who classification of lung cancer 2014

New World Health Organisation Classification of Lung Cancer

The XXXth Congress of the International Academy of

Pathology, Bangkok, Thailand. 6th October 2014

Professor Andrew G Nicholson, DM, FRCPath Consultant Histopathologist, Royal Brompton and Harefield NHS Foundation Trust

Professor of Respiratory Pathology National Heart and Lung Division Imperial College, London, United Kingdom

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.)

WHO classification 1981-1999-2004-2015


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.)

WHO CLASSIFICATIONS 1967 Histologic Typing of Lung Tumours 1981 Histologic Typing of Lung Tumours 1999 Histologic Typing of Tumours of the

Lung and Pleura 2004 Pathology and Genetics: Tumours of

the Lung, Pleura, Thymus and Heart 2015 - Pathology and Genetics: Tumours of

the Lung, Pleura, Thymus and Heart

INCREASING COMPLEXITY 1967 WHO 1981 WHO 1999 WHO 2004 WHO

2015 WHO

H&E H&E & Mucin H&E, EM & IHC H&E, EM, IHC &

Genetics H&E, Cytology, IHC,

Genetics, Mucin, Radiology

PERSONALISED MEDICINE: INCREASING RELEVANCE

2015 WHO CLASSIFICATION 1-1: Introduction 1-1A Lung cancer staging and grading 1-1B Rationale for classification in small biopsies and cytology 1-1C Terminology and criteria in non-resection specimens 1-1D Molecular testing for treatment selection in lung cancer

1-2: Adenocarcinoma 1-2A Invasive adenocarcinoma 1-2B Variants of invasive adenocarcinoma 1-2C Minimally invasive adenocarcinoma

1-2: Adenocarcinoma (continued) 1-2D Preinvasive lesions 1-2D-i: Atypical adenomatous hyperplasia 1-2D-ii: Adenocarcinoma in situ

1-3: Squamous cell carcinoma 1-3A: Keratinizing and nonkeratinizing squamous cell carcinoma 1-3B: Basaloid carcinoma 1-3C: Preinvasive lesion: Squamous carcinoma in situ

2015 WHO CLASSIFICATION

1-4: Neuroendocrine Tumours 1-4A: Small cell carcinoma 1-4B: Large cell neuroendocrine carcinoma 1-4C: Carcinoid tumors 1-4D: Preinvasive lesion: Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia 1-5: Large cell carcinoma

1-6: Adenosquamous carcinoma

1-7: Sarcomatoid carcinoma 1-7A: Pleomorphic, spindle cell and giant cell carcinoma 1-7B: Carcinosarcoma 1-7C: Pulmonary blastoma 1-8: Other carcinomas 1-8A: Lymphoepithelioma-like carcinoma 1-8B: NUT-carcinoma

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

Outline

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.)


Large cell carcinoma Adenocarcinomas Squamous cell carcinoma Neuroendocrine tumours Sarcomatoid carcinomas Other carcinomas Classification of biopsies in lung cancer

LARGE CELL CARCINOMA 2004 2015.

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

ADC on IHC (NOW UNDER ADC,

solid subtype) SQCC on IHC (NOW UNDER

NON-KERAT SQCC)

** Clear cell and rhabdoid (more

aggressive) are cytologic features with no current prognostic/predictive significance, but may be relevant to differential diagnosis comment as a percentage of tumour

Recent studies on correspondence of IHC profiles and mutations in LCC

Virchows Arch Epub Nov 2013

Mod Pathol Epub Oct 2012

Arch of Pathol Epub June 2013

Sci Transl Med Epub Oct 2013

Large cell carcinoma. Large tumour cells have abundant cytoplasm with large nuclei, vesicular nuclear chromatin and prominent nucleoli. There is no glandular or squamous differentiation, and no mucin vacuoles are present. Courtesy of Dr L Carvalho.

A C P40

F E D

G H I

Figure 1-05 4 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

P40

P40

TTF-1

TTF-1

TTF-1

Subtyping of resected morphologically undifferentiated non-small 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. 1In cases where there is morphological evidence of either squamous cell carcinoma or adenocarcinoma, then immunohistochemistry is not required to assess undifferentiated areas.

IHC typing of CK + morphologically undifferentiated NSCLC (mucin stains already undertaken to exclude solid pattern ADC**).

Focal = 0-10% of cells positive, Diffuse = >10% of cells positive TTF-1 P63 P40 CK5/6 DIAGNOSIS

(RESECTION)

DIAGNOSIS

(BIOPSY/CYTO)

Positive focal or diffuse

Negative Negative Negative ADC NSCLC, favour ADC

Positive focal or diffuse Positive, focal or diffuse

Negative Negative ADC NSCLC, favour ADC

Positive focal or diffuse Positive, focal or diffuse

Positive, focal Negative ADC NSCLC, favour ADC

Positive focal or diffuse Negative Negative Positive, focal ADC NSCLC, favour ADC

Negative Any one of above diffusely positive SQCC NSCLC, favour SQCC

Negative Any one of above focally positive LCC-unclear# NSCLC-NOS

Negative Negative Negative Negative LCC-null*** NSCLC-NOS

No stains available No stains available

No stains available No stains available

LCC with no additional stains

NSCLC-NOS (no stains available)

*Napsin may be used as an alternative to TTF-1. Although a sensitive marker, CK7 is not recommended as a marker of adenocarcinomatous differentiation due to a lack of specificity. ** Positive for mucin is defined as (5 or more droplets in 2 consecutive high power fields in resections {2004 WHO book} and mucin droplets in two or more cells within a biopsy). Fewer positive cells are regarded as negative. *** Sarcomatoid carcinoma and neuroendocrine tumours should be excluded (i.e. undifferentiated morphology with no spindle/giant cells). # Negativity for TTF1 and focal positivity for p63/p40/CK5-6 point to adenocarcinoma cell lineage once neuroendocrine tumours are excluded

Outline



Large cell carcinoma Adenocarcinomas Squamous cell carcinoma Neuroendocrine tumours Sarcomatoid carcinomas Other carcinomas Classification of biopsies in lung cancer

Adenocarcinoma Mixed subtype Acinar Papillary Bronchioloalveolar carcinoma Nonmucinous Mucinous Mixed mucinous and non-mucinous Solid adenocarcinoma with mucin formation Variants

WHO Classification Of Adenocarcinoma 2004

Rationale For New ADC Classification IASLC/ATS/ERS sponsored meeting(s)

Multidisciplinary criticisms in relation to 2004 classification

Bronchioloalveolar carcinoma (BAC) confusing used many different ways despite 99/04 WHO; mucinous and non-mucinous

No classification for biopsies

Greater clinical relevance (too for pathologists by pathologists)

Take into account rapid evolving molecular advances (EGFR)

BAC BRONCHIOLOALVEOLAR

CARCINOMA RIP REST IN PEACE

BAC RIP

March 31, 2008

PREINVASIVE LESIONS AAH ADC-in-situ (formerly pure BAC) *most non-mucinous (NM) (30mm or

less) INVASIVE

Minimally invasive (< 5mm invasion) (30mm or less) Lepidic pattern predominant Acinar pattern predominant/pure Papillary pattern predominant/pure Micropapillary pattern predominant/pure Solid pattern predominant/pure

Invasive mucinous carcinomas

Colloid Fetal (low and high grade) Enteric

l

ADENOCARCINOMA CLASSIFICATION Travis WD et al. JTO Feb 2011;6:244-286

A multidisciplinary approach Respiratory Physician Imaging Surgery Oncology Pathology Molecular Biology

Adenocarcinoma in situ (AIS)

ADENOCARCINOMA-IN-SITU

Minimally Invasive Adenocarcinoma (MIA)

? 5mm or less = microinvasion No necrosis No lymphatic or pleural invasion No spread through alveolar spaces (STAS)

Minimally invasive adenocarcinoma

2a 2b

2c 2d

??? New pattern 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.

Kadota K et al. Mod Pathol Mod Pathol 2014; 27: 690-700

The many faces of BAC

PREINVASIVE LESIONS AAH ADC-in-situ (formerly pure BAC) *most non-mucinous (NM) (30mm or less)

INVASIVE ADC

Minimally invasive (< 5mm invasion,

Updated ADC Classification ...is it working?

IO variation Kappas range from moderate to good for

classic cases (problem with definition of invasion)

PREDOMINANT PATTERN Several papers, higher stages different

countries CORRELATION WITH MOLECULAR

SUBTYPES Predominant pattern, Signet ring, TTF-1 +ve

REPRODUCIBILITY Mod Path 25:1574, 2012 Selected images: kappa Typical patterns: 0.77 Difficult cases: 0.38 Invasion vs noninvasion Typical: 0.55 Difficult: 0.08

ERJ 40:1221-27, 2012 Predominant pattern : Kappa Lung Pathologists: substantial (0.44-.72) Residents: fair (0.38-0.47)

Virch Arch 461:185-93, 2012 Digital images: Consensual votes: 59.6-75% Disagreement decreased significantly after educational sessions (p

Predominant pattern - Validation... Does lung adenocarcinoma

subtype predict patient survival?;. Russell PA et al. JTO 2011;6:1496

A grading system of lung ADC based on histologic pattern

is predictive.in stage I tumors. Sica G AJSP

2010;34:1155

Prognostic significance of ADC patterns... Von der Thusen JTO 2013;8:37-

44

USA Australia

UK

Xu L et al: AJSP 2012;36:273-282

Warth A, J Clin Oncol 2013; 30: 1438-46

Yoshizawa A, et al: J Thor Oncol 2013;8: 52-61

Adenocarcinoma Cell morphology variants

(note, if present, in 5% increments)

Poorer prognosis >50% tumour signet ring

Correlation with EML4-ALK translocation

- Moderate positive predictor - Poor negative predictor

Ensure not metastasis (GI)

Poorer prognosis >10% tumour

No molecular correlation

Ensure not sarcoma metastasis

No prognostic significance

No molecular

correlation

Ensure not metastasis

ADENOCARCINOMA CLASSIFICATION

PREINVASIVE LESIONS AAH ADC-in-situ (formerly pure BAC) *most non-mucinous (NM)

INVASIVE ADC

Minimally invasive (to be defined: < 5mm invasion,

INVASIVE MUCINOUS ADENOCARCINOMA

MUCINOUS AIS and MIA ARE VERY RARE BUT CAN OCCUR

Prognostic Significance of Adenocarcinoma In Situ, Minimally Invasive Adenocarcinoma, and Nonmucinous Lepidic Predominant Invasive Adenocarcinoma of the Lung in Patients With Stage I Disease. Kadota, K et al. American Journal of Surgical Pathology. 38(4):448-460, April 2014.

Variants

Enteric Adenocarcinoma

Well-differentiated fetal adenocarcinoma

Low and high Grade variants of WDFA....

Colloid carcinoma

Outline



Large cell carcinoma Adenocarcinomas and new subtypes Squamous cell carcinoma Neuroendocrine tumours Sarcomatoid carcinomas Other carcinomas Classification of biopsies in lung cancer

SQUAMOUS CELL CARCINOMA (SQCC)

A malignant epithelial tumour showing keratinization and/or intercellular bridges that arises from bronchial epithelium

ADC now more common but SQCC still comprises 20-30% of lung cancers.

Images from WHO 2004

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)

1979-2003: 90 of 1418 NSCLCs were classified as: Basaloid variant of large cell carcinoma

(n=46) Basaloid variant of squamous cell carcinoma

(n=44) Diagnostic criteria:

Relatively small cells with high mitotic rate Forming lobular pattern with peripheral palisading and comedo-type

necrosis Negative NE IHC markers (or

WHO/IASLC grading system (mild moderate and severe dysplasia,

ca-in-situ).

Reproducible (Nicholson AG et al. Histopathology 2001: 38; 202-208.)

Basal Cell hyperplasia

Squamous Metaplasia/ Mild Dysplasia

Normal

Squamous carcinoma sequence

Carcinoma in situ

Outline



Large cell carcinoma Adenocarcinomas and new subtypes Squamous cell carcinoma Neuroendocrine tumours Sarcomatoid carcinomas Classification of biopsies in lung cancer

2015 WHO CLASSIFICATION NEUROENDOCRINE TUMORS

Small cell carcinoma Combined SCLC

Large cell neuroendocrine carcinoma Combined LCNEC

Carcinoid tumor Typical carcinoid Atypical carcinoid

Pre-invasive lesion: Diffuse idiopathic neuroendocrine cell hyperplasia (DIPNECH)

Typical carcinoid Gross pathology.

Typical carcinoid Microscopic patterns.

Typical carcinoid Tricks that it may play.

Spindle Rhabdoid

Atypical carcinoid Number crunching.

Make up 11-24% of bronchopulmonary carcinoid tumours

Greater percentage are peripheral Patients slightly older than for TC More often seen in smokers Commoner to have ectopic endocrine activity 5yr survival - 60-70% (versus 90-98% for TC) 10yr survival -35-59% (versus 82-95% for

TC)

Atypical carcinoid Diagnostic features.

Foci of necrosis (generally small)

and/or

2-10 mitoses/2mm 2 **

Greater architectural disorganisation

Increased pleomorphism Increased incidence of regional

metastases

** ?further subdivision into 2-5 and 6-10 per 2mm2

NEH

CD56

A

C

B

TUMOURLET

Pre-neoplastic disease NEH vs DIPNECH

DIPNECH + OB

C

A

B

DIPNECH Review of 19 cases

9 symptomatic cases (Group 1) 10 cases as an incidental finding during

investigation for another disorder, most frequently malignant disease (Group 2) 7 of these presenting since 2004

Most patients were female (n=15) and never-smokers (n=12/17), aged 31-67.

** Only two series in the literature over 14 years (of 6 and 5 cases respectively)

DIPNECH +

Obliterative Bronchiolitis

Large cell neuroendocrine carcinoma

NE morphology AND NE differentiation on IHC

necrosis more than punctate mitoses >10/10hpf (usually

much higher)

large cell size >3 resting lymphocytes

Low N:C ratio Vesicular nuclei, nucleoli

frequent

Poorly responsive to chemotherapy

Small cell carcinoma Cytological criteria

Size < 3 resting lymphocytes occasional large pleomorphic

nuclei accepted cell borders not seen high N:C ratio finely granular chromatin absent/inconspic nucleoli

Architectural features solid nested trabecular rosettes palisading

Nuclear moulding encrustation nuclear material

vessel walls

CD56 Ki 67 = >95%

Mitoses + Apoptosis Dot-like +ve MNF116

Outline



Large cell carcinoma Adenocarcinomas and new subtypes Squamous cell carcinoma Neuroendocrine tumours Sarcomatoid carcinomas Other carcinomas Classification of biopsies in lung cancer

1.7 Sarcomatoid carcinoma

Pleomorphic carcinoma Spindle cell carcinoma Giant cell carcinoma Carcinosarcoma Pulmonary blastoma

Pleomorphic carcinoma Pleomorphic carcinoma

Malignant giant/spindle cell component (>10%) and NSCLC component

Spindle cell carcinoma NSCLC composed solely of

spindle cells Giant cell carcinoma

NSCLC highly pleomorphic giant cells

Rich inflammatory cell infiltrate

Poorer prognosis than other NSCLC

Should we be using TTF-1, CK5/6, P63, etc to refine LCUC to ADC and SQCC if adjuvant therapy is going to be related to, for example non-squamous histology?

Carcinosarcoma A mixture of

carcinoma and sarcoma containing heterologous elements

Pulmonary blastoma

Biphasic tumour with WDFA type epithelial component but primitive mesenchymal stroma which may contain sarcomatous elements

Lymphoepithelioma-like carcinoma

CD3 +ve, CD1a -ve

MNF116

EBV

1-8: Other carcinomas

NUT-carcinoma

Young adults and children P63 and CK positive NUT-IHC and NUT-FISH to confirm diagnosis

1-8: Other carcinomas

Outline



Large cell carcinoma Adenocarcinomas and new subtypes Squamous cell carcinoma Neuroendocrine tumours Pleomorphic carcinomas Other carcinomas Classification of biopsies in lung cancer

(1999/2004) Malignant Ca NSCLC

(2008-9) NSCLC SQCa

Poorly diff NSCLC ADC

Architecture (BAC/pap/acinar) Grade - IHC (CK5/6,34BE12,p63,TTF-1)

- Mucin stain - Expert referral - Another sample

If clinically relevant

TTF-1,mucin +ve, others ve ..favours ADC TTF-1,mucin ve others +ve ..favours SQCa

CLINICAL DATA MOLECULAR DATA IMAGING DATA

1-1B Rationale for classification in small biopsies and cytology and 1-1C Terminology and

criteria in non-resection specimens:

BIOPSY SUBCLASSIFICATION VALIDATION Practice overtook publication of JTO paper!

Evaluation of adjunct immunohistochemistry on reporting patterns of non-small cell lung carcinoma diagnosed histologically in a regional pathology centre. McLean EC et al. J Clin Pathol. 2011

Immunhistochemistry by Means of Widely Agreed-Upon Markers (Cytokeratins 5/6 and 7, p63, Thyroid Transcription Factor-1, and Vimentin) on Small Biopsies of Non-small Cell Lung Cancer Effectively Parallels the Corresponding Profiling and Eventual Diagnoses on Surgical Specimens. Pelosi G et al. J Thorac Oncol. 2011;6:1039-1049

Suitability of thoracic cytology for new therapeutic paradigms in non-small cell lung carcinoma: high accuracy of tumor subtyping and feasibility of EGFR and KRAS molecular testing. Rekhtman N et al. J Thorac Oncol. 2011;6:451-8

Immunohistochemical algorithm for differentiation of lung adenocarcinoma and squamous cell carcinoma based on large series of whole-tissue sections with validation in small specimens. Rekhtman N et al. Mod Pathol. 2011

Rapid Multiplex Immunohistochemistry Using the 4-antibody Cocktail YANA-4 in Differentiating Primary Adenocarcinoma From Squamous Cell Carcinoma of the Lung. Yanagita E et al. Appl Immunohistochem Mol Morphol. 2011

Subclassification of non-small cell lung carcinomas lacking morphologic differentiation on biopsy specimens: Utility of an immunohistochemical panel containing TTF-1, napsin A, p63, and CK5/6. Mukhopadhyay S, Katzenstein AL. Am J Surg Pathol. 2011;35:15-25

Role of fine needle aspiration cytology, cell block preparation and CD63, P63 and CD56 immunostaining in classifying the specific tumor type of the lung. Kim DH, Kwon MS. Acta Cytol. 2010;54:55-9

Subtyping of undifferentiated non-small cell carcinomas in bronchial biopsy specimens. Loo PS et al. J Thorac Oncol. 2010 ;5:442-7.

Refining the diagnosis and EGFR status of non-small cell lung carcinoma in biopsy and cytologic material, using a panel of mucin staining, TTF-1, cytokeratin 5/6, and P63, and EGFR mutation analysis. Nicholson AG et al. J Thorac Oncol. 2010 Apr;5(4):436-41.

NSCLC-NOS rates are mainly below 15% in the UK (aim for 10%)

SPECIFIC TERMINOLOGY AND CRITERIA FOR ADENOCARCINOMA, SQUAMOUS CELL CARCINOMA AND NON-SMALL CELL CARCINOMA-NOS IN SMALL BIOPSIES AND CYTOLOGY

New Small Biopsy/Cytology Terminology

Morphology/Stains 2015 WHO Classification in resection specimens

Adenocarcinoma (describe identifiable patterns present)

Morphologic adenocarcinoma patterns clearly present

ADENOCARCINOMA (Predominant pattern) Acinar Papillary Solid Micropapillary

Adenocarcinoma with lepidic pattern (if pure, add note: an invasive component cannot be excluded)

Lepidic (nonmucinous) Variants

Invasive mucinous adenocarcinoma (describe patterns present; use term mucinous adenocarcinoma with lepidic pattern if pure lepidic pattern see text) Adenocarcinoma with mucinous features Adenocarcinoma with fetal features Adenocarcinoma with enteric features

Invasive mucinous adenocarcinoma Colloid adenocarcinoma Fetal adenocarcinoma Enteric adenocarcinoma

Squamous cell carcinoma

Morphologic squamous cell patterns clearly present

SQUAMOUS CELL CARCINOMA

Adapted from: Travis WD et al. IASLC/ATS/ERS classification of ADCs J Thor Oncol 2011;6:244-285

SPECIFIC TERMINOLOGY AND CRITERIA FOR ADENOCARCINOMA, SQUAMOUS CELL CARCINOMA AND NON-SMALL CELL CARCINOMA-NOS IN SMALL BIOPSIES AND CYTOLOGY

(continued)

New Small Biopsy/Cytology Terminology

Morphology/Stains 2015 WHO Classification in resection specimens

Non-small cell carcinoma, favor adenocarcinoma

Morphologic adenocarcinoma patterns not present, but supported by special stains, i.e. +TTF-1

Adenocarcinoma (solid pattern may be just one component of the tumor)

Non-small cell carcinoma, favor squamous cell carcinoma

Morphologic squamous cell patterns not present, but supported by stains i.e. +p40

Squamous cell carcinoma, (nonkeratinizing pattern may be just one component of the tumor)

Non-small cell carcinoma, not otherwise specified NSCLC-NOS

No clear adenocarcinoma, squamous or neuroendocrine morphology or staining pattern

LARGE CELL CARCINOMA

Metastatic carcinomas should be carefully excluded with clinical and appropriate but judicious immunohistochemical examination. The categories do not always correspond to solid predominant adenocarcinoma or non-keratinizing squamous cell carcinoma respectively. Poorly differentiated components in adenocarcinoma or squamous cell carcinoma may be sampled. NSCLC-NOS pattern can be seen not only in large cell carcinomas but also when the solid poorly differentiated component of adenocarcinomas or squamous cell carcinomas are sampled but do not express immunohistochemical markers or mucin Thyroid transcription factor-1 (TTF-1), WHO World Health Organization


CLASSIFICATION FOR SMALL BIOPSIES/CYTOLOGY COMPARING 2015 WHO TERMS WITH NEW TERMS FOR SMALL CELL CARCINOMA, LARGE CELL NEUROENDOCRINE CARCINOMA, ADENOSQUAMOUS CARCINOMA AND

SARCOMATOID CARCINOMA

SMALL BIOPSY/CYTOLOGY: IASLC/ATS/ERS 2015 WHO Classification Small cell carcinoma SMALL CELL CARCINOMA Non-small cell carcinoma with neuroendocrine (NE) morphology and positive NE markers, possible LCNEC

Large cell neuroendocrine carcinoma (LCNEC)

Morphologic squamous cell and adenocarcinoma patterns present: Non-small cell carcinoma, NOS, (comment that adenocarcinoma and squamous components are present and this could represent adenosquamous carcinoma).

ADENOSQUAMOUS CARCINOMA

Morphologic squamous cell or adenocarcinoma patterns not present but immunostains favor separate glandular and adenocarcinoma components Non-small cell carcinoma, NOS, (specify the results of the immunohistochemical stains and the interpretation) Comment: this could represent adenosquamous carcinoma.

No counterpart in 2015 WHO classification

NSCC with spindle and/or giant cell carcinoma (mention if adenocarcinoma or squamous carcinoma are present)

Pleomorphic, spindle and/or giant cell carcinoma


No clear ADC or SQCC morphology: NSCLC-NOS

POSITIVE BIOPSY (FOB, TBBx, Core, SLBx)

Classic Morphology: SQCC Keratinization, pearls and/or intercellular bridges

NE morphology, small cells, no nucleoli, NE IHC+, TTF-1 +/-, CK

+

SCLC

NSCLC NOS

SQCC marker +ve ADC marker -ve/or

Mucin -ve

POSITIVE CYTOLOGY (effusion, aspirate, washings,

brushings)

IHC ve and Mucin -ve

Histology: Lepidic, papillary, micropapillary and/or acinar

architecture(s) Cytology: 3-D arrangements, delicate

foamy/ vacuolated (translucent) cytoplasm, Fine nuclear chromatin

and often prominent nucleoli Nuclei are often eccentrically

situated

Classic morphology: ADC

ADC marker and/or

Mucin +ve; SQCC

marker ve (or weak in same cells)

STEP 1

STEP 2

NSCLC, favor SQCC

NSCLC, favor ADC

NE morphology, large cells, NE IHC+

NSCLC, ?LCNEC

Molecular analysis: e.g. EGFR mutation, ALK

rearrangement

Apply ancillary panel of one SQCC and one ADC marker

+/or Mucin

If tumor tissue inadequate for molecular testing, discuss need for further sampling - back to Step 1

STEP 3

ADC marker or Mucin +ve; as well as SQCC marker +ve

in different cells

NSCLC, NOS, possible adenosquamous ca

Adapted from:

Travis WD et al. IASLC/ATS/ERS

classification of ADCs J Thor Oncol 2011;6:244-

285

TTF-1

NSCLC, favouring ADC

P63 or P40

TTF-1

NSCLC, favouring SQCC

Fix quickly Only cut tissue once unless absolutely necessary (take spare sections) H&E (diagnosis in ~ 60% of cases) TTF-1 and P40, P63, or CK5/6 (diagnosis In ~90% of cases)

1-1D Molecular testing for treatment selection in lung cancer

Predictive markers

Excision repair cross-complementation group-1 (ERCC-1) - Platin-based

therapies Ribonucleotide reductase messenger-1(RRM-1) - Gemcitabine-based

therapies Thymidylate synthase (TS) - Pemetrexed-based therapies PD1, PDL1

ADC SQCC

IMPLICATIONS OF NEW WHO CLASSIFICATION FOR TNM STAGING

OF ADENOCARCINOMAS

Multiple tumors: Metastasis vs synchronous/metachronous primaries

Tumor size (use only invasive size)

Terminology: implication of AIS and MIA

Girard, N, et al: AJSP AJSP 33: 1752-64, 2009

DISEASE FREE SURVIVAL COMPARING MARTINI MELAMED VS MOLECULAR VS

SURGICAL PATHOLOGY

Martini Melamed P=0.052

Molecular P=0.013

Surgical Pathology P=0.001

IMPLICATIONS OF NEW WHO CLASSIFICATION FOR TNM STAGING

OF ADENOCARCINOMAS

Multiple tumors: Metastasis vs synchronous/metachronous primaries

Terminology: implication of AIS and MIA

Tumor size

Yoshizawa A, et al Mod Pathol. 2011 May;24(5):653-64.

Should we only be measuring the invasive area?

(b) T1a and T1b defined according to invasive size (P2cm or 3cm).

(a) T1a and T1b defined according to gross tumor

size (P=0.04).

IMPLICATIONS OF IN SITU CONCEPT ON CT MEASURMENT OF TUMOR SIZE: GGO VS SOLID

GROUND GLASS OPACITY PART SOLID

Contributed by C. Henschke & colleagues

POTENTIAL NEW APPROACH TO TUMOR SIZE MEASUREMENT

IMPLICATIONS FOR TNM STAGING

AIS would be classified as Tis Tis (squamous CIS) Tis (AIS)

Similar to breast cancer Tis (DCIS) Tis (LCIS)

MIA would be classified as Tmi T factor size - change to invasive size?

Papers proposing changes for the 8th TNM revision will be published over next 12 months.

Conclusion WHO Classification - 2015

.is a more biologically based classification, although will be based on

microscopic features. . is more relevant to both clinical management of patients and more

closely allied to molecular classifications .takes into account the need for a clinically relevant classification for

biopsy samples

All staff dealing with lung cancer patients should use the classification (e.g. in drug trials) and ensure that tissue is handled in as efficiently as possible to ensure optimal patient management.

Pre-examination phase Examination phase Post-examination phase

Slide Number 1Slide Number 2Slide Number 3WHO CLASSIFICATIONSINCREASING COMPLEXITY2015 WHO CLASSIFICATION2015 WHO CLASSIFICATION2015 WHO CLASSIFICATIONOutlineLARGE CELL CARCINOMA20042015.Recent studies on correspondence of IHC profiles and mutations in LCCSlide Number 14Slide Number 15Subtyping of resected morphologically undifferentiated non-small cell carcinomas (formerly large cell carcinoma)IHC typing of CK + morphologically undifferentiated NSCLC (mucin stains already undertaken to exclude solid pattern ADC**). Focal = 0-10% of cells positive, Diffuse = >10% of cells positiveOutlineWHO Classification Of Adenocarcinoma 2004Rationale For New ADC ClassificationIASLC/ATS/ERS sponsored meeting(s)Multidisciplinary criticisms in relation to 2004 classificationSlide Number 22Slide Number 23Adenocarcinoma in situ (AIS)Slide Number 27Minimally Invasive Adenocarcinoma (MIA)Slide Number 29Slide Number 31Slide Number 32??? New patternThe 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. Kadota K et al. Mod Pathol Mod Pathol 2014; 27: 690-700The many faces of BACUpdated ADC Classification ...is it working? REPRODUCIBILITYPredominant pattern - Validation...Adenocarcinoma Cell morphology variants (note, if present, in 5% increments)ADENOCARCINOMA CLASSIFICATION INVASIVE MUCINOUS ADENOCARCINOMAVariantsOutlineSlide Number 53Squamous cell carcinoma (WHO 2004)Slide Number 55Slide Number 60Outline2015 WHO CLASSIFICATIONNEUROENDOCRINE TUMORSTypical carcinoidGross pathology.Typical carcinoidGross pathology.Typical carcinoidMicroscopic patterns.Typical carcinoidMicroscopic patterns.Typical carcinoidTricks that it may play.Atypical carcinoidNumber crunching.Atypical carcinoidDiagnostic features.Slide Number 78Slide Number 79DIPNECH Review of 19 casesDIPNECH+ Obliterative BronchiolitisLarge cell neuroendocrine carcinomaSmall cell carcinomaSlide Number 84Outline1.7 Sarcomatoid carcinomaPleomorphic carcinomaCarcinosarcomaPulmonary blastomaSlide Number 92NUT-carcinomaOutlineSlide Number 95BIOPSY SUBCLASSIFICATION VALIDATIONPractice overtook publication of JTO paper! SPECIFIC TERMINOLOGY AND CRITERIA FOR ADENOCARCINOMA, SQUAMOUS CELL CARCINOMA AND NON-SMALL CELL CARCINOMA-NOS IN SMALL BIOPSIES AND CYTOLOGY SPECIFIC TERMINOLOGY AND CRITERIA FOR ADENOCARCINOMA, SQUAMOUS CELL CARCINOMA AND NON-SMALL CELL CARCINOMA-NOS IN SMALL BIOPSIES AND CYTOLOGY (continued)CLASSIFICATION FOR SMALL BIOPSIES/CYTOLOGY COMPARING 2015 WHO TERMS WITH NEW TERMS FOR SMALL CELL CARCINOMA, LARGE CELL NEUROENDOCRINE CARCINOMA, ADENOSQUAMOUS CARCINOMA AND SARCOMATOID CARCINOMA Slide Number 100Slide Number 1011-1D Molecular testing for treatmentselection in lung cancerIMPLICATIONS OF NEW WHO CLASSIFICATION FOR TNM STAGING OF ADENOCARCINOMAS DISEASE FREE SURVIVAL COMPARINGMARTINI MELAMED VS MOLECULAR VS SURGICAL PATHOLOGYIMPLICATIONS OF NEW WHO CLASSIFICATION FOR TNM STAGING OF ADENOCARCINOMAS Slide Number 121IMPLICATIONS OF IN SITU CONCEPT ON CT MEASURMENT OF TUMOR SIZE: GGO VS SOLIDIMPLICATIONS FOR TNM STAGINGConclusion

who classification of lung cancer 2014

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