Small-cell lung cancer in never-smokers: A case series

doi:10.1016/j.lungcan.2016.01.006

Lung Cancer

Volume 93, March 2016, Pages 82-87

https://doi.org/10.1016/j.lungcan.2016.01.006 Get rights and content

Highlights

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We present four clinical cases of never-smokers diagnosed with SCLC.
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We performed a detailed questionnaire to all patients, which excluded second-hand smoking or occupational hazards.
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Increasing information will enhance contribute to the better understanding of a rare association.

Abstract

Small-cell lung cancer (SCLC) is closely correlated with smoking and only sporadic cases have been reported in non-smoking patients. Environmental tobacco smoke and/or occupational risk factors have been suggested as possible causes of lung cancer in this subset of patients. However, particularly in relation to SCLC there is not enough reliable information.

All patients with lung cancer in follow-up for a period of three-months at the Pulmonology Unit of Coimbra University Hospital were retrospectively assessed. From a total of 303 patients, 35 had SCLC, 4 of which were never-smokers and their clinical cases are hereby presented. A detailed questionnaire was given to all patients, which excluded second-hand smoking or occupational hazards. They were all female with a mean age of 63.0 ± 15.7 years. The most frequent complaints were cough, dyspnoea, anorexia and significant weight loss. Diagnosis was obtained by transbronchial biopsies in all cases. Two patients had locally advanced disease and the other two had extensive-disease due to distant metastases. Treatment approaches included first-line chemotherapy with platin and etoposide duplet and partial remission was achieved in half the cases. All patients died; mean survival was 15.8 ± 3.8 months.

Further studies are needed for a better understanding of the pathogenicity of non-smoking related SCLC and we hope that this case series with its meticulous exclusion of potential risk factors will be a useful contribution.

Introduction

Lung cancer is the leading cause of cancer-related death and the second most commonly diagnosed cancer in women [1]. Small-cell lung cancer (SCLC) represents a particularly aggressive subtype that accounts for 15–20% of all lung cancers, with an incidence that has been progressively declining as the smoking rate has declined [2], [3]. In fact, SCLC is strongly correlated to tobacco smoking and, despite the fact that lung cancer in never-smokers is approximately the seventh most important cause of cancer-related mortality after smoking [1], [4], [5], [6], it is very rare to find reports describing SCLC in never-smoking patients [7], [8], [9], [10], [11], [12]. The aetiology and pathogenicity of SCLC in these contexts are still unclear; this is mostly due to the paucity of cases and lack of solid research, especially compared to the research developed among non-small cell lung cancer (NSCLC) in patients with no smoking-history [13], [14].

We present four cases of non-smoker patients diagnosed with SCLC in the Pulmonology Unit of Coimbra University Hospital accounting for 11.4% of all SCLC at follow-up during the same period. Each non-smoker patient completed a detailed telephone questionnaire which addressed, firstly, second-hand smoking habits and, secondly, occupational exposure to carcinogens including asbestos, chromium, arsenic, cadmium, silica, nickel, and polycyclic aromatic hydrocarbons. Five patients diagnosed with SCLC, all females, had never smoked and had had no significant exposure to environmental tobacco smoke (ETS) or other known carcinogenic agents. The cumulative dose of ETS was assessed as the sum of the number of exposure years at home, social gatherings and/or workplace, similar to what has been previously reported [15]. Those with significant cumulative ETS were considered to be passive smokers and thus excluded from our study.

Section snippets

Case 1

A 75-year-old female was referred to our Unit for a 3-month history of productive cough, hemoptoic sputum, left chest pain, asthenia and anorexia. Computed tomography (CT) revealed a pulmonary mass in the upper left lobe. Transbronchial biopsies diagnosed SCLC: sheets of small cells with focal nuclar crushing in scarce hyaline stroma, where trabecular pattern was also evident. There the cells revealed positive staining for AE1/AE3, cytokeratin (CK) 7, thyroid transcription factor-1 (TTF1) and

Discussion

The four never-smoking patients, with the diagnosis of SCLC were treated in the Pulmonology Unit. The histological diagnosis were obtained by transbronchial and bronchial biopsy and confirmed with immunohistochemical staining (Ki-67 staining was not interpretable in one of the cases due to lack of material).

To the best of our knowledge, this is the first report to definitely exclude smoking, either active or passive, as the underlying cause of SCLC in all the patients in the subset. Previously

Conflict of interest

The authors have no conflict of interests to declare.

Acknowledgments

To Dr. Tiago Alfaro, for his guidance and support.

References (18)

A. Jemal et al.
Cancer statistics
CA Cancer J. Clin.
(2010)
W.J. Scott et al.
Treatment of non-small cell lung cancer stage I and stage II: ACCP evidence-based clinical practice guidelines (2nd edition)
Chest
(2007)
R. Govindan et al.
Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database
J. Clin. Oncol.
(2006)
M.J. Thun et al.
Lung cancer death rates in lifelong nonsmokers
J. Natl. Cancer Inst.
(2006)
W.J. McCarthy et al.
Lung cancer in never smokers: epidemiology and risk prediction models
Risk Anal.
(2012)
S. Sun et al.
Lung cancer in never smokers—a different disease
Nat. Rev. Cancer
(2007)
Y. Kurahara et al.
Small-cell lung cancer in never-smokers: a case series with information on family history of cancer and environmental tobacco smoke
Clin. Lung Cancer
(2012)
I. Okamoto et al.
EGFR mutation in gefitinib-responsive small-cell lung cancer
Ann. Oncol.
(2006)
M.F. Zakowski et al.
EGFR mutations in small-cell lung cancers in patients who have never smoked
N. Engl. J. Med.
(2006)

There are more references available in the full text version of this article.

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Doll et al. [25] confirmed that smoking causes lung cancer through 50 years of epidemiological investigation. According to epidemiological statistics, small cell lung cancer (SCLC) is closely related to smoking and second-hand smoke exposure, and most patients with SCLC have a history of smoking [26]. And the markers of methylation caused by smoking persist years after quitting smoking.
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Clinical and Genomic Characteristics of Small Cell Lung Cancer in Never Smokers: Results From a Retrospective Multicenter Cohort Study
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Small cell lung cancer (SCLC) has the strongest association with smoking among lung cancers. The characteristics of never smokers with SCLC is not known.
Are the clinical characteristics, prognostic factors, survival, genomic alterations, and tumor mutational burdens of SCLC in patients who have never smoked different from those who have smoked?
A retrospective multicenter cohort study of patients with clinician-confirmed SCLC was performed with the use of a longitudinal and nationally representative electronic medical records database. Smoking history was assessed through technology-enabled abstraction and confirmed for never smokers via chart review. Genomic characteristics of never smoker patients with SCLC were examined with the use of a next-generation sequencing-based gene panel and whole exome sequencing.
One hundred of 5,632 patients (1.8%) with SCLC were never smokers. Relative to smokers, never smokers were more likely to be female (66.0% vs 52.4%; P = .009) and present with extensive stage (70.0% vs 62.2%; P = .028). Never smokers had a higher proportion of patients in age groups 35 to 49 years (7.0% vs 3.0%; P = .006) and ≥80 years (17.0% vs 8.2%; P = .006). Known risk factors for lung cancer were found in <20% of never smokers. There were no overall survival differences between never smokers and smokers. Among patients with available genomic data (n = 9), never smoker SCLC were characterized by lower tumor mutational burden, a lower frequency of TP53 mutations, and an absence of mutational signatures related to tobacco exposure.
The sex- and age-specific distribution of SCLC among never smokers, along with differences that were identified by genomic analyses, suggests a distinct biology of SCLC in never smokers compared with smokers.
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Of the 231 patients, 101 (44%) had central-type and 130 (56%) had peripheral-type SCLC. Peripheral-type SCLC was associated with a better performance status, higher frequency of ILD, and higher rate of limited disease stage. Patients with peripheral-type SCLC had a significantly longer OS than did those with central-type SCLC (median, 502 vs 370 days, respectively; p = 0.0186). Tumor location was not associated with PFS. PFS was poorer in patients with than without ILD (median, 143 vs 213 days, respectively; p = 0.0038), as was OS (median, 245 vs 545 days, respectively; p = 0.0014). Among patients without ILD, OS was longer in those with peripheral- than central-type tumors (median, 662 vs 421 days, respectively; p = 0.0074). Surgical resection was more often chosen for peripheral-type tumors, and this was one reason for the prolonged survival. There was no difference in the response to chemotherapy and/or radiotherapy between central- and peripheral-type SCLC. Multivariate analysis by a Cox proportional hazards model showed that male sex, a poor performance status, extensive disease, the presence of ILD, an elevated serum neuron-specific enolase concentration, and central-type SCLC were poor prognostic factors for OS.
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The effectiveness of EGFR-TKI therapy for de novo SCLCs with EGFR mutations should be examined to determine whether or not such mutations lead to a more favorable prognosis. In never-smoker SCLCs, the rate of female patients was higher than that of male patients, as has been reported thus far [3–6,29]. While the precise reason for this result is uncertain, several may be presumed.
Small-cell lung cancer (SCLC) is known to be closely associated with smoking; therefore, never-smokers with SCLC are very rare. We conducted a retrospective study to investigate the clinicopathological features of SCLC in never-smokers.
We reviewed the medical charts of SCLC patients treated at our institution from December 2000 to May 2016, and identified SCLCs in never-smokers. We collected the clinicopathological data, treatment regimen, and efficacy and survival data. In addition, we compared these data with those of SCLCs in smokers. The EGFR mutations were examined in available samples of SCLCs in never-smokers.
A total of 196 SCLC patients were reviewed, and 8 never-smokers were identified (4.1%). All of them had de novo SCLC. The median age was 71 years (range: 66–84 years), and 6 patients were female (75%). Seven patients (88%) had been exposed to environmental tobacco smoke (ETS), and the other patient was an atomic bomb survivor. Only 1 patient had an EGFR mutation (13%). The overall response rate (ORR) to anticancer treatments was 88%. The median progression-free survival (PFS) was 6.1 months (95% confidence interval: 2.6-infinity), and the median overall survival (OS) was 74.6 months (95% confidence interval: 4.8-infinity). No marked differences were found in the ORR or PFS between never-smokers and smokers. However, the OS of never-smokers was statistically longer than that of smokers (median: 17.3 months, p=0.0371).
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View full text

Small-cell lung cancer in never-smokers: A case series

Highlights

Abstract

Introduction

Section snippets

Case 1

Discussion

Conflict of interest

Acknowledgments

Cancer statistics

CA Cancer J. Clin.

Treatment of non-small cell lung cancer stage I and stage II: ACCP evidence-based clinical practice guidelines (2nd edition)

Chest

Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database

J. Clin. Oncol.

Lung cancer death rates in lifelong nonsmokers

J. Natl. Cancer Inst.

Lung cancer in never smokers: epidemiology and risk prediction models

Risk Anal.

Lung cancer in never smokers—a different disease

Nat. Rev. Cancer

Small-cell lung cancer in never-smokers: a case series with information on family history of cancer and environmental tobacco smoke

Clin. Lung Cancer

EGFR mutation in gefitinib-responsive small-cell lung cancer

Ann. Oncol.

EGFR mutations in small-cell lung cancers in patients who have never smoked

N. Engl. J. Med.