Elsevier

Clinical Lung Cancer

Volume 18, Issue 3, May 2017, Pages 316-323.e1
Clinical Lung Cancer

Original Study
Non–Small-cell Lung Cancer Patients With Adenocarcinoma Morphology Have a Better Outcome Compared With Patients Diagnosed With Non–Small-cell Lung Cancer Favor Adenocarcinoma

https://doi.org/10.1016/j.cllc.2017.01.009Get rights and content

Abstract

Background

Non–small-cell lung cancer (NSCLC) includes 2 major histologic subtypes: squamous cell carcinoma and non-squamous carcinoma, mainly adenocarcinoma, a distinction that carries significant clinical and therapeutic implications. NSCLC is diagnosed as adenocarcinoma or as squamous cell carcinoma on the basis of histologic parameters. However, when morphology is inconclusive, tumors with immunohistochemistry (IHC) findings characteristic of adenocarcinoma are referred to as “NSCLC favor adenocarcinoma” (NFA). Our aim was to evaluate whether pulmonary adenocarcinoma diagnosis on the basis of morphology had a similar prognosis compared with NFA.

Patients and Methods

Patients with advanced NSCLC non-squamous carcinoma who were treated with a platinum-pemetrexed doublet as first-line combination chemotherapy were identified. Demographic, clinical, laboratory, and pathological data including the method of pathological diagnosis (morphology or IHC) was extracted from the clinical charts. The correlation between the various parameters and overall survival was evaluated.

Results

Lack of adenocarcinoma morphology, male sex, smoking history, and negative thyroid transcription factor 1 IHC were associated with worse prognosis and shorter overall survival in multivariate analysis. High white blood cell count, absolute neutrophil count, neutrophil to lymphocyte ratio, and low albumin levels were associated with shorter overall survival only in univariate analysis.

Conclusion

Pulmonary adenocarcinoma has a better prognosis than NFA, regarding advanced NSCLC treated with platinum-pemetrexed combination chemotherapy. This distinction should be a stratification factor in clinical trials and a prognostic factor to consider in analysis of previous trials.

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.

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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

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