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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

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 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

1-6: Adenosquamous
carcinoma

1-7: Sarcomatoid carcinoma

1-4A: Small cell carcinoma


1-4B: Large cell
neuroendocrine
carcinoma

1-7A: Pleomorphic, spindle


cell and giant cell carcinoma

1-4C: Carcinoid tumors

1-7B: Carcinosarcoma

1-4D: Preinvasive lesion:


Diffuse idiopathic pulmonary
neuroendocrine cell
hyperplasia

1-7C: Pulmonary blastoma

1-5: Large cell carcinoma

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:
1-11B:
1-11C:
1-11D:

Sclerosing pneumocytoma
Alveolar adenoma
Papillary adenoma
Mucinous cystadenoma

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 EWSR1CREB1 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

1-11E: 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

1-14: 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...

WHO classification
1981-1999-2004-2015

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

Null phenotype on IHC


Unclear phenotype on IHC
No IHC available

carcinoma 8013/3
Combined large cell
neuroendocrine carcinoma 8013/3
Basaloid carcinoma 8123/3
Lymphoepithelioma-like carcinoma
8082/3

ADC on IHC (NOW UNDER ADC,

Clear cell carcinoma 8310/3


Large cell carcinoma with rhabdoid
phenotype 8014/3

Large cell carcinoma

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

Mod Pathol Epub Oct 2012

Arch of Pathol Epub June 2013

Virchows Arch Epub Nov 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.

P40

C
TTF-1

P40
E

F
TTF-1

H
P40

ITTF-1

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

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.
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

DIAGNOSIS

(RESECTION)

(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

THE REQUIREMENTS OF A CLASSIFICATION SYSTEM...

WHO classification
1981-1999-2004-2015

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

WHO Classification Of Adenocarcinoma 2004

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

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
RIP
March 31,
2008

BAC
BRONCHIOLOALVEOLAR
CARCINOMA
RIP REST IN PEACE

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

PREINVASIVE LESIONS

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

INVASIVE
l invasive (< 5mm invasion) (30mm or less)
Minimally

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

A multidisciplinary approach
Respiratory Physician
Imaging
Surgery
Oncology
Pathology
Molecular Biology

Adenocarcinoma in situ (AIS)

ADENOCARCINOMA-IN-SITU

Minimally Invasive Adenocarcinoma (MIA)

Minimally invasive adenocarcinoma

? 5mm or less = microinvasion


No necrosis
No lymphatic or pleural invasion
No spread through alveolar spaces (STAS)

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, <5mm scar (30mm or less)


Lepidic pattern predominant
Acinar pattern predominant/pure
Papillary pattern predominant/pure
Micropapillary pattern predominant/pure
Solid pattern predominant/pure

Mucinous carcinomas
Fetal (low and high grade)
Enteric

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<0.001)

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

USA

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;8:3744

Australia

Warth A, J Clin Oncol


2013; 30: 1438-46
Xu L et al: AJSP
2012;36:273-282
Yoshizawa A, et al: J Thor Oncol
2013;8: 52-61

UK

Adenocarcinoma
Cell morphology variants
(note, if present, in 5% increments)

No prognostic
significance

No molecular correlation

No molecular
correlation

Ensure not sarcoma


metastasis

Ensure not metastasis

Poorer prognosis
>50% tumour signet ring

Poorer prognosis
>10% tumour

Correlation with EML4-ALK


translocation
- Moderate positive predictor
- Poor negative predictor

Ensure not metastasis (GI)

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 carcinomas


Fetal (low and high grade)
Colloid
Enteric

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

THE REQUIREMENTS OF A CLASSIFICATION SYSTEM...

WHO classification
1981-1999-2004-2015

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 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
Images from WHO 2004 and Pathology of the Lung. Ed. Corrin and Nicholson)
situ

Moro-Sibilot et al. ERJ 2008;31:854-59


Lung carcinomas with a baslaoid pattern

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 <10% tumor cells) to exclude NE carcinoma

LCC variant: No intercellular bridges or individual cell keratinization, foci


of abrupt pearl formation without progressive squamous maturation

SCC variant: Presence of squamous differentiation in <50%

The survival of basaloid variants of LCC and SCC was


comparable.

Median and overall survival were significantly lower


for BC than for NSCLC in stage I-II patients, with a
median survival of 29 and 49 months, respectively,
and 5-yr survival rates of 27 and 44% for BC and
NSCLC.
When disease-specific survival was considered, BC
had a shorter survival than both NSCLC and SCC

Kim DJ, Kim KD, Shin DH, Ro JY, Chung KY. Basaloid
carcinoma of the lung: a really dismal histologic variant?
Ann Thorac Surg 2003 December;76(6):1833-7.
(N=35)
Basaloid carcinoma of the lung does not have a worse
prognosis than the other nonsmall cell lung cancers.

Basaloid pattern confers a poor prognosis in nonsmall cell lung carcinoma,


especially in stage I-II patients.

Squamous carcinoma sequence


Normal

Basal
Cell
hyperplasia

WHO/IASLC grading system


(mild moderate and severe dysplasia,
ca-in-situ).

Reproducible (Nicholson AG et al.


Histopathology 2001: 38; 202-208.)

Squamous
Metaplasia/
Mild
Dysplasia

Carcinoma in situ

Outline

THE REQUIREMENTS OF A CLASSIFICATION SYSTEM...

WHO classification
1981-1999-2004-2015

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 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
Gross pathology.

Typical carcinoid
Microscopic patterns.

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

Greater architectural
disorganisation
Increased pleomorphism
Increased incidence of regional
metastases

**

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

Pre-neoplastic disease NEH vs DIPNECH

NEH

TUMOURLET

B
CD56

DIPNECH + OB

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 neversmokers (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

Mitoses + Apoptosis

Ki 67 = >95%

Dot-like +ve MNF116

CD56

Outline

THE REQUIREMENTS OF A CLASSIFICATION SYSTEM...

WHO classification
1981-1999-2004-2015

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 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

1-8: Other carcinomas

MNF116

Lymphoepithelioma-like carcinoma

CD3 +ve, CD1a -ve

EBV

1-8: Other carcinomas

NUT-carcinoma

Young adults and children


P63 and CK positive
NUT-IHC and NUT-FISH to confirm diagnosis

Outline

THE REQUIREMENTS OF A CLASSIFICATION SYSTEM...

WHO classification
1981-1999-2004-2015

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

1-1B Rationale for classification in


small biopsies and cytology and 1-1C Terminology and
criteria in non-resection specimens:

(1999/2004) Malignant
(2008-9)

Ca

NSCLC

SQCa

Poorly diff NSCLC


If clinically relevant
- IHC (CK5/6,34BE12,p63,TTF-1)
- Mucin stain
- Expert referral
- Another sample

NSCLC

ADC
Architecture (BAC/pap/acinar)
Grade

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


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

CLINICAL DATA
MOLECULAR DATA
IMAGING DATA

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

Adenocarcinoma
(describe identifiable patterns
present)

Morphologic adenocarcinoma
patterns clearly present

2015 WHO Classification


in resection specimens
ADENOCARCINOMA
(Predominant pattern)
Acinar
Papillary
Solid
Micropapillary
Lepidic (nonmucinous)

Adenocarcinoma with lepidic


pattern (if pure, add note: an
invasive component cannot be
excluded)
Variants
Invasive mucinous
adenocarcinoma

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

Squamous cell carcinoma

Colloid adenocarcinoma
Fetal adenocarcinoma
Enteric adenocarcinoma

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 NSCLCNOS

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

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

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
Small cell carcinoma
Non-small cell carcinoma with neuroendocrine (NE) morphology and
positive NE markers, possible LCNEC

2015 WHO Classification


SMALL CELL CARCINOMA
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

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

STEP 1
POSITIVE BIOPSY (FOB,
TBBx, Core, SLBx)
POSITIVE CYTOLOGY
(effusion, aspirate, washings,
brushings)

Adapted from:
Travis WD et al.
IASLC/ATS/ERS
classification of ADCs J
Thor Oncol 2011;6:244285

NE morphology, large cells,


NE IHC+

NSCLC, ?LCNEC

NE morphology, small cells, no


nucleoli, NE IHC+, TTF-1 +/-, CK
+

SCLC

Keratinization, pearls
and/or intercellular bridges

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

No clear ADC or SQCC


morphology:
NSCLC-NOS

NSCLC, favor SQCC

Classic morphology:
ADC
ADC marker
and/or
Mucin +ve;
SQCC
marker ve
(or weak in
same cells)

Classic Morphology: SQCC

STEP 2

SQCC marker +ve


ADC marker -ve/or
Mucin -ve

Apply ancillary panel of


one SQCC and one ADC marker
+/or Mucin

IHC ve and
Mucin -ve

ADC marker or Mucin +ve;


as well as SQCC marker +ve
in different cells

NSCLC, favor ADC


NSCLC NOS

NSCLC, NOS, possible


adenosquamous ca

Molecular analysis:
e.g. EGFR mutation, ALK
rearrangement
STEP 3

If tumor tissue inadequate for molecular testing,


discuss need for further sampling - back to Step 1

Fix quickly
Only cut tissue once
unless absolutely
necessary (take spare
sections)

P63 or P40

H&E (diagnosis in
~ 60% of cases)
NSCLC, favouring ADC

TTF-1

NSCLC, favouring SQCC

TTF-1

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

ADC

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

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

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

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

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

Should we only be measuring the invasive


area?
Disease-free survival (DFS) comparing T1a (2cm) versus T1b (>2cm or 3cm).

(a) T1a and T1b defined


according to gross tumor
size (P=0.04).

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

(b) T1a and T1b defined according


to invasive size (P<0.001).

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

POTENTIAL NEW
APPROACH
TO TUMOR SIZE
MEASUREMENT

GROUND GLASS OPACITY

PART SOLID

Contributed by C. Henschke & colleagues

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