial carcinomas involving the bladder are uncommon and often diagnostically challenging. These carcinomas may show squamous, adenocarcinomatous or neuroendocrine features, with immunohistochemical stains aiding the diagnosis in only a subset of cases. The clinical history in non-urothelial bladder carcinomas is important, given that the differential diagnosis often includes secondary involvement of the bladder by direct extension or metastasis from carcinomas at other sites. This paper will review non-urothelial carcinomas in each of these three morphological categories, emphasising recent changes in diagnostic grouping and challenges in the histopathological diagnosis. Review of bladder cancers with squamous morphology will include discussion of conventional squamous cell carcinoma and verrucous carcinoma and their distinction from urothelial carcinoma with extensive squamous differentiation. Bladder carcinomas with adenocarcinomatous change will include primary bladder adenocarcinoma, urachal adenocarcinoma and tumours of Müllerian type. Finally, neuroendocrine neoplasms of the bladder, including well-differentiated neuroendocrine tumour and neuroendocrine carcinomas, will be discussed. Associated surface findings, risk factors and prognostic features will be described.

Grading of Neuroendocrine Carcinomas: Correlation of 68Ga-PET/CT Scan with Tissue Biomarkers.

There is a growing need for more accurate biomarkers to facilitate the diagnosis and prognosis of patients with grade (G) 3 neuroendocrine carcinomas (NECs). In particular, the discrimination between well-differentiated neuroendocrine carcinomas (WD-NECs) and poorly differentiated neuroendocrine carcinomas (PD-NECs) is still an unmet need. We previously showed that 68Gallium-(68Ga-) PET/CT positivity is a prognostic factor in patients with gastroenteropancreatic (GEP) G3 NECs, correlating with a better outcome in terms of overall survival. Here, we hypothesize that 68Ga-PET/CT could help to discriminate between WD-NECs and PD-NECs, adding complementary information to that obtained from morphologic and biologic factors. A retrospective, single-institution study was performed on 11 patients with histologically confirmed, measurable G3 large- or small-cell GEP-NECs according to the 2017 WHO classification. The staging procedures included a 68Ga-PET/CT scan. Results of 68Ga-PET/CT were correlated in univariate analysis with loss of tissue immunohistochemical expression of DAXX/ATRX or RB1 frequently associated with WD-NECs or PD-NECs, respectively. None of the patients with positive 68Ga-PET/CT showed loss of RB1 expression, whereas among those (n = 6) with negative 68Ga-PET/CT, 4 showed loss of expression. A trend towards a correlation between loss of RB1 expression and negative 68Ga-PET/CT was observed. Our preliminary data support the hypothesis that PD-NECs carrying RB1 mutation and loss of its expression may be associated with negative 68Ga-PET/CT. If confirmed in a larger clinical trial, 68Ga-PET/CT would help in the stratification of G3 NECs.