High-grade Neuroendocrine Tumors Research Articles

The Lung Cancer Surgical Study Group of the Japan Clinical Oncology Group: past activities, current status and future direction.

The Lung Cancer Surgical Study Group of the Japan Clinical Oncology Group was organized in 1986. Initially, 26 collaborative institutions participated. In the early period, the Lung Cancer Surgical Study Group focused on combined modality therapies and conducted nine trials, including JCOG9101: adjuvant chemotherapy for resected small-cell lung cancer, and JCOG9806: induction chemoradiotherapy followed by surgery for superior sulcus tumor, which greatly impacted the treatment strategies for some special kinds of lung cancer. Since the 2000s, the Lung Cancer Surgical Study Group has defined radiologically noninvasive adenocarcinoma: JCOG0201 and investigated adequate modes of surgical resection for small-sized non-small cell lung cancer: JCOG0802, JCOG0804 and JCOG1211. The accrual of these trials is now complete and we are waiting for the maturation of follow-up data. In addition, two adjuvant trials have been conducted: JCOG0707; a Phase III study of adjuvant chemotherapy for resected pathological stage I (T1 > 2 cm) non-small cell lung cancer, and JCOG1205; a Phase III study of adjuvant chemotherapy for completely resected pulmonary high-grade neuroendocrine tumor. The accrual of JCOG0707 is complete and we are waiting for the maturation of follow-up data. At present, 44 institutions are active members of the Lung Cancer Surgical Study Group. In addition to thoracic surgeons, medical oncologists, pathologists and radiotherapists are participating in the Lung Cancer Surgical Study Group. The Lung Cancer Surgical Study Group continues to conduct various clinical trials in an effort to improve survival in patients with lung cancer. In this review, we provide an overview of the past 30 years, as well as the present status and future direction of the Lung Cancer Surgical Study Group.

High-grade neuroendocrine tumours of the oesophagus: a single centre experience

High-grade neuroendocrine tumours of the oesophagus: a single centre experience

Small Cell Lung Cancer.

Small cell lung cancer (SCLC) is a high-grade neuroendocrine tumor characterized by rapid growth, early metastatic spread, and initial responsiveness to therapy. Although the incidence of SCLC is declining, it remains one of the common causes of cancer-related mortality. Initial evaluation of patients with SCLC should focus on determining the extent of disease and the ability of the patient to tolerate specific therapy. Positron emission tomography (PET) can improve the accuracy of staging and treatment planning in many patients. Limited-stage (LS) SCLC is a potentially curable disease with long-term survival of 20 to 25% when treated with platinum-based chemotherapy plus concurrent thoracic radiation. Hyperfractionated (twice daily) thoracic radiation and prophylactic cranial irradiation (PCI) may improve survival in selected patients with LS-SCLC. For patients with extensive-stage (ES) SCLC, combination chemotherapy prolongs survival and improves quality of life, but long-term survival is rare. The use of PCI and sequential thoracic radiation has been reported to improve survival in selected patients with ES-SCLC. Many chemotherapeutic drugs have activity in SCLC, but little progress has been made in the systemic treatment of SCLC in almost three decades. Although many potential molecular targets have been identified in the preclinical studies of SCLC, molecularly targeted therapy has yet to demonstrate consistent clinical activity. Nevertheless, future advances in SCLC will depend on the development of rational therapeutic strategies which target the molecular mechanisms that drive cellular proliferation, survival, and immunological avoidance.

A Practical Approach to the Classification of WHO Grade 3 (G3) Well-differentiated Neuroendocrine Tumor (WD-NET) and Poorly Differentiated Neuroendocrine Carcinoma (PD-NEC) of the Pancreas.

High-grade neuroendocrine neoplasms (World Health Organization [WHO] G3) of the pancreas include both well-differentiated neuroendocrine tumor (WD-NET) and poorly differentiated neuroendocrine carcinoma (PD-NEC). According to the WHO classification scheme, the diagnosis of this group of tumors is based on both the histopathology of the tumor and the assessment of proliferation fraction. However, the former can be challenging due to the lack of well-defined histologic criteria, and the latter alone (ie, >20 mitoses/10 high-power fields or Ki67>20%) may not sufficiently distinguish WD-NETs from PD-NECs. Given the considerable differences in treatment strategies and clinical outcome, additional practical modalities are required to facilitate the accurate diagnosis of high-grade pancreatic neuroendocrine neoplasms. We examined 33 cases of WHO G3 neuroendocrine neoplasms of the pancreas and attempted to classify them into WD-NET, small cell PD-NEC (PD-NEC-SCC), and large cell PD-NEC (PD-NEC-LCC) or to designate them as "ambiguous" when an uncertain diagnosis was rendered by any of the observers or there was any disagreement in classification among the 3 observers. To simplify the interpretation, both PD-NEC-SCC and PD-NEC-LCC were considered together as PD-NECs in the final analysis. The initial approach was to assess microscopically a single morphologically challenging hematoxylin and eosin section from each case without the knowledge of Ki67 values, performed independently by 3 pathologists to assess the degree of diagnostic concordance, and then evaluate immunohistochemical staining for surrogate biomarkers of known genotypes of WD-NET and PD-NEC, respectively, and, lastly, complete a clinicopathologic review to establish a final definitive classification. Loss of DAXX or ATRX protein expression defined WD-NET, and abnormal p53, Rb, SMAD4 expression signified PD-NEC. When the chosen section displayed an element of WD histopathology, or other tumor sections contained WHO G1/G2 components, or there had been a prior established diagnosis of a primary WD-NET, the final diagnosis was rendered as a WD-NET with high-grade (G3) progression. If a component of conventional adenocarcinoma was present (in slides not seen in the initial review), the diagnosis was established as a combined adenocarcinoma and PD-NEC. All 3 pathologists agreed on the morphologic classification of 33% of the cases (6 WD-NET, 3 PD-NEC-SCC, and 2 PD-NEC-LCC), were conflicted on 2 cases between PD-NEC-SCC and PD-NEC-LCC, and disagreed or were uncertain on the classification for the remaining 20 cases (61%), which were therefore categorized as ambiguous. In the group of cases in which all pathologists agreed on the classification, the 6 WD-NET cases had either loss of DAXX or ATRX or had evidence of a WD-NET based on additional or prior pathology slides. The 7 PD-NEC cases had abnormal expression of p53, Rb, and/or SMAD4 or a coexisting adenocarcinoma. In the ambiguous group (n=20), 14 cases were established as WD-NETs, based upon loss of DAXX or ATRX in 7 cases and additional pathology evidence of high-grade progression from WD-NET in the other 7 cases; 5 cases were established as PD-NEC based upon abnormal expression of p53, Rb, and/or SMAD4; 1 case remained undetermined with normal expression of all markers and no evidence of entity-defining histologic findings in other slides. On the basis of the final pathologic classifications, the disease-specific survival was 75 and 11 months for the WD-NET and PD-NEC groups, respectively. Thus, we conclude that morphologic diagnosis of high-grade pancreatic neuroendocrine neoplasms is challenging, especially when limited pathologic materials are available, and necessitates better defined criteria. The analysis of both additional sections and prior material, along with an immunohistochemical evaluation, can facilitate accurate diagnosis in the majority of cases and guide the appropriate clinical management and prognosis.

Localized high-grade gastroenteropancreatic neuroendocrine tumors: Defining prognostic and therapeutic factors for a disease of increasing clinical significance

BackgroundDue to the limited sample size in the existing series, the natural history and management of high-grade gastroenteropancreatic neuroendocrine tumors (GEP-NET) is poorly understood. In order to better understand high-grade GEP-NET, a large cohort study was undertaken. ObjectiveTo determine the prognostic factors associated with high-grade GEP-NET. MethodsPatients diagnosed with non-metastatic high-grade GEP-NET from 1988 to 2010 were identified in SEER. ResultsIncidence of high-grade GEP-NETs increased from 0.03 to 0.19/100,000 over the study period. The median age was 65 years, and the majority of the patients were white and females. The most common primary site was colorectal, and the most frequent T classification was T3. Surgical resection was performed in 89% of patients that varied by site (p < 0.0001). Nodal involvement was frequent and varied by site (p = 0.0002). The 5-year disease-specific survival was 63.3% and was the greatest for small bowel (p = 0.0003). Survival was associated with age, node status and surgery (p < 0.05). On multivariate analysis, the node status, surgery, and site continued to be associated with survival (p < 0.05); however, age (p = 0.08) no longer influenced the patient's survival. ConclusionHigh-grade GEP-NETs are neoplasms with exponentially increasing in incidence. Tumor location and nodal status are predictors of survival. Surgery is associated with a survival advantage and could be considered for localized disease.

Prise en charge thérapeutique des tumeurs neuroendocrines peu différenciées pulmonaires et des carcinomes neuroendocrines digestifs

Poorly differentiated neuroendocrine tumors are rare but their incidence is rising. High-grade neuroendocrine lung tumors, including small-cell lung cancer, are part of this group. Outside of the lung, they most often arise within the gastrointestinal tract (oesophagus, guts and pancreas) and are called neuroendocrine carcinomas. Due to their rarity, very little is known about neuroendocrine carcinomas of the pancreas and the gastrointestinal tract and few studies have been done. Therefore, most therapeutic recommendations are issued from studies on small-cell lung cancers. Histological scores have grown more accurate these past few years: poorly differentiated neuroendocrine tumors regroup various entities such as small-cells, large-cells and mix tumors, which seem to have different prognosis. They are diagnosed at a metastatic state in more than 50% of cases. In localised disease, surgery is performed on selected patients. Adjuvant chemotherapy is administered in poorly differentiated neuroendocrine tumors of the lung and is an option in neuroendocrine carcinomas, without proof of efficacy. If not operable, radiochemotherapy is done for tumors of the lung, rectum, and eosophagus. If the disease is diagnosed at a metastatic state, chemotherapy is administered with a combination of platin salts (cisplatin or carboplatin) and etoposide. In poorly differentiated neuroendocrine tumors of the lung, prophylactic cranial irradiation is performed in localized disease if there is a good response to chemotherapy. Even if these therapies have improved the overall survival, no improvement has been made during the past four decades and the prognosis remains low.

ASCL1 and NEUROD1 Reveal Heterogeneity in Pulmonary Neuroendocrine Tumors and Regulate Distinct Genetic Programs

Small cell lung carcinoma (SCLC) is a high-grade pulmonary neuroendocrine tumor. The transcription factors ASCL1 and NEUROD1 play crucial roles in promoting malignant behavior and survival of human SCLC cell lines. Here, we find that ASCL1 and NEUROD1 identify heterogeneity in SCLC, bind distinct genomic loci, and regulate mostly distinct genes. ASCL1, but not NEUROD1, is present in mouse pulmonary neuroendocrine cells, and only ASCL1 is required invivo for tumor formation in mouse models of SCLC. ASCL1 targets oncogenic genes including MYCL1, RET, SOX2, and NFIB while NEUROD1 targets MYC. ASCL1 and NEUROD1 regulate different genes that commonly contribute to neuronal function. ASCL1 also regulates multiple genes in the NOTCH pathway including DLL3. Together, ASCL1 and NEUROD1 distinguish heterogeneity in SCLC with distinct genomic landscapes and distinct gene expression programs.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

Grading of neuroendocrine tumors

The current WHO classification of neuroendocrine tumors (NET) differentiates between typical carcinoids (low grade NET), atypical carcinoids (intermediate grade NET) and small cell and large cell carcinomas (high grade NET) according to the prognosis. Neuroendocrine neoplasms (NEN) of the gastrointestinal tract and the pancreas are graded in an identical way. Together with the TNM system this enables a preoperative estimation of the prognosis in biopsies and fine needle aspirates. Well-differentiated tumors are graded into G1 tumors by the number of mitoses, <2 per 10 high-power fields (HPF) and the Ki-67 (index <3 %) and G2 tumors (2-20 mitoses/10 HPF, Ki-67 3-20 %). Discrepancies between the number of mitoses and the Ki-67 index are not uncommon and in these cases the higher value of the two should be applied. The more differentiated tumors of the G3 type have to be differentiated from undifferentiated carcinomas of the small cell type and large cell type with a much poorer prognosis. Prognosis relevant grading of thyroid cancers is achieved by special subtyping so that the G1-G3 system is not applicable. The rare cancers of the parathyroid gland and of the pituitary gland are not graded. Adrenal tumors also have no grading system. The prognosis is dependent on the Ki-67 index and with some reservations on the established scoring systems.

Transcription Factor NFIB Is a Driver of Small Cell Lung Cancer Progression in Mice and Marks Metastatic Disease in Patients

SummarySmall cell lung cancer (SCLC) is an aggressive neuroendocrine tumor, and no effective treatment is available to date. Mouse models of SCLC based on the inactivation of Rb1 and Trp53 show frequent amplifications of the Nfib and Mycl genes. Here, we report that, although overexpression of either transcription factor accelerates tumor growth, NFIB specifically promotes metastatic spread. High NFIB levels are associated with expansive growth of a poorly differentiated and almost exclusively E-cadherin (CDH1)-negative invasive tumor cell population. Consistent with the mouse data, we find that NFIB is overexpressed in almost all tested human metastatic high-grade neuroendocrine lung tumors, warranting further assessment of NFIB as a tumor progression marker in a clinical setting.

Expression of Somatostatin Receptor Type 2A and PTEN in Neuroendocrine Neoplasms Is Associated with Tumor Grade but Not with Site of Origin.

Neuroendocrine neoplasms (NENs) are derived from endocrine cells in various organs and share common morphological features. This study aimed to clarify whether NENs of different organs are comparable at the molecular pathologic level. We retrospectively collected 99 cases of NENs from gastro-entero-pancreatic, lung, and other organs and reclassified these according to identical criteria. Grade, site, and molecular expression profile including NE markers, Ki-67, p53, somatostatin receptor type 2A (SSTR2A), and phosphatase and tensin homolog (PTEN) were compared. PTEN immunoreactivity was also compared with genomic copy number by fluorescence in situ hybridization (FISH) and droplet digital polymerase chain reaction (ddPCR). No significant differences were observed in the immunoreactivities of NE markers, p53, SSTR2A, or PTEN expression in NENs between the different organ sites. PTEN and p53 functional inactivation along with the loss of membranous SSTR2A expression appeared to be commonly involved in high-grade NEN. FISH results were significantly correlated with the level of PTEN immunoreactivity and with the findings of ddPCR analyses. The demonstration that these tumors are comparable at the molecular level will likely contribute to the broadening of therapeutic options such as the use of somatostatin analogues and mTOR inhibitors against NENs regardless of the affected organ, whereas molecular characterization of tumor grade will be useful for determining treatment strategy.

Stage III pulmonary large cell neuroendocrine carcinoma (LNEC).

8536Background: Pulmonary large cell neuroendocrine carcinoma (LNEC) is an uncommon lung cancer subtype, initially described in 1991 and classified as a high grade neuroendocrine tumor. Since the d...

Large Cell Neuroendocrine Carcinoma of the Head and Neck: A Clinicopathologic Series of 10 Cases With an Emphasis on HPV Status.

Large cell neuroendocrine carcinoma (LCNEC) is a high-grade neuroendocrine neoplasm first described in the lung and subsequently well documented in many other anatomic sites. It has only recently been recognized that LCNEC can also occasionally arise in the head and neck. The role of human papillomavirus (HPV), which is associated with some small cell carcinomas of the head and neck, has not been investigated for LCNEC. We sought to further characterize the histologic, immunophenotypic, and clinical features of LCNEC and also investigate the role of HPV in this newly described group of tumors. The surgical pathology archives of 2 large academic institutions were searched for cases of LCNEC arising in the head and neck. p16 immunohistochemistry and HPV in situ hybridization were performed, and clinical information was obtained from electronic medical records. Ten cases of head and neck LCNEC were identified. The tumors arose in 6 men and 4 women ranging in age from 14 to 70 years (median, 63.5 y). The primary tumor sites were the oropharynx (n=4), the sinonasal tract (n=3), and the larynx (n=3). The LCNECs consisted of nests and trabeculae of medium-large cells with abundant cytoplasm, coarse chromatin, and prominent nucleoli with very high mitotic rates. The tumor nests were often associated with necrosis, peripheral palisading, and rosette formations. The LCNECs were positive for pan-cytokeratin and at least 1 neuroendocrine marker (most often synaptophysin) and were largely negative for p63 (focal staining in 2/10) and CK5/6 (staining in 1/10). The LCNECs demonstrated aggressive clinical behavior: 8 of 10 presented with advanced disease, 5 of 10 died, with 4 more living but with persistent tumor. Three of 10 LCNECs were HPV-related (HPV-LCNEC); they arose in the oropharynx (n=2) and sinonasal tract (n=1). The HPV-LCNECs did not differ from the HPV-negative tumors in histologic appearance or behavior: 2 patients with HPV-LCNEC have died because of their disease and 1 remains alive but with widespread metastases. LCNEC is a rare but distinct form of head and neck carcinoma that exhibits aggressive clinical behavior. A subset of oropharyngeal and sinonasal LCNEC is HPV related, but the presence of HPV may not impart a more favorable prognosis. Because of its aggressive behavior, LCNEC should be distinguished from moderately differentiated neuroendocrine carcinoma and squamous cell carcinoma. The morphology of LCNEC overlaps considerably with the nonkeratinizing appearance of HPV-related squamous cell carcinoma, and as a result a high index of suspicion is needed to identify LCNEC. Immunohistochemical studies for synaptophysin and p63 are helpful tools for making this distinction.

Use of alkylating chemotherapy in high-grade neuroendocrine tumours: Evaluation of real-world data.

78 Background: High-grade neuroendocrine tumours (NETs) are believed to have activity to certain alkylating agents, although data are scant. These regimens include streptozotocin (STZ) (used in combination with doxorubicin or 5-fluorouracil) and dacarbazine (DTIC). Current series report variable responses between 6 – 69%. Our objective was to evaluate our real world data to better understand treatment decision-making and clinical outcomes with alkylating agents in advanced high-grade NETs. Methods: We reviewed the medical records of 36 patients with metastatic NETs who received alkylating systemic chemotherapy with either a DTIC regimen (n = 15) or STZ based regimen (n = 21). Patient cases were evaluated for age, time to treatment failure (TTF), time to progression (TTP Results: Among 36 patients treated, the predominant primary NET was pancreas (n = 28) with a median age at treatment of 61.9 years. Observed TTF was similar with both regimens (STZ: 3 months and DTIC: 4 months), however there was prolonged TTP of 11 months with STZ vs. 5.3 months with DTIC (p = 0.047). There was no significant difference in OS with a mean of 48.7 months (DTIC) vs. 47.6 months (STZ) (p = 0.47). Baseline progression at treatment initiation was higher in DTIC at 77% versus 57% in STZ. The predominant cause of treatment discontinuation in both groups was progressive disease; DTIC (71%) versus STZ (42%). Toxicity resulted in treatment discontinuation in 19% for STZ vs 7% for DTIC. Other causes of treatment cessation were completion of the intended treatment. Conclusions: In the groups evaluated, STZ containing regimens demonstrated prolonged PFS in comparison to DTIC, but there was no difference in OS between the two groups. Additionally, despite STZ appearing to have an increased toxicity rate, the rate of cessation between the groups was similar. This real world evaluation suggests similar efficacy with improved tolerability of DTIC based chemotherapy as a potential alternative to other alkylating agents.

A Single-Institution Analysis of the Surgical Management of Pulmonary Large Cell Neuroendocrine Carcinomas

Large cell neuroendocrine carcinoma (LCNEC) is an uncommon tumor of the lung and represents approximately 3% of all lung cancers. LCNEC displays biological behaviors resembling those of small cell lung carcinomas and features of high-grade neuroendocrine tumors. LCNEC of the lung are considered aggressive. Reported prognoses are heterogeneous, and the optimum treatment remains undefined. We conducted a retrospective study of all patients who were treated for LCNEC in our Department of Thoracic Surgery between May 2005 and December 2013. Primary outcomes of interest were patient survival and prognostic factors. Kaplan-Meier analysis was performed to determine the significant predictors of overall survival. Within the prescribed period, 127 patients were treated for LCNEC, and 125 underwent surgical resection with curative intent. Induction chemotherapy or radiochemotherapy was given to 9 patients, and 63patients received postoperative chemotherapy. Complete resection was achieved in 99.2%. The overall 1-, 3- and 5-year survival rates were 83.7%, 63.2%, and53.8% of all patients, and the 5-year survival in patients at stages I, II, and III was 64.5%, 40%, and 29.7%. There was a significant survival difference at 5years between pT1/2 (58.5%) and pT3 tumors (22.4%;p= 0.043) and for patients with lymphatic involvement (L0 vs L1, p= 0.001; pN1 or pN2 vs pN0, p= 0.04). Surgical treatment can achieve satisfactory results in early tumor stages, which are comparable with other non-small cell lung cancers, with a low perioperative mortality rate.

Well-Differentiated Neuroendocrine Tumors with a Morphologically Apparent High-Grade Component: A Pathway Distinct from Poorly Differentiated Neuroendocrine Carcinomas.

Most well-differentiated neuroendocrine tumors (WD-NET) of the enteropancreatic system are low-intermediate grade (G1, G2). Elevated proliferation demonstrated by either a brisk mitotic rate (>20/10 high power fields) or high Ki-67 index (>20%) defines a group of aggressive neoplasms designated as high-grade (G3) neuroendocrine carcinoma (NEC). High-grade NEC is equated with poorly differentiated NEC (PD-NEC) and is associated with a dismal outcome. Progression of WD-NETs to a high-grade neuroendocrine neoplasm very rarely occurs and their clinicopathologic and molecular features need to be characterized. We investigated 31 cases of WD-NETs with evidence of a component of a high-grade neoplasm. The primary sites included pancreas, small bowel, bile duct, and rectum. Histopathology of the cases was retrospectively reviewed and selected IHC and gene mutation analyses performed. The high-grade component occurred either within the primary tumor (48%) or at metastatic sites (52%). The clinical presentation, radiographic features, biomarkers, and the genotype of these WD-NETs with high-grade component remained akin to those of G1-G2 WD-NETs. The median disease-specific survival (DSS) was 55 months (16-119 months), and 2-year and 5-year DSS was 88% and 49%, respectively-significantly better than that of a comparison group of true PD-NEC (DSS 11 months). Mixed grades can occur in WD-NETs, which are distinguished from PD-NECs by their unique phenotype, proliferative indices, and the genotype. This phenomenon of mixed grade in WD-NET provides additional evidence to the growing recognition that the current WHO G3 category contains both WD-NETs as well as PD-NECs.

Intraindividual Tumor Heterogeneity in Neuroendocrine Tumors Revealed with 18F-FDG and 68Ga-DOTA-TATE PET/CT

68Ga-DOTA-TATE PET/CT is widely used in functional imaging of neuroendocrine tumors (NETs) and is superior to conventional somatostatin receptor scintigraphy (SRS), which is recommended for low grade NETs according to NANETS/ENETS guidelines. On the contrary 18F-FDG PET is suggested in patients with high grade NETs or when SRS is negative. However, tumor heterogeneity is a common finding along with NETs and causes differential expression of somatostatin receptor (sstr) and various FDG metabolisms. Here, we present a case where tumor heterogeneity is revealed with combined use of 18F-FDG PET/CT and 68Ga-DOTA-TATE PET/CT in the same patient and how does it influence clinical decision-making Conclusion: We here present the first report of FFF-VMAT achieving a comparable plan quality with less delivery time to that of FF-VMAT and HT in head and neck cancer. FFF-VMAT is a highly efficient and feasible option for the treatment of head and neck cancer in clinical practice.

化学放射線療法が奏功した喉頭神経内分泌癌（NEC/G3）例

Neuroendocrine tumors is a generic term for tumors arising from neuroendocrine cells. In the present study, we encountered a patient with a Grade 3 laryngeal neuroendocrine carcinoma with liver and bone metastases who was successfully treated with a small cell lung cancer (SCLC) regimen. We report herin on this case with a review of the diagnosis, classification, and management of neuroendocrine tumors. Classically, neuroendocrine tumors have their own classification by the organs involved, and in some previous studies, the histopathology has been inconsistent with the clinical course. Then, in 2010, the WHO advocated a new pathological classification, whereby neuroendocrine tumors were to be stratified into 3 groups: Grade (G) 1, G2 and G3 based on the mitotic count and Ki67 index. A previously reported series of high-grade neuroendocrine tumors were equivalent to G3, and some reports have described that SCLC treatment was given. In our case, the patient was also treated as an SCLC patient, and the response of the primary lesion was evaluated as complete response (CR). Currently, 18 months have elapsed since the completion of therapy, the patient enjoys satisfactory levels of QOL without recurrence. We believe that this classification would be of assistance in discussion about prediction of the prognosis and statistical treatment.

Surgical management of large-cell neuroendocrinelung carcinoma: an analysis of 25 cases.

Large-cell neuroendocrine carcinoma (LCNEC) of the lung is a relatively uncommon and aggressive subset of pulmonary neuroendocrine tumors, which include typical and atypical carcinoid, and small-cell lung cancer. LCNEC of the lung accounts for no more than 1% of all lung cancers. LCNECs show features of high-grade neuroendocrine tumors and patients with LCNEC have a very poor prognosis. Twenty-five patients (22 males and 3 females; mean years 60.7; range 48 to 77 years) who underwent pulmonary resection for large-cell neuroendocrine carcinoma between January 2004 and December 2014 were investigated retrospectively. Type of surgery, pathologic TNM stage, adjuvant chemotherapy, time of recurrence, site of recurrence, response to treatment, and long-term results were evaluated. The longest patient follow-up period was 83 months. One-, two-, and three-year survival rates of these patients were, respectively, 80.95%, 76.47%, and 50%. Complete surgical resection is the treatment of choice for early-stage LCNEC and chemotherapy after radical surgical treatment improves survival. Follow-up periods after surgery adjuvant chemotherapy will prevent recurrence and patients may survive for many years if complete surgical resection and adjuvant chemotherapy are possible.

Rectal Small Cell Type Neuroendocrine Tumor: A Rare Mimicker of Internal Hemorrhoids

Introduction: Neuroendocrine cells secrete hormones in response to neural or chemical stimuli and are present throughout the body. They contain secretory granules in the cytoplasm, which stain positive for chromongranin A (CgA), synaptophysin, neuron-specific enolase and CD-56. The presenting symptoms of neuroendocrine tumor (NET) are related to the hormone secreted. Case presentation: 81-year-old man presented with dizziness, constipation and intermittent hematochezia of 1.5 years duration. A colonoscopy only revealed sigmoid diverticulosis. A rectal exam was felt to demonstrate large internal hemorrhoids, which bled with light touch. A repeat colonoscopy showed active bleeding in rectum which was not amenable to endoscopic control. An urgent exam under anesthesia (EUA) revealed a 8x3x3cm friable bleeding mass in the rectum, which had benn previously mistaken for hemorrhoids. Biopsies revealed it to be a high-grade NET. CT, PET scan and bone scan did not show any evidence of metastasis. The patient initially declined surgery and received chemotherapy with cisplatin/etoposide. He subsequently developed a perineal abscess leading to a recto-cutaneous fistula necessitating debridement and diverting colostomy. He died 6 months later from infectious sequelae. Discussion: The World Health Organization in 2010, classified NETs into three grades depending on mitotic and Ki-67 indices: G1 = low grade (well differentiated with 2/hpf); intermediate grade (welldiff erentiated with 2-20/hpf mitotic index and 3-20% Ki-67 index) and G3 = high grade (poorly differentiated with >20/hpf mitotic index and >20% Ki-67 index). The majority of GI tract NETs are G1 which are commonly referred to as carcinoid tumors. They have a low tendency for metastasis and an overall favorable prognosis. NET-G3 are very rare comprising only 0.1-3.9% of all colorectal malignancies and have a high potential for metastasis as well as a dismal prognosis. They present as a mass with constipation, pain, hematochezia or obstruction, but rarely have accompanying carcinoid syndrome symptoms. These patients may have elevated 24-hour urinary 5-HIAA and serum CgA. A biopsy is warranted for definitive diagnosis and tumor grading which then determines appropriate management strategy. G1/G2 tumors can be surgically resected but G3 tumors respond better to systemic chemotherapy. NETs must be considered in the differential diagnosis when evaluating patients with hematochezia.