Recent Developments in Pathological Diagnosis and Classification of Lung Cancer Serpil Dizbay Sak Ankara ÜTF, Patoloji ABD 15. Toraks Kongresi Nisan 2012/Antalya

Conflict of Interest: NONE TO DECLARE

Topics “Old” classification Why do we need change? The new (proposed) classification

OLD CLASSIFICATION

TC Sağlık Bakanlığı

T.C. Sağlık Bakanlığı Kanserle Savaş Dairesi Yaşa spesifik insidans  Erkek Kadın Kaba insidens hızı 74,85 10,68 Yaşa standardize insidens hızı (YSH)  75,80 9,58 Expected number of new cases in Turkey 30.239 Türkiye’nin Akciğer Kanseri Haritası Projesi Türk Toraks Derneği/ Akciğer ve Plevra Maligniteleri Çalışma Grubu T.C. Sağlık Bakanlığı Kanserle Savaş Dairesi

2004 Written by pathologists for pathologists Surgical resection specimens

Akciğerin malign epitelyal tümörleri (WHO 2004) İNVAZİV 1.Yassı hücreli karsinoma 2.Küçük hücreli karsinoma 3. Adenokarsinoma 4. Büyük hücreli karsinoma 5. Adenoskuamöz karsinoma 6. Sarkomatoid karsinoma 7. Karsinoid tümör 8.Tükrük bezi tipi karsinomalar PREKÜRSÖR-ÖNCÜ 9.Preinvaziv lezyonlar Displazi- CIS AAH DIPNECH

Adeno carcinoma(25-40%) ↑ SCC (25-40%) ↓ Small cell (20-25%) WHO 2004 Adeno carcinoma(25-40%) ↑ SCC (25-40%) ↓ Small cell (20-25%) Large cell (%10-25)

Akciğerin malign epitelyal tümörleri Mevcut Sınıflama (WHO2004) 4. Büyük hücreli karsinoma a. Büyük hücreli nöroendokrin karsinoma b.Bazoloid karsinoma c.Lenfoepitelyoma benzeri karsinoma d. Şeffaf (berrak) hücreli karsinoma g.  Rabdoid fenotipli büyük hücreli karsinoma 5. Adenoskuamöz karsinoma 6. Sarkomatoid karsinomalar a.       Pleomorfik karsinoma b.       İğsi hücreli karsinoma c.       Dev hücreli karsinoma b.       Karsinosarkoma c.       Pulmoner blastoma 7. Karsinoid tümör a.Tipik karsinoid b.Atipik karsinoid 8.Tükrük bezi tipi karsinomalar a.       Mukoepidermoid karsinoma b.       Adenoid kistik karsinoma c.       Epitelyal-myoepitelyal 9.Preinvaziv l ezyonlar a.İn situ yassı hücreli karsinoma b.Atipik adenomatöz hiperplazi c. Diffüz idiyopatik pulmoner nöroendokrin hücre hiperplazisi   1.Yassı hücreli karsinoma a.       Papiller b.       Şeffaf (berrak) hücreli c.       Küçük hücreli d.       Bazaloid 2.Küçük hücreli karsinoma Kombine küçük hücreli karsinoma 3. Adenokarsinoma a.       Asiner b.       Papiller c.       Bronkioloalveolar karsinoma: müsinöz/nonmüsinöz/mikst d.       Müsin bulunduran solid e.       Mikst adenokarsinoma Varyantlar: Fetal Müsinöz karsinom Müsinöz kistadeno karsinom Taşlı yüzük hücreli karsinom Berrak hücreli karsinom 3. Adenokarsinoma a.       Asiner b.       Papiller c.       Bronkioloalveolar karsinoma: müsinöz/nonmüsinöz/mikst d.       Müsin bulunduran solid e.       Mikst adenokarsinoma

WHO 2004

WHO 2004

Adenokarsinoma a. Asiner b. Papiller c. Bronkioloalveolar karsinoma d. Müsin bulunduran solid adenokarsinoma e. Mikst adenokarsinoma %90 Mikst tipte (asiner, papiller ve BAK patterni bulunduran) adenokarsinoma

Stage of NSCLC by the time of diagnosis Number (%) IA 72 1.8 IB 336 8.3 IIA 21 0.5 IIB 234 5.8 IIIA 446 11.0 IIIB 1248 30.8 IV 1696 41.8 Total 4053 100.0 72.6 % Türkiye’nin Akciğer Kanseri Haritası Projesi Türk Toraks Derneği/ Akciğer ve Plevra Maligniteleri Çalışma Grubu T.C. Sağlık Bakanlığı Kanserle Savaş Dairesi

Only small biopsy and cytology specimens are available in advanced disease

Classification is difficult in small specimen Necrosis Artefacts Lack of differantiation Tumor heterogeneity

Non-small cell carcinoma Adenocarcinoma SCC Large cell

Simple Reproducable Sufficient for patient management Chemo for small cell Surgery or cytotoxic therapy for NSCLC

CHANGE, WHY?

NEED FOR NEW PROGNOSTIC CATEGORIES Why Change? New and Targeted therapies Prognostic information on small BAC’s Molecular characterization of lung cancer New agents for adenocarcinoma Histologic eligibility criteria for some new drugs Excellent prognosis of pure BAC and BAC with minimal invasion DEMISE OF NSCLC NEED FOR NEW PROGNOSTIC CATEGORIES

NEED FOR NEW PROGNOSTIC CATEGORIES Why Change? New and Targeted therapies Prognostic information on small BAC’s Molecular characterization of lung cancer New agents for adenocarcinoma Histologic eligibility criteria for some new drugs Excellent prognosis of pure BAC and BAC with minimal invasion DEMISE OF NSCLC NEED FOR NEW PROGNOSTIC CATEGORIES

Normal akciğere bi daha bi görelim

Lung adenocarcinoma measuring 2 cm or less A Lokalized BAC Noguchi M, Morikawa A, Kawasaki M, et al. Small adenocarcinoma of the lung. Histologic characteristics and prognosis. Cancer. 1995;75:2844–2852. Lung adenocarcinoma measuring 2 cm or less A Lokalized BAC B Lokalized BAC-focal alveolar collapse C Lokalized BAC-focal aktve fibroblastic proliferation 4. D Poorly differentiated AC E Tubular adenocarcinoma F Papillary adenocarcinoma with compressive and destructive growth

LOH in tumor supressor genes: Noguchi A (BAC): 17% Aoyagi Y, Yokose T, Minami Y, et al. Accumulation of losses of heterozygosity and multistep carcinogenesis in pulmonary adenocarcinoma. Cancer Res. 2001;61:7950–7954. LOH in tumor supressor genes: Noguchi A (BAC): 17% Noguchi B (BAK-focal alveolar collapse):40% Noguchi C (BAK-focal active fibroblastic proliferation): 96%

In-situ adenocarcinoma: BAC 0 % Koga T, Hashimoto S, Sugio K, et al. Clinicopathological and molecular evidence indicating the independence of bronchioloalveolar components from other subtypes of human peripheral lung adenocarcinoma. Clin Cancer Res. 2001;7:1730–1738. P53 mutation In-situ adenocarcinoma: BAC 0 % Early invazive adenocarcinoma (Minimally invazive adenocarcinoma) : Mixt type adenocarcinoma with a major BAC component 11% Late adenocarcinoma: Other adenocarcinomas 48%

In-situ adenocarcinoma Early invazive adenocarcinoma (Minimally invazive adenocarcinoma) Late adenocarcinoma

NEED FOR NEW PROGNOSTIC CATEGORIES Why Change? New and Targeted therapies Prognostic information on small BAC’s Molecular characterization of lung cancer New agents for adenocarcinoma Histologic eligibility criteria for some new drugs Excellent prognosis of pure BAC and BAC with minimal invasion DEMISE OF NSCLC NEED FOR NEW PROGNOSTIC CATEGORIES

New Agents Agent Trade name Type Erlotinib Tarceva Adenocarcinoma Gefitinib Iressa Bevacizumab Avastin Non-squamous Pemetrexed Alimta Etkinlik Toksisite Etkinlik NSCLC is not enough now

NEW (PROPOSED) CLASSIFICATION

2011 Multidisciplinary approach Small specimens

WHAT İS NEW? ReSECTIONS

Strong Recommendations For nonmucinous adenocarcinomas previously classified as mixed subtype where the predominant subtype consists of the former nonmucinous BAC, the use of the term LPA and discontinuing the term “mixed” subtype In patients with early-stage adenocarcinoma, the addition of “micropapillary predominant adenocarcinoma” as a major histologic subtype due to its association with poor prognosis Discontinuing the use of the term “BAC” For small (3 cm), solitary adenocarcinomas with pure lepidic growth, the use of term “Adenocarcinoma in situ” For small (3 cm), solitary, adenocarcinomas with predominant lepidic growth and small foci of invasion measuring 0.5 cm, the use of a new concept: “Minimally invasive adenocarcinoma”

Other Recommendations For invasive adenocarcinomas, comprehensive histologic subtyping be used to assess histologic patterns semiquantitatively in 5% increments, choosing a single predominant pattern. Individual tumors be classified according to the predominant pattern In patients with multiple lung adenocarcinomas, comprehensive histologic subtyping in the comparison of the complex, heterogeneous mixtures of histologic patterns to determine whether the tumors are metastases or separate synchronous or metachronous primaries

WHO 2004

100 % DFS

Micropapillary Solid Lepidic Aciner Papillary

Micropapillary pattern: Poor prognosis

Örnek: İNVAZİV ADENOKARSİNOMA, ASİNER TİP BASKIN ( % 50 ASİNER, %25 PAPİLLER, %25 LEPİDİK TİP) İNVAZİV ADENOKARSİNOMA, MÜSİN OLUŞTURAN SOLİD TİP BASKIN ( % 70 MÜSİN OLUŞTURAN SOLİD , %30 ASİNER TİP) İNVAZİV ADENOKARSİNOMA, MİKROPAPİLLER TİP BASKIN ( % 80 MİKROPAPİLLER, % 15 PAPİLLER, %5 ASİNER TİP)

Limited (Sublobar) resections For a limited resection to be adequate: A precise intraoperative diagnosis Evaluation of resection margins Evaluation of lymph nodes FROZEN SECTIONS

TTF1 SPA CDX2 MUC5A A subset of AC morphologically and immunohistochemically resembling colonic carcinoma

WHAT IS NEW? SMALL BIOPSY

RECOMMENDATION For small biopsies and cytology, NSCLC be further classified into a more specific type, such as adenocarcinoma or squamous cell carcinoma, whenever possible The term NSCLC-NOS be used as little as possible, only when a more specific diagnosis is not possible by morphology and/or special stains

Special Stains Adenocarcinoma Squamous Cocktails (nuclear/cytoplasmic) Mucin TTF1, Napsin, PE10 Squamous P63, CK5/6, 34BE12 Cocktails (nuclear/cytoplasmic) Adeno TTF1/napsin Squamous p63/ck5/6

Summary Classify by morphology if possible Squamous Adeno Define patterns

Summary If NSCL-NOS by H&E IHC Squamous markers +, adeno -: NSCL- favor squamous Squamous markers -, adeno +: NSCL- favor adeno If both negative, inconsistent NSCL-NOS

Morphology should be adequate for most cases IHC should be used if necessary Tissue must be used very carefully and saved for molecular studies

p63

NSCLC Favor adenocarcinoma TTF1

Molecular: When? Every case if it is adenocarcinoma; and when adenocarcinoma can not be ruled out safely: Adenocarcinoma NSCLC- favor adenocarcinoma NSCLC-NOS

Molecular: What? EGFR (mutation) EML4-ALK translocation (FISH) K-Ras (mutation)

Role of Pathology Differentiate cancer from non-cancer Differentiate viable tissue from non-viable tissue Differentiate adequate sample size from non- adequate sample size Tumor type Suggesting/performing the appropriate molecular test for the tumor type