Carcinoid Group Research Articles

ES17.03 Updates in Squamous Cell Carcinoma and Neuroendocrine Tumors of the Lung

ES17.03 Updates in Squamous Cell Carcinoma and Neuroendocrine Tumors of the Lung

Results of Surgical Resection of Locally Advanced Pulmonary Neuroendocrine Tumors

Pulmonary neuroendocrine tumors include well-differentiated and poorly differentiated histology for which cell type has proved to be a determinant of survival in many studies. In patients diagnosed with bronchial carcinoid and large cell neuroendocrine carcinoma (LCNEC), surgery is the treatment of choice even in the case of locally advanced disease with lymph node involvement. We retrospectively analyzed patients undergoing anatomic lung resection for bronchial carcinoid or LCNEC with lymph node involvement (N1/N2) at the final pathologic examination (pN+). Characteristics of patients and differences in overall survival and disease-free survival are presented according to tumor type. Overall survival of distinct histologic groups was compared with survival in our institutional experience in stage I patients, without nodal involvement (pN0). In all, 325 patients underwent surgical resection for neuroendocrine tumors; 89 patients had nodal involvement. Five-year survival was 89% in pN+ bronchial carcinoid both for typical carcinoid and atypical carcinoid but worse for pN+ LCNEC (47%). Cell type did not influence the prognosis in N0 disease, and no differences in survival were evident between N0 and N+ in the bronchial carcinoid group. In the group of LCNEC, 5-year overall survival was much worse for pN+ LCNEC (47%) compared with pN0 LCNEC (91%). Bronchial carcinoids have the best prognosis, and surgery remains the treatment of choice for both early and locally advanced disease. On the contrary, aggressive forms (LCNEC) with lymph nodal metastasis have a poor prognosis, and they need to be treated with an aggressive multidisciplinary approach.

Spread through air spaces (STAS) is a predictor of poor outcome in atypical carcinoids of the lung.

Spread through air spaces (STAS) have been recently recognized as a prognostic factor for adenocarcinoma and squamous cell carcinoma of the lung. Pulmonary neuroendocrine neoplasms (NENs) include tumors with different morphology and a heterogeneous clinical behavior. Among atypical carcinoids (ACs), new prognostic factors able to refine prognosis are needed. In the present study, a retrospective series of 91 surgically resected ACs was investigated, in parallel with 191 control cases of typical carcinoids (TCs) and of high-grade small- and large-cell neuroendocrine carcinomas, to assess the presence and potential prognostic role of STAS. STAS was defined by the presence of neoplastic nests or single cells in air spaces beyond the tumor edge. Clinicopathological parameters and survival were correlated by univariate and multivariate analyses. STAS was identified in 48% of ACs (44/91) compared to 20.5% of TCs and 71-88% of high-grade large- and small-cell carcinomas in the control group. In the carcinoid group, presence of STAS was significantly correlated with unfavorable parameters, such as high tumor stage, positive nodal status, high Ki-67 index, presence of angioinvasion, and with adverse disease outcome, shorter overall survival, and time to progression. In conclusion, the presence of STAS is an additional relevant adverse prognostic factor in pulmonary AC that currently has the most unpredictable outcome and the most controversial treatment strategy.

Multiple Assays to Determine Methylguanine-Methyltransferase Status in Lung Carcinoids and Correlation with Clinical and Pathological Features

Background: O6-methylguanine-methyltransferase (MGMT) is a key enzyme for the DNA repair machinery strongly associated with response to alkylating agents in different tumors. Data on its expression and related clinical impact in neuroendocrine tumors are limited to the gastro-entero-pancreatic system, with controversial results in terms of prognostic or predictive value. In lung carcinoids, although clinical efficacy of alkylating agents has been shown in small studies, very few data to date are available on MGMT status. Objective: To assess MGMT status in lung carcinoids using multiple assays and to compare data with major clinical and pathological features. Methods: A retrospective series of 95 lung carcinoids and 51 control cases of high-grade neuroendocrine lung carcinomas was analyzed for MGMT promoter methylation, MGMT gene expression, and MGMT protein expression using pyrosequencing, quantitative real-time PCR, and immunohistochemistry, respectively. Results: MGMT protein expression was inversely correlated with MGMT promoter methylation and positively with MGMT gene expression. MGMT promoter methylation progressively increased from carcinoids to high-grade carcinomas. In the carcinoid group, decreased MGMT gene expression was significantly associated with aggressive features (atypical histotype, grade G2, larger tumor size, higher T stage, and positive nodal status) but not with survival. MGMT promoter methylation was associated with lower stage and negative nodal status. Conclusions: Our study investigated MGMT status in a large series of lung carcinoids in the attempt to move forward a rational use of alkylating agents in these tumors. Interestingly, low MGMT gene expression defines a subgroup of lung carcinoids with aggressive features.

Clinicopathologic and prognostic features in appendiceal malignancies: Tumor invasiveness matters.

Appendiceal tumors are rare and mostly present as acute appendicitis. Its estimated lifetime prevalence has been reported as 8%, and the annual incidence is approximately 0.1% in Western countries. The only treatment approach is still surgery, but surgical management still remains unclear in appendiceal malignancy. Histopathological examination of 2840 specimens obtained from patients who underwent appendectomy between January 2012 and December 2015 was investigated. Data from 23 patients diagnosed with the malignancy had been analyzed in terms of age, gender, and preoperative and postoperative clinical parameters. The overall survival rates of the patients and prognostic parameters affecting survival were also evaluated. Statistical analyses were performed using the SPSS software. The study was performed according to the Declaration of Helsinki. The overall median age of the patients was 28 years with a male/female ratio of 1.55. Pediatric group between 1 and 6 years, late pediatric group between 7 and 11 years, and adolescent group between 12 and 17 years did not present appendix tumors. Carcinoid tumors were reported in 17 patients. Adenocarcinoma of the appendix was reported in 6 patients. Patients with carcinoid tumors were significantly younger than those with adenocancer (p=0.01). The mean tumor size of the carcinoid group was significantly smaller than that of the adenocancer group (p=0.02). Patients with adenocancer were significantly more likely to have tumor extension beyond the appendix (p=0.05). All patients in the adenocancer group and 4 patients in the carcinoid group with mesoappendix invasion underwent right hemicolectomy. Univariate analyses demonstrated that serosal invasion, advanced tumor stage, and tumor invasion depth were associated with poor survival rates. Tumor subtype and tumor invasiveness are important risk factors for survival in appendiceal malignancies. Appendectomy alone presents satisfactory results, but complete staging of the tumor should always be considered. In addition, surgical choice is not presented as an effective factor for improved clinical outcomes and survival rates. Further prospective studies are needed to evaluate the proper staging of the tumors.

Mutational landscape of goblet cell carcinoids and adenocarcinoma ex goblet cell carcinoids of the appendix is distinct from typical carcinoids and colorectal adenocarcinomas

AbstractThere is limited data on the spectrum of molecular alterations in goblet cell carcinoids and adenocarcinoma ex goblet cell carcinoids of the appendix. We used next generation sequencing to determine mutations of potential pathogenetic and therapeutic significance in this rare group of tumors. Adequate DNA was successfully extracted in 34/46 cases and the final group included 18 goblet cell carcinoids and 16 adenocarcinoma ex goblet cell carcinoids. Illumina TruSeq™ was used for sequencing exons of a custom 282 gene panel using an Illumina HiSeq 2000. All cases had a minimum coverage depth of at least 50 reads. After filtering through the Exome Sequencing Project, the number of mutations per case ranged from 0–9 (mean:3). The mutational burden in adenocarcinoma ex goblet cell carcinoids was significantly higher than goblet cell carcinoids (mean 5 vs. 3; p < 0.05) but the spectrum of alterations overlapped between the two groups. The most frequent mutations included ARID1A (4/34), ARID2 (4/34), CDH1 (4/34), RHPN2 (4/34), and MLL2 (3/34). Some mutations typically seen in conventional colorectal adenocarcinomas were also identified but with much lower frequency (APC :4/34; KRAS :2/34). MLL2 and KRAS mutations were only seen in adenocarcinoma ex goblet cell carcinoids and TP53 mutations were limited to poorly differentiated adenocarcinoma ex goblet cell carcinoids (2/34). Copy number changes could be evaluated in 15/34 cases and showed low copy number gains in CDKN1B (6/15) and NFKBIA (6/15), among others. The overlapping molecular alterations suggest that goblet cell carcinoids and adenocarcinoma ex goblet cell carcinoids are best considered two grades of differentiation of the same tumor rather than two distinct histological types. Mutations in TP53, CDH1 and MLL2 mutations were predominantly present in the adenocarcinoma ex goblet cell carcinoid group consistent with transformation to a higher grade lesion. The unique mutational profile also offers an explanation for the poor chemosensitivity in these tumors and highlights the need for developing new targeted therapies.

JCES01.21 Molecular Profiling and Survival of Primary Pulmonary Neuroendocrine Carcinoma with Completely Resection

According to the 2015 World Health Organization classification of lung tumors, pulmonary large cell neuroendocrine carcinoma (PLCNC) is grouped with the small cell lung cancer (SCLC) and carcinoid as pulmonary neuroendocrine carcinoma (PNC) for the common features of neuroendocrine characteristics. Molecular profiles and prognosis of primary pulmonary neuroendocrine carcinoma (PNC) are not well investigated currently. We conducted present study to evaluate genomic abnormality and survivals in patients with primary PNC. Tumor samples of PNC after completely resection from Zhejiang Cancer Hospital were collected from 2008 to 2015. Nine driver genes including six mutation (EGFR, KRAS, NRAS, PIK3CA, BRAF, HER2) and three fusions (ALK, ROS1, RET) were evaluated by RT-PCR. Survival analysis was evaluated using the Kaplan-Meier method. Totally, 108 patients with pathologic confirmed PNC were enrolled. Samples included 52 PLCNC, 44 small cell lung cancer (SCLC) and 12 carcinoid. Twelve patients were found to harbor genomic aberrations (11.1%). The most frequent gene abnormality was PIK3CA (n=5, 4.6%), followed with EGFR (n=3, 2.8%), KRAS (n=2, n=1.9%), ALK (n=1, 0.9%), RET (n=1,0.9%). No ROS1, BRAF, NRAS and HER2 mutations were observed. The frequencies of gene aberrations in PLCNC, SCLC and carcinoid were 15.4%, 6.8% and 8.3%, respectively. Sixty-seven patients were with recurrence or metastasis after surgery, including 32 PLCNC, 33 of SCLC, and two of carcinoid (both were atypical carcinoid). Among the 32 patients with PLCNC, none received molecular targeted treatment, 28 received first-line chemotherapy, including 18 of etoposide/platinum regimen and 10 of other platinum-based treatment. The progression free survival in patients with etoposide/platinum regimen was longer than patients with non-etoposide/platinum treatment (4.8 vs. 3.4 months, P=0.019). Survival difference was observed among the PLCNC, SCLC and carcinoid group (37.0 vs. 34.0 vs. not reached, P=0.035), but no difference existed between the PLCNC and SCLC group (P=0.606). Common genomic abnormality is rare in PNC patients and most frequently observed in PLCNC. Patients with carcinoid had a superior survival than PLCNC and SCLC.

P1.04-024 Molecular Profiling and Survival of Primary Pulmonary Neuroendocrine Carcinoma with Completely Resection

According to the 2015 World Health Organization classification of lung tumors, pulmonary Large cell neuroendocrine carcinoma (PLCNC) is grouped with the small cell lung cancer (SCLC) and carcinoid as pulmonary neuroendocrine carcinoma (PNC) for the common features of neuroendocrine characteristics. Molecular profiles and prognosis of primary pulmonary neuroendocrine carcinoma (PNC) are not well investigated currently. We conducted present study to evaluate genomic abnormality and survivals in patients with primary PNC. Tumor samples of PNC after completely resection from Zhejiang Cancer Hospital were collected from 2008 to 2015. Nine driver genes including six mutation (EGFR, KRAS, NRAS, PIK3CA, BRAF, HER2) and three fusions (ALK, ROS1, RET) were evaluated by RT-PCR. Survival analysis was evaluated using the Kaplan-Meier method. Totally, 108 patients with pathologic confirmed PNC were enrolled. Samples included 52 PLCNC, 44 small cell lung cancer (SCLC) and 12 carcinoid. Twelve patients were found to harbor genomic aberrations (11.1%). The most frequent gene abnormality was PIK3CA (n=5,4.6%),followed with EGFR (n=3,2.8%), KRAS (n=2,n=1.9%), ALK (n=1,0.9%), RET (n=1,0.9%). No ROS1,BRAF,NRAS and HER2 mutations were observed. The frequencies of gene aberrations in PLCNC, SCLC and carcinoid were 15.4%,6.8% and 8.3%,respectively. Sixty-seven patients were with recurrence or metastasis after surgery, including 32 PLCNC, 33 of SCLC, and two of carcinoid (both were atypical carcinoid). Among the 32 patients with PLCNC, none received molecular targeted treatment,28 received first-line chemotherapy, including 18 of etoposide/platinum regimen and 10 of other platinum-based treatment. The progression free survival in patients with etoposide/platinum regimen was longer than patients with non-etoposide/platinum treatment (4.8 vs.3.4 months, P=0.019) . Survival difference was observed among the PLCNC,SCLC and carcinoid group (37.0 vs. 34.0 vs. not reached, P=0.035), but no difference existed between the PLCNC and SCLC group (P=0.606). Common genomic abnormality is rare in PNC patients and most frequently observed in PLCNC. Patients with carcinoid had a superior survival than PLCNC and SCLC.

Molecular Profiling and Survival of Completely Resected Primary Pulmonary Neuroendocrine Carcinoma

BackgroundCurrently, molecular profiles and prognosis of primary pulmonary neuroendocrine carcinoma (PNC) are poorly elucidated. The present study was designed to evaluate genomic abnormalities and survival in patients with primary PNC. MethodsCompletely resected PNC samples were collected from Zhejiang Cancer Hospital during the period of 2008 to 2015. Nine driver genes, including 6 mutations (EGFR, KRAS, NRAS, PIK3CA, BRAF, and HER2) and 3 fusions (ALK, ROS1, and RET), were evaluated by reverse transcription-polymerase chain reaction (RT-PCR). Survival analysis was conducted by the Kaplan-Meier method. ResultsA total of 108 patients with pathologically confirmed PNC were enrolled. The types were pulmonary large-cell neuroendocrine carcinoma (PLCNC, n = 52), small-cell lung cancer (SCLC, n = 44), and carcinoid (n = 12). Twelve patients (11.1%) harbored genomic aberrations. The most frequent gene abnormalities in decreasing order were PIK3CA (n = 5, 4.6%), EGFR (n = 3, 2.8%), KRAS (n = 2, 1.9%), ALK (n = 1, 0.9%), and RET (n = 1, 0.9%). No ROS1, BRAF, NRAS, or HER2 mutation was detected. The frequencies of gene aberrations were 15.4%, 6.8%, and 8.3% in PLCNC, SCLC, and carcinoid, respectively. Survival differences existed among PLCNC, SCLC, and carcinoid groups (37.0 vs. 34.0 vs. not reached, P = .035); however, no difference existed between PLCNC and SCLC groups (P = .606). ConclusionsGenomic abnormality is rare in patients with PNC and it is the most frequently observed in PLCNC.

Laryngeal Neuroendocrine Carcinomas: A Retrospective Study of 14 Cases

Laryngeal neuroendocrine carcinomas (LNECs) are rare and highly heterogeneous which present a wide spectrum of pathological and clinical manifestations. Fourteen patients with histologically demonstrated LNEC were collected and analyzed retrospectively. The 14 cases were classified into 3 subtypes: typical carcinoid in 2, atypical carcinoid in 5, and small cell neuroendocrine carcinoma in 7. The mean survival time of the 14 patients in this study was 112.5 months (95% CI, 81.5–143.6). Surgeries were performed for 2 patients of typical carcinoid, and they were alive with no evidence of recurrence after 24 and 47 months of follow-ups. Patients in the atypical carcinoid group were treated with surgeries and postoperative radiotherapy. After 58.4 months of follow-ups (range: 9–144), 2 patients showed no evidence of disease and 1 was lost to follow-up after 72 months. The other 2 patients died of other unrelated diseases. In the small cell neuroendocrine carcinoma group, a combination of chemotherapy and radiotherapy was applied. The mean survival time was 79.7 months (95% CI, 37.9–121.4), and the 5-year survival rate was 53.6%. In conclusion, the clinical behaviors, treatment protocols, and prognosis are different for each subtype of LNECs.

Thymic neuroendocrine tumors (paraganglioma and carcinoid tumors): a comparative immunohistochemical study of 46 cases.

Twenty-two paragangliomas from different anatomical sites and 24 thymic neuroendocrine carcinomas (carcinoid tumors) were analyzed for traditional and novel immunohistochemical markers. In the paraganglioma group, there were 8 men and 14 women between the ages of 23 and 79 years (mean, 46 years). Their symptoms depended on the location of the tumor and included neck swelling and Horner syndrome for neck tumors, whereas abdominal and chest pain was present in tumors of the abdomen and mediastinum, respectively. One patient had Carney triad. In the carcinoid group, the patients were 20 men and 4 women between the ages of 25 and 78 years (mean, 48 years). These patients were symptomatic with chest pain, shortness of breath, and dyspnea. One patient presented with multiple endocrine neoplasia syndrome. Complete surgical resection was accomplished in all patients. The 46 neuroendocrine tumors were evaluated for GATA-3, pancytokeratin, thryoid transcription factor 1 (TTF-1), napsin A, chromogranin A, and synaptophysin. All paragangliomas were universally positive for chromogranin A and synaptophysin, but negative for pancytokeratin, TTF-1, and napsin A. GATA-3 was expressed in 12 (55%) of 22 tumors. The thymic neuroendocrine carcinomas (carcinoid tumors) were universally positive for pancytokeratin, but negative for GATA-3 and napsin A. Chromogranin A and synaptophysin were expressed in 92% and 88% of cases, respectively, and TTF-1 in 4 (17%) of 24 cases. Based on these results, we recommend that the workup of neuroendocrine tumors should include not only the conventional neuroendocrine markers and pancytokeratin but also other markers such as GATA-3 and TTF-1 in order to arrive at a better interpretation.

FDG-PET Imaging in Patients With Pulmonary Carcinoid Tumor

This study aimed to assess the imaging findings in patients with pathologically proven carcinoid tumors and determine if SUV can help to differentiate typical from atypical (more aggressive) pulmonary carcinoid tumors. A retrospective review of patients with a biopsy-proven diagnosis of a pulmonary carcinoid tumor at our institution from 2002 to 2010 that had a preoperative PET scan was performed after institutional review board approval was obtained. PET results, including SUV uptake and location, were recorded as well as all data from pathology reports. Carcinoids were considered to be more aggressive if they showed pathological diagnosis consistent with atypical carcinoid, lymph node invasion, poor histological grade (poorly differentiated), or evidence of systemic metastases. Atypical carcinoid pathology consisted of focal necrosis or a higher mitotic index (2-10 per square millimeter) with features of nests, trabeculae, pleomorphic cells, or dense hyperchromasia. SUV uptake was then evaluated and compared between the typical and atypical carcinoid groups using nonparametric statistical methods. We identified 29 patients from 2002 to 2010 at our institution with a pathological diagnosis of pulmonary carcinoid. Twenty-three were histopathologically typical, and the other 6 showed atypia. Mean (SD) nodule size was 2.4 (1.3) cm in the typical group versus 5.0 (3.2) cm in the atypical group (P = 0.065). Mean (SD) SUV uptake in the typical carcinoid group was 2.7 (1.6) and in the atypical group the SUV was 8.1 (4.1) (P < 0.01). A cutoff SUV of 6 or greater is predictive of malignancy (odds ratio, 23.6; P < 0.01), as well as a nodule size of 3.5 cm or greater (odds ratio, 5.1; P = 0.024). Preoperative PET imaging result is frequently positive in carcinoid tumors, and the biological behavior correlates well with SUV; however, size is not as strong of a predictor of malignancy. Size of 3.5 cm or greater and SUV of 6 or greater have a predictive value of greater than 95% for malignant histology.

Chirurgische Behandlung von Lungenkarzinoiden – Zehnjahresergebnisse

Carcinoids are malignant neuro-endocrine tumours occurring in the bronchopulmonary location in about 25 %, and accounting for approximately 2 % of all pulmonary tumours. Our retrospective analysis included 27 patients, 14 men and 13 women, mean age 58.4 years, treated from 2000 to 2009 for carcinoids in bronchopulmonary locations. The tumour manifested clinically in 52 % of the cases, the most common symptom being cough; one tumour manifested as carcinoid syndrome. All patients underwent fibrobronchoscopy that was positive in 20 cases (74.1 %). Pre-surgery histological diagnoses were made in 13 patients (48.1 %). Chest CT scans were carried out in 26 patients, and the investigation failed to detect the expected pathological process in 2 of the patients. Octreoscans were carried out in 12 patients, and were successful in identifying a primary neuroendocrine tumour in 75 %. All patients in the sample underwent rad-ical surgical therapy; the most common surgical procedure was lobectomy (70.4 %). Perioperative morbidity and mortality were zero. Typical carcinoids were found in 20 cases while 7 cases were atypical carcinoids, 20 tumours were located centrally. 74 % of the tumours were consistent with stage I A disease. Mean follow-up period was 47 (range: 6-134) months. Local recurrences were observed in 2 patients (7.4 %), but the tumour disseminated in 4 patients (14.8 %). Two patients (7.4 %) died during the follow-up period. Overall five-year survival in the sample was 92.3 %, 90.9 % in the typical carcinoid group and 100 % for atypical carcinoids. We found a statistically significant association between disease-free interval and histological type of the tumour; the risk of progression was 8 times higher in -patients with atypical carcinoids compared to patients with typical carcinoids (Log-Rank-Test: p-value = 0.0049). Radical surgical treatment of bronchopulmonary carcinoids is the optimum therapeutic approach that results in the best results both regarding perioperative morbidity and mortality and regarding long-term survival of the patients.

090 Cardiac involvement in carcinoid disease: evidence of myocardial abnormalities in the absence of overt carcinoid heart disease: Abstract 090 Table 1

<h3>Introduction</h3> Cardiac abnormalities are seen in 15–70% of patients with carcinoid disease, typified by fibrosis of the right sided valves. Myocardial abnormalities in subjects without overt carcinoid heart disease have not been previously described. Tissue Doppler imaging has demonstrated early myocardial abnormalities in diabetic and hypertrophic cardiomyopathies (disease processes characterised by myocardial fibrosis). We investigated whether, myocardial fibrosis manifesting as early myocardial abnormalities, might be present in patients with carcinoid disease using tissue Doppler imaging. <h3>Method</h3> We prospectively recruited 59 patients with metastatic mid-gut carcinoid disease and 10 normal controls. Six patients with 2D echocardiographic evidence of overt carcinoid heart disease were excluded. Subjects underwent transthoracic echocardiography using a GE Vivid 7 or Vivid Q machine (2.5 MHz phased array transducer). Colour tissue Doppler loops (3 cardiac cycles) in each of the apical 4-chamber, 2-chamber and long axis imaging planes were acquired triggered to the ECG and saved digitally for subsequent off line analysis by a single experienced operator data (Echopac V9.01, GE, Horten, Norway). Regional myocardial velocity curves were derived using a 6x6 mm sample volume placed in the basal segment of each of the septal, lateral, anterior, inferior, posterior and antero-septal left ventricular walls. For the right ventricle the basal segment in the 4-chamber view was used. Strain and strain rate curves were generated from the same data set using a 5×12 mm sample volume placed in the basal segment. All sample volumes were manually tracked to correct for cardiac displacement. <h3>Results</h3> The age of control subjects and carcinoid disease patients was 54±13.2 and 62±11.4 years respectively, (p=ns). The proportion of males were 50% in control and 51% in the carcinoid disease groups respectively (p=ns). Characteristics of the carcinoid group included: 70% (n=37) with carcinoid syndrome, 58% (n=31) with liver metastases on cross sectional imaging and 58% (n=31) taking somatostatin analogues (treatment to reduce symptoms of carcinoid syndrome). Abstract 090 Table 1 shows the tissue Doppler results for the two groups. Left ventricular diastolic tissue velocities (E9 and A9) and peak early diastolic strain rate (PEDSR) were reduced in carcinoid patients compared to controls. There were no significant differences in the right ventricular data. <h3>Conclusion</h3> We have demonstrated abnormal diastolic myocardial characteristics in the left but not the right ventricle in patients without overt carcinoid heart disease. Our results support a hypothesis of sub-clinical myocardial fibrosis in these patients. Further investigation into the natural history of these changes, progression to valvular heart disease and their modification by treatment is warranted.

The Features and Accuracy of Endosonography (EUS) On Diagnosis of Gastroduodenal Carcinoid Tumors

Background: Gastroduodenal carcinoid tumors are rare, indolent neuroendocrine tumors, identified incidentally during endoscopy for upper GI symptoms although some present as a bleeder. EUS is a sensitive method in the detection of gastroduodenal carcinoid, but the interobserver agreement was poor for carcinoid in diagnosis of subepithelial tumors (SET) even to experienced endosonographers. Aims: To evaluate the features and diagnostic accuracy of high-frequency ultrasound probe (HFUP) on gastroduodenal carcinoid tumors from other SETs. Methods: From Jan.2002 to Jul.2008, there were 65 patients with polyp or SETs, identified as suspected gastric or duodenal carcinoids by HFUP (Olympus UM-2R/3R) from EUS database of one institute (CGMH). After excluding tumors from muscularis propira, papillary location, and without histologic diagnosis, a total of 49 cases (stomach 28, duodenum 21) were analyzed retrospectively on EUS images/video, blind to final clinopathological outcomes. The Fisher's exact and The Mann-Whitney U-test was also used to compare the categorical and continuous variables. Results: There were total 20 patients (M: F=12: 8), mean age 57.5 yrs (39-84 yrs) with carcinoid tumors (gastric 10, duodenal 10), confirmed by endoscopic biopsy or resection. The size of carcinoid tumor is 7.6 mm +/-3.7 mm (mean +/- SD) on stomach, and 7.2 mm +/- 2.4 mm on duodenum. The three common EUS features included: distinct margin (75%), homogeneous hypoechoic lesion (80%) and deep mucosa to submucosal location (70%). Applying these EUS features (at least 2 criteria) for diagnosis of carcinoid tumors on all 49 cases, the positive predictive value is 62% and the negative predictive value is 83%, accuracy 71%. Comparing the tumor location showed: gastric body, 90% on carcinoid group, 33% on other gastric SETs (P=0.005); Duodenal bulb, 100% on carcinoid group, 27% on other duodenal SETs (P<0.001). Pathology of the misdiagnosed 29 SETs included: 9 ectopic pancreas, 8 inflammations, 3 GIST, 2 lipomas, 2 cysts, 1 MALT lymphoma, 1 Brunner's gland adenoma, 1 polyp. 2 undiagnosed lesion. Their mean sizes are 10.9mm +/- 6.1mm (stomach) and 9.2 mm +/- 3.4mm (duodenum). Conclusions: Most of gastroduodenal carcinoid tumors are less than 10 mm in size, with well-defined margin and hypoechoic nature in deep mucosal and submucosal layers. Tumor locations (eg. proximal stomach and duodenal bulb) are good predictive factors on differential diagnosis in addition to EUS features.

The term "carcinoid" is a misnomer: the evidence based on local invasion

BackgroundSince Oberndorfer proposed the term "carcinoid" in 1907, over 100 years have passed. This attractive term was initially proposed for 6 cases of his own experience with 12 submucosal lesions in the small intestine.Oberndorfer summarized the characteristic features of these lesions as follows: (1) small in size and often multiple, (2) histologically undifferentiated with a suggestion of gland-formation, (3) well-defined without any tendency to infiltrate the surroundings, (4) no metastases, and (5) apparently slow-growing reaching no significant size with a seemingly harmless nature.ReviewThis article stresses the malignant nature of "carcinoid" on the basis of local invasion prior to metastases in the first two sessions, (1) with Oberndorfer's original diagram, and (2) with an experimental observation on extraglandular microcarcinoid in a form of "budding".Next, (3) a statistical comparison between a carcinoid group and a non-carcinoid ordinary carcinoma group is introduced on metastasis rates at an early stage with two prescribed factors of the depth of invasion restricted within the submucosa (sm-lesion) and a small tumor size category of 1 cm to 2 cm: the carcinoid group exhibited metastasis rates higher than those in the ordinary carcinoma group when calculated in the stomach and rectum.In the author's experience, "carcinoids" are malignant not only in the gastrointestinal tract but also in the other sites on the basis of local invasion.Lastly, (4) discussion on the terminology of "carcinoid" as a misnomer is carried out.Adequate terms referring to the entity of this malignant tumor group are discussed. One of the most adequate and brief terms for "carcinoid" that is included now in neuroendocrine tumor group would be "endocrinocarcinoma" as per the author's proposal, followed by NEC (neuroendocrinocarcinoma) or GEC (gut endocrinocarcinoma).ConclusionThe term "carcinoid" is a misnomer that can be confirmed on the basis of local invasion prior to metastases. "No metastases without local invasion" is not of a negligible importance.

Clinico-pathologic study of pulmonary carcinoid tumours – A retrospective analysis and review of literature

To determine the characteristic clinico-pathologic features of pulmonary carcinoid tumours in India. Retrospective analysis of the clinico-pathologic and radiologic data of patients with pulmonary carcinoid tumours from the department of Pulmonary Medicine of the Christian Medical College, a tertiary care teaching hospital in Southern India, over a study period of 3 years (2001-2004). There were 25 cases of pulmonary carcinoid tumours: typical 22 (88%) and atypical 3 (12%). The ratio of female to male was 0.8:1. There were 3 smokers (all of whom were males) in the typical carcinoid group and none in the atypical carcinoid group. Haemoptysis and cough were the commonest presenting symptoms. The common radiologic findings were post-obstructive pneumonitis or atelectasis, and mass lesion. Carcinoid syndrome was not present in any patient. Most of the tumours were central (n=23; 92%) and in the main bronchi (n=13; 52%). The most common site was the right main bronchus (n=9; 36%). Diagnosis was made by flexible bronchoscopy and bronchial biopsy in 23 patients (92%). The tumour bled significantly following biopsy in most patients; however, there was no mortality, and only 1 patient required blood transfusion. Surgical option was offered to most; 13 patients (52%) had pneumonectomy and 4 patients (16%) had lobectomy. A review of large series from the literature is also presented. The clinico-pathologic and radiologic features of pulmonary carcinoid tumours are presented. We report the first series of pulmonary carcinoid tumours from India.

LKB1 protein expression in neuroendocrine tumors of the lung

During a recent investigation of LKB1 gene abnormality in lung lesions, strong expression of LKB1 protein in normal neuroendocrine (NE) cells of the bronchial epithelium was found. Because LKB1 functions as a tumor suppressor gene, the question of whether alteration of LKB1 expression is related to the development of pulmonary NE tumors of various grades was investigated. LKB1 immunohistochemistry was examined in a total of 68 primary pulmonary NE tumors consisting of 30 specimens of small cell lung carcinoma (SCLC), 23 large cell neuroendocrine carcinomas (LCNEC), two atypical carcinoids, and 13 typical carcinoids. Loss or low expression (<20% immunoreactive cells) of LKB1 protein expression was more frequently observed in high-grade NE tumors (SCLC and LCNEC; 45/53, 84.9%) than in typical and atypical carcinoids (3/15; 20%). The difference in LKB1 immunoreactivity between the high-grade NE tumors and the carcinoid group was statistically significant (P < 0.0001). In conclusion, marked reduction of LKB1 expression in high-grade NE tumors of the lung suggests a possible role of LKB1 inactivation in its tumorigenesis. Although a few previous studies indicated rare genetic alterations of LKB1 in SCLC, further studies including analysis of other NE tumors and focusing on epigenetic abnormalities of LKB1 gene are warranted.

Octreotide acetate (LAR) dose effect on plasma octreotide levels: Impact on neuroendocrine tumor management

3177 Background: Octreotide acetate (LAR) is commonly used for symptom control in carcinoid tumors. At doses of 20 or 30 mg, up to 40% of carcinoid patients require additional aqueous octreotide several times a week for symptom control. 20–40% of patients receiving LAR are given monthly doses higher than the current maximum recommended 30 mg dose. This implies that patients may need higher octreotide blood levels than 20 or 30mg LAR doses can provide. In vitro, octreotide acetate binds to the sst 2 receptor with an affinity (Kd, 50% receptor saturation) of 1x10-9 M (≈1,000 pg /ml) but higher (≈10,000 pg/ml) concentrations of octreotide are required for saturation. Aim: The current study determined the plasma octreotide levels in patients receiving 20, 30 or 60 mg/month of LAR and calculated the effect of weight BSA and BMI on drug levels. Methods: Thirty- seven patients from the www.Yahoo.com carcinoid group sent height and weight information and sent plasma and serum samples for octreotide levels, determined by specific and sensitive RIA. Samples were drawn immediately before the patient’s next dose of LAR. Patients were on 20mg (n=8), 30mg (n=19) or 60 mg/month (n=10) of LAR. Results: Serum and plasma octreotide levels in individuals were essentially identical (p= ns, ANOVA). Mean ± SD plasma octreotide levels for patients receiving 20, 30 or 60 mg/month LAR doses were 2,518 ±1,020, 5,241± 3,004 and 10,926 ± 5,530 pg/ml respectively. No adverse events were reported with patients receiving 60 mg/month LAR dose. Weight, BSA and BMI were inversely related to plasma octreotide levels. Conclusions: The clinical availability of a plasma octreotide assay may be useful to guide octreotide therapy in patients with poorly controlled symptoms or those with progressive tumor growth. Circulating octreotide levels in patients receiving 20 or 30 mg/month LAR doses are often inadequate to saturate sst 2. These individuals may require LAR doses of 60 mg/month to completely saturate sst 2 and optimize symptom or tumor control. The decision to increase LAR doses should be made with the help of plasma octreotide level measurements. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis

Carcinoid Tumors of the Lung and Multimodal Therapy

To report our experience with bronchial carcinoids. From January 1990 to March 2003 we treated 42 such patients, 30 females and 12 males. All patients underwent preoperative total body computed tomography (CT), total body In-111 octreotide scintigraphy, and SPECT of the thorax, with evaluation of serum levels of CEA, CgA, NSE, and urinary 5-HIAA. Diagnosis was obtained in 28 patients with fibre-optic bronchoscopy and in 14 patients with CT-guided trans-thoracic needle biopsy. There were 26 typical and 16 atypical carcinoids. 30 lobectomies, 5 bilobectomies, 6 wedge resections, and 1 pneumonectomy were carried out. The 3-year and the 5-year survival rates in the typical and atypical carcinoid groups were 100 % and 96 % vs. 81 % and 68 %, respectively (p < 0.001). Long-term survival is based on histological completeness of surgical treatment. Octreotide scintigraphy and SPECT document N (1) and N (2) precisely.