When is IHC required for subtyping of NSCLC and what is the optimal IHC panel?

From Cancer Guidelines Wiki

Introduction

For patients with advanced stage disease, accurate subclassification of different subtypes of NSCLC is needed to help determine optimal treatment.[1][2] In small biopsy and cytology specimens of non-small cell lung carcinoma (NSCLC), however, it is not always possible to distinguish squamous cell carcinoma from adenocarcinoma or other subtypes of NSCLC using morphological features alone. In these cases, immunohistochemical stains can be used to help distinguish those tumours likely to be adenocarcinomas from those more likely to represent squamous cell carcinomas.[3] Review of the literature shows that various IHC markers can be used to assist in distinction of squamous cell carcinoma from adenocarcinoma subtypes of NSCLC, although the number of IHC markers used and which specific combinations of IHC markers is quite variable, and most of the studies were at risk of bias. In addition, many of the studies that assessed reliability of IHC subtyping did not provide information regarding how morphologically undifferentiated the tumours were or if subtyping could be inferred from morphology alone.

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Evidence summary and recommendations

Evidence summary Level References
IHC is useful in subtyping NSCLC using a small panel of IHC markers. III-2 [4], [5], [6], [7], [8], [9], [10], [11]
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A small panel of IHC markers should be used to subtype morphologically undifferentiated NSCLC in small biopsy and cytology samples, with 2 markers usually sufficient (1 adenocarcinoma marker and 1 squamous marker).
C


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IHC to assist in subtyping NSCLC is only required when there is no morphological evidence of glandular or squamous differentiation.The optimal panel of IHC markers is not clear from the literature with many studies using a different range of markers (eg TTF-1, Napsin A, CK5, CK5/6, p40, p63, CK7, surfactant protein A, as well as histochemical markers for mucin such as PAS.) The WHO Classification of Tumours of the Lung (Travis WD et al 2015) recommends using only one squamous marker (ie p40, p63 or CK5/6) and one adenocarcinoma marker (TTF-1 or a histochemical stain for mucin) so as to preserve tissue for molecular testing in the setting of a small biopsy showing a non-small cell carcinoma lacking definite squamous or glandular morphology.

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It is advisable to limit the number of IHC markers used to 2 so as to preserve tissue for molecular testing if required (1 adenocarcinoma marker such as TTF1, and 1 squamous marker such as p40).

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In some instances, IHC may also be needed to help determine if the tumour is of lung origin or a metastasis. Clinicopathological correlation and multidisciplinary team meeting discussion can often assist in excluding the possibility of a metastasis to the lung in the setting of a solitary lung lesion, and can help avoid unnecessary use of IHC markers and thereby preserve tissue for molecular testing. IHC markers are not useful in distinguishing primary from metastatic disease in the case of a squamous cell carcinoma in the lung.

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References

  1. Cooper WA, O'toole S, Boyer M, Horvath L, Mahar A. What's new in non-small cell lung cancer for pathologists: the importance of accurate subtyping, EGFR mutations and ALK rearrangements. Pathology 2011 Feb;43(2):103-15 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21233671.
  2. Cancer Council Australia Lung Cancer Guidelines Working Party. Clinical practice guidelines for the treatment of lung cancer. [homepage on the internet] Sydney: Cancer Council Australia; 2017 Nov 22 Available from: http://wiki.cancer.org.au/australia/Guidelines:Lung_cancer.
  3. Travis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin JH, Beasley MB, et al. The 2015 World Health Organization Classification of Lung Tumors: Impact of Genetic, Clinical and Radiologic Advances Since the 2004 Classification. J Thorac Oncol 2015 Sep;10(9):1243-60 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26291008.
  4. Ikeda S, Naruse K, Nagata C, Kuramochi M, Onuki T, Inagaki M, et al. Immunostaining for thyroid transcription factor 1, Napsin A, p40, and cytokeratin 5 aids in differential diagnosis of non-small cell lung carcinoma. Oncol Lett 2015;9(5):2099-2104 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26137020.
  5. Pelosi G, Rossi G, Bianchi F, Maisonneuve P, Galetta D, Sonzogni A, et al. Immunhistochemistry by means of widely agreed-upon markers (cytokeratins 5/6 and 7, p63, thyroid transcription factor-1, and vimentin) on small biopsies of non-small cell lung cancer effectively parallels the corresponding profiling and eventual diagnoses on surgical specimens. J Thorac Oncol 2011 Jun;6(6):1039-49 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21512408.
  6. Jorda M, Gomez-Fernandez C, Garcia M, Mousavi F, Walker G, Mejias A, et al. P63 differentiates subtypes of nonsmall cell carcinomas of lung in cytologic samples: implications in treatment selection. Cancer 2009 Feb 25;117(1):46-50 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19347829.
  7. Ocque R, Tochigi N, Ohori NP, Dacic S. Usefulness of immunohistochemical and histochemical studies in the classification of lung adenocarcinoma and squamous cell carcinoma in cytologic specimens. Am J Clin Pathol 2011 Jul;136(1):81-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21685035.
  8. Righi L, Graziano P, Fornari A, Rossi G, Barbareschi M, Cavazza 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 Aug 1;117(15):3416-23 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21246522.
  9. Koh J, Go H, Kim MY, Jeon YK, Chung JH, Chung DH. A comprehensive immunohistochemistry algorithm for the histological subtyping of small biopsies obtained from non-small cell lung cancers. Histopathology 2014 Dec;65(6):868-78 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25130792.
  10. da Cunha Santos G, Lai SW, Saieg MA, Geddie WR, Pintilie M, Tsao MS, et al. Cyto-histologic agreement in pathologic subtyping of non small cell lung carcinoma: review of 602 fine needle aspirates with follow-up surgical specimens over a nine year period and analysis of factors underlying failure to subtype. Lung Cancer 2012 Sep;77(3):501-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22656670.
  11. Montezuma D, Azevedo R, Lopes P, Vieira R, Cunha AL, Henrique R. A panel of four immunohistochemical markers (CK7, CK20, TTF-1, and p63) allows accurate diagnosis of primary and metastatic lung carcinoma on biopsy specimens. Virchows Arch 2013 Dec;463(6):749-54 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24126803.

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Appendices


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