Objectives: To determine the diagnostic accuracy of cytomorphology for subclassifying non-small cell lung cancer into adenocarcinoma (AC) and squamous cell carcinoma (SqC), and the utility of immunocytochemistry (ICC) for poorly differentiated cases. Study Design: Preoperative cytologic diagnoses of SqC, AC, or non-small cell carcinoma (NSCC) were compared with surgical resection diagnoses. NSCC cases with adequate cell block material were stained with CK7, CK5/6, TTF-1 and p63 antibodies and subclassified as SqC, AC, or equivocal. Results: 123 of 140 (88%) preoperative cytologic specimens had a malignant diagnosis, including 36 SqC, 72 AC, 6 adenosquamous carcinomas (ASC), and 9 large cell carcinomas (LCC). Accurate cytologic diagnoses were rendered in 18 (50%) SqC and 49 (68%) AC; 26 of 54 cases with a diagnosis of NSCC had adequate cell block material for ICC. TTF-1 and p63 accurately classified 8 of 9 (89%) SqC and 8 of 8 (100%) AC. One SqC, 2 ASC and 3 LCC had equivocal staining, while 1 ASC and 3 LCC stained as AC. Conclusions: The majority of SqC and AC (56%) can be classified by cytomorphology alone. TTF-1 and p63 ICC on cell blocks can provide accurate subclassification for NSCC in the vast majority of cases.

1.
Chirieac LR, Dacic S: Targeted therapies in lung cancer. Surg Pathol Clin 2010;3:71–82.
2.
Johnson DH, Fehrenbacher L, Novotny WF, Herbst RS, Nemunaitis JJ, Jablons DM, Langer CJ, DeVore RF 3rd, Gaudreault J, Damico LA, Holmgren E, Kabbinavar F: 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 2004;22:2184–2191.
3.
Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH: Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;355:2542–2550.
4.
Sandler A, Yi J, Dahlberg S, Kolb MM, Wang L, Hambleton J, Schiller J, Johnson DH: Treatment outcomes by tumor histology in Eastern Cooperative Group Study E4599 of bevacizumab with paclitaxel/carboplatin for advanced non-small cell lung cancer. J Thorac Oncol 2010;5:1416–1423.
5.
Scagliotti G, Hanna N, Fossella F, Sugarman K, Blatter J, Peterson P, Simms L, Shepherd FA: The differential efficacy of pemetrexed according to NSCLC histology: a review of two phase III studies. Oncologist 2009;14:253–263.
6.
Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Goksel T, de Marinis F, Simms L, Sugarman KP, Gandara D: 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 2008;26:3543–3551.
7.
Selvaggi G, Scagliotti GV: Histologic subtype in NSCLC: does it matter? Oncology (Williston Park) 2009;23:1133–1140.
8.
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;136:81–87.
9.
Bishop JA, Teruya-Feldstein J, Westra WH, Pelosi G, Travis WD, Rekhtman N: p40 (ΔNp63) is superior to p63 for the diagnosis of pulmonary squamous cell carcinoma. Mod Pathol 2012;25:405–415.
10.
Bishop JA, Benjamin H, Cholakh H, Chajut A, Clark DP, Westra WH: Accurate classification of non-small cell lung carcinoma using a novel microRNA-based approach. Clin Cancer Res 2010;16:610–619.
11.
Camilo R, Capelozzi VL, Siqueira SA, Del Carlo Bernardi F: Expression of p63, keratin 5/6, keratin 7, and surfactant-A in non-small cell lung carcinomas. Hum Pathol 2006;37:542–546.
12.
Conde E, Angulo B, Redondo P, Toldos O, Garcia-Garcia E, Suarez-Gauthier A, Rubio-Viqueira B, Marron C, Garcia-Lujan R, Sanchez-Cespedes M, Lopez-Encuentra A, Paz-Ares L, Lopez-Rios F: The use of P63 immunohistochemistry for the identification of squamous cell carcinoma of the lung. PLoS One 2010;5:e12209.
13.
Downey P, Cummins R, Moran M, Gulmann C: If it’s not CK5/6 positive, TTF-1 negative it’s not a squamous cell carcinoma of lung. APMIS 2008;116:526–529.
14.
Fatima N, Cohen C, Lawson D, Siddiqui MT: TTF-1 and napsin A double stain: a useful marker for diagnosing lung adenocarcinoma on fine-needle aspiration cell blocks. Cancer Cytopathol 2011;119:127–133.
15.
Kalhor N, Zander DS, Liu J: TTF-1 and p63 for distinguishing pulmonary small-cell carcinoma from poorly differentiated squamous cell carcinoma in previously Pap-stained cytologic material. Mod Pathol 2006;19:1117–1123.
16.
Kargi A, Gurel D, Tuna B: The diagnostic value of TTF-1, CK 5/6, and p63 immunostaining in classification of lung carcinomas. Appl Immunohistochem Mol Morphol 2007;15:415–420.
17.
Khayyata S, Yun S, Pasha T, Jian B, McGrath C, Yu G, Gupta P, Baloch Z: Value of p63 and CK5/6 in distinguishing squamous cell carcinoma from adenocarcinoma in lung fine-needle aspiration specimens. Diagn Cytopathol 2009;37:178–183.
18.
Loo PS, Thomas SC, Nicolson MC, Fyfe MN, Kerr KM: Subtyping of undifferentiated non-small cell carcinomas in bronchial biopsy specimens. J Thorac Oncol 2010;5:442–447.
19.
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.
20.
Nicholson AG, Gonzalez D, Shah P, Pynegar MJ, Deshmukh M, Rice A, Popat S: 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.
21.
Pelosi G, Fabbri A, Bianchi F, Maisonneuve P, Rossi G, Barbareschi M, Graziano P, Cavazza A, Rekhtman N, Pastorino U, Scanagatta P, Papotti M: ΔNp63 (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;7:281–290.
22.
Pu RT, Pang Y, Michael CW: Utility of WT-1, p63, MOC31, mesothelin, and cytokeratin (K903 and CK5/6) immunostains in differentiating adenocarcinoma, squamous cell carcinoma, and malignant mesothelioma in effusions. Diagn Cytopathol 2008;36:20–25.
23.
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;24:1348–1359.
24.
Righi L, Graziano P, Fornari A, Rossi G, Barbareschi M, Cavazza A, Pelosi G, Scagliotti GV, Papotti M: 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;117:3416–3423.
25.
Ring BZ, Seitz RS, Beck RA, Shasteen WJ, Soltermann A, Arbogast S, Robert F, Schreeder MT, Ross DT: A novel five-antibody immunohistochemical test for subclassification of lung carcinoma. Mod Pathol 2009;22:1032–1043.
26.
Rossi G, Marchioni A, Milani M, Scotti R, Foroni M, Cesinaro A, Longo L, Migaldi M, Cavazza A: TTF-1, cytokeratin 7, 34βE12, and CD56/NCAM immunostaining in the subclassification of large cell carcinomas of the lung. Am J Clin Pathol 2004;122:884–893.
27.
Stoll LM, Johnson MW, Gabrielson E, Askin F, Clark DP, Li QK: The utility of napsin-A in the identification of primary and metastatic lung adenocarcinoma among cytologically poorly differentiated carcinomas. Cancer Cytopathol 2010;118:441–449.
28.
Terry J, Leung S, Laskin J, Leslie KO, Gown AM, Ionescu DN: Optimal immunohistochemical markers for distinguishing lung adenocarcinomas from squamous cell carcinomas in small tumor samples. Am J Surg Pathol 2010;34:1805–1811.
29.
Tsuta K, Tanabe Y, Yoshida A, Takahashi F, Maeshima AM, Asamura H, Tsuda H: Utility of 10 immunohistochemical markers including novel markers (desmocollin-3, glypican 3, S100A2, S100A7, and Sox-2) for differential diagnosis of squamous cell carcinoma from adenocarcinoma of the lung. J Thorac Oncol 2011;6:1190–1199.
30.
Uke M, Rekhi B, Ajit D, Jambhekar NA: The use of p63 as an effective immunomarker in the diagnosis of pulmonary squamous cell carcinomas on de-stained bronchial lavage cytological smears. Cytopathology 2010;21:56–63.
31.
Wu M, Szporn AH, Zhang D, Wasserman P, Gan L, Miller L, Burstein DE: Cytology applications of p63 and TTF-1 immunostaining in differential diagnosis of lung cancers. Diagn Cytopathol 2005;33:223–227.
32.
Wu M, Wang B, Gil J, Sabo E, Miller L, Gan L, Burstein DE: p63 and TTF-1 immunostaining. A useful marker panel for distinguishing small cell carcinoma of lung from poorly differentiated squamous cell carcinoma of lung. Am J Clin Pathol 2003;119:696–702.
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