Minimally invasive adenocarcinoma. 5mm or less = microinvasion No necrosis No lymphatic or pleural invasion No spread through air-spaces (STAS)
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1 Minimally invasive adenocarcinoma 5mm or less = microinvasion No necrosis No lymphatic or pleural invasion No spread through air-spaces (STAS)
2 2b lepidic acinar 2c papillary micropapillary solid 2d cribriform v Kadota K et al. The cribriform pattern identifies a subset of acinar predominant tumors with poor prognosis in patients with stage I lung adenocarcinoma: a conceptual proposal to classify cribriform predominant tumors as a distinct histologic subtype. Mod Pathol. 2014;27: Warth A et al. Prognostic impact and clinicopathological correlations of the cribriform pattern in pulmonary adenocarcinoma. J Thorac Oncol. 2015;10:638-44
3 How does this new classification help management of surgically resected ADC patients? Not embarrassing.(evidence-based and validated) Correlates with molecular abnormalities Reproducible amongst pathologists Predicts survival and recurrence Defines AIS & MIA: 100% & near 100% survival if completely resected Importance of histologic patterns Predicts survival benefit with adjuvant cisplatin based chemotherapy
4 ADENOCARCINOMA CLASSIFICATION PREINVASIVE LESIONS AAH ADC-in-situ (formerly pure BAC) *most non-mucinous (NM) INVASIVE ADC Minimally invasive (to be defined: < 5mm invasion, <10% invasion, <5mm scar) Lepidic pattern predominant Acinar pattern predominant/pure Papillary pattern predominant/pure Micropapillary pattern Solid pattern predominant/pure Invasive mucinous adenocarcinoma Fetal (low and high grade) Colloid Enteric Signet ring morphology 2b EGFR mutations TTF-1 positive K-ras mutations TTF-1 negative ALK and ROS gene rearrangements
5 REPRODUCIBLE AMONGST PATHOLOGISTS Reference ADC Subtypes Statistics Comments Thunnissen E: Mod Path 25:1574, 2012 Experts Typical patterns Difficult patterns Kappa = 0.77 Kappa = 0.38 Selected images Warth A: ERJ 40: , 2012 Experts Residents Kappa ( ) Kappa ( ) Glass slides Warth A: Virch Arch 461:185-93, 2012 Duhig E JTO 20:673, 2015 Nakazato Y: JTO 8: Thunnissen E: Mod Path 25:1574, 2012 Experts Consensual votes: % Experts & non-experts Experts Invasive vs noninvasive Typical patterns Difficult patterns Intraclass correlation coefficient 88-98% Digital Slides educational session disagreement (p<0.001) Glass slides: High degree of concordance 5 class Kappa= class Kappa=0.66 LP/AC/Pap vs Sol/MP Kappa = 0.55 Kappa = 0.08 Selected images REPRODUCIBLE (strict and recognisable set of criteria )
6
7 Predominant pattern - Validation... A grading system of lung ADC based on histologic pattern is predictive.in stage I tumors. Sica G AJSP 2010;34:1155 Does lung adenocarcinoma subtype predict patient survival?;. Russell PA et al. JTO 2011;6:1496 Prognostic significance of ADC patterns... Von der Thusen JTO 2013;8:37-44 USA Australia Warth A, J Clin Oncol 2013; 30: UK Xu L et al: AJSP 2012;36: Yoshizawa A, et al: J Thor Oncol 2013;8: 52-61
8 - 575 Resected Adenoca from LACE-Bio Disease free survival: studyacinar/papillary subgroups Chemotherapy vs observation Tsao MS, et al: J Clin Oncol 2015; epub Disease free survival: Micropapillary/solid subgroups Chemotherapy vs observation Solid and micropapillary histologic patterns predict survival benefit from cisplatin based adjuvant chemotherapy in resected lung adenocarcinoma patients
9 SQUAMOUS CELL CARCINOMA (SQCC) A malignant epithelial tumour showing keratinization and/or intercellular bridges that arises from bronchial epithelium. THE REQUIREMENTS OF A CLASSIFICATION SYSTEM... REPRODUCIBLE (strict and recognisable set of criteria) GLOBALLY APPLICABLE (that everyone can apply) THOROUGH (which can deal with atypical variants DYNAMIC (adapts to recent advances) (CAN BECOME SIMPLER) Images from WHO 2004 and 2015
10 Squamous cell carcinoma (WHO 2004) Squamous cell carcinoma; variants: Papillary Clear cell Small cell Basaloid Adenosquamous carcinoma Large cell carcinoma: Basaloid carcinoma subtype Pre-invasive lesions: Squamous cell carcinoma in situ Images from WHO 2004 and Pathology of the Lung. Ed. Corrin and Nicholson)
11 2015 WHO CLASSIFICATION SQUAMOUS CELL CARCINOMA Keratinizing Non-keratinizing now need IHC P40 positive, TTF-1 negative Basaloid carcinoma now need IHC (+p40, -TTF-1 & NE markers) r/o LCNEC & SCLC
12 2015 WHO CLASSIFICATION NEUROENDOCRINE TUMOURS Small cell carcinoma Combined SCLC Large cell neuroendocrine carcinoma Combined LCNEC Diagnostic IHC, if appropriate TTF-1 CD56 chromogranin synaptophysin MNF116 P40 Carcinoid tumor Typical carcinoid Atypical carcinoid
13 LARGE CELL CARCINOMA Large cell carcinoma Large cell neuroendocrine carcinoma 8013/3 Combined large cell neuroendocrine carcinoma 8013/3 Basaloid carcinoma 8123/3 Lymphoepithelioma-like carcinoma 8082/3 Clear cell carcinoma 8310/3 Large cell carcinoma with rhabdoid phenotype 8014/3 Large cell carcinoma Null phenotype on IHC Unclear phenotype on IHC No IHC available
14 ADENOCARCINOMA, SOLID SUBTYPE A P40 TTF-1 C NON-KERATINISING SQUAMOUS CELL CARCINOMA D P40 E TTF-1 F LARGE CELL CARCINOMA G P40 H ITTF-1 Figure Large cell carcinoma. (A-C) A resected morphologically undifferentiated non-small cell carcinoma, that would hitherto have been classified as large cell carcinoma, stains for TTF-1 but not for p40, with subsequent classification as an adenocarcinoma, solid subtype (B p40; C TTF-1). (B-F) A resected morphologically undifferentiated non-small cell carcinoma, that would hitherto have been classified as large cell carcinoma, stains for p40 but not for TTF-1, with subsequent classification as a non-keratinising squamous cell carcinoma (E p40; F TTF-1). (G-I) A resected morphologically undifferentiated non-small cell carcinoma does not stain for P40 or TTF-1. The tumour cells also did not contain mucin, with subsequent classification as a large cell carcinoma, null phenotype (H p40; I TTF-1). Courtesy of Dr L Sholl
15 Subtyping of resected morphologically undifferentiated nonsmall cell carcinomas (formerly large cell carcinoma) *p63 (4A4) can rarely be more diffusely positive in some TTF-1 positive tumours. These should be classified as adenocarcinomas. 1 In cases where there is morphological evidence of either squamous cell carcinoma or adenocarcinoma, then immunohistochemistry is not required to assess undifferentiated areas.
16 Sci Transl Med Epub Oct 2013 Carc SCLC AD SQ c c
17 SEER data on incidence of non-small cell carcinomas (Lewis DR et al. Cancer. 2014;120(18): )
18 2015 WHO CLASSIFICATION 1-9: Salivary gland-type tumours 1-9A Mucoepidermoid carcinoma 1-9B Adenoid cystic carcinoma 1-9C Epithelial-myoepithelial carcinoma 1-2D Pleomorphic adenoma 1-10: Papillomas 1-10A: Squamous papilloma 1-10B: Glandular papilloma 1-10C: Mixed squamous and glandular papilloma 1-11: Adenomas 1-11A: Sclerosing pneumocytoma 1-11B: Alveolar adenoma 1-11C: Papillary adenoma 1-11D: Mucinous cystadenoma 1-11E: Mucus gland adenoma 1-12: Mesenchymal tumours 1-12A: Hamartoma 1-12B: Chondroma 1-12C: PEComatous tumours (LAM, PEComa) 1-12D: Congenital peribronchial myofibroblastic tumour 1-12E: Diffuse lymphangiomatosis 1-12F: IMT 1-12G: Epithelioid haemangioedothelioma 1-12: Mesenchymal tumours, contd 1-12H: Pleuropulmonary blastoma 1-12I: Synovial sarcoma 1-12J: Pulmonary artery intimal saraoma 1-12K: Pulmonary myxoid sarcoma with EWSR1- CREB1 translocation 1-12L: Myoepithelial tumours 1-12M: Others 1-13: Lymphoproliferative disorders 1-13A: Marginal zone B-cell lymphoma of MALT origin 1-13B: Diffuse large B-cell lymphoma 1-13C: Lymphomatoid granulomatosis 1-13D: Intravascular lymphoma 1-13E: Langerhans cell histiocytosis 1-13F: Erdheim Chester disease 1-14: Tumours of ectopic origin 1-14A: Germ cell tumours 1-14B: Intrapulmonary thymoma 1-14C: Melanoma 1-14D: Meningioma 1-15: Metastases to the lung
19 MISCELLANEOUS 1999 &2004 WHO 2015 Hamartoma Sclerosing haemangioma Clear cell tumour Germ cell tumours Thymoma Melanoma Others Mesenchymal (1-12) (Adenoma) Sclerosing pneumocytoma (1-10) Mesenchymal (1-12) Ectopic origin (1-14) Ectopic origin (1-14) Ectopic origin (1-14)
20 Clear cell tumour 1.12C PEComatous tumours Lymphangioleiomyomatosis PEComatosis PAS HMB 45 Mutations in the TSC gene
21 1-8: Other carcinomas NUT-carcinoma Young adults and children P63 and CK positive NUT (Nuclear protein of the testis)-ihc and NUT-FISH to confirm diagnosis BETi (bromodomain and extra-terminal domain inhibitor) and HDACi (histone deacetylase inhibitor) in clinical trials.
22 New tumours IHC Negative other than vimentin Resembles extraskeletal myxoid chondrosarcoma but histochemically different. Low-grade endobronchial myxoid tumour Nicholson AG. Histopathology Oct;35(4):313-8
23 1-12K Primary pulmonary myxoid sarcoma with EWSR1- CREB1 fusion: a new tumor entity. Thway K et al. AJSP 2011;35: pulmonary myxoid sarcomas - Recurrent fusion gene, that appear to represent a distinct tumor entity at this site. 7 were shown to harbor a specific EWSR1-CREB1 fusion by RT-PCR and direct sequencing, with 7 of 10 showing EWSR1 rearrangement by FISH. This gene fusion has been described previously in 2two different sarcomas: clear cell sarcoma-like tumors of the gastrointestinal tract and angiomatoid fibrous histiocytomas; Novel finding in tumors with the morphology we describe and that occur in the pulmonary region.
24 Endobronchial pulmonary angiomatoid fibrous histiocytoma: two cases with EWSR1-CREB1 and EWSR1-ATF1 fusions. Thway K et al. AJSP 2012;36:883-8 Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue neoplasm of intermediate biological potential, predominantly occurring in the extremities of children and young adults. 2 cases arising endobronchially harboring EWSR1 gene rearrangements by FISH and, respectively, EWSR1- CREB1 and EWSR1-ATF1 gene fusions by RT-PCR
25 MOLECULAR ABNORMATLITIES IN RARE LUNG TUMOURS 1-8 Other carcinomas 1-8A NUT-carcinoma NUT translocations 1-9: Salivary gland-type tumours 1-9A Mucoepidermoid carcinoma MECT1-MAML2 gene rearrangement 1-12: Mesenchymal tumours 1-12C: PEComatous tumours TSC gene mutations in LAM 1-12E: Diffuse lymphangiomatosis 1-12F: Inflammatory myofibroblastic tumour ALK/ROS/RET rearrangements 1-12G: Epithelioid haemangioedothelioma WWTR1--CAMTA1/YAP1-TFE3 fusions. 1-12H: Pleuropulmonary blastoma DICER-1 mutations 1-12I: Synovial sarcoma X:18 translocation 1-12K: Pulmonary myxoid sarcoma with EWSR1-CREB1 translocation 1-12L: Myoepithelial tumours EWSR1 and FUS fusions 1-12M: Others Localized fibrous tumour NAB2-STAT6 gene fusion 1-13: Lymphoproliferative disorders 1-13E: Langerhans cell histiocytosis BRAF mutation 1-13F: Erdheim Chester disease BRAF mutation
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