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M. Garassino

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    MS21 - Practical Problems in Lung Cancer Diagnosis - Application of the 2011 Adenocarcinoma Classification (ID 38)

    • Event: WCLC 2013
    • Type: Mini Symposia
    • Track: Pathology
    • Presentations: 1
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      MS21.3 - Immunohistochemistry and the New Classification (ID 558)

      14:00 - 15:30  |  Author(s): M. Garassino

      • Abstract
      • Presentation
      • Slides

      Most lung cancers are readily diagnosed by using light microscope without attaining special stains [1], but at least 30% of NSCLC could benefit from immunohistochemistry (IHC) to unveil the cell differentiation lineages, especially when dealing with cytology and biopsy specimens [2]. Molecular methods, including micro-RNA expression analysis [3], are cumbersome and unlikely to be directly transferred into the everyday diagnostic workflow [2, 4]. IHC is not a perfect mathematic model, since there is a small (<5%) subset of NSCLC with ambiguous co-expression of glandular and squamous cell differentiation markers or negative reaction for any marker [5, 6]. a) What is the best combination of biomarkers to use? The coordinated expression for TTF-1 for adenocarcinoma and p40 for squamous carcinoma is currently emerging as the most reasonable and reliable biomarker duet in terms of sensitivity and specificity [2, 7-9]. Other promising biomarkers include napsin A for adenocarcinoma [10] and desmocollin-3 for squamous carcinoma [11, 12]. While TTF1 is the best marker for adenocarcinoma and p40 equivalent to p63 for squamous carcinoma, p40 is by far superior in terms of specificity since only rare adenocarcinomas are focally positive in comparison with p63 [2, 7-9]. b) Be aware of antibody clones and other technical issues. The monoclonal antibody 8G7G3/1 for TTF1 seems to be more specific for adenocarcinoma than other clones (such as SPT24) [8, 13], but it has also been recorded in gynecologic [14] and breast [15] carcinomas. Monoclonal antibody to napsin A for adenocarcinoma is less sensitive, but more specific than polyclonal antiserum [16]. The single best marker for squamous carcinoma is a polyclonal rabbit antiserum against p40 [7-9][,17], but very recently a monoclonal antibody has been made commercially available. c) Practical hints to surgical pathologists. NSCLC-NOS upon morphology with negativity for p40 and some TTF-1 positivity should be equated to poorly differentiated adenocarcinomas, once large cell neuroendocrine carcinoma (LCNEC) by relevant markers (e.g., synaptophysin) has been excluded. NSCLC-NOS upon morphology showing double negativity or with only erratic labeling for p40 in < 5% tumor cells in absence of TTF-1 should be considered as poorly differentiated non-squamous carcinomas corresponding, in most instances, to poorly differentiated adenocarcinoma once metastatic cancer has been reasonably excluded, keeping in mind however that the same immunoprofile may be shared by sarcomatoid carcinomas (excludible by morphology and vimentin IHC) [17] and LCNEC (excludible by synaptophysin IHC). Poorly differentiated squamous carcinomas are instead highlighted by strong and diffuse p40 expression and TTF-1 negativity, hence lack of p40 exclude by definition this tumor according to the axiom “no p40, no squamous” [9]. When morphology fails to conclusively subtype NSCLC, it is recommended specifying in the pathology report the real contribution of IHC to render the final diagnosis according to the relevant cell differentiation lineages (e.g., NSCLC-NOS, favor adenocarcinoma or squamous carcinoma by IHC) [6]. References 1. Travis W, Brambilla E, Muller-Hermelink H, Harris C. Tumours of the lung, pleura, thymus and heart. Lyon: IARC Press; 2004. 2. Rossi G, Pelosi G, Barbareschi M, et al. Subtyping non-small cell lung cancer: relevant issues and operative recommendations for the best pathology practice. Int J Surg Pathol 2013;21:326-36. 3. Lebanony D, Benjamin H, Gilad S, et al. Diagnostic assay based on hsa-miR-205 expression distinguishes squamous from nonsquamous non-small-cell lung carcinoma. J Clin Oncol 2009;27:2030-7. 4. Rossi G, Papotti M, Barbareschi M, Graziano P, Pelosi G. Morphology and a limited number of immunohistochemical markers may efficiently subtype non-small-cell lung cancer. J Clin Oncol 2009;27:e141-2; author reply e3-4. 5. Travis W, Brambilla E, Noguchi M, et al. International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 2011;6:244-85. 6. Travis WD, Brambilla E, Noguchi M, et al. Diagnosis of lung cancer in small biopsies and cytology: implications of the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification. Arch Pathol Lab Med 2013;137:668-84. 7. Bishop JA, Teruya-Feldstein J, Westra WH, et al. p40 (DeltaNp63) is superior to p63 for the diagnosis of pulmonary squamous cell carcinoma. Mod Pathol 2012;25:405-15. 8. Pelosi G, Fabbri A, Bianchi F, et al. DeltaNp63 (p40) and thyroid transcription factor-1 immunoreactivity on small biopsies or cellblocks for typing non-small cell lung cancer: a novel two-hit, sparing-material approach. J Thorac Oncol 2012;7:281-90. 9. Pelosi G, Rossi G, Cavazza A, et al. DeltaNp63 (p40) distribution inside lung cancer: a driver biomarker approach to tumor characterization. Int J Surg Pathol 2013;21:229-39. 10. Turner BM, Cagle PT, Sainz IM, et al. Napsin A, a new marker for lung adenocarcinoma, is complementary and more sensitive and specific than thyroid transcription factor 1 in the differential diagnosis of primary pulmonary carcinoma: evaluation of 1674 cases by tissue microarray. Arch Pathol Lab Med 2012;136:163-71. 11. Monica V, Ceppi P, Righi L, et al. Desmocollin-3: a new marker of squamous differentiation in undifferentiated large-cell carcinoma of the lung. Mod Pathol 2009;22:709-17. 12. Righi L, Graziano P, Fornari A, et al. Immunohistochemical subtyping of nonsmall cell lung cancer not otherwise specified in fine-needle aspiration cytology: a retrospective study of 103 cases with surgical correlation. Cancer 2011;117:3416-23. 13. Rekhtman N, Ang DC, Sima CS, Travis WD, Moreira AL. Immunohistochemical algorithm for differentiation of lung adenocarcinoma and squamous cell carcinoma based on large series of whole-tissue sections with validation in small specimens. Mod Pathol 2011;24:1348-59. 14. Siami K, McCluggage WG, Ordonez NG, et al. Thyroid transcription factor-1 expression in endometrial and endocervical adenocarcinomas. Am J Surg Pathol 2007;31:1759-63. 15. Robens J, Goldstein L, Gown AM, Schnitt SJ. Thyroid transcription factor-1 expression in breast carcinomas. Am J Surg Pathol 2010;34:1881-5. 16. Bishop JA, Sharma R, Illei PB. Napsin A and thyroid transcription factor-1 expression in carcinomas of the lung, breast, pancreas, colon, kidney, thyroid, and malignant mesothelioma. Hum Pathol 2010;41:20-5. 17. Pelosi G, Melotti F, Cavazza A, et al. A modified vimentin histological score helps recognize pulmonary sarcomatoid carcinoma in small biopsy samples. Anticancer Res 2012;32:1463-73.

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