Originally published as JCO Early Release 10.1200/JCO.2009.24.0515 on August 31 2009

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Morphology and a Limited Number of Immunohistochemical Markers May Efficiently Subtype Non–Small-Cell Lung Cancer

Pathology Division, Azienda Ospedaliero-Universitaria Policlinico, Modena, Italy

Mauro Papotti

Pathology Division, University of Turin at San Luigi Hospital, Orbassano, Italy

Mattia Barbareschi

Pathology Division, Santa Chiara Hospital, Trento, Italy

Paolo Graziano

Pathology Division, San Camillo-Forlanini Hospital, Rome, Italy

Giuseppe Pelosi

Diagnostic Histopathology Unit, European Institute of Oncology and University of Milan School of Medicine, Milan, Italy

To the Editor:

In the April 20 issue of Journal of Clinical Oncology, Lebanony et al¹ reported on the high sensitivity and specificity of hsa-miR-205 expression in squamous cell carcinoma of the lung. This method provides an accurate subclassification of non–small-cell lung cancer (NSCLC) in the light of novel histology-based therapeutic strategies, such as antiangiogenetic agents, multityrosine kinase inhibitors, and pemetrexed.^2,3 Although microRNA (miR) expression profiling seems a promising tool in the classification and understanding of human cancers,⁴ this issue deserves some practical comments and a note of caution, in our opinion.

In our multi-institutional experience, a careful routine morphologic examination on appropriately hematoxylin and eosin– or Papanicolaou-stained slides is perfectly adequate for subtyping NSCLC on either biopsy or cytology samples, respectively. Approximately 20% to 30% of NSCLCs, however, do not show clear-cut signs of differentiation on light microscope examination and thus require further investigation by immunohistochemistry for highlighting tumor cell lineages.

Bearing this in mind, a limited panel of immunohistochemical markers, including thyroid transcription factor-1 (TTF-1), cytokeratin 7 (CK7), p63, and high-molecular-weight cytokeratins such as CK5 and CK6, can, in our opinion, reproduce the results obtained with much more expensive (5 to 10 v thousands of Euros/USDs) and time-consuming (one v several days) molecular techniques, as it involves the investigation of specific miRs.

Most important, although ambiguous and apparently confounding immunophenotypes can occasionally be found in some NSCLCs (for example, the coexpression of TTF-1 and p63 in the same adenocarcinoma), the reproducibility and reliability of the immunohistochemistry results mainly rely on the knowledge and experience of the specific pathologist; the use of adequate positive and negative controls; and the application of robust but simple rules, as follows: (1) TTF-1 expression almost always rules out squamous cell carcinoma irrespective of the immunoreactivity one might observe for the other tested markers; (2) strong and diffuse immunostaining for p63 or CK5/6 is basically restricted to squamous cell carcinoma; (3) negative coordinated staining for TTF-1 and p63 rules out squamous cell carcinoma.

In addition, immunohistochemistry can be easily and reliably performed even on cytology or biopsy samples that include limited amounts of tumor cells, whereas miR analysis seems to necessarily require biopsies with at least 40% to 50% tumor cells.¹

Again, in the study by Lebanony et al,¹ the sensitivity and specificity comparison between hsa-miR-205 expression and tumor histology were performed using literature data based on the old classification scheme of lung tumors.

With regard to the value of immunohistochemistry, Lebanony et al¹ have not considered the excellent results reported with a couple of antibodies in distinguishing squamous from nonsquamous cell carcinoma.^5–7 Finally, there was no mention of recent articles that highlight the promising results obtained by means of new markers, such as desmocollin-3 for squamous cell carcinoma⁸ and napsin-A⁹ for adenocarcinoma.

In conclusion, the study by Lebanony et al¹ has elegantly highlighted the efficacy of miR in NSCLC subclassification by using hsa-miR-205 expression to significantly predict squamous cell carcinoma histology. Nevertheless, we strongly believe that a careful morphological analysis of tumor cell features and a stringent interpretation of a limited marker panel are currently sufficient and fully appropriate tools for subtyping NSCLC, at least as far as the basic distinction between squamous and nonsquamous cell carcinomas in most laboratories and for purely therapeutic purposes is concerned.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES

1. Lebanony D, Benjamin H, Gilad S, et al: Diagnostic assay based on has-miR-205 expression distinguishes squamous from nonsquamous non-small-cell lung carcinoma. J Clin Oncol 27:2030–2037, 2009.[Abstract/Free Full Text]

2. Johnson DH, Fehrencbacher L, Novotny WF, et al: Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small cell lung cancer. J Clin Oncol 22:2184–2191, 2004.[Abstract/Free Full Text]

3. Scagliotti GV, Parikh P, von Pawel J, et al: Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 26:3543–3551, 2008.[Abstract/Free Full Text]

4. Lu J, Getz G, Miska EA, et al: MicroRNA expression profiles classify human cancers. Nature 435:834–838, 2005.[CrossRef][Medline]

5. Rossi G, Marchioni A, Milani M, et al: TTF-1, cytokeratin 7, 34beta E12, and CD56/NCAM immunostaining in the subclassification of large cell carcinomas of the lung. Am J Clin Pathol 122:884–893, 2004.[Abstract/Free Full Text]

6. Wu M, Szporn AH, Zhang D, et al: Cytology applications of p63 and TTF-1 immunostaining in differential diagnosis of lung cancers. Diagn Cytopathol 33:223–227, 2005.[CrossRef][Medline]

7. Downey P, Cummins R, Moran M, et al: If it's not CK5/6 positive, TTF-1 negative it's not a squamous cell carcinoma of lung. APMIS 116:526–529, 2008.[CrossRef][Medline]

8. 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 22:709–717, 2009.[CrossRef][Medline]

9. Suzuki A, Shijubo N, Yamada G, et al: Napsin A is useful to distinguish primary lung adenocarcinoma from adenocarcinomas of other organs. Pathol Res Pract 201:579–586, 2005.[CrossRef][Medline]

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