[Long-Term Survival of a Case with Peritoneal Dissemination from Appendiceal Goblet Cell Carcinoid Treated with Systemic Chemotherapy].

A 64-year-old man complained of lower abdominal pain and vomiting. The CT scan showed adhesional ileus; therefore, small bowel resection procedure was performed. Histological findings showed signet-ring cell carcinoma and poorly differentiated adenocarcinoma. We performed ileocecal resection as an additional surgery. The operative findings revealed peritoneal nodules. The histological findings suggested goblet cell carcinoid with peritoneal dissemination. mFOLFOX+bevacizumab was administered, and no progression was observed for 30 months after the surgery. Appendiceal goblet cell carcinoid is rare and its prognosis is poor. Here, we report a case of appendiceal GCC that achieved a relatively long-term survival despite peritoneal dissemination.

Gender-related differences in patients with carcinoid syndrome: new insights from an Italian multicenter cohort study.

BACKGROUND: The incidence of neuroendocrine neoplasm (NEN) and related carcinoid syndrome (CaS) has increased markedly in recent decades, and women appear to be more at risk than men. As per other tumors, gender may be relevant in influencing the clinical and prognostic characteristics of NEN-associated CS. However, specific data on carcinoid syndrome (CaS) are still lacking. PURPOSE: To evaluate gender differences in clinical presentation and outcome of CaS. METHODS: Retrospective analysis of 144 CaS patients from 20 Italian high-volume centers was conducted. Clinical presentation, tumor characteristics, therapies, and outcomes (progression-free survival, PFS, overall survival, OS) were correlated to gender. RESULTS: Ninety (62.5%) CaS patients were male. There was no gender difference in the site of primary tumor, tumor grade and clinical stage, as well as in treatments. Men were more frequently smokers (37.2%) and alcohol drinkers (17.8%) than women (9.5%, p = 0.002, and 3.7%, p = 0.004, respectively). Concerning clinical presentation, women showed higher median number of symptoms (p = 0.0007), more frequent abdominal pain, tachycardia, and psychiatric disorders than men (53.3% vs 70.4%, p = 0.044; 6.7% vs 31.5%, p = 0.001; 50.9% vs. 26.7%, p = 0.003, respectively). Lymph node metastases at diagnosis were more frequent in men than in women (80% vs 64.8%; p = 0.04), but no differences in terms of PFS (p = 0.51) and OS (p = 0.64) were found between gender. CONCLUSIONS: In this Italian cohort, CaS was slightly more frequent in males than females. Gender-related differences emerged in the clinical presentation of CaS, as well as gender-specific risk factors for CaS development. A gender-driven clinical management of these patients should be advisable.

Multiomic sequencing of paired primary and metastatic small bowel carcinoids.

Background: Small bowel carcinoids are insidious tumors that are often metastatic when diagnosed. Limited mutation landscape studies of carcinoids indicate that these tumors have a relatively low mutational burden. The development of targeted therapies will depend upon the identification of mutations that drive the pathogenesis and metastasis of carcinoid tumors. Methods: Whole exome and RNA sequencing of 5 matched sets of normal tissue, primary small intestine carcinoid tumors, and liver metastases were investigated. Germline and somatic variants included: single nucleotide variants (SNVs), insertions/deletions (indels), structural variants, and copy number alterations (CNAs). The functional impact of mutations was predicted using Ensembl Variant Effect Predictor. Results: Large-scale CNAs were observed including the loss of chromosome 18 in all 5 metastases and 3/5 primary tumors. Certain somatic SNVs were metastasis-specific; including mutations in ATRX, CDKN1B, MXRA5 (leading to the activation of a cryptic splice site and loss of mRNA), SMARCA2, and the loss of UBE4B. Additional mutations in ATRX, and splice site loss of PYGL, leading to intron retention observed in primary and metastatic tumors. Conclusions: We observed novel mutations in primary/metastatic carcinoid tumor pairs, and some have been observed in other types of neuroendocrine tumors. We confirmed a previously observed loss of chromosome 18 and CDKN1B. Transcriptome sequencing added relevant information that would not have been appreciated with DNA sequencing alone. The detection of several splicing mutations on the DNA level and their consequences at the RNA level suggests that RNA splicing aberrations may be an important mechanism underlying carcinoid tumors.

Clinicopathological features of appendiceal goblet cell adenocarcinoma in Japan: a multicenter retrospective study.

PURPOSE: In the 5th edition of the World Health Organization classification, appendiceal goblet cell adenocarcinoma (GCA) is categorized separately from neuroendocrine tumors and other appendiceal adenocarcinomas. We clarified the clinicopathological characteristics of Japanese appendiceal GCA. METHODS: We designed a retrospective multicenter cohort study and retrieved the data of patients with appendiceal neoplasms and histologically diagnosed appendiceal goblet cell carcinoid (GCC) treated from January 2000 to December 2017 in Japan. The available GCC slides were reviewed and diagnosed with a new grading system of GCA. RESULTS: A total of 922 patients from 43 institutions were enrolled; of these, 32 cases were patients with GCC (3.5%), and 20 cases were ultimately analyzed. The 5-year survival rate was 61.4% (95% confidence interval: 27.4-83.2), and the median survival time was 93.1 months. For peritoneal metastasis, regional lymph node metastasis was a significant factor (p = 0.04), and Grade 3 was a potential factor (p = 0.07). No peritoneal metastasis was observed in either T1/2 patients (n = 2) or Grade 1 patients (n = 4). We were unable to detect any significant factors associated with regional lymph node metastasis. CONCLUSION: For peritoneal metastasis, regional lymph node metastasis was a significant factor, and Grade 3 was a potential factor.

The occurrence and associated risk factors of brain metastases in well differentiated grade 1 and 2 bronchial neuroendocrine tumours: A single centre retrospective analysis of 280 patients.

Typical and atypical bronchial carcinoid account for around 2% of all neuroendocrine neoplasms of pulmonary origin. Fewer than 5% of patients with these cancers are thought to develop brain metastases, and hence routine intracranial imaging is not currently included in staging investigations. In this study, retrospective case note analysis was performed on 280 patients diagnosed with either typical carcinoid (TC) or atypical carcinoid (AC) at a large, single-site cancer centre. None of the 219 patients with TC developed brain metastases during the course of their disease, whereas seven of the 61 AC (11.5%) were found to have intracranial spread, four of which were present at the point of diagnosis. A Cox proportional hazard model showed that a Ki-67 expression ≥18%, patient age ≥65 years and disease stage at diagnosis were all independently and significantly associated with the development of brain metastases in AC. This study has found new evidence that the incidence of brain metastases in AC is significantly higher than previously thought. Of all the variables reviewed, Ki-67 expression was most strongly associated with the development of intracranial disease in AC and could be readily translated into clinical practice. Predictive factors such as age, disease stage and Ki-67 expression could be used to identify patients at particularly increased risk of brain metastases, who would benefit from early intracranial imaging. This could allow for earlier detection and treatment of metastases, with the potential to improve clinical outcomes and patient quality of life.

Metastasis of lung carcinoid in the thyroid gland after 18 years: it is never too late. A case report and review of the literature.

Metastasis to the thyroid gland is a rare event. To date, only 11 cases of metastasis from neuroendocrine tumors (NETs) originating in the lung have been reported. We present a case of a patient in his 40s harboring two nodules in the thyroid gland that were diagnosed as well-differentiated NET (G1). Eighteen years before the patient underwent a lung lobectomy of the right upper lobe for a bronchial typical carcinoid with metastasis in one lymph node. Normal blood levels of calcitonin virtually ruled out the diagnosis of medullary thyroid carcinoma (MTC) and supported the diagnosis of a possible thyroid metastasis of the previous bronchial NET. Mutational analysis performed on both primary and metastasis tumor tissue did not show any mutation in the 409 genes analyzed.

mTOR Inhibitor-Induced Transient Acantholytic Dermatitis.

A 61-year-old Caucasian male with a medical history of metastatic carcinoid presented to dermatology with a new onset severely pruritic “breakouts” on the arms, neck, and chest. Approximately ten years prior, he was diagnosed with a small bowel carcinoid tumor and liver metastases treated with a combination of resection and ablation.

The rarest of rare cases within the one thousand faces of atypical carcinoid: Pseudomesotheliomatous manifestation in a pregnant woman.

Carcinoid tumors in pregnant women are rare, and there have been no previous studies of atypical carcinoid tumor reported in pregnancy. Also, pseudomesotheliomatous manifestation in atypical carcinoid is an extremely rare finding, there being only two cases reported. Here, we present the first case of pseudomesotheliomatous manifestation of atypical carcinoid in a pregnant woman. Upon image analysis, we found that atypical carcinoids with multiple metastatic lesions can exhibit variability in vascularity and metabolism, resulting in heterogeneous image characteristics among metastatic lesions, even those with identical histology. In addition, even with extensive metastasis, patients can exhibit good performance explained by long-standing presentation of indolent cancer.

The Cancers-Specific Survival of Metastatic Pulmonary Carcinoids and Sites of Distant Metastasis: A Population-Based Study.

BACKGROUND: Lung cancer is the leading cause of cancer-related deaths and pulmonary carcinoids (PCs) account for almost 2% of all pulmonary malignancies. However, few published articles have reported prognosis and related factors of pulmonary carcinoid patients. MATERIAL AND METHOD: The Surveillance, Epidemiology, and End Results (SEER) database was used to collect data of patients diagnosed with metastatic PCs from 2010 to 2016. The prognosis and survival of these patients were compared by employing Cox proportional hazards and the Kaplan-Meier survival analysis. RESULTS: A total of 1763 patients were analyzed. The liver (668, 25.6%) was shown to be the most common metastatic site in the isolated organ metastasis cohort, followed by the lung (636, 24.4%), bone (562, 21.6%), and brain (460, 17.6%). Among the patients, the tumor metastasized to a single distant site included the liver, bone, lung, and brain. Cancer-specific survival (CSS) in metastatic PCs is determined by the site of metastasis and the total number of such sites. Pulmonary carcinoid patients with isolated liver metastasis manifested more favorable survival rates in comparison to patients having isolated metastasis in the lung, brain, or bone. The median CSS was 45, 7, 6, 5 months (P = 0.011). The number of distant metastatic sites and the location of distant metastasis were found to be independent risk factors for CSS. For patients with distant isolated metastasis, liver metastasis (P < 0.0001) had better CSS in comparison to those with bone metastasis. When compared to patients whose carcinoids had metastasized to the bones, patients with a brain (P = 0.273) or lung (P = 0.483) metastasis had the same CSS. CONCLUSION: Cancer-specific survival in metastatic PCs depends on the site of metastasis and the total number of such locations. PC patients with isolated liver metastasis manifested more favorable survival in comparison to patients with isolated metastasis in the lung, brain, or bone.

Subcutaneous metastasis from an atypical pulmonary carcinoid tumor.

Pulmonary carcinoid tumors are uncommon neuroendocrine tumors that rarely metastasize to the skin. We report the case of a 71-year-old woman with a longstanding history of primary atypical pulmonary carcinoid tumor who presented with a new tender cutaneous nodule. Immunostaining of the nodule was consistent with metastatic atypical carcinoid tumor of the skin including positive staining for neuroendocrine markers chromogranin and synaptophysin. Dermatologists should consider cutaneous neuroendocrine metastasis when evaluating new nodules in patients with stable pulmonary carcinoid tumors or in those with concomitant concerning respiratory symptoms.

Case Report: Metastatic Bronchopulmonary Carcinoid Tumor to the Pineal Region.

Intracranial spread of a systemic malignancy is common in advanced staged cancers; however, metastasis specifically to the pineal gland is a relatively rare occurrence. A number of primary lesions have been reported to metastasize to the pineal gland, the most common of which is lung. However, metastasis of a bronchial neuroendocrine tumor to the pineal gland is a seldom-reported entity. Here, we present a 53-year-old female who presented with worsening headaches and drowsiness. MRI brain revealed a heterogeneously enhancing partially cystic mass in the pineal region. The patient had an extensive oncologic history consisting of remote stage IIA invasive breast ductal carcinoma as well as a more recently diagnosed atypical bronchopulmonary neuroendocrine tumor with lymph node metastases. She underwent microsurgical volumetric resection of the large pineal mass and a gross total removal of the tumor was achieved. Histopathology confirmed a metastatic tumor of neuroendocrine origin and the immunohistochemical profile was identical to the primary bronchopulmonary carcinoid tumor. Eight weeks after surgery, she underwent stereotactic radiosurgical treatment to the resection cavity. At 1-year follow-up, the patient remains clinically stable without any new focal neurological deficits and without any evidence of residual or recurrent disease on postoperative MRI. Metastatic neuroendocrine tumors should be considered in the differential diagnosis of pineal region tumors and aggressive surgical resection should be considered in selected patients. Gross total tumor resection may afford excellent local disease control. We discuss the relevant literature on neuroendocrine tumors and current treatment strategies for intracranial metastases of neuroendocrine origin.

Sclerosing Pneumocytoma: A Host for a Typical Carcinoid With Pleural Metastasis-A Wolf in Sheep`s Clothing.

Sclerosing pneumocytoma (SP) is a rare primary lung tumor. Typical carcinoids (TCs) count for 2% of lung malignancies. A description of a combined neoplasm of SP with a nodal and pleural metastasized TC has, to our knowledge, never been published. A 57-year-old actively smoking woman received a diagnosis of a lesion in the left lower lobe via a screening CT scan for rheumatoid arthritis. A fluorodeoxyglucose-PET scan confirmed a 21 × 26 × 16 mm (standardized uptake maximum value, 3.0), well-circumscribed round lesion with calcification, which was thought to be most probably benign. No mediastinal lymph node enlargement or fluorodeoxyglucose uptake was detected. The results of routine laboratory tests, respiratory function tests, and physical examination were unremarkable. In diagnostic thoracoscopy pleural, diaphragmatic, and pericardial lesions were discovered and biopsied in addition to a wedge resection. After diagnosis of a pleural metastasized TC mixed with SP, radical resection and systemic lymph node dissection were performed. The patient is in remission after 36 months of follow-up.

Appendiceal tumors with glandular and neuroendocrine features exhibiting peritoneal metastases - Critical evaluation of outcome following cytoreductive surgery with perioperative chemotherapy.

BACKGROUND: A rare appendiceal malignancy is characterized by both glandular and neuroendocrine histology. It often presents with dissemination of the perforated tumor to peritoneal surfaces. Current treatments involve systemic chemotherapy, cytoreductive surgery and perioperative intraperitoneal chemotherapy. METHODS: The impact of clinical, histological and treatment-related characteristics on survival were evaluated and subjected to univariate statistical analyses. All patients had stage IV disease and were treated by a uniform treatment strategy. Survival was determined from onset of disease until death or most recent follow-up. RESULTS: There were 47 patients available for study of whom 17 were male. Median age was 48 with a range of 27-65. None or a single symptom vs. 2 or more symptoms had a significant effect on survival. Median survival of the entire cohort was 45 months and 34.88% and 8.72% of patients survived 5 and 10 years, respectively. The use of neoadjuvant chemotherapy showed no impact on survival. Patients with a peritoneal cancer index (PCI) of 0-20 as compared to PCI > 20 survived longer (p = 0.012). The survival of patients able to have a complete resection as compared to an incomplete resection of disease was significant (p = 0.0087). The type of perioperative chemotherapy did not alter survival. CONCLUSIONS: These data show that patients with a lesser extent of disease with a complete cytoreduction had an improved prognosis. No benefit from systemic or perioperative regional chemotherapy was apparent. With long-term follow-up, patients with the combined glandular and neuroendocrine histology exhibiting peritoneal metastases have a guarded prognosis.

Octreotide for resuscitation of cardiac arrest due to carcinoid crisis precipitated by novel peptide receptor radionuclide therapy (PRRT): A case report.

Peptide receptor radionuclide therapy (PRRT) is an effective treatment for metastatic carcinoid tumours but can precipitate a carcinoid crisis through release of stored bioamines. Cardiac arrest is an uncommon manifestation of carcinoid crisis and has never been reported as a complication of PRRT. We report a case of a 58-year old female who suffered from cardiac arrest following PRRT for metastatic carcinoid tumour. She was successfully resuscitated using intravenous octreotide following 22 min of failure to resuscitate with a standard advanced cardiac life support protocol. Following resuscitation, severe carcinoid heart disease was diagnosed, and the patient subsequently underwent successful surgical valve replacement. Although there is no trial evidence, considering pharmacological rationale and successful outcome in this case, we suggest early administration of intravenous octreotide during resuscitation of patients suffering cardiac arrest post PRRT for carcinoid disease and recommend preventive strategies.

Development and Validation of an Individualized Nomogram for Predicting Overall Survival in Patients With Typical Lung Carcinoid Tumors.

OBJECTIVE: We aim to develop and validate an effective nomogram prognostic model for patients with typical lung carcinoid tumors using a large patient cohort from the Surveillance, Epidemiology, and End Results (SEER) database. MATERIALS AND METHODS: Data from patients with typical lung carcinoid tumors between 2010 and 2015 were selected from the SEER database for retrospective analysis. Univariate and multivariate Cox analysis was performed to clarify independent prognostic factors. Next, a nomogram was formulated to predict the probability of 3- and 5-year overall survival (OS). Concordance indexes (c-index), receiver operating characteristic analysis and calibration curves were used to evaluate the model. RESULTS: The selected patients were randomly divided into a training and a validation cohort. A nomogram was established based on the training cohort. Cox analysis results indicated that age, sex, T stage, N stage, surgery, and bone metastasis were independent variables for OS. All these factors, except surgery, were included in the nomogram model for predicting 3- and 5-year OS. The internally and externally validated c-indexes were 0.787 and 0.817, respectively. For the 3-year survival prediction, receiver operating characteristic analysis showed that the areas under the curve in the training and validation cohorts were 0.824 and 0.795, respectively. For the 5-year survival prediction, the area under the curve in the training and validation cohorts were 0.812 and 0.787, respectively. The calibration plots for probability of survival were in good agreement. CONCLUSION: The nomogram brings us closer to personalized medicine and the maximization of predictive accuracy in the prediction of OS in patients with typical lung carcinoid tumors.

Prognostic score for survival with pulmonary carcinoids: the importance of associating clinical with pathological characteristics.

OBJECTIVES: Lung carcinoids (LCs) are staged using the non-small-cell lung cancer tumour/node/metastasis staging system; the possibility of an LC-specific staging system is still being debated. The goal of our study was to construct a composite prognostic score for LC. METHODS: From January 2002 to December 2014, data from 293 patients who underwent surgical treatment for LC in 7 research institutes were retrospectively analysed. A panel of established prognostic factors in addition to lymph node metastasis patterns (single/multiple N1-N2 station, skip metastasis, lobe specific), numbers of lymph nodes resected and the ratio between the numbers of metastatic lymph nodes and the numbers of lymph nodes resected (node ratio) were correlated to overall survival (OS) and disease-free survival (DFS). The log-hazard ratio (HR), obtained from the Cox model, was used to derive weighting factors for a continuous prognostic index, designed to identify differential outcome risks. The score was dichotomized according to maximally selected log-rank statistics. RESULTS: Pathological analysis showed typical carcinoids in 223 (76.1%) and atypical carcinoids in 70 (23.9%) patients; the tumour/node/metastasis pattern was stage I in 72.4%, stage II in 18.1%, stage III in 9.5% and stage IV in 0.03% cases. The median numbers of lymph nodes resected was 12 (range 0-53); hilar and mediastinal node metastases were identified in 14% and 6.8% of cases, respectively. Overall, the 5-year OS and 5-year DFS rates were 90.6% and 76.7%, respectively. At multivariable analysis, sex, age, pathological T stage and node ratio were significantly related to a better OS; age, histological type, pathological T stage and node ratio were related to DFS. These factors were used to generate the prognostic score, which showed statistically significant differences between the high-risk and low-risk groups: 5-year OS = 96.6% if score <3.1 vs 63.5% if score ≥3.1 [P < 0.0001; HR 17.56, 95% confidence interval (CI) 5.45-56.53]; 5-year DFS 92.3% if score <1.5 vs 52.5% if score ≥ 1.5 (P < 0.0001; HR 7.95, 95% CI 3.48-18.16). CONCLUSIONS: The proposed prognostic scores seem to be effective in predicting outcomes for patients with LCs.

Surgical Principles in the Management of Small Bowel Neuroendocrine Tumors.

OPINION STATEMENT: Small bowel neuroendocrine tumors (SB NETs) are increasing in frequency and becoming more common in surgical practice. It is often difficult to make the diagnosis of a SB NET at an early stage, as the primary tumor tends to be small and patients are asymptomatic until there is regional or distant metastasis, when they develop abdominal pain, partial obstruction, or bleeding and/or develop carcinoid syndrome. Despite this advanced presentation at the time of diagnosis, patients with metastatic SB NETs, as compared to other gastrointestinal malignancies, have favorable survival, which can be improved by appropriate surgical interventions. With the lack of randomized studies, there is reasonable controversy surrounding the optimal management of patients with SB NETs. As such, treatment of these patients is driven primarily by physician experience and available data based predominantly on retrospective studies. Based on this, current recommendations advocate for patients with SB NETs (localized or metastatic) to be managed at experienced centers by a multidisciplinary team. Eligible patients should undergo surgical resection of primary and regional disease as outlined in this article. Additionally, patients with metastatic disease should be evaluated on a case by case basis to evaluate surgical options that may mitigate bowel symptoms (i.e., pain, intestinal angina, obstruction) and carcinoid symptoms (flushing, diarrhea, hemodynamic instability) and prolong survival. Unlike other gastrointestinal malignancies, aggressive surgical management of these patients, even in the context of unresectable metastatic disease, can improve patients' symptoms and long-term survival. The principles outlined in this article are geared to guide appropriate management of SB NET patients with improvement in quality of life and overall survival outcomes.

Left bundle branch block revealing a primary small bowel carcinoid metastasizing to the interventricular septum.

Carcinoid tumours of the heart occur most commonly as a result of metastatic disease and usually affect the right side of the heart. We report a case of a solitary carcinoid metastasis to the interventricular septum without hepatic involvement in a 74-year-old man.