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Best Pathology Practice

Learn about the latest guidelines for diagnosis and treatment of lung adenocarcinoma. Discover key criteria, tools, and techniques to maximize tissue for molecular studies. Stay updated with international multidisciplinary classifications and diagnostic methods.

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Best Pathology Practice

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  1. Best Pathology Practice International association for the study of lung cancer/American thoracic society/European respiratory society international multidisciplinary classification of lung adenocarcinoma. Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger KR, Yatabe Y, Beer DG, Powell CA, Riely GJ, Van Schil PE, Garg K, Austin JH, Asamura H, Rusch VW, Hirsch FR, Scagliotti G, Mitsudomi T, Huber RM, Ishikawa Y, Jett J, Sanchez-Cespedes M, Sculier JP, Takahashi T, Tsuboi M, Vansteenkiste J, Wistuba I, Yang PC, Aberle D, Brambilla C, Flieder D, Franklin W, Gazdar A, Gould M, Hasleton P, Henderson D, Johnson B, Johnson D, Kerr K, Kuriyama K, Lee JS, Miller VA, Petersen I, Roggli V, Rosell R, Saijo N, Thunnissen E, Tsao M, Yankelewitz D. J Thorac Oncol. 2011 Feb;6(2):244-85. Tissue specimens should be managed not only for diagnosis but also to maximize the amount of tissue available for molecular studies To guide therapy for patients with advanced lung adenocarcinoma, each institution should develop a multidisciplinary team that coordinates the optimal approach to obtaining and processing biopsy/cytology specimens to provide expeditious diagnostic and molecular results

  2. Best Pathology Practice When paired cytology and biopsy specimens exist, they should be reviewed together to achieve the most specific and nondiscordant diagnoses Cell blocks should be prepared from all cytology samples including pleural fluids International association for the study of lung cancer/American thoracic society/European respiratory society international multidisciplinary classification of lung adenocarcinoma. Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger KR, Yatabe Y, Beer DG, Powell CA, Riely GJ, Van Schil PE, Garg K, Austin JH, Asamura H, Rusch VW, Hirsch FR, Scagliotti G, Mitsudomi T, Huber RM, Ishikawa Y, Jett J, Sanchez-Cespedes M, Sculier JP, Takahashi T, Tsuboi M, Vansteenkiste J, Wistuba I, Yang PC, Aberle D, Brambilla C, Flieder D, Franklin W, Gazdar A, Gould M, Hasleton P, Henderson D, Johnson B, Johnson D, Kerr K, Kuriyama K, Lee JS, Miller VA, Petersen I, Roggli V, Rosell R, Saijo N, Thunnissen E, Tsao M, Yankelewitz D. J Thorac Oncol. 2011 Feb;6(2):244-85.

  3. Criteria for Morphologic Diagnosis of ADC and SQC on H&E Stained Slides Morphologic features of glandular (adenomatous) differentiation: Gland formation Mucin production Morphologic features of squamous differentiation: Intercellular bridges Single cell keratinization Keratin production (keratin pearl formation)

  4. Large Cell Carcinoma This diagnosis should not be made on small samples (biopsies or cytology) The diagnosis should be NSCLC NOS

  5. What Is The Rate Of NSCLC NOS? • Study of California Cancer Registry: 175, 298 lung cancer patients diagnosed from 1989 to 2006 • On histology: 22.1% (may be higher) • On cytology: 37% • The rate increases with decrease in sample size • The rate has risen over time Ou, S and Zell, J (2009) J Thorac Oncol 4(10): 1202.

  6. Reproducibility of Pathologic Diagnosis in NSCLC • Digitalized H&E from 94 surgically resected specimens were reviewed by 24 Pathologists (12 lung expert Pathologists, 12 community Pathologists) • Inter-rater agreement on differentiating SQC vs. non-SQC • Kappa 0.55 for all pathologists • Kappa 0.64 among lung expert pathologists • Kappa 0.41 among non-expert community pathologists Grilley-Olson, J et al (2009) ASCO Meeting Abstracts 27(15S): 8008.

  7. IHC as a Diagnostic Tool in NSCLCReview of Literature No marker is 100% sensitive or specific Most frequently cited stains are: For ADC TTF-1, mucin histochemical stains For SQC p63, CK5/6, HMWK 34bE12 (MA903) Travis, W et al (2010) J Thorac Oncol 5(4): 4.

  8. IHC as a Diagnostic Tool in NSCLC Mucin Histochemical Stains in Lung ADC PAS Mucicarmine Alcian Blue

  9. IHC as a Diagnostic Tool in NSCLC TTF-1 in Lung ADC Nuclear staining Sensitivity 54%* Specificity 97%* Positive PV 88%* Negative PV 83%* Loo, P et al (2010) J Thorac Oncol 5(4): 442.

  10. IHC as a Diagnostic Tool in NSCLC TTF-1 in Lung ADC Cytoplasmic staining should be interpreted as NEGATIVE

  11. False Positive Immunostaining —TTF-1 200x Type II Pneumocytes

  12. Summary—Napsin A and TTF-1 IHC Staining (I) • Sensitivity seems ≥ TTF-1 • Often positive in renal neoplasms • Rarely positive in thyroid neoplasms • Complementary to TTF-1? • Not ready for prime time Bishop, J et al (2010) Hum Pathol 41(1): 20.

  13. IHC as a Diagnostic Tool in NSCLC p63 in Lung SQC Nuclear staining Sensitivity 92%* Specificity 74%* Positive PV 82%* Negative PV 88%* Loo, P et al (2010) J Thorac Oncol 5(4): 442.

  14. IHC as a Diagnostic Tool in NSCLC CK5/6 in Lung SQC Cytoplasmic staining Sensitivity 84%* Specificity 79%* Positive PV 84%* Negative PV 79%* Loo, P et al (2010) J Thorac Oncol 5(4): 442.

  15. Modern Pathology (2012) 25, 405–415

  16. IHC as a Diagnostic Tool in NSCLC—Review of Literature Predictive scoring cutoffs TTF-1 Moderate > 50% or strong > 10% CK5/6 and p63 Moderate or strong > 10% AB/PAS Any droplet Proportion 1 : 1-10% 2 : 10-50% 3 : > 50% Loo, P et al (2010) J Thorac Oncol 5(4): 442.

  17. Diagnostic Algorithm for Classification of NSCLC in Small Biopsy Samples 75% subtyped (87% accuracy-SQC; 80% accuracy-ADC) Malignant bronchial biopsy (NSCLC) 18% have subtype predicted (86% accuracy) H&E stain 7% not typed “Null” IHC on biopsy IHC and AB/PAS “Null” Case Resection histology 14% Squamous cell (1% total) 43% Adenocarcinoma (3% total) 43% Large cell (3% total) Loo, P et al (2010) J Thorac Oncol 5(4): 442.

  18. IHC as a Diagnostic Tool in NSCLC Review of Literature Large cell carcinoma of the lung: an endangered species? Pardo J, Martinez-Peñuela AM, Sola JJ, Panizo A, Gúrpide A, Martinez-Peñuela JM, Lozano MD. Appl Immunohistochem Mol Morphol. 2009 Oct;17(5):383.

  19. IHC as a Diagnostic Tool in NSCLC Review of Literature 101 LCC TMA, including 82 « classic » LCC 31 monoclonal antibodies Reclassification of 82 « classic » LCC 33% ADC TTF1(+) CK7(+) CK19(+) p63(-) 37% SQC 34bE12(+) p63(+) TM(+) CD44v6(+) 20% AS* Hybrid AC-SQC immunophenotype Panel of 7 useful antibodies TTF-1, CK7, CK19, p63, 34bE12, TM, CD44v6 < 10% of residual LCC > 90% reclassified ADC, SQC or ASC ADC: Adenocarcinoma; SQC: Squamous cell carcinoma; LCC: Large cell carcinoma; ASC: Adenosquamous carcinoma; NOS: Not Otherwise Specified; IHC: Immunohistochemistry Pardo, J et al (2009) Appl Immunohistochem Mol Morphol 17(5): 383.

  20. Reporting Small Lung Samples International association for the study of lung cancer/American thoracic society/European respiratory society international multidisciplinary classification of lung adenocarcinoma. Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger KR, Yatabe Y, Beer DG, Powell CA, Riely GJ, Van Schil PE, Garg K, Austin JH, Asamura H, Rusch VW, Hirsch FR, Scagliotti G, Mitsudomi T, Huber RM, Ishikawa Y, Jett J, Sanchez-Cespedes M, Sculier JP, Takahashi T, Tsuboi M, Vansteenkiste J, Wistuba I, Yang PC, Aberle D, Brambilla C, Flieder D, Franklin W, Gazdar A, Gould M, Hasleton P, Henderson D, Johnson B, Johnson D, Kerr K, Kuriyama K, Lee JS, Miller VA, Petersen I, Roggli V, Rosell R, Saijo N, Thunnissen E, Tsao M, Yankelewitz D. J Thorac Oncol. 2011 Feb;6(2):244-85. The term NSCLC-NOS should be used as little as possible, and be applied only when a more specific diagnosis is not possible by morphology and/or special stains The term large cell carcinoma should not be used for diagnosis in small biopsy or cytology specimens and should be restricted to resection specimens where the tumor is thoroughly sampled to exclude a differentiated component

  21. Algorithm for adenocarcinoma diagnosis in small biopsies and/or cytology STEP 1 NE morphology, large cells, NE IHC+ NSCLC,?LCNEC POSITIVE BIOPSY (FOB, TBBx, Core, SLBx) NE morphology, small cells, no nucleoli, NE IHC+, TTF-1 +/-, CK+ SCLC POSITIVE CYTOLOGY (effusion, aspirate, washings, brushings) Keratinization, pearls and/or intercellular bridges Classic Morphology: SQCC Histology: Lepidic, papillary, 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 STEP 2 Apply ancillary panel ofOne SQCC and one ADC marker +/OR Mucin Classic morphology: ADC

  22. Algorithm for adenocarcinoma diagnosis in small biopsies and/or cytology NSCLC, favor SQCC STEP 2 Apply ancillary panel ofOne SQCC and one ADC marker +/OR Mucin SQCC marker +veADC marker -ve/orMucin -ve ADC marker and/or Mucin +ve;SQCC marker -ve (or weak in same cells) IHC -ve andMucin -ve ADC, marker or Mucin +ve;as well as SQCC marker +vein different cells NSCLC, favor ADC NSCLC NOS NSCLC, NOS,possible adenosquamous ca

  23. Algorithm for adenocarcinoma diagnosis in small biopsies and/or cytology Classic morphology: ADC NSCLC, favor ADC NSCLC NOS Molecular analysis:e.g. EGFR mutation† NSCLC, NOS,possible adenosquamous ca STEP 3 If tumor tissue inadequate for molecular testing, discuss need for further sampling – back to STEP 1

  24. Mano, H (2008) Cancer Sci 99(12): 2349. Perner, S et al. (2008) Neoplasia 10(3): 298. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, Fujiwara S, Watanabe H, Kurashina K, Hatanaka H, Bando M, Ohno S, Ishikawa Y, Aburatani H, Niki T, Sohara Y, Sugiyama Y, Mano H. Nature. 2007 Aug 2;448(7153):561. Oncogenic Chr. 2p23-22

  25. ALK Break Apart FISH e20 ~12 Mb ALK EML4

  26. Clinical Activity Observed in an Updated Phase I-II Trial of an Oral C-met and ALK Inhibitor Crizotinib (PF–02341066) 60 Progressive disease Stable disease 40 Confirmed partial response 20 Confirmed complete response 0 Maximum change in tumour size (%) -20 -30% -40 ONLY 3-5% OF NSCLC -60 Overall Response Rate = 57% Disease Control Rate (CR+PR+SD) at 8 weeks= 87% -80 -100 * Partial response patients with 100% change have non-target disease present Bang, Y et al. (2010). ASCO Meeting Abstracts 28(18_suppl): 3.

  27. (EML4)-ALK Fusion Gene Tumors Occur Mainly in Adenocarcinoma

  28. Histological Features of Adenocarcinoma Associated with EML4-ALK Aberration Rodig SJ, et al. CCR 2009;15:5216-23; Inamura K, et al. Modern Pathol 2009;22:508-15

  29. SIGNET RING CRIBRIFORM Am J Pathol 2011;35:1226-34

  30. ALK1 antibody with ADVANCED detection system (DAKO) 3+ 2+ 1+ 0 2+/3+ IHC: Sensitivity 90% Specificity 97.8% J ThoracOncol. 2011;6: 466–472

  31. J Thoracic Oncol 2011;6:466-72

  32. Lung Cancer 2012 (Epub)

  33. A novel, highly sensitive antibody allows for the routine detection of ALK-rearranged lung adenocarcinomas by standard immunohistochemistry. Mino-Kenudson M, Chirieac LR, Law K, Hornick JL, Lindeman N, Mark EJ, Cohen DW, Johnson BE, Jänne PA, Lafrate AJ, Rodig SJ. Clin Cancer Res. 2010 Mar 1;16(5):1561.

  34. Conclusions • Current practice of pathology in lung cancer requires more precise classification of tumor type • For poorly differentiated NSCLC, a minimal set of immunohistochemistry markers (TTF1, mucin, p63 and CK5) should reduce the number of NOS to <5%. • Cell block preparation should be part of the routine practice of cytology (especially for FNA and fluid) • For both small biopsy and cytology, every attempt should be made to preserve some samples for molecular studies of predictive biomarkers • It is likely that in the future, histopathology/immunohistochemistry may play important role in the development of cost-effective diagnostic algorithm for molecular assays

  35. ACKNOWLEDGEMENTS • Dr. Diana Ionescu (British Columbia Cancer Agency) • Dr. Tony Magliocco (Tom Baker Cancer Centre and Calgary Laboratory Services) • Dr. Christian Couture (Université Laval) • Maritz Canada & Eli Lilly Canada

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