THE SPECTRUM OF NEUROENDOCRINE LUNG TUMORS, CLINICOPATHOLOGICAL FEATURES AND MORPHOLOGY First author: Roman Adina Co-author: Andone Sebastian Coordinator: Tibor Mezei, MD

Introduction First described as carcinoid tumors in the ileum in 1888 (in 1937 bronchial carcinoid) Clear cells belonging to the APUD system Capability of producing hormonal products or substances commonly found in cells belonging to the nervous system introduced the idea of NEUROENDOCRINE CONCEPT Hago et al “Update in Pulmonary Carcinoid Tumors: A review article” Annals of Surgical Oncology, 10(6): 697-704

Introduction Neuroendocrine lung tumors widely accepted histological classification: Typical carcinoids (TC) Atypical carcinoids (AC) Small cell lung carcinoma (SCLC) Large cell neuroendocrine carcinoma (LCNEC) Brambilla, Travis et al : “The new World Health [..] “ERJ December 1, 2001 vol. 18 no. 6 1059-1068

Introduction Common morphologic, ultrastructural, molecular characteristics Specific histological features: Presence or lack of mitosis Presence or lack of necrosis Tissue architecture, cellular shape and size Nuclear characteristics Immunohistochemistry findings: Chromogranin A Synaptophysin CD56 Cytokeratin Hammar et al “Neuroendocrine tumors”, Dail And Hammar 3rd Edition, vol 2, 308-370

Objective Main purpose: Secondary purposes: To review and study neuroendocrine lung tumors incidence and pathological features Secondary purposes: The evaluation of immunohistochemistry features Establish a minimal antibody panel sufficient for diagnosing most of the cases

Material and method 52 cases diagnosed between 2003-2013 at the Pathology Department of Targu Mures County Clinical Emergency Hospital Inclusion criteria: Tumor morphology Immunohistochemistry suggestive neuroendocrine differentiation Surgical resection specimens (no biopsy, core/fine needle aspiration or other cytology specimens)

Results The following parameters were included in the database: Histological type Location, dimension, focality Histological grade, tumor extension, resection margin status TNM descriptors and stage Immunohistochemical profiles

Results We included neuroendocrine tumors into two groups: Well differentiated tumors Typical carcinoids Atypical carcinoids Undifferentiated tumors Small cell lung carcinoma Large cell neuroendocrine carcinoma

Results 10.8% of all malignant tumors included in our study Data shows that neuroendocrine tumors predominantly affects men (68%) Mean age: 56 years Well-differentiated tumors present a younger age of diagnosis (p=0.02)

Age distribution of neuroendocrine tumors Results Age distribution of neuroendocrine tumors

Results Well differentiated tumors average size: 25 mm Undifferentiated tumors average size: 38 mm P=0.07 Location data: First group presented an even distribution, the latter presented an inferior lobe extension preference Unifocal type distribution (one tumor per lobe)

Results Immunohistochemical markers: Chromogranin A Synaptophysin CD56 Other markers: CTK7, TTF1, NSE, CK20 (CK – dot like) 59.6 % of cases presented immunohistochemical staining results Both groups were intensly positive for Chromogranin A

Discussions Neuroendocrine tumors comprise worldwide approximately 0.5 -2% of all malignancies [1] The importance of differentiating AC, TC, SCLC or LCNEC and it’s impact on survival rate (87% to 2% for undifferentiated tumors) [2] Impact on treatment: perioperative chemotherapy and surgical resection for all NSCLC [1]Taal, B.G.; Visser, O. Epidemiology of neuroendocrine tumours.  Neuroendocrin 2004, 80, 3–7 [2] Anette Fisseler: “Neuroendocrine tumors of the lung” , Cancers 2012, 4(3), 777-798

Discussions It is speculated that NSCLC with neuroendocrine differentiation present a higher rate of response to treatment Currently, there is no consensus on clinical management and therefore no treatment guideline for LCNEC [1] All neuroendocrine tumors present high risk of metastasis (20-80%) [2] [1] Travis et al: “World Health Organization Classification of Tumors [..] “; IARC Press: Lyon, France, 2004; pp. 19–25. [2] Anette Fisseler: “Neuroendocrine tumors of the lung” , Cancers 2012, 4(3), 777-798

Conclusions Comparison with other studies showed the importance of other markers as well as the necessity of immunohistochemical stains to support diagnosis Verifying large cell carcinoma for it’s possible neuroendocrine differentiation (in case of suggestive architecture) Reevaluation of some cases without immunohistochemical staining results Establishing an antibody panel sufficient for immunohistochemical valid diagnosis in neuroendocrine tumors International Registry of Pulmonary Neuroendocrine Tumors

Novelty and limitations Despite the fact that there are studies regarding lung tumors in selected Romanian population, to our best knowledge so far there are no recently published data concerning tumors with neuroendocrine differentiation in particularly Limitations include funding regarding immunohistochemical markers use of immunohistochemical stains to a less extent in the past