Trends in Prognostic Factors for Neuroendocrine Lung Tumors

Neuroendocrine tumors of the lung represent a broad spectrum of morphologic types that share specific morphologic, immunohistochemical, ultrastructural, and molecular characteristics. The classification of neuroendocrine lung tumors has changed over the last decades and currently four categories are distinguished: typical carcinoid tumor, atypical carcinoid tumor, large cell neuroendocrine carcinoma and small cell carcinoma. Neuroendocrine tumors of the lung comprise approximately 20% of all primary lung cancers. Among them, the most frequent is small cell carcinoma (13-17%). Because of differences in clinical behavior, therapy, and prognosis, a reliable histological diagnosis, as well as clinical and pathological staging system are essential for an appropriate medical proceedings. The most effective treatment of bronchial carcinoids and large cell neuroendocrine carcinoma in an early stage is complete surgical resection, whereas chemotherapy remains the primary treatment for small cell carcinoma. All carcinoids are malignant tumors with the potential to metastasize. The majority of patients with pulmonary carcinoid have an excellent survival, even if they present with lymph node metastases. Large cell neuroendocrine and small cell carcinoma progress rapidly and are generally widespread at the moment of diagnosis. Their overall prognosis is poor. Increased knowledge about pulmonary neuroendocrine tumors biology and the genetic characteristics, imply that carcinoid tumors appear to have a different etiology and pathogenesis than large cell neuroendocrine and small cell carcinoma. In practice, it could be easiest to conceptualize this group of pulmonary tumors as a spectrum of malignancy ranging from the low grade typical carcinoid to the highly malignant large cell neuroendocrine and small cell carcinoma. Typical carcinoid tumors associated with a fairly benign behavior should be classified as low-grade neuroendocrine tumor/carcinoma (G1) and atypical carcinoid tumors as intermediate-grade tumor/carcinoma (G2). Whereas, large cell neuroendocrine and small cell carcinoma should be grouped together under the designation of high-grade neuroendocrine tumor/carcinoma (G3).

Typical and Atypical Pulmonary Carcinoids: Outcome in Patients Presenting With Regional Lymph Node Involvement

The spectrum of pulmonary neuroendocrine tumors is very wide, encompassing several diagnostic entities. Their classification is quite complex, as is the terminology. Some neoplasms are encountered more frequently than are others. Not all are identified in cytologic specimens, especially the preneoplastic neuroendocrine lesions that are included in the most recent World Health Organization (WHO) and International Association for the Study of Lung Cancer (IASLC) classification of the lung tumors. This chapter will focus only on neoplasms that are more frequently encountered, including: (1) typical carcinoid tumor; (2) atypical carcinoid tumor; (3) large cell neuroendocrine carcinoma; and (4) small cell (undifferentiated) carcinoma. These four neoplasms present a spectrum of morphologic features ranging from benign-appearing uniform cellular patterns to highly anaplastic ones. Their biologic behavior likewise ranges from that of a benign protracted course in typical carcinoid to an aggressive one with a fatal outcome, as seen in large cell neuroendocrine and small cell carcinomas. Despite the differences, pulmonary neuroendocrine tumors share several features: namely, their origin (Kulchitsky cells), certain morphologic features (e.g., neuroendocrine growth patterns), and positive reactivity to most neuroendocrine markers. They all ultrastructurally exhibit dense core neurosecretory granules, and some are associated with ectopic hormone production.

A century ago, it was a signiWcant accomplishment to distinguish between laryngeal epithelial malignancies (carcinomas), mesenchymal malignancies (sarcomas) and hematopoietic malignancies (lymphomas). A great deal has changed since that time; while the vast majority of laryngeal malignancies will prove to be carcinomas, the family of carcinomas has grown to encompass an impressively large array of diVerent pathologically deWned entities. One subset of epithelial malignancies of the larynx that can give rise to some confusion is one of the more uncommon subsets, the group of neuroendocrine carcinomas of the larynx. To be clear, this group—to be discussed here— comprises the epithelial-derived neuroendocrine tumors, and so excludes the neurally derived tumors (such as paraganglioma, neuroblastoma, Ewing’s sarcoma, and primitive neuroectodermal tumor). As such, this group of epithelial neuroendocrine carcinomas of the larynx encompasses four discrete pathologically deWned entities: carcinoid tumor, atypical carcinoid tumor, small cell neuroendocrine carcinoma, and large cell neuroendocrine carcinoma (as well, combined tumors—such as atypical carcinoid tumors, small cell and large cell neuroendocrine carcinomas—may be encountered, but are not further discussed here in light of their extreme rarity) [1–4]. While these four tumor types are marked by widely diVering light microscopic appearances, they are united by the presence of some combination of positivity by immunohistochemistry with antibodies including cytokeratin, chromogranin, synaptophysin, CD56, CD57, neuron-speciWc enolase, serotonin, somatostatin, bombesin, and protein gene product 9.5 [5].

According to the 1999 World Health Organisation classification of lung tumors, the classification of neuroendocrine (NE) tumors is solely based on light-microscopic features. Typical and atypical carcinoid tumors are distinguished from large cell (LCNEC) and small cell neuroendocrine carcinomas (SCLC). We used comparative genomic hybridization (CGH) on 50 samples to investigate the cytogenetic relationships between NE tumors. On average, carcinoid tumors showed markedly fewer chromosomal imbalances (1.8/case, 23 cases) than LCNEC (13.3/case, 17 cases) or SCLC (17/case, 10 cases). The frequency of amplicons increased accordingly. Typical carcinoid tumors exhibited significant defects on chromosomes 11 and 13 only. Interestingly, only the frequency of losses on chromosome arm 11q was very similar for all three tumor entities (about 30%). In conclusion, the CGH results support the classification of typical carcinoid tumors as a separate entity in clear distinction from the NE carcinomas.

Typical and Atypical Carcinoid Tumors of the Lung Are Characterized by 11q Deletions as Detected by Comparative Genomic Hybridization

To the Editor: Large cell neuroendocrine carcinoma (LCNEC) is a rare aggressive cervical neoplasm, considerably rarer than the well-recognized small cell neuroendocrine carcinoma of the cervix. It is histologically similar to the more common LCNEC of the lung. In the largest series to date (1), Gilks et al. reported 12 cases, and were able to find only 24 previously reported nonsmall cell neuroendocrine carcinomas of the cervix. Of the 12 reported cases in their series, 8 showed adjacent adenocarcinoma in situ. We recently encountered a case of a LCNEC of the cervix with coexisting adenocarcinoma in situ. The latter showed neuroendocrine features by immunohistochemistry, a finding that suggests a common origin of the lesions. A 35-year-old female, G2P2002 presented with a history of two mildly abnormal Pap smears, ASCUS, and subsequent AGUS. Examination revealed a 5.0 cm polypoid lesion protruding from the os that was clinically confined to the cervix. The lesion was removed in the office. The patient was referred to a gynecologic oncologist, and a colposcopically directed biopsy was negative. The patient was treated with two cycles of chemotherapy with carboplatin, taxol, and etoposide and then underwent radical hysterectomy with pelvic and paraaortic lymphadenectomy. Histology of the polypoid lesion revealed a tumor with a trabecular pattern and extensive geographic necrosis (Fig. 1A). The tumor cells had abundant cytoplasm, large nuclei, and prominent nucleoli. There were more than 30 mitoses per 10 high-power fields. The cells were focally positive for mucin, and were positive for keratin and chromogranin on immunohistochemistry. A diagnosis of LCNEC was made. The uterus in the radical hysterectomy specimen was grossly unremarkable and weighed 105 grams. The cervix was submitted entirely for microscopic examination. No residual LCNEC was seen microscopically in cervix, vaginal cuff, or parametria, and the pelvic and paraaortic lymph nodes were negative. Multiple foci of adenocarcinoma in situ were noted in the cervix (Fig. 2A). Immunohistochemistry revealed positivity for chromogranin in these foci (Fig. 2B).FIG. 1.: A) Large cell neuroendocrine carcinoma of the cervix showing a trabecular pattern and geographic necrosis. B) The tumor cells have moderate to abundant cytoplasm and there are numerous mitotic figures.Figure 1: ContinuedFIG. 2.: A) Adenocarcinoma in situ in the hysterectomy specimen. B) The cells of the adenocarcinoma in situ are immunoreactive for chromogranin.In the uterine cervix, neuroendocrine carcinomas are uncommon, particularly those composed of large cells (1). A recent College of American Pathologists workshop has adopted a standardized terminology that has been in use for histologically similar lung neoplasms (2) that includes small (oat) cell carcinomas, typical carcinoid tumors, atypical carcinoid tumors, and LCNECs. The last three are distinguished by the degree of mitotic activity, nuclear atypia, and necrosis. LCNECs of the uterine cervix are aggressive tumors, with a similarly poor prognosis to that of small cell neuroendocrine carcinoma of the cervix (1). Adenocarcinomatous differentiation in association with neuroendocrine carcinomas has been described in the cervix, endometrium, and ovary (1). Eight of Gilks' (1) 12 cases of LCNEC of the uterine cervix had coexisting adenocarcinoma in situ, and in 3 cases, an invasive adenocarcinoma component was present. Savargaonkar et al. (3) suggest that neuroendocrine differentiation is not rare in invasive glandular lesions of the cervix. Neuroendocrine carcinomas have been postulated to arise from cervical glandular reserve cells (4), as well as from cervical endocrine cells (5). The high frequency of in situ and invasive adenocarcinoma with LCNECs of the cervix suggests divergent differentiation rather than synchronous carcinomas. The strong chromogranin staining pattern in both the LCNEC and adenocarcinoma in situ in our case also suggests they are of common origin. Shijun Cui, M.D. Pierre Lespinasse, M.D. Bernadette Cracchiolo, M.D., M.P.H. Jahir Sama, M.D. Michael S. Kreitzer, M.D. Debra S. Heller, M.D

BackgroundFew studies on how to diagnose pulmonary neuroendocrine tumors through morphometric analysis have been reported. In this study, we measured and analyzed the characteristic parameters of pulmonary neuroendocrine tumors using an image analyzer to aid in diagnosis.MethodsSixteen cases of typical carcinoid tumor, 5 cases of atypical carcinoid tumor, 15 cases of small cell carcinoma, and 51 cases of large cell neuroendocrine carcinoma were analyzed. Using an image analyzer, we measured the nuclear area, perimeter, and the major and minor axes.ResultsThe mean nuclear area was 0.318±0.101 µm2 in typical carcinoid tumors, 0.326±0.119 µm2 in atypical carcinoid tumors, 0.314±0.107 µm2 in small cell carcinomas, and 0.446±0.145 µm2 in large cell neuroendocrine carcinomas. The mean nuclear circumference was 2.268±0.600 µm in typical carcinoid tumors, 2.408±0.680 µm in atypical carcinoid tumors, 2.158±0.438 µm in small cell carcinomas, and 3.247±1.276 µm in large cell neuroendocrine carcinomas. All parameters were useful in distinguishing large cell neuroendocrine carcinoma from other tumors (p=0.001) and in particular, nuclear circumference was the most effective (p=0.001).ConclusionsPulmonary neuroendocrine tumors showed nuclear morphology differences by subtype. Therefore, evaluation of quantitative nuclear parameters improves the accuracy and reliability of diagnosis.

ED07.02 The 2015 WHO Classification of Neuroendocrine Tumors

Next-Generation Sequencing Identified a Novel Crizotinib-Sensitive PLB1-ALK Rearrangement in Lung Large-Cell Neuroendocrine Carcinoma

ObjectiveThis study aimed to explore the prognostic factors and outcomes of patients with neuroendocrine tumors (NETs) of the cervix and to determine appropriate treatment.MethodsA single-institution retrospective analysis of 172 patients with NETs was performed based on the new International Federation of Gynecology and Obstetrics (FIGO 2018) staging system.ResultsAmong the 172 eligible patients, 161 were diagnosed with small cell neuroendocrine carcinoma (SCNEC), six with large cell neuroendocrine carcinoma, four with typical carcinoid tumors and one with SCNEC combined with an atypical carcinoid tumor. According to the FIGO 2018 staging guidelines, 31 were stage I, 66 were stage II, 57 were stage III, and 18 were stage IV. The 5-year survival rates of patients with stage I–IV disease were 74.8%, 56.2%, 41.4% and 0%, respectively. The 5-year progression-free survival rates of patients with stage I–IV disease were 63.8%, 54.5%, 30.8% and 0%, respectively. In the multivariate analysis, advanced FIGO stage, large tumor and older age were identified as independent variables for 5-year survival in patients with stage I–IV disease. FIGO stage, tumor size and para-aortic lymph node metastasis were independent prognostic factors for 5-year progression-free survival in patients with stage I–IV disease. For the patients receiving surgery (n = 108), tumor size and pelvic lymph node metastasis were independent prognostic factors for 5-year survival, and pelvic lymph node metastasis for 5-year progression-free survival. In stage IVB, at least six cycles of chemotherapy (n = 7) was associated with significantly better 2-year OS (83.3% vs. 9.1%, p < 0.001) and 2-year PFS (57.1% vs. 0%, p = 0.01) than fewer than six cycles of chemotherapy(n = 11).ConclusionAdvanced FIGO stage, large tumor, older age and lymph node metastasis are independent prognostic factors for NETs of the cervix. The TP/TC and EP regimens were the most commonly used regimens, with similar efficacies and toxicities. Standardized and complete multimodality treatment may improve the survival of patients with NETs.

BACKGROUNDGastric neuroendocrine carcinoma (GNEC) is a rare histological subtype of gastric cancer, which is categorized into small cell and large cell neuroendocrine carcinomas. It is characterized by strong invasiveness and poor prognosis. Mixed large and small cell neuroendocrine carcinoma (L/SCNEC) is an extremely rare pathological type of gastric cancer, and there have been no reports on this situation until now.CASE SUMMARYHerein, we first present a 57-year-old patient diagnosed with L/SCNEC of the stomach. A 57-year-old Chinese male presented with epigastric discomfort. Outpatient gastroscopic biopsy was performed, and pathological examination revealed that the cardia was invaded by adenocarcinoma. The patient underwent laparoscopic-assisted radical proximal subtotal gastrectomy and was diagnosed with L/SCNEC. He refused adjuvant treatment and was followed up every 3 mo. Eight months after the operation, the patient showed no evidence of local recurrence or distant metastasis.CONCLUSIONWe advocate conducting further genomic studies to explore the origin of gastric large cell and small cell neuroendocrine carcinoma and using different chemotherapy schemes according to large or small cell neuroendocrine carcinoma of the stomach for clinical research to clarify the heterogeneity of GNEC and improve the prognosis of patients with GNEC.

A retrospective study was conducted on 32 patients who had had bronchial carcinoid tumors between 1965 and 1989. The average age of the patients was 48.5 years, with a male to female ratio of 3.6:1. Of the 32 patients, 28 were diagnosed pathologically to have typical bronchial carcinoid tumors and the other four, atypical bronchial carcinoid tumors. Twenty-two of the 28 typical bronchial carcinoid tumors were classified as stage I, but only one of the four atypical bronchial carcinoid tumors was at stage I. Two typical carcinoid tumor patients and two atypical carcinoid tumor patients were found, pathologically, to have lymph node metastasis. The typical carcinoid tumors showed a more significant endobronchial polypoid growth than the atypical carcinoid tumors (P = 0.0138). The five-year-survival rate was 100% in patients with typical carcinoid tumors and 25% in those with atypical carcinoid tumors. The difference between the five-year-survival rate for the typical carcinoid and atypical carcinoid patients was statistically significant (P = 0.001).

Introduction: In terms of well-differentiated neuroendocrine tumors (NETs), the lung is the second most common site of occurrence, after the gastro-entero-pancreatic axis, and comprises ∼ 25% of all NETs which may occur in various parts of the body. Pulmonary NETs are classified into four groups including typical carcinoid tumors, atypical carcinoid tumors, small cell lung carcinoma and large cell neuroendocrine carcinomas. Among pulmonary NETs, typical and atypical carcinoid tumors of the lung are generally indolent, but do have a (albeit low) potential to metastasize.Areas covered: The molecular biology and novel molecular pathways and drug targets in bronchial carcinoids are reviewed in this paper. A full data search is performed through PubMed over the years 2000 – 2010 with key words ‘neuroendocrine tumors of the lung, bronchial carcinoid, lung carcinoid, foregut carcinoid, pulmonary carcinoid, pulmonary NETs, lung NETs, molecular biology, autoradiography, nuclear medicine, treatment’; all relevant publications are included, together with selected publications prior to that date.Expert opinion: Although lying at the benign end of the spectrum of pulmonary NETs, bronchial carcinoids can metastasize, and the pathogenesis of these tumors is poorly understood. Several intracellular signaling pathways are under investigation to define new targets for the successful treatment of these tumors. In terms of treatment, further research should additionally focus on the already known but promising drug options.

EP1.12-08 Programmed Death-Ligand 1 and Human Leukocyte Antigen Class I Expression in Various Neuroendocrine Tumors of the Lung