ADVANCES IN LUNG CANCER DIAGNOSIS - pathcme.com · ADVANCES IN LUNG CANCER DIAGNOSIS 3rd Annual Southeastern Pathology Conference Greenville, South Carolina Saturday, November 3,

ADVANCES IN LUNG CANCER DIAGNOSIS

3rd Annual Southeastern Pathology

ConferenceGreenville, South Carolina

Saturday, November 3, 2018

William D. Travis, M.D.Attending Thoracic Pathologist

Memorial Sloan Kettering Cancer Center

New York, NY

http://whobluebooks.iarc.fr/

NON-SMALL CELL LUNG CANCER: 70% PRESENT IN

ADVANCED STAGE

70%

30%

Percent

Advanced StageEarly Stage

Results in EGFR mutation positive and negative patients ( All Asian, 94% Never Smokers)

–EGFR mutation positive –EGFR mutation negative

–HR (95% CI) = 0.48 (0.36, 0.64) p<0.0001

–No. events gefitinib: 97No. events Chemo: 111

Gefitinib (n=132)Carboplatin / paclitaxel (n=129)

–HR (95% CI) = 2.85 (2.05, 3.98)p<0.0001

–No. events gefitinib: 88No. events Chemo: 70

–132 –71 –31 –11 –3 –0–129 –37 –7 –2 –1 –0

–108–103

–0 –4 –8 –12 –16 –20 –24

–Gefitinib–C / P

–0.0

–0.2

–0.4

–0.6

–0.8

–1.0

–Pro

babi

lity

of p

rogr

essi

on-fr

ee s

urvi

val

–At risk :–91 –4 –2 –1 –0 –0–85 –14 –1 –0 –0 –0

–21–58

–0 –4 –8 –12 –16 –20 –24–0.

0

–0.2

–0.4

–0.6

–0.8

–1.0

–Pro

babi

lity

of p

rogr

essi

on-fr

ee s

urvi

val

Gefitinib (n=91)Carboplatin / paclitaxel (n=85)

–Months –Months

–Gefitinib CR/PR Rate 71%–CBP/PTX CR/PR Rate 47%

–Gefitinib CR/PR Rate 1%–CBP/PTX CR/PR Rate 24%

–Mok N Engl J Med 361: 947-57, 2009

Initial Therapy of Advanced Adenoca or NSCLC-NOS–Adenocarcinoma–Large cell ca–NSCLC-NOS

–EGFR Mutation–Exon 19 del

–Exon 21 L858R, L861X–Exon 18 G719A/S

–Unknown EGFR

Mutation & ALKStatus

–Neg EGFR mut

–Pos ALK fusion

–Erlotinib/Gefitinib–±

–Pem/Bev/Cis

–Pemetrexed–Bevacizumab–Cisplatin

Modified from Mark Kris, Thoracic Oncology, MSKCC

–Crizotinib

–Neg EGFR mut

–Neg ALK fusion

CLASSIFICATION OF LUNG CANCER NOW REQUIRES GENETIC TESTING

MSK-IMPACT NGD data, 2017 – now includes 468 genesCourtesy of Marc Ladanyi

–Jordan EJ Ca Discovery 7:596-609, 2017

MOLECULAR TARGETED THERAPYTarget Drug

EGFRErlotinibAfatinib

ALK fusions CrizotinibCeritinib, Alectinib

BRAF V600E DabrafenibROS1 fusions Loatinib, CrizotinibRET fusions Cabozantinib

MET splice site Exon 14 mutations

Cabozantinib (and crizotinib)

Courtesy of Greg Riely

Targeted therapy for fusion-positive lung cancers

Fusion gene FDA-approved NCCN guidelines for NSCLCs

FDA breakthrough

designation

Clinical trials

ALK

AlectinibCeritinib

BrigatinibCrizotinib

Lorlatinib

ROS1 Crizotinib Ceritinib LorlatinibCabozantinib

RETCabozantinibVandetanib

LOXO-292BLU-667

NTRK1-3LarotrectinibEntrectinib

NRG1HER2 and HER3

inhibitors

FGFR1-3 FGFR inhibitors

BRAF RAF inhibitors

Courtesy Alex Drilon

Initial Therapy of Advanced Adenoca or NSCLC-NOS–Adenocarcinoma–Large cell ca–NSCLC-NOS

–EGFR Mutation–Exon 19 del

–Exon 21 L858R, L861X–Exon 18 G719A/S

–Unknown EGFR

Mutation & ALKStatus

–Neg EGFR mut

–Pos ALK fusion

–Erlotinib/Gefitinib–±

–Pem/Bev/Cis

–Pemetrexed–Bevacizumab–Cisplatin

Modified from Mark Kris, Thoracic Oncology, MSKCC

–Crizotinib

–Neg EGFR mut

–Neg ALK fusion

Could add ROS1 fusion, BRAF mutation, RET fusion, MET splice site exon14 mutation to this algorithm

2015 WHO Classification of Lung Tumors

NEW CHAPTER:CLASSIFICATION IN SMALL

BIOPSY AND CYTOLOGY SPECIMENS

SMALL BIOPSY/CYTOLOGY LUNG CANCER DIAGNOSIS: IN USA OVER 139,000 CASES IN 2018

▪ 2018: ACS estimates for USA: • 234,030 Lung Cancers• Sigel RA et al: CA Cancer J Clin 2018:68:7-30

85% NSCLC = 198,926 (15% SCLC)▪ 70% Advanced Stage = 139,248

• Unresectable: Diagnosed by small biopsies/cytology

PHASE III STUDY COMPARING CISPLATIN PLUS GEMCITABINE WITH CISPLATIN &

PEMETREXED IN ADVANCED NSCLC

Scagliotti G, et al: JCO 26:3543-51, 2008

50%

29%

9%

12%

Percent

Adenoca Squamous Ca Large cell Ca NSCLC, NOS

PHASE III STUDY COMPARING CISPLATIN PLUS GEMCITABINE WITH CISPLATIN &

PEMETREXED IN ADVANCED NSCLC

Scagliotti G, et al: JCO 26:3543-51, 2008

50%

29%

9%

12%

Percent

Adenoca Squamous Ca Large cell Ca NSCLC, NOS

–IN THIS STUDY APPROXIMATELY 20% OF CASES REPRESENT NSCLC-NOS

2015 WHO TERMINOLOGY FOR SMALL BIOPSIES AND CYTOLOGY

2015 WHO Resections Small Biopsy/CytologyADENOCARCINOMA

LepidicAcinarPapillaryMicropapillarySolid

Morphologic adenocarcinoma patterns clearly present:

Adenocarcinoma, describe identifiable patterns present

No 2004 WHO counterpart – most will be solid adenocarcinomas

Morphologic adenocarcinoma patterns not present (supported

by special stains; i.e TTF-1 +; p40 -):

Non-small cell carcinoma, favor adenocarcinomaSQUAMOUS CELL CARCINOMA

KeratinizingNonkeratinizingBasaloid

Morphologic squamous cell patterns clearly present:

Squamous cell carcinoma

No 2004 WHO counterpart Morphologic squamous cell patterns not present (supported by

stains; i.e. p40+, TTF-1 -):

Non-small cell carcinoma, favor squamous cell carcinomaLARGE CELL CARCINOMA Non-small cell carcinoma, not otherwise specified (NOS)

2015 WHO Classification

Nonsmall cell carcinoma, favor squamous cell carcinoma

P40 (TTF-1 was negative)

NONSMALL CELL CARCINOMA, FAVOR ADENOCARCINOMA

TTF-1 (p40 was negative)

IMMUNOHISTOCHEMICAL MARKERS

▪ ADENOCARCINOMA (ONE MARKER)• TTF-1 (best), Napsin, PE-10

▪ SQUAMOUS CARCINOMA (ONE MARKER)• p40 (best), p63, CK5/6, 34βE12• Desmocolin-3 (need more testing)

▪ Cocktails – nuclear/cytoplasmic antibodies• Adenoca – TTF-1/Napsin• Squamous – p63/CK5/6

LIGHT MICROSCOPY

ADENO-CARCINOMA

NSCLC-NOS

20-30%

20-40%

40-50%NSCLC-NOS

Goal <5%

FORMER NSCLC-

NOS:20-40% OF NSCLC

SQUAMOUS CELL CARCINOMA

NEW CLASSIFI-

CATION

TISSUE MANAGEMENT▪ Each group of thoracic physicians

(clinicians, radiologists, surgeons, pathologists, molecular biologists) must develop a strategy to manage tissues

▪ Obtaining biopsies or cytology samples▪ Optimal processing by

laboratories/pathologists for diagnosis AND molecular studies

▪ Pathologists are the ideal leader of this

PERSONALIZED MEDICINE IN ADVANCED LUNG CANCER

PATIENTS IS DRIVEN BY HISTOLOGY AND GENETICS

BELLAGIO CENTERROCKEFERLLER

FOUNDATION

WRITINGCOMMITTEE

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

INCREASING RELEVANCE FORPERSONALIZED MEDICINE

NEW CONCEPTS IN 2015 WHO CLASSIFICATION OF LUNG TUMORS

▪ Use of immunohistochemistry throughout▪ New emphasis on genetic studies &

personalized therapeutic strategies▪ New classification of lung cancer in small

biopsy & cytology samples▪ Adopted the 2011 IASLC/ATS/ERS Lung

Adenocarcinoma classification▪ Solid adenocarcinomas: pneumocyte

marker or mucin positive

▪ Restrict large cell carcinoma to tumors lacking clear differentiation by both IHC and morphology

▪ Reclassify squamous cell ca: keratinizing, nonkeratinizing and basaloid

▪ Diagnosis of nonkeratinizing squamous cell carcinoma requires IHC (p40+, TTF1-)

▪ Group NE tumors together (TC,AC, LCNEC, SCLC)

NEW CONCEPTS IN 2015 WHO CLASSIFICATION OF LUNG TUMORS

LARGE CELL CARCINOMA

GENOMICS-BASED CLASSIFICATION OF HUMAN LUNG TUMORS (CLCGP) Sci Transl Med 5, 209ra153, 2013

SEER DATA BY HISTOLOGIC TYPE: RATES PER 100,000 PY

–Lewis D et al; Cancer 2014; 120: 2883-92

LARGE CELL CARCINOMA1999 & 2004 WHO Classification

▪ Large cell carcinoma▪ Large cell neuroendocrine carcinoma• Combined LCNEC

▪ Basaloid carcinoma▪ Lymphoepithelioma-like carcinoma▪ Clear cell carcinoma▪ Large cell carcinoma with rhabdoid

phenotype

IMMUNOHISTOCHEMICAL, CLINICAL AND MOLECULAR HETEROGENEITY OF LARGE CELL CARCINOMA

–Virchows Arch 464:61-8, 2014

–Mod Pathol 26:511-22, 2013

–Arch of Pathol 138:626-35, 2014

–Sci Transl Med 5:209ra 153, 2013

–Rekhtman et al Mod Pathol 26:511-22, 2013

DISTRIBUTION OF MUTATIONS AND IMMUNOMARKER DEFINED TYPES OF LARGE CELL CARCINOMA

2015 WHO CLASSIFICATION: WHERE WILL THE LARGE CELL CARCINOMAS GO?

▪ Pneumocyte marker (TTF-1) positive LCC solid adenoca

▪ Squamous marker positive (p40) LCC nonkeratinizing squamous cell ca

▪ Large cell neuroendocrine carcinoma• Combined LCNEC NE tumors

▪ Basaloid carcinoma Squamous ca

2015 WHO CLASSIFICATION: WHERE WILL THE LARGE CELL CARCINOMAS GO?

▪ Lymphoepithelioma-like carcinoma Other carcinomas

▪ Clear cell carcinoma (Cytologic pattern not subtype)

▪ Large cell carcinoma with rhabdoid phenotype (Cytologic pattern not subtype)

LARGE CELL CARCINOMA2015 WHO Classification

▪ Large cell carcinoma with null immunohistochemical features and no mucin

▪ Large cell carcinoma with unclear immunohistochemical features

▪ Large cell carcinoma with no stains available

PSEUDOSQUAMOUS SOLID ADENOCARCINOMA

TTF-1 Mucicarmine

EGFR Exon 19 Deletion

PSEUDOKERATINIZING ADENOCARCINOMA

TTF-1 p40

2015 WHO CLASSIFICATION SQUAMOUS CELL CARCINOMA

▪ Keratinizing

▪ Non-keratinizing

▪ Basaloid carcinoma

now need IHC –P40 positive,

TTF-1 negative

now need IHC –(+p40, -TTF1 & NE markers) r/o

LCNEC & SCLC

52%

40%

8%

NK SqC 86%

LCNEC 1%

Adenoca7%

Adc 4%

LCC 2%

K SqC 99.6%

AdSq 0.4%

SCLC & LCNEC 5% each

B Sq 90%

–Kadota K et al; AJSP 39:1170-80, 2015

SQUAMOUS CARECLASSIFICATON

Two TTF-1 Abs–8G7G3 – more specific–SPT24 – more sensitive, less specific

52%

40%

8%

NK SqC86%

LCNEC 1%

Adenoca7%

Adc 4%

LCC 2%

K SqC 99.6%

AdSq 0.4%

SCLC & LCNEC 5% each

B Sq 89%

SQUAMOUS CARECLASSIFICATON

Total 480 Cases Previously Dx’d Sq Ca449 (93.5%) remained as squamous cell carcinoma20 (4.2%) – Adenocarcinoma6 (1.3%) High grade NE carcinoma

(4 LCNEC, 2 SCLC)4 (0.8%) – Large cell carcinoma1 (0.2%) – Adenosquamous carcinoma

–Kadota K et al; AJSP 39:1170-80, 2015

KEY ISSUESSQUAMOUS CELL CARCINOMA

▪ Tumor budding and tumor nest size are the most significant histologic prognostic factors

▪ Histologic subtyping (keratinizing, nonkeratinizing, basaloid) not clearly prognostically important

SQUAMOUS CELL CARCINOMATUMOR BUDDING AND NEST SIZE

SINGLE CELL INVASION

TUMOR BUDDING AND NEST SIZE < 5 CELLS

Kadota K et al: JTO 9:1126-39, 2014

Maeshima AM: Lung Ca 52:53-58, 2006Masuda R: Mol Med Rep 6:937-43, 2012Taira T: Lung Ca 76:423-30, 2012Weichert W et al; ERJ 47:938-46, 2015Zhao Y: Medicine 94:e1634, 2015Kadota K: AJSP 41: 750-60, 2017

SQUAMOUS CELL CARCINOMASurvival by Budding & Nest Size

Weichert W et al : Eur Resp J 47: 938-46, 2015

Tumor Budding: 0, 1-15 vs >=15/10HPF Tumor Nest Size: Single, <5, 5-15, >15

SUMMARY▪ 2015 WHO Classification provides diagnostic

criteria and terminology to be used in small bxand cytology

▪ Need strategic approach to use of small specimens not only for diagnosis but for molecular testing

▪ Rapidly evolving field requires following new technology (IHC, molecular)

▪ Need multidisciplinary team▪ Large cell carcinoma – largely reclassified▪ Squamous cell ca – tumor budding/nest size is

prognostic