2012/11/06 23:16

Case study for non small lung cell cancer

A biopsy of a lung tumor showing a poorly differentiated non–small-cell carcinoma is obtained from a 49-year-old smoker. The patient has a destructive bone lesion in T4 that the treating physician is concerned for a metastatic process. No other tissue will be obtained from this patient. The treating physician asks you to rule out nonsquamous histology, so he can decide on the best systemic treatment for this patient. Which of the following is a minimal panel of immunohistochemical markers that can be used to better classify this carcinoma?

Thyroid transcription factor-1 (TTF-1) and napsin A

Napsin A and cytokeratin 5/6 (CK5/6)

TTF-1 and p63

Surfactant and cytokeratin 34BE12

EGFR (epidermal growth factor receptor)-specific mutation antibodies

Immunohistochemistry is increasingly used to differentiate lung adenocarcinoma and squamous cell carcinoma. Several markers such as napsin-A, TTF-1, high–molecular-weight cytokeratins (34BE12 and CK5/6) have been used.1-4 There is no firmly established panel to make the distinction between adenocarcinoma and squamous cell carcinoma. The literature on the subject is a bit confusing because most authors use different antibodies and, most importantly, the use of these immunomarkers is tested in small biopsy specimen and later correlated with the surgical specimen. This approach does not address the distribution and co-expression of these markers within tumors, which leads to inconclusive results in biopsy specimen. Analysis of whole tissue sections showed that squamous cell carcinoma has a highly consistent immunoprofile (TTF-1–negative and p63-diffuse positivity). In contrast, adenocarcinoma showed significant heterogeneity in the expression of these markers with demonstrated positivity for TTF-1 that ranges from 80% to 90% and with an average of 30% to 40% positivity for p63.

As a single marker, only diffuse TTF-1 is specific for adenocarcinoma. TTF-1 in combination with CK5/6 and 34BE12 has lower predictive values than TTF-1/p63 because these markers can be seen in a higher percentage of tumors. TTF-1 with any positivity for p63 can be seen in approximately 84% of adenocarcinoma and not in squamous cell carcinoma. TTF-1–negative and diffuse expression of p63 is seen in approximately 96% of squamous cell carcinoma. Double negative TTF-1 and p63 is seen in 10% of adenocarcinoma and 0% of squamous cell carcinoma. In fact, negative stain for p63 tends to exclude the diagnosis of squamous cell carcinoma. A panel of TTF-1/p63 used in small specimens (biopsy and cytology) showed 100% accuracy of adenocarcinoma versus squamous cell carcinoma tumor type prediction as determined by subsequent resection.

In conclusion, although reactivity for “squamous markers” (p63/34BE12, and ck5/5) is common in lung adenocarcinoma and presents a potential diagnostic pitfall, a 2-marker panel of TTF-1/p63 is sufficient for subtyping the majority of tumors as adenocarcinomas versus squamous cell carcinoma. This simple algorithm achieves excellent accuracy in small specimens while conserving the tissue for potential predictive marker testing, which is becoming an essential consideration in advanced lung cancer specimens.5,6


  1. 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. 2010.41:20-25.
  2. Mukhopadhyay S, Katzenstein AL. Subclassification of non-small cell lung carcinomas lacking morphologic differentiation on biopsy specimens: Utility of an immunohistochemical panel containing TTF-1, napsin A, p63, and CK5/6. Am J Surg Pathol. 2011;35:15-25. 
  3. Rossi G, Pelosi G, Graziano P, et al. A reevaluation of the clinical significance of histological subtyping of non--small-cell lung carcinoma: diagnostic algorithms in the era of personalized treatments. Int J Surg Pathol. 2009;17:206-218.
  4. Nicholson AG, Gonzalez D, Shah P, et al. Refining the diagnosis and EGFR status of non-small cell lung carcinoma in biopsy and cytologic material, using a panel of mucin staining, TTF-1, cytokeratin 5/6, and P63, and EGFR mutation analysis. J Thorac Oncol. 2010;5:436-441.
  5. Rekhtman N, Brandt SM, Sigel CS, et al. Suitability of thoracic cytology for new therapeutic paradigms in non-small cell lung carcinoma: high accuracy of tumor subtyping and feasibility of EGFR and KRAS molecular testing. J Thorac Oncol. 2011;6:451-458.
  6. Rekhtman N, Ang DC, Sima CS, et 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 May 27. [Epub ahead of print]


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