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INTRODUCTION • Lung cancer was considered a rare entity until the mid 1930s when its incidence has increased mainly due to the habit of smoking Lung Cancer Mortality (male population) in the USA FEINSTEIN et al. Epidemiology of lung cancer. Chest Surg. Clin. N Am., v. 10, n. 4, p. 653-661, 2000. Câncer de Pulmão Mortality rate (female population) in the U.S.A FEINSTEIN et al. Epidemiology of lung cancer. Chest Surg. Clin. N Am., v. 10, n. 4, p. 653-661, 2000. Estimated New Cancer Cases and Deaths Worldwide for Leading Cancer Sites by Level of Economic Development, 2008. Source: : GLOBOCAN2008.Global Cancer Statistics72 CA Airway - Organization Fishman’s Pulmonary Diseases and Disorders 3rd e pp 24 Airway - Histology Fishman’s Pulmonary Diseases and Disorders 3rd ed pp 25 Alveolar septum – M.E. O2 CO2 From Weibel ER. In Fishman’s Pulmonary Diseases and Disorders 3rd e pp 25 Neoplasia • Impact of molecular genetic alterations in the cell cycle – neoplasia = phenotypic expression= accumulation of genetic changes over time in cells – Genetic Changes = uncontrolled cellular proliferation by interfering with the cell cycle or inhibition of programmed cell death (apoptosis). Mutation Pro-growth E E E Inhalation of airway irritants • Acute Changes – Aggression covering epithelium. – Mucus secretion by submucosal glands and goblet cells • Chronic Changes – Squamous metaplasia of the bronchial columnar epithelium – Acinar gland hyperplasia Smoking: Irritating, alteration of ciliary beating and mutagenic Occupational agents and exposure circumstances WHO 2004 Chronic Bronchitis Squamous metaplasia Normal epithelium to cancer “in situ” progression Classification • Even with advances in surgical treatment, chemotherapy and radiotherapy, the prognosis is considered bleak. • In general, less than 15% of the patients remain alive at 5 years. Classification (WHO 2004) -Non Small Cell Lung Carcinoma(*) -Squamous Cell Carcinoma Variants: Papillary, Clear Cell, Small cell, Basaloid - Small cell carcinoma Variants: Combined Small Cell Carcinoma -Adenocarcinoma Variants: Mixed Subtype, Acinar, Papillary, Solid, Fetal, Mucinosous (Colloid), Signet ring, Cistadenocarcinoma Mucinoso, Clear cell - Large Cell Carcinoma Subtype: Combined Large Cell Carcinoma Neuroendocrine, Combined Large Cell Carcinoma Neuroendocrine, Basaloid carcinoma, Clear cell carcinoma, Carcinoma linfoepithelioma like carcinoma, Large cel carcinomna with rhabdoid fenotype. - Bronquioloalveolar Adenocarinoma Variants: Mucinous , Nonmucinous. - Adenosquamous carcinoma - Typical Carcinoid - Atypical Carcinoid - Sarcomatoid carcinoma - Adenóid cystic carcinoma - Mucoepidermoid carcinoma -Others (Lymphomas, Metastatic tumors, Rare neoplasia) Classification (IASLAC/ATS 2009) -Non Small Cell Lung Carcinoma(*) avoid this term -Squamous Cell Carcinoma Variants: Papillary, Clear Cell, Small cell, Basaloid - Small cell carcinoma Variants: Combined Small Cell Carcinoma -Adenocarcinoma Variants: Mixed Subtype, Acinar, Papillary, Solid, Fetal, Mucinosous (Colloid), Signet ring, Cistadenocarcinoma Mucinoso, Clear cell - Large Cell Carcinoma Subtype: Combined Large Cell Carcinoma Neuroendocrine, Combined Large Cell Carcinoma Neuroendocrine, Basaloid carcinoma, Clear cell carcinoma, Carcinoma linfoepithelioma like carcinoma, Large cel carcinomna with rhabdoid fenotype. - Adenocarcinoma “in situ” (≤ 3,0cm) (AIS-formerly known as BAC) Variants: Mucinous , Nonmucinous. -MINIMALLY INVASIVE ADENOCARCINOMA (≤0.5cm)(MIA) - Adenosquamous carcinoma - Typical Carcinoid - Atypical Carcinoid - Sarcomatoid carcinoma - Adenóid cystic carcinoma - Mucoepidermoid carcinoma -Others (Lymphomas, Metastatic tumors, Rare neoplasias) • Because of this poor prognosis, the WHO used to separates the two groups most comprehensive lung cancer: – 1) Small Cell Lung Carcinoma (SCLC) - 20% – 2) Non Small Cell Lung Carcinoma (NSCLC) - 80% • This has been established by different prognosis and treatment among these entities and the prognosis group SCLC worse than NSCLC. Classification • Currently we avoid using the term NSCLC even in small biopsies. • Due to improvements in treatment target with specific drugs and the advent of specific molecular markers, try define ADENOCARCINOMA or SQCC even in small specimens. 66yo, right upper lobe mass, Core biopsy Negative IHQ for p63 Positive IHQ for TTF-1 Adenocarcinoma 74yo, left lower lobe lobe mass, Core biopsy Positive IHQ for p63 Negative for TTF-1 Squamous Cell carcinoma • http://cancergrace.org/lung/files/2010/08/his tologybrhttp://cancergrace.org/lung/files/2010/08/ histology-breakdown-of-lungcancer.jpgeakdown-of-lung-cancer.jpg ADENOCARCINOMAS (40% of tumors) • Adenocarcinoma is a cancer (malignant neoplasm) that originates in glandular tissue. • To be classified as adenocarcinoma cells need not necessarily be part of a gland, as long as they have secretory patterns. ATYPICAL ADENOMATOUS HIPERPLASIA (AAH) SMALL AND LOCALIZED PROLIFERATION ≤ 0.5CM , NO INVASIVE COMPONENT International Association for the Study of LungCancer/American Thoracic Society/EuropeanRespiratory Society International Multidisciplinary Classification of Lung AdenocarcinomaWilliam D. Travis, MD, Elisabeth Brambilla, MD ADENOCARCINOMA “ IN SITU” (AIS) NONMUCINOUS FORMELY NONMUCINOUS BAC,AtYPICAL PROLIFERATION ≤3,0cm ADENOCARCINOMA “ IN SITU” (AIS) MUCINOUS FORMELY MUCINOUS BAC,AYPICAL PROLIFERATION ≤3,0cm ADENOCARCINOMA MICROPAPILLARY ADENOCARCINOMA MIXED SUBTYPE ACINAR/LEIPDIC(AIS) ADENOCARCINOMA SOLID MOLECULAR FEATURES: For adenocarcinomas: 1) EGFR MUTATIONS IS A PREDICTIVE FACTOR WITH THE USE OF INHIBITORS EGFR (TKIs), FIRST LINETREATING EVEN IN AVANCED TUMORS 2) Tumors with EGFR mutation have a more indolent course 3) EGFR and KRAS mutations are excludents. The epidermal growth factor receptor (EGFR, HER-1/ErbB1) is a receptor tyrosine kinase (TK) EGFR mutation: Women, Never smokers Asian Non mucinosos EGFR Mutation Is a Better Predictor of Response to Tyrosine Kinase Inhibitors in Non–Small Cell Lung Carcinoma Than FISH, CISH, and Immunohistochemistry PCR IS A GOLD STANDAERD The PCR method is designed to detect the most frequent EGFR mutations (exon 19 deletions and exon 21 L858R substitutions), which account for 85% to 90% of reported EGFR mutations. Lung adenocarcinoma: guiding EGFR-targetedtherapy and beyond Marc Ladanyi and William Pao Departments of Pathology and Medicine, and Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA ADENOCARCINOMA EGFR mutation positive Treatment with anti EGFR, gefitinib Kras mutation negative ADENOCARCINOMA EGFR mutation negative Traditional chemotherapy Kras mutation Positive or Negative ADENOCARCINOMA EGFR mutation Negative EML4/ALK (5%) Kras mutation Negative ADENOCARCINOMA EML4/ALK negative EML4/ALK Positive Traditional chemotherapy ALK inhibitor therapy crizotinib FISH IS A GOLD STANDARD Squamous cell carcinoma. (30% of tumors) Squamous cell carcinoma. • • • • p63 gene is amplified in some cases SOX2 gene is amplified Seen in lung and esophagus SOX2 expression is observed in progression from dysplasia to carcinoma Squamous cell carcinoma. Sox 2 •Transcription factor important for large airway development •Invitro SOX2 amplification upregulates p63 •May help maintain pluripotency, may allow for squamous differentiation. These discoveries have ushered in a new era of targeted therapeutic agents for patients with Squamous Cell Carcinoma. Lung cancer genomics –Gene expression profiling and lung cancer classificationAlain Borczuk, MDColumbia University Medical Center Small Cell Carcinoma (15% of tmors) Tumores Neuroendócrinos • Small Cell Carcinoma (SCLC) • Large Cell Neuroendocrine Carcinoma (LCNEC). • Atypical carcinoid (AT) • Typic carcinoid (TC) TC 99% sobrevida AC 75% sobrevida AFIP, 1995 Histogenesis of Neuroendocrine Tumors • There are normal neuroendocrine cells in the airways. • Various stimuli can occur for Ne cell hyperplasia. • Diffuse neuroendocrine cell hyperplasia is a rare entity and recognized as a preneoplastic lesions. Tumores neuroendócrinos histogênese • Under-representation of chromosome 11q (MEN1 gene) by 50% and 70% of TC CA.. • P53 shows no mutation in TC • Aberrant p53 is present in rare cases of AC. • Other tumor suppressor genes are rare in TCs. Classification of neuroendocrine tumors Feyter 1938 Órgão Epitelial Endócrino Difuso Fröhlich 1949 Células Claras- na Mucosa Brônquica Hamperl 1952 Células K-Kulschitsky Bench 1968 Grânulos Ne-ME Corrin 1968 TC, SCLC Arrigone 1972 TC, AC, SCLC WHO 1982 TC,AC,SCLC, GCelAnaplas Capelozzi 1986 TC, AC, SCLC, LCC com Diferenciação NE-IHQ e ME Travis 1991 TC,AC,SCLC,LCC,LCNEC WHO 1999/ 2004 TC,AC,SCLC,LCC,LCNEC, (LCCNM*) Carcinoma Pequenas Células Capelozzi VL & Sheppard MN. Morphometric characterization of typical carcinoid, atypical carcinoid, large cell NE carcinoma and small cell carcinoma based on ultrastructural and sterological procedure. Chest 106: 90S, 1994 Carcinóide Atípico Capelozzi VL & Sheppard MN. Morphometric characterization of typical carcinoid, atypical carcinoid, large cell NE carcinoma and small cell carcinoma based on ultrastructural and sterological procedure. Chest 106: 90S, 1994 Carcinoma Grandes Células Neuroendócrino Capelozzi VL & Sheppard MN. Morphometric characterization of typical carcinoid, atypical carcinoid, large cell NE carcinoma and small cell carcinoma based on ultrastructural and sterological procedure. Chest 106: 90S, 1994 Classificação dos Carcinomas de Grandes Células (LCC) • 1.3.4-Large Cell Carcinoma (LCC) – 1.3.4.1-Large Cell Neuroendocrine Carcinoma – 1.3.4.1.1-Combined Large Cell Neuroendocrine Carcinoma. – 1.3.4.2 -Basaloid Carcinoma – 1.3.4.3-Lymphoepithelioma like Carcinoma. – 1.3.4.4-Clear Cell Carcinoma – 1.3.4.5-Large Cell Carcinoma with Rhabdoid Phenotype. WHO ,4th Ed,Geneva ,Switzerland,2004. HE 200X LCNEC HE 400X Imunohistoquímica Cromogranina 200X Molecular profile of LCC • •Large cell carcinoma –EGFR mutation 6%–KRAS mutations 16% • TrkB and its ligand brain-derived neurotrophic factor (BDNF) in clinical specimens and their influences on phenotypes of invasiveness and tumorigenicity for LCNEC. • In particular, LCNEC, a subtype of NET, exhibited significantly higher TrkB and BDNF expressions than another NET type: small cell lung cancer (SCLC). • Significant correlation between TrkB and BDNF expressions was noted in LCNEC but not in SCLC. Odate S, Nakamura K, Onishi H, Kojima M, Uchiyama A, Nakano K, Kato M, Tanaka M, Katano M. TrkB/BDNF signaling pathway is a potential therapeutic target for pulmonary large cell neuroendocrine carcinoma. Lung Cancer. 2013 Mar;79(3):205-14. doi: 10.1016/j.lungcan.2012.12.004. Epub 2013 Jan 9. PubMed PMID: 23312550. Survival IPX DIAGNOSTIC Small biopsy Sclc Cromogranin A Positive 50% Adenocarcinomas Squamos Ceell Rare Positive Negative 5% TTF-1 Positive 94% Positive 63% Rare Positive (10%) CEA-monoclonal Positive 39% Positive 86% Negative P63 Negative Negative Positive 98% Mucicarmin Negative Positive Negative IPX DIAGNOSTIC AE1 / E3 TTF-1 Ber-EP4 p63 34BE12 (Ck alto PM) 35BH11 (Ck baixo PM) Cromogra nina A Mucicarmi m* LCC 96% 75% 9% 0 17% 23% 0 - Adenocarci noma 100% 73% 92% 0 57% 99% 5% + Squamous Cell 100% 4% 3% 90% 96% 7% 0 - LCNEC 96% 75% 9% 0 15% 23% 67% - NATURAL HISTORY