Reclassificação do carcinoma broncopulmonar: Diferenciação do tipo histológico em biópsias por imuno-histoquímica

Carvalho, Lina

doi:10.1016/S0873-2159(15)30195-1

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Os conhecimentos actuais da patologia molecular do cancro do pulmão requerem outra caracterização histológica, para além de carcinoma de células pequenas e carcinoma não pequenas células para suporte da terapia personalizada e entendimento do valor real dos fármacos actualmente disponíveis.

Como o diagnóstico e seguimento clínico da maioria dos casos de cancro do pulmão se baseia em produtos de biópsia e citologia, a classificação imunoistoquímica do carcinoma broncopulmonar (IBPCC) é necessária para suporte morfológico da classificação da WHO 1999/2004, clarificando as características celulares das neoplasias e o entendimento da carcinogénese.

O painel imunoistoquímico reforça os tipos histológicos principais do carcinoma bronco – pulmonar: carcinoma epidermóide (queratinas de alto peso molecular – HWMC), carcinoma adenoscamoso (CK/ /TTF1, MWMC), carcinoma neuroendócrino (Chrg, Syn, CD56, TTF1, Ki67) e adenocarcinoma (CK7, Ck20, TTF1); as variantes do carcinoma de células grandes e do carcinoma sarcomatóide são englobados num único grupo de carcinomas pleomórficos (CK7, TTF1, HWMC, VMT, desmina, actina), onde cabe o polimorfismo e o pleomorfismo celular.

A quimioterapia do carcinoma broncopulmonar continuará baseada no platino e na gemcitabina no futuro próximo e a IBPCC será uma ferramenta simples e eficiente para o registo das características e tipos histológicos do carcinoma do pulmão presentes nas biópsias e amostras citológicas para suporte da evidência clínica e dos ensaios farmacêuticos.

Rev Port Pneumol 2009; XV (6): 1101-1119

Palavras-chave:

Carcinoma broncopulmonar

imunoistoquímica

Abstract

The current state of molecular knowledge on lung cancer demands a histological classification which goes beyond small-cell and non-small-cell carcinoma to provide support for tailored therapy in aiding in understanding of the drugs currently available.

As diagnosis and follow-up in the vast majority of lung cancer cases is based on biopsies and cytology samples, Immunohistochemical Bronchial Pulmonary Carcinoma Classification (IBPCC) is necessary to reveal the raft of characteristics available. This provides morphological support for the WHO’s 1999/2004 classification, in addition to an understanding of carcinogenesis.

The immunohistochemical panel clarifies the main morphology and cytology characteristics to maintain the leading histological types as squamous cell carcinoma (high weight molecular cytokeratins/HWMC), adenosquamous carcinoma (CK7, TTF1, HWMA), neuroendocrine carcinoma (Chrg, Syn, CD56, TTF1, Ki67), adenocarcinoma (CK7, CK20, TTF1) and bring the polymorphic and pleomorphic carcinomas under a single banner of pleomorphic carcinoma (Ck7, TTF1, HWMC, VMT, Desmin, Actin) which shelters large cell carcinomas and sarcomatoid carcinomas.

Lung cancer chemotherapy will still be based on platinum and gemcitabine for the near future and the IBPCC is a simple and efficient tool for streamlining the registration of lung cancer histological characteristics in biopsies and other reduced samples to support clinical evidence and trials.

Rev Port Pneumol 2009; XV (6): 1101-1119

Key-words:

Bronchial-pulmonary carcinoma

immunohistochemistry

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Bibliography

[1.]

R.A. Bernarda.

Cancro: Cronologia histórica e génese de ideias.

(1996),

[2.]

L. Kreyberg.

Histological lung cancer types.

Acta Pathologica e Microbiologica Scandinavica, 157 (1962), pp. 1-93

[3.]

L. Kreyberg, A.A. Liebow, E.A. Uehlinger.

Histological typing of lung tumours, World Health Organization, (1969),

[4.]

The World Health Organization histological typing of lung tumours.

Am J Clin Pathol, 77 (1982), pp. 123-136

Medline

[5.]

W. Travis, E. Brambilla, H.K. Muller-Hermelink, C. Harris.

Tumours of the lung, pleura, thymus and heart. Pathology and Genetics.

World Health Organization Classification of Tumours, IARCPress, (2004),

[6.]

Y. Sakao, H. Miyamoto, S. Oh, et al.

The impact of cigarette smoking on prognosis in small adenocarcinomas of the lung: the association between histologic subtype and smoking status.

J Thorac Oncol, 3 (2008), pp. 958-962

http://dx.doi.org/10.1097/JTO.0b013e31818396e0 | Medline

[7.]

C.Q. Zhu, S.G. da Cunha, K. Ding, et al.

Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21.

J Clin Oncol, 26 (2008), pp. 4268-4275

http://dx.doi.org/10.1200/JCO.2007.14.8924 | Medline

[8.]

F.R. Hirsch, R.S. Herbst, C. Olsen, et al.

Increased EGFR gene copy number detected by fluorescent in situ hybridization predicts outcome in non-small-cell lung cancer patients treated with cetuximab and chemotherapy.

J Clin Oncol, 26 (2008), pp. 3351-3357

http://dx.doi.org/10.1200/JCO.2007.14.0111 | Medline

[9.]

L. Carvalho, E. Cardoso, H. Nunes, V. Baptista, A. Gomes, P. Couceiro.

Projecto de estadiamento do cancro do pulmão pela IASLC: Estudo comparativo entre a 6.ª edição TNM em vigor e a 7.ª edição proposta.

Rev Port Pneumol, 15 (2009), pp. 67-76

Medline

[10.]

M. Varella-Garcia, T. Mitsudomi, Y. Yatabe, T. Kosaka, et al.

EGFR and HER2 genomic gain in recurrent non-small cell lung cancer after surgery.

J Thorac Oncol, 4 (2009), pp. 318-325

http://dx.doi.org/10.1097/JTO.0b013e31819667a3 | Medline

[11.]

P. Seve, R. Lai, K. Ding, et al.

Class III beta-tubulin expression and benefit from adjuvant cisplatin/vinorelbine chemotherapy in operable non-small cell lung cancer: analysis of NCIC JBR 10.

Clin Cancer Res, 13 (2007), pp. 994-999

http://dx.doi.org/10.1158/1078-0432.CCR-06-1503 | Medline

[12.]

P. Seve, T. Reiman, R. Lai, et al.

Class III beta-tubulin is a marker of paclitaxel resistance in carcinomas of unknown primary site.

Cancer Chemother Pharmacol, 60 (2007), pp. 27-34

http://dx.doi.org/10.1007/s00280-006-0343-1 | Medline

[13.]

S.M. Hewitt, F.A. Lewis, Y. Cao, et al.

Tissue handling and specimen preparation in surgical pathology: issues concerning the recovery of nucleic acids from formalin-fixed, paraffin-embedded tissue.

Arch Pathol Lab Med, 132 (2008), pp. 1929-1935

http://dx.doi.org/10.1043/1543-2165-132.12.1929 | Medline

[14.]

E. Giovannetti, V. Mey, S. Nannizzi, et al.

Cellular and pharmacogenetics foundation of synergistic interaction of pemetrexed and gemcitabine in human non-small-cell lung cancer cells.

Mol Pharmacol, 68 (2005), pp. 110-118

http://dx.doi.org/10.1124/mol.104.009373 | Medline

[15.]

J.R. Izbicki, B. Passlick, S.B. Hosch, et al.

Mode of spread in the early phase of lymphatic metastasis in non-small-cell lung cancer: significance of nodal micrometastasis.

J Thorac Cardiovasc Surg, 112 (1996), pp. 623-630

http://dx.doi.org/10.1016/S0022-5223(96)70044-2 | Medline

[16.]

P. Ceppi, M. Volante, S. Saviozzi, et al.

Squamous cell carcinoma of the lung compared with other histotypes shows higher messenger RNA and protein levels for thymidylate synthase.

Cancer, 107 (2006), pp. 1589-1596

http://dx.doi.org/10.1002/cncr.22208 | Medline

[17.]

L. Carvalho.

Wild type of exons 19 and 21 and polysomy of chromosome 7 were defined for EGFR gene in squamous cell carcinoma of the lung.

Journal of Thoracic Oncology, 3 (2008), pp. S1:S35-S36

http://dx.doi.org/10.1097/JTO.0b013e31817c60ae | Medline

[18.]

V. Sousa, M. Silva, A. Alarcão, P. Couceiro, A. Gomes, L. Carvalho.

Squamous cell carcinoma of the lung: polysomy of chromosome 7 and wild type of exon 19 and 21 were defined for EGFR gene.

Virchows Archiv, 452 (2008), pp. S1

http://dx.doi.org/10.1007/s00428-008-0613-x | Medline

[19.]

V. Boggaram.

Thyroid transcription factor-1 (TTF-1/Nkx2.1/TITF1) gene regulation in the lung.

Clin Sci (Lond), 116 (2009), pp. 27-35

[20.]

A. Araujo, F. Barata, B. Parente, et al.

Pemetrexed in second line treatment of non-small cell lung cancer. The Portuguese experience.

Rev Port Pneumol, XIV (2008), pp. S9-S20

[21.]

K.M. Kerr.

Pathologist and molecular biologist, ever the twain shall meet?.

Lung Cancer, 63 (2009), pp. 161-163

http://dx.doi.org/10.1016/j.lungcan.2008.10.010 | Medline

[22.]

A.M. Oliveira, H.D. Tazelaar, J.L. Myers, L.A. Erickson, R.V. Lloyd.

Thyroid transcription factor-1 distinguishes metastatic pulmonary from well-differentiated neuroendocrine tumors of other sites.

Am J Surg Pathol, 25 (2001), pp. 815-819

Medline

[23.]

M.I. Ramirez, A.K. Rishi, Y.X. Cao, M.C. Williams.

TGT3, thyroid transcription factor I, and Sp1 elements regulate transcriptional activity of the 1.3-kilobase pair promoter of T1alpha, a lung alveolar type I cell gene.

J Biol Chem, 272 (1997), pp. 26 285-26 294

[24.]

E.S. Ngan, B.H. Lang, T. Liu, et al.

A germline mutation (A339V) in thyroid transcription factor-1 (TITF-1/ NKX2.1) in patients with multinodular goiter and papillary thyroid carcinoma.

J Natl Cancer Inst, 101 (2009), pp. 162-175

http://dx.doi.org/10.1093/jnci/djn471 | Medline

[25.]

H. Ninomiya, M. Hiramatsu, K. Inamura, et al.

Correlation between morphology and EGFR mutations in lung adenocarcinomas Significance of the micropapillary pattern and the hobnail cell type.

Lung Cancer, 63 (2009), pp. 235-240

http://dx.doi.org/10.1016/j.lungcan.2008.04.017 | Medline

[26.]

M. Nakazato, H.K. Chung, L. Ulianich, A. Grassadonia, K. Suzuki, L.D. Kohn.

Thyroglobulin repression of thyroid transcription factor 1 (TTF-1) gene expression is mediated by decreased DNA binding of nuclear factor I proteins which control constitutive TTF-1 expression.

Mol Cell Biol, 20 (2000), pp. 8499-8512

Medline

[27.]

N. Motoi, J. Szoke, G.J. Riely, et al.

Lung adenocarcinoma: modification of the 2004 WHO mixed subtype to include the major histologic subtype suggests correlations between papillary and micropapillary adenocarcinoma subtypes, EGFR mutations and gene expression analysis.

Am J Surg Pathol, 32 (2008), pp. 810-827

http://dx.doi.org/10.1097/PAS.0b013e31815cb162 | Medline

[28.]

K. Kerr.

Pulmonary adenocarcinomas: classification and reporting.

Histopathology, 54 (2009), pp. 27

[29.]

R. Ullman, M. Bongiovanni, I. Halbwedl, S. Petzmann, M. Gogg-Kammerer, A. Sapino, M. Papotti, G. Bussolati, H. Popper.

Bronchiolar columnar cell dysplasia-genetic analysis of a novel preneoplastic lesion of peripheral lung.

Virchows Archiv, 442 (2003), pp. 429-436

http://dx.doi.org/10.1007/s00428-003-0797-z | Medline

[30.]

S. Lantuéjul, D. Salameire, C. Salon.

Brambilla E.

Pulmonary preneoplasia. sequential molecular carcinogenetic events. Histopathology, 54 (2009), pp. 43-54

http://dx.doi.org/10.1111/j.1365-2559.2008.03182.x | Medline

[31.]

M. Noguchi, A. Morikawa, M. Kawasaki, et al.

Small adenocarcinoma of the lung. Histologic characteristics and prognosis.

Cancer, 75 (1995), pp. 2844-2852

Medline

[32.]

S.A. Silver, F.B. Askin.

True papillary carcinoma of the lung: a distinct clinicopathologic entity.

Am J Surg Pathol, 21 (1997), pp. 43-51

Medline

[33.]

V.K. Anagnostou, K.N. Syrigos, G. Bepler, R.J. Homer, D.L. Rimm.

Thyroid transcription factor 1 is an independent prognostic factor for patients with stage I lung adenocarcinoma.

J Clin Oncol, 27 (2009), pp. 271-278

http://dx.doi.org/10.1200/JCO.2008.17.0043 | Medline

[34.]

M. Noguchi, Y. Minami, T. Iijima, Y. Matsuno.

Reproducibility of the diagnosis of small adenocarcinoma of the lung and usefulness of an educational program for the diagnostic criteria.

Pathol Int, 55 (2005), pp. 8-13

http://dx.doi.org/10.1111/j.1440-1827.2005.01782.x | Medline

[35.]

A. Sakurada, M.S. Tsao.

Predictive biomarkers for EGFR therapy.

I Drugs, 12 (2009), pp. 34-38

Medline

[36.]

N.S. Goldstein, A. Mani, G. Chmielewski, R. Welsh, S. Pursel.

Immunohistochemically detected micrometastases in peribronchial and mediastinal lymph nodes from patients with T1, N0, M0 pulmonary adenocarcinomas.

Am J Surg Pathol, 24 (2000), pp. 274-279

Medline

[37.]

J. Pohlenz, A. Dumitrescu, D. Zundel, et al.

Partial deficiency of thyroid transcription factor 1 produces predominantly neurological defects in humans and mice.

J Clin Invest, 109 (2002), pp. 469-473

http://dx.doi.org/10.1172/JCI14192 | Medline

[38.]

B. Parente.

Mesothelioma treatment.

Rev Port Pneumol, XIV (2008), pp. S35-S44

[39.]

M.V. Brock, C.M. Hooker, E. Ota-Machida, et al.

DNA methylation markers and early recurrence in stage I lung cancer.

N Engl J Med, 358 (2008), pp. 1118-1128

http://dx.doi.org/10.1056/NEJMoa0706550 | Medline

[40.]

M.B. Beasly.

Immunohistochemistry of pulmonary and pleural neoplasia.

Arch Pathol Lab Med, 132 (2008), pp. 1062-1072

http://dx.doi.org/10.1043/1543-2165(2008)132[1062:IOPAPN]2.0.CO;2 | Medline

[41.]

B. Addis, H. Roche.

Problems in mesothelioma diagnosis.

Histopathology, 54 (2009), pp. 55-68

http://dx.doi.org/10.1111/j.1365-2559.2008.03178.x | Medline

[42.]

H. Terasaki, T. Niki, Y. Matsuno, et al.

Lung adenocarcinoma with mixed bronchioloalveolar and invasive components: clinicopathological features, subclassification by extent of invasive foci, and immunohistochemical characterization.

Am J Surg Pathol, 27 (2003), pp. 937-951

Medline

[43.]

D.A. Eberhard, G. Giaccone, B.E. Johnson.

Biomarkers of response to epidermal growth factor receptor inhibitors in Non-small-cell lung cancer working group: standardization for use in the clinical trial setting.

J Clin Oncol, 26 (2008), pp. 983-994

http://dx.doi.org/10.1200/JCO.2007.12.9858 | Medline

[44.]

H. Suehisa, S. Toyooka, K. Hotta, et al.

Epidermal growth factor receptor mutation status and adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung.

J Clin Oncol, 25 (2007), pp. 3952-3957

http://dx.doi.org/10.1200/JCO.2007.11.8646 | Medline

[45.]

Z. Zheng, T. Chen, X. Li, E. Haura, A. Sharma, G. Bepler.

DNA synthesis and repair genes RRM1 and ERCC1 in lung cancer.

N Engl J Med, 356 (2007), pp. 800-808

http://dx.doi.org/10.1056/NEJMoa065411 | Medline

[46.]

M.S. Tsao, S. Viel-Ronen, K. Ding, et al.

Prognostic and predictive importance of p53 and RAS for adjuvant chemotherapy in non small-cell lung cancer.

J Clin Oncol, 25 (2007), pp. 5240-5247

http://dx.doi.org/10.1200/JCO.2007.12.6953 | Medline

[47.]

K.A. Olaussen, A. Dunant, P. Fouret, et al.

DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy.

N Engl J Med, 355 (2006), pp. 983-991

http://dx.doi.org/10.1056/NEJMoa060570 | Medline

[48.]

G. Bepler, I. Kusmartseva, S. Sharma, et al.

RRM1 modulated in vitro and in vivo efficacy of gemcitabine and platinum in non-small-cell lung cancer.

J Clin Oncol, 24 (2006), pp. 4731-4737

http://dx.doi.org/10.1200/JCO.2006.06.1101 | Medline

[49.]

G. Sica, P.L. Wagner, N. Altorki, et al.

Immunohistochemical expression of estrogen and progesterone receptors in primary pulmonary neuroendocrine tumors.

Arch Pathol Lab Med, 132 (2008), pp. 1889-1895

http://dx.doi.org/10.1043/1543-2165-132.12.1889 | Medline

[50.]

C. Moran, S. Suster, D. Coppola, M. Wick.

Neuroendocrine carcinomas of the lung.

Am J Clin Pathol, 131 (2009), pp. 206-221

http://dx.doi.org/10.1309/AJCP9H1OTMUCSKQW | Medline

[51.]

G. Fellegara, T. D’Adda, F.P. Pilato, et al.

Genetics of a combined lung small cell carcinoma and large cell neuroendocrine carcinoma with adenocarcinoma.

Virchows Arch, 453 (2008), pp. 107-115

http://dx.doi.org/10.1007/s00428-008-0620-y | Medline

[52.]

P. Wagner, N. Kitabayashi, Y.-T. Chen, A. Saqi.

Combined small cell lung carcinoma.

Am J Clin Pathol, 131 (2009), pp. 376-382

http://dx.doi.org/10.1309/AJCPYNPFL56POZQY | Medline

[53.]

P. Ferolla, N. Daddi, M. Urbani, A. Semeraro, et al.

Tumorlets, multicentric carcinoids, lymph-nodal metástases and long term behaviour in bronchial carcinoids.

Journal of Thoracic Oncology, 4 (2009), pp. 383-387

http://dx.doi.org/10.1097/JTO.0b013e318197f2e7 | Medline

[54.]

A. Wurtz, L. Benhamed, M. Conti, B. Bouchindhomme, H. Porte.

Results of systematic nodal dissection in typical nad atypical carcinoid tumors of the lung.

Journal of Thoracic Oncology, 4 (2009), pp. 388-394

http://dx.doi.org/10.1097/JTO.0b013e3181951aa6 | Medline

[55.]

C. Gomez-Fernandez, M. Jorda, P.I. Delgado, P. Ganjei-Azar.

Thyroid transcription factor 1: a marker for lung adenoarinoma in body cavity fluids.

Cancer, 96 (2002), pp. 289-293

http://dx.doi.org/10.1002/cncr.10743 | Medline

[56.]

S. Miccadei, L.R. De, E. Zammarchi, P.G. Natali, D. Civitareale.

The synergistic activity of thyroid transcription factor 1 and Pax 8 relies on the promoter/enhancer interplay.

Mol Endocrinol, 16 (2002), pp. 837-846

http://dx.doi.org/10.1210/mend.16.4.0808 | Medline

[57.]

R. Rosell, E. Felip, L. Paz-Ares.

How could pharmacogenomics help improve patient survival?.

Lung Cancer, 57 (2007), pp. S35-S41

http://dx.doi.org/10.1016/S0169-5002(07)70426-9 | Medline

[58.]

W. Wallace.

The challenge of classifying poorly differentiated tumours of the lung.

Histopathology, 54 (2009), pp. 28-42

http://dx.doi.org/10.1111/j.1365-2559.2008.03181.x | Medline

[59.]

A.R. Hanauske, U. Eismann, O. Oberschmidt, et al.

In vitro chemosensitivity of freshly explanted tumor cells to pemetrexed is correlated with target gene expression.

Invest New Drugs, 25 (2007), pp. 417-423

http://dx.doi.org/10.1007/s10637-007-9060-9 | Medline

[60.]

S. Yendamuri, A.A. Vaporciyan, T. Zaidi, et al.

3p22.1 and 10q22.3 deletions detected by fluorescence in situ hybridization (FISH): a potential new tool for early detection of non-small cell lung Cancer (NSCLC).

J Thorac Oncol, 3 (2008), pp. 979-984

http://dx.doi.org/10.1097/JTO.0b013e3181834f3a | Medline

[61.]

V.P. Hespanhol.

Lung câncer treatment. Biology based decision, from gene to histology.

Rev Port Pneumol, XIV (2008), pp. S27-S34

[62.]

F. Barata.

Pemetrexed in second line of non-small cell lung cancer.

Rev Port Pneumol, XIV (2008), pp. S21-S26

[63.]

C. Edwards.

Pulmonary adenocarcinoma: review of 106 cases and proposed new classification.

J Clin Pathol, 40 (1987), pp. 125-135

Medline

[64.]

J. Rosai.

Evidence-based pathology and the pathologic evaluation of thymomas.

Arch Pathol Lab Med, 132 (2008), pp. 1859

http://dx.doi.org/10.1043/1543-2165-132.12.1859.c | Medline

[65.]

L. Zhong, J. Roybal, R. Chaerkady, et al.

Identification of secreted proteins that mediate cell-cell interactions in an in vitro model of the lung cancer microenvironment.

Cancer Res, 68 (2008), pp. 7237-7245

http://dx.doi.org/10.1158/0008-5472.CAN-08-1529 | Medline

[66.]

P. Seve, C. Dumontet.

Is class III beta-tubulin a predictive factor in patients receiving tubulin-binding agents?.

Lancet Oncol, 9 (2008), pp. 168-175

http://dx.doi.org/10.1016/S1470-2045(08)70029-9 | Medline

[67.]

T. Donnem, S. Al-Saad, K. Al-Shibli, S. Andersen, L.T. Busund, R.M. Bremnes.

Prognostic impact of platelet-derived growth factors in non-small cell lung cancer tumor and stromal cells.

J Thorac Oncol, 3 (2008), pp. 963-970

http://dx.doi.org/10.1097/JTO.0b013e3181834f52 | Medline

[68.]

K. Crysam, J. Lee, M. Dohadwala, B. Gardner, et al.

Inflammation, epithelial to mesenchimal transition and epidermal growth factor receptor tyrosine kinase inhibitor resistence.

J Thorac Oncol, 3 (2008), pp. 107-110

http://dx.doi.org/10.1097/JTO.0b013e3181630ece | Medline

[69.]

R.S. Herbst, S.M. Lippman.

Molecular signatures of lung cancer-toward personalized therapy.

N Engl J Med, 356 (2007), pp. 76-78

http://dx.doi.org/10.1056/NEJMe068218 | Medline

[70.]

F. Cappuzzo, C. Ligorio, P.A. Janne, et al.

Prospective study of gefitinib in epidermal growth factor receptor fluorescence in situ hybridization-positive/phospho-Akt-positive or never smoker patients with advanced non-small-cell lung cancer: the ONCOBELL trial.

J Clin Oncol, 25 (2007), pp. 2248-2255

http://dx.doi.org/10.1200/JCO.2006.09.4300 | Medline

[71.]

M. Filipits, R. Pirker, A. Dunant, et al.

Cell cycle regulators and outcome of adjuvant cisplatin-based chemotherapy in completely resected non-small-cell lung cancer: the International Adjuvant Lung Cancer Trial Biologic Program.

J Clin Oncol, 25 (2007), pp. 2735-2740

http://dx.doi.org/10.1200/JCO.2006.08.2867 | Medline

[72.]

G.V. Scagliotti, P. Parikh, P.J. Von, 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 (2008), pp. 3543-3551

http://dx.doi.org/10.1200/JCO.2007.15.0375 | Medline

[73.]

R.S. Herbst, J.V. Heymach, S.M. Lippman.

Lung cancer.

N Engl J Med, 359 (2008), pp. 1367-1380

http://dx.doi.org/10.1056/NEJMra0802714 | Medline

[74.]

S. Maheswaran, L.V. Sequist, S. Nagrath, et al.

Detection of mutations in EGFR in circulating lung-cancer cells.

N Engl J Med, 359 (2008), pp. 366-377

http://dx.doi.org/10.1056/NEJMoa0800668 | Medline