Pulmonary adenocarcinoma Issues, Issues and more issues. Why the headache?

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1 Issues Pulmonary adenocarcinoma Issues, Issues and more issues. Why the headache? Classification Multiple nodules Invasive size Alain Borczuk, MD Weill Cornell Medicine Chronic headache - Classification International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society International Multidisciplinary Classification of Lung Adenocarcinoma. Travis, William; Brambilla, Elisabeth; Noguchi, Masayuki; Nicholson, Andrew; Geisinger, Kim; Yatabe, Yasushi; Beer, David; Powell, Charles; Riely, Gregory; Van Schil, Paul; Garg, Kavita; Austin, John; Asamura, Hisao; Rusch, Valerie; Hirsch, Fred; Scagliotti, Giorgio; Mitsudomi, Tetsuya; Huber, Rudolf; Ishikawa, Yuichi; Jett, James; Sanchez-Cespedes, Montserrat; Sculier, Jean-Paul; Takahashi, Takashi; Tsuboi, Masahiro; Vansteenkiste, Johan; Wistuba, Ignacio; Yang, Pan-Chyr; Aberle, Denise; Brambilla, Christian; Flieder, Douglas; Franklin, Wilbur; Gazdar, Adi; Gould, Michael; MD, MS; Hasleton, Philip; Henderson, Douglas; Johnson, Bruce; Johnson, David; Kerr, Keith; Kuriyama, Keiko; Lee, Jin; Miller, Vincent; Petersen, Iver; MD, PhD; Roggli, Victor; Rosell, Rafael; Saijo, Nagahiro; Thunnissen, Erik; Tsao, Ming; Yankelewitz, David Journal of Thoracic Oncology. 6(2): , February DOI: /JTO.0b013e318206a International Association for the Study of Lung Cancer. Published by Lippincott Williams & Wilkins, Inc.

2 Ground glass opacity - GGO Adenocarcinoma-in-situ (nonmucinous) Adenocarcinoma in situ Gross pathology Gross - Adenocarcinoma in situ (non-mucinous BAC) Usually less than 3.0 cm. No central depression/scarring No pleural thickening or puckering. Often ill defined, difficult to palpate. Slightly paler than adjacent lung, slightly raised does not collapse as much.

3 Adenocarcinoma in situ (non-mucinous) - histology Alveolar architecture/ no architectural effacement No broad area of scarring/ central scarring. Alveolar macrophages can be seen. Alveolar walls often thickened. Adenocarcinoma in situ Non-mucinous Alveolar architecture maintained HISTOLOGY high power Adenocarcinoma in situ (non-mucinous BAC) Airspaces to center Vessels and elastic tissue like normal lung Alveolar architecture Cells are cuboidal to low columnar Nuclear grade is variable, usually low Alveolar walls have increased collagen and elastic tissue. Often retained alveolar macrophages. Little to no stratification. No true papillae.

4 Problem area in recognizing alveolar architecture - Lepidic involvement of emphysema Minimally invasive adenocarcinoma, nonmucinous. Indolent, non-metastatic Gross size < 3.0 cm, invasive size < =5.0 mm What do you call the biopsy? Previously Adenocarcinoma, BAC pattern or features, nonmucinous. Now Lepidic pattern adenocarcinoma, nonmucinous

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6 What about invasion over 5.0 mm? There does seem to be a relationship between invasive size and survival, and in lepidic predominant tumors may be a better predictor than gross size However, over 5.0 mm, every series shows a low but demonstrable rate of lymph node metastasis.

7 Lepidic predominant with 0.8 cm of invasion Lepidic predominant with 0.8 cm of invasion PAPILLARY ACINAR

8 SOLID MICROPAPILLARY Reproducibility Patterns - ring study confirmed reproducibility Typical patterns.77, lepidic and solid was best Difficult patterns.38 Papillary vs micropapillary poorest Allowing choice of secondary patterns reduced reproducibility Why enumerate invasive patterns? May help in future molecular classification/correlations. May have prognostic value (e.g. solid, micropapillary) In multiple nodules, histologic patterns may be evidence for metastasis or synchronous primary. Thunnissen et al, Mod Pathol 2012

9 Yoshizawa et al, Mod Pathol 2011 Borczuk, AC Eur Respir Rev Dec;25(142): Bigger headache Multiple nodules AJCC 8 th Edition - Springer

10 Multiple nodules as separate primaries Different histology Squamous with CIS component Different comprehensive histologic assessment AIS, MIA or LPA Not pneumonic type (often mucinous) Different oncogenic driver Exactly matching CGH Radiologically Distinct Multiple nodules - Resolvable

11 Multiple nodules - difficult KRAS G12D,EGFR no mutation KRAS and EGFR no mutations Acinar patterns are common Do they mean common primary? AJCC 8 th Edition

12 AJCC 8 th Edition - Multiple ground glass nodules History T2a N0 right upper lobe adenocarcinoma 4 years prior Detected after a staging procedure for a suspected leg sarcoma (non-neoplastic ultimately) Former smoker, 50 pack year 1.1 cm but with pleural invasion EGFR and ALK negative CURRENT CT SCAN History Left Right Right lung nodule was biopsied and negative Reduced interval size Left upper lobe was semisolid and showed increased FDG-PET avidity Radiation therapy was recommended but patient obtained 2 nd opinion Biopsied lepidic pattern adenocarcinoma Left upper lobectomy was performed All nodal stations were negative

13 Left upper lobectomy Staging AJCC 8 th Edition Tumor 1 - Lepidic predominant, 0.9 cm invasion or T1a (not MIA) correct 2.0 cm to 1.0 for invasive size 1 3 Tumor 2 - Lepidic predominant, 0.7 cm invasion or T1a (also invasive size) 2 Tumor 3 AIS 4-5 Tumor 4 Minimally invasive, 0.3 cm AJCC 8 th Edition (paraphrased) Table 36.9 Pathological criteria identifying multifocal Ground glass or lepidic lung adenocarcinoma Tumors should be considered multifocal lung adenocarcinoma if: There are multiple foci of LPA, MIA or AIS Foci of AAH are not counted This applies regardless of detailed histologic assessment Applies to clinical or pathology only detection Staging AJCC 8 th Edition Tis, T1a (mi), T1a. Highest T is T1a So, T1a (4/m) then N0 (in this case) AJCC 8 th edition, Springer

14 AJCC 8 th Edition - Multiple ground glass nodules TP53 c.711g>t, p.m237i Lepidic predominant BRAF c.1742a>g, p.n581s AIS Lepidic predominant EGFR c.2573t>g, p.l858r in Exon 21 BRAF c.1803a>t, p.k601n MIA EGFR c.2281g>t, p.d761y in Exon 19 AJCC 8 th edition pneumonic type AdCA What about pneumonia-like BAC? Not a solitary mass, replaces whole segment/lobe. This is not AIS. In my experience either mucinous or have a non-lepidic component.

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16 AJCC 8 th Edition - pneumonic type AdCA Biggest headache Staging and invasive size pt changes size strata T AIS T1 MI T1 T1a: <=1.0, T1b <= 2.0 cm, T1c <= 3.0 cm With N0 1A1, 1A2, 1A3 T2 T2a: = >3 or <= 4 or <= 3 with pleural invasion T2 T2b: >4 or <=5 cm T3 - >5 or <= 7.0 cm T4: > 7.0 cm

17 pt changes other changes T2: lobar atelectasis Mediastinal pleura invasion no longer impacts stage T4: Diaphragm invasion Direct invasion of lobe at least T2a T3: Parietal pericardium T4: visceral pericardium T3: rib T4: Mediastinal fat T4: Pancoast with bone, vessel or nerve T3: Pancoast without bone vessel or nerve What about T stage? T stage based on Gross size in many tumors Include invasive size as well in a lepidic predominant tumor (?>50% or over) Lepidic predominant adenocarcinoma (2.5 cm) with area of invasion (1.0 cm). Microscopic invasive patterns acinar, papillary. How to adjust for invasive size? About grossing

18 Invasive size YES! Applies to tumors with non-mucinous lepidic component which are generally part solid by imaging. NO!

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20 4.0 mm 1.8 cm total 0.5 cm solid

21 No need to correct for invasive size Two methods to adjust for invasive size Method 1 Linear extent Method 2 Percent x diameter

22 Method gross 1.3 cm invasive Method 2 13% invasive (used pixel area) 85% lepidic 15% invasive? Equals 4.2 mm Invasive size Chronic headache - Classification Method gross 1.3 cm invasive size 3.2 cm 1.2 cm solid Method 2 13% invasive (used pixel area) 85% lepidic 15% invasive?equals 4.2 mm Invasive size Measure invasion to distinguish AIS from MIA from LPA Enumerate primary pattern Mention high grade pattern such as micropapillary WHO recommends enumeration of patterns to 5% increments

23 Bigger headache Multiple nodules Several scenarios establish multiple nodules as multiple primaries Biggest headache Staging and invasive size Size criteria have new strata Correction for invasive size in lepidic predominant tumors