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As a member and also as , i feel as a host too.

LARGE CELL NEUROENDOCRINE CARCINOMA OF LUNG Case 55 AMR SPLIT 2018 Lovorka Batelja Vuletić Departmen of pathology School of Medicine University of Zagreb

LCNEC WHO classification (3th edition) a NSCLC that shows histological features of neuroendocrine morphology and expresses immunohistochemical neuroendocrine markers LCNEC COMBINED LCNEC with adenocarcinoma, squamous cell carcinoma, spindle cell carcinoma / giant cell carcinoma

Case history LCNEC- Literature date a man born 1957. a former smoker periodically febrile: 2016.y, without cough and dyspnoea highly related to smoking most commonly located in the peripheral lung in 20% of cases- a central location cough, haemoptysis, dyspnoea, pneumonia and chest pain ! unlike SCLC paraneoplastic syndrome are uncommon

9/2016 a chest x-ray : nodules 1.8 cm in diametar Radiological findings 9/2016 a chest x-ray : nodules 1.8 cm in diametar 5/2017 MSCT: a soft tissue mass opened etiology 2.5 cm in diametar 12 /2017 CT of torax: a solide lesion in the left superior lung’s lobe 3.6 cm in diametar 3/ 2018 an operation precedure: Thoracotomy Superior Lobectomy Mediastinal Lymphadenectomy MSCT: multislides CT

Literature date Macroscopy average diametar 3-4cm circumscribed tumor occasionally present haemorrhage

Macroscopic features superior lung lobe with stasis changes tumor 4 cm in diametar, ~40% necrotic lymph nodes; regions I-X

LARGE OR NOT SMALL Medium size

What is the mesaure www.medical.labs.net www.pathpedia.com

T cells are about 7-8 micrometers www.medical.labs.net www.pathpedia.com

Ø of tumor cell> Ø

Histological Findings or giant multinuclear cells and probably represents SCC and AD. One histological variant is large cell neuroendocrine carcinoma, and confirmation of neuroendocrine differentiation is required using immune histochemical markers (Figure 1D). sheets or nests of middle size polygonal tumor cells

Histopathology of LCNEC Neuroendocrine morphology: organoid nesting, trabecular growth, rosette-like structures Nucleoli are frequent Mitotic counts> 10 M / 2mm2 Necrosis: punctate or large Confirmation of neuroendocrine differentiation is required One positive marker is enoug

Histopathology of LCNEC Neuroendocrine morphology: organoid nesting, trabecular growth, rosette-like structures Nucleoli are frequent Mitotic counts> 10 M / 2mm2 Necrosis: punctate or large Confirmation of neuroendocrine differentiation is required One positive marker is enoug

MI >10 M / 10HPF

Differential diagnosis SCLC Carcinoid (atypical) Basaloid squamous cell carcinoma Other large cell carcinoma !!the diagnosis can be difficult in small biopsy speciments

Immunohistochemical Findings LCA p40

CK 7 TTF1

A confirmation of neuroendocrine differentiation CD56

Literature date IHC profile: 92-100 % LCNET + CD 56 80-85% LCNET+ chromogranin A 50-60% LCNET + synaptophisin ~ 50 % LCNET + TTF1 ~ 100 % LCNET + AE1 / AE3, CK7; dot- like / diffuse

Diagnosis: large (non small cell) neuroendocrine carcinoma pTNM: pT2apN0

PDL1 status DAKO 22C3 negative

Molecular profiling ALK + (Cell signaling antibody) EGFR -

Why did we choose this case ? Rare pulmonary tumor Heterogenic group of tumors Tumor spread: lymph nodes lung parenhima liver brain bone

Kerr K. M. , Bubendorf L. , Edelman M. J. et. all Kerr K.M., Bubendorf L., Edelman M.J. et. all. Second ESMO consensus conference on lung cancer: pathology and molecular biomarkers for non-small-cell lung cancer.Annals of Oncology 2014. 25: 1681-1690 CAP/ IASLC (the International Association for the Study of Lung Cancer) /AMP Molecular Testing Guideline for Selection of Patients with Lung Cancer for Treatment with ALK Thyrosine Kinase Inhibitors; Summary of Recomendation 2013, 2015 Dietel M et al. Diagnostic procedures for non-small-cell lung cancer (NSCLC): recommendations of the European Expert Group Thorax 2016;71:177–184 routine EGFR i ALK mutation analysis „..has been recommended for all non-squamous tumours..”

according Guideline From the College of American Pathologists, the International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology, published in March 2018. ...Upon systematic review, no new evidence established the routine molecular testing of any genes for typical squamous cell carcinoma, small cell carcinoma, or other neuroendocrine lung tumors... !!!

!! ...In nonadenocarcinoma non–small cell histologies, the finding of EGFR, ALK,or ROS1 alterations has been most commonly reported in situations in which patients had a minimal (1–10 packs per year) or no history of tobacco exposure. Similarly, some studies have suggested associations between the presence of ALK or ROS1 alterations and younger patient age...

References Kerr K. M., Bubendorf L., Edelman M. J. et all. Second ESMO consensus conference on lung cancer:pathology and molecular biomarkers for non-small-cell lung cancer. Annals of Oncology. 2014.25: 1681–1690. Bergethon K., . Shaw A.T, Ignatius Ou Sai-Hong, et all.ROS1 Rearrangements Define a Unique Molecular Class of Lung Cancers. Journal of Clinical Oncology 2012 (8) 863-870. Kim H, Yoo SB, Choe JY, et al. Detection of ALK gene rearrangement in non-small cell lung cancer: a comparison off fluorescence in situ hybridization and chromogenic in situ hybridization with correlation of ALK protein expression.JThoracOncol.2011;6(8):1359–1366 Lindeman NI,Cagle PhT,Aisner DL et all. Updated Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment With Targeted Tyrosine Kinase Inhibitors Guideline From the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. Journal of Thoracic Oncology 2018. Vol. 13 No. 3: 323-358 Rodig SJ, Mino-Kenudson M, Dacic S, et al. Unique clinicopathologic features characterize ALK-rearranged lung adenocarcinoma in the western population. Clin Cancer Res. 2009;15(16):5216–5223. Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol.2009;27(26):4247–4253 WHO classification of Tumours of the Lung, Thymus and Heart. Edited by Travis WD, Brambilla E, Burke AP , Marx A and Nicholson AG.