Original StudyNon–Small-cell Lung Cancer Patients With Adenocarcinoma Morphology Have a Better Outcome Compared With Patients Diagnosed With Non–Small-cell Lung Cancer Favor Adenocarcinoma
Introduction
Non–small-cell lung cancer (NSCLC) includes 2 major histologic subtypes: squamous cell carcinoma (SQCC) and adenocarcinoma (ADC) and an additional smaller group of poorly differentiated, large cell carcinoma.1 Of patients with NSCLC, 60% to 70% present with advanced disease, usually diagnosed on the basis of small needle biopsies or cytology samples. Strategic tissue management of small biopsies is critical not only for pathologic diagnosis but also for molecular studies.2
Adenocarcinoma and SQCC differ in their gene expression profiles3, 4, 5 and in their clinical management. Endothelial growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements are almost exclusively seen in lung ADC, and carry with them critical information for patient management and outcome.6, 7, 8, 9, 10, 11, 12, 13 Patients with non-squamous NSCLC have been reported to benefit from cisplatin-pemetrexed compared with cisplatin-gemcitabine chemotherapy treatment14, 15 and from second-line treatment with pemetrexed compared with docetaxel, unlike SQCC.15 Pemetrexed maintenance for patients with advanced NSCLC shown to be effective only in patients with non-squamous histology.16 Separating ADC and SQCC is critically important with regard to bevacizumab administration, as this treatment is contraindicated in SQCC, because of risk of fatal pulmonary hemorrhage in this subgroup.17 Importantly, in all studies that showed a difference between ADC and SQCC, this distinction was solely on the basis of light microscopy with or without mucin stains. No immunohistochemistry (IHC) or other special techniques were used in the past to classify the tumors further in these studies.18
In a substantial proportion of NSCLC cases, standard morphology on hematoxylin and eosin-stained slides cannot be used to classify the tumor as ADC or SQCC. The previously described findings enhanced efforts to subclassify NSCLC as ADC versus SQCC for cases when morphology was inconclusive. Diffuse positive thyroid transcription factor 1 (TTF1) staining was reported to be relatively specific for ADC, whereas SQCC typically is negative for TTF1 and positive for p63 and cytokeratin (CK)5/6.17, 18, 19, 20, 21, 22, 23, 24, 25, 26 In a study by Nicholson et al,19 NSCLC tumor specimens without definite morphology were re-evaluated with IHC, allowing refinement of diagnosis in 65% of cases to either SQCC or ADC. Only 19% of cases remained unclassified and were attributed as NSCLC-not otherwise specified (NOS).19, 23, 27 Minimal IHC workup is required to preserve as much tissue as possible for molecular testing in small biopsies.2, 19, 20, 21 NSCLC without clear morphology of ADC or SQCC, but showing positive IHC staining typical of ADC (eg, TTF1) and/or positive for mucin, with a negative squamous marker (eg, p63) would be currently classified as NSCLC favor ADC (NFA).21
Immunohistochemistry-based presumptive diagnosis has become acceptable, although its prognostic value has not been evaluated until recently. Pelosi et al reported that NFA on the basis of IHC was not significantly different but showed a trend for a more aggressive clinical course and poorer prognosis compared with ADC diagnosis on the basis of morphology.26 According to our preliminary data, NSCLC with ADC morphology was associated with a better prognosis than NFA.27 Our aim in this study was to further evaluate whether pulmonary ADC diagnosis on the basis of morphology had a prognosis similar to NFA according to IHC, in a large cohort of platinum–pemetrexed-treated advanced NSCLC patients.
Section snippets
Patients and Methods
Approximately 300 new NSCLC patients are treated at the Sheba Medical Center Institute of Oncology each year. Starting in 2007 a working database was implemented, in which the basic demographic, diagnostic, and treatment details of each patient are registered. We used this database to identify advanced NSCLC patients diagnosed with ADC or NFA, who were treated using a platinum-pemetrexed doublet (without bevacizumab) as first-line combination chemotherapy. Between September 2007 and January
Patient Characteristics
The study population included 160 patients. At the time of data cutoff, 114 patients had died and 46 were still alive. Patients’ clinical and pathological characteristics are described in Table 1. One hundred eleven patients had tumor specimens with clear morphology of ADC whereas 49 patients whose tumor specimen did not have a clear morphology, were classified as NFA on the basis of IHC. Most demographic and clinical characteristics were balanced between ADC and NFA groups, except for initial
Discussion
Advanced ADC as well as NFA are treated similarly with platinum-pemetrexed doublet. We have found that in advanced nonsquamous NSCLC treated with platinum-pemetrexed, the presence of ADC morphology is a positive prognostic factor regarding survival, supporting our initial observation27 as well as data reported by Pelosi et al.26 Our findings might be explained by the fact that non-squamous NSCLC lacking clear morphology of ADC are mostly poorly differentiated, and thus expected to have a more
Conclusion
The findings of our study emphasize the need for future clinical trials to consider the effect of IHC-based designation as ADC of tumors formerly classified as NSCLC-NOS. Additional studies are also required to evaluate the predictive value of ADC morphology versus NFA on platinum-pemetrexed regimen efficacy, as well as on targeted therapy or immunotherapy.
Disclosure
The authors have stated that they have no conflicts of interest.
Acknowledgments
E.H. received a scholarship from the Israel Cancer Association.
References (49)
- et al.
Gefitinib versus cisplatin plus docetaxel in patients with non–small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial
Lancet Oncol
(2010) - et al.
Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non–small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial
Lancet Oncol
(2012) - et al.
Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non–small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study
Lancet Oncol
(2011) - et al.
Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non–small-cell lung cancer: a randomised, double-blind, phase 3 study
Lancet
(2009) - et al.
Pathologic diagnosis of advanced lung cancer based on small biopsies and cytology: a paradigm shift
J Thorac Oncol
(2010) - 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) - et al.
Subtyping of undifferentiated non–small-cell carcinomas in bronchial biopsy specimens
J Thorac Oncol
(2010) - et al.
International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society international multidisciplinary classification of lung adenocarcinoma
J Thorac Oncol
(2011) - 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) - 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)
A grading system combining architectural features and mitotic count predicts recurrence in stage I lung adenocarcinoma
Mod Pathol
Impact of proposed IASLC/ATS/ERS classification of lung adenocarcinoma: prognostic subgroups and implications for further revision of staging based on analysis of 514 stage I cases
Mod Pathol
Histologic grade is an independent prognostic factor for survival in non–small-cell lung cancer: an analysis of 5018 hospital- and 712 population-based cases
J Thorac Cardiovasc Surg
Pretreatment neutrophil-to-lymphocyte ratio is associated with advanced pathologic tumor stage and increased cancer-specific mortality among patients with urothelial carcinoma of the bladder undergoing radical cystectomy
Eur Urol
Neutrophil/lymphocyte ratio and its association with survival after complete resection in non–small-cell lung cancer
J Thorac Cardiovasc Surg
Prognostic models to predict survival in non–small-cell lung cancer patients treated with first-line paclitaxel and carboplatin with or without bevacizumab
J Thorac Oncol
Prognostic relevance of TTF-1 and MMP-9 expression in advanced lung adenocarcinoma
Lung Cancer
New pathologic classification of lung cancer: relevance for clinical practice and clinical trials
J Clin Oncol
A preliminary transcriptome map of non–small-cell lung cancer
Cancer Res
Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses
Proc Natl Acad Sci U S A
Expression profile-defined classification of lung adenocarcinoma shows close relationship with underlying major genetic changes and clinicopathologic behaviors
J Clin Oncol
Gefitinib or chemotherapy for non–small-cell lung cancer with mutated EGFR
N Engl J Med
Gefitinib or carboplatin–paclitaxel in pulmonary adenocarcinoma
N Engl J Med
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Iris Shiran and Eyal Heller contributed equally to this work
Amir Onn and Jair Bar contributed equally to this work
Current address: Iris Shiran, Rabin Medical Center, Petah Tikva, Israel
Current address: Shlomit Jessel, New Haven, CT
This work was performed by Shlomit Jessel in partial fulfillment of the MD thesis requirements of the Sackler Faculty of Medicine, Tel Aviv University