- Email: [email protected]
Small-cell lung cancer in never-smokers: A case series
Lung Cancer 93 (2016) 82–87
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Small-cell lung cancer in never-smokers: A case series Ana Tavares e Castro a,∗ , Joana Clemente a , L. Carvalho b , Sara Freitas a , Jessica Cemlyn-Jones a a b
Pulmonology Unit, Hospitais da Universidade de Coimbra, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal Pathology Unit, Hospitais da Universidade de Coimbra, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
a r t i c l e
i n f o
Article history: Received 23 May 2014 Received in revised form 4 January 2016 Accepted 7 January 2016 Keywords: Small-cell lung cancer Never-smoker Women
a b s t r a c t 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. © 2016 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Lung cancer is the leading cause of cancer-related death and the second most commonly diagnosed cancer in women [1]. Smallcell 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 [1,4–6], it is very rare to find reports describing SCLC in never-smoking patients [7–12]. 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].
∗ Corresponding author at: Hospitais da Universidade de Coimbra, Praceta Prof. Mota Pinto, 3000-075 Coimbra, Portugal. E-mail address: [email protected] (A. Tavares e Castro). http://dx.doi.org/10.1016/j.lungcan.2016.01.006 0169-5002/© 2016 Elsevier Ireland Ltd. All rights reserved.
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.
A. Tavares e Castro et al. / Lung Cancer 93 (2016) 82–87
83
2. Case reports
2.2. Case 2
2.1. Case 1
A 40-year-old female with no relevant comorbidities was admitted to our Unit for chronic complaints of non-productive cough, bilateral chest pain, exertional dyspnoea, anorexia and weight loss of 10 kg. She had been medicated with antibiotics but there was no significant improvement. CT scan revealed a left hilar mass causing collapse of the left upper lobe, and obliteration of the left pulmonary artery and main bronchus. The lesion had no cleavage plane with the aortic arch and the proximal segment of the left superior pulmonary vein. Transbronchial biopsies in the upper left bronchus diagnosed SCLC: tumoral cells were small with scant cytoplasm and predominantly fibroblastic stroma; CK7, CD56, CGA, synaptophysin and nuclear TTF1 were expressed; there was focal positivity for Vimentin while negativity was seen for CGA, CK5/6, p63 and CD45. Ki-67 staining was inconclusive. It was an extended-disease due to bone metastasis. After chemotherapy with carboplatin and etoposide there was disease progression with liver and adrenal metastases. She was also treated for malignant superior vena cava
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 synaptophysin; chromogranin A (CGA) was focally positive while cluster of differentiation (CD) 56, CD45, CK5/6, p63 and Vimentin were negative. Ki-67 was positive in 90 to 100% of the cells. Staging revealed extended-disease due to multiple liver and brain metastases. She achieved partial remission of the pulmonary lesion after chemotherapy with carboplatin and etoposide, and holocranial radiotherapy. She died 17 months after the diagnosis (Fig. 1).
Fig. 1. Case 1 (Images 1a–e). (1a) Chest computed-tomography shows a nodular lesion of about 2.7 cm in the left upper lobe, invading the upper and lower lobar arteries, and causing collapse of the lobe and occlusion of the corresponding bronchus. (1b) No hilar or mediastinal lymphadenopathy were observed. (1c–e) Fragments of bronchial biopsy showed small cells arranged in cords with scant cytoplasm and hyperchromatic round nuclei, expressing AE1 + AE3, CD45, TTF1 and synaptophysin and negative for CD45. Case 2 (Images 2a–e). (2a) Chest CT-scan showing a left hilar mass measuring 5 × 3.9 cm causing stenosis of the left pulmonary artery and left main bronchus, and partial collapse of the upper left lobe. (2b) Chest CT-scan showing the pulmonary mass invading the aorto-pulmonary window and the anterior mediastinum. The lesion has no cleavage plane with the aortic arch and the proximal segment of the left superior pulmonary vein. (2c–e) Bronchial biopsy collected small pieces of tumoral tissue of round and elongated cells with scares cytoplasm, expressing CK7 and CD56 with nuclear TTF1.
84
A. Tavares e Castro et al. / Lung Cancer 93 (2016) 82–87
Fig. 1. (Continued).
syndrome with endovascular stent insertion. She died 20 months after the diagnosis (Fig. 1).
our Unit due to disorientation and incoherent speech resulting from extensive brain metastasis and died from the disease 11 months after the diagnosis (Fig. 2).
2.3. Case 3 A 67-year-old female was referred to our hospital by her family doctor due to clinical and radiological worsening of bilateral pneumonia despite empiric antibiotherapy. She also suffered from anorexia and had lost 5 kg in the previous five months. She had arterial hypertension, dyslipidaemia and asthma. CT scan revealed a right hilar mass extending to the right lower lobe and to the mediastinum, and invading the right main bronchus and the right pulmonary artery. There was no cleavage plane with the left atrium, the left pulmonary artery, the pulmonary vein or the ascending aorta. SCLC was diagnosed through bronchial biopsy from the right intermediate bronchus, corresponding to sheets of small cells in desmoplastic stroma, with nuclear crushing phenomena. Immunohistochemistry stains revealed positivity for CD56, synaptophysin and CGA; there was focal positivity for p63 and negativity for CK7, CK5/6, Vimentin and TTF1. The proliferation index determined by Ki67 was 100%. The disease was locally advanced and progressed after chemotherapy with carboplatin and etoposide. While on second-line chemotherapy with topotecan she was admitted to
2.4. Case 4 A 70-year-old female was admitted to our Unit for further study on a chest CT showing a mass in the upper left lobe of the lung, bilateral nodules and ipsilateral hilar and mediastinal lymphadenopathy. She had a 9-month history of non-productive cough, fatigue and significant weight loss. Her comorbidities were arterial hypertension, dyslipidaemia, epilepsy and a stoke 10 years ago. Chest CT showed a left hilar mass invading the left pulmonary artery. Bronchial biopsy from the upper left bronchus diagnosed SCLC after revealing sheets of tumoral cells with hyperchromatic nuclei, crushing phenomena focally and scarce vascular stroma. There was positivity for CK7, CD56 and synaptophysin; negativity for CGA, CK5/6, p63, Vimentin and TTF1. The proliferation index determined by Ki67 was 75%. Due to super vena cava syndrome an endovascular stent was placed. There was a partial response to chemotherapy with carboplatin and etoposide but she died 15 months after the diagnosis (Fig. 2).
A. Tavares e Castro et al. / Lung Cancer 93 (2016) 82–87
3. 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 published case reports have not provided information about ETS or have included passive smokers, and in these circumstances, secondhand smoke exposure was likely to have been responsible for lung cancer [7–10,12,16]. We also excluded additional occupational carcinogen exposure which suggests that other aspects involved in carcinogenesis, such as genetic, hormonal and viral factors, ought
85
to be considered in the development of lung cancer in patients without known risk factors. All patients in our study were female like most of the cases of lung cancer in never-smokers reported so far [7–10,12,13,16]. In fact, although SCLC is a predominantly male disease, the proportion of female patients has considerably increased [3]. Some studies have suggested that female hormones may play a pivotal role leading to lung cancer but no definite conclusions can be drawn [17]. Our study had some limitations. First, the number of cases found was small but it mirrors the low incidence of lung cancer in neversmokers as well as its higher frequency in female patients. A second limitation was that we did not provide data concerning other risk factors, including diet, family history of lung cancer and oncogenic viral diseases, but their role in lung cancer are still under review.
Fig. 2. Case 3 (Images 3a–e). (3a) Chest CT-scan showing a large lung mass, occupying the right lower lobe and extending to the mediastinum, and a parenchymal densification in the posterior segment of the right upper lobe. (3b) Chest CT-scan showing the mass invading and bronchus and the esophagus, and incarcerating the right pulmonary artery and its branches, the right pulmonary vein. (3c–e) Bronchial biopsy collected small pieces of small cell carcinoma with crushing phenomena and clusters of small round cells with large nuclei expressing Ki67 80%. Cytoplasmic expression of chromogranin A and CD56 was observed in over 50% of cells. CK7, TTF1 and CD5/6 were negative. Case 4 (Images 4a–e). (4a) Chest CT-scan showing a right hilar mass involving the left hilar arteries and main bronchus. (4b) The mass invades the mediastinum and the terminal portion of the trachea. (4c–e) Small fragments of bronchial mucosae with lamina propria occupied by malignant cells with large nuclei expressing Ki67 75% and scarse cytoplasm with positivity for CD56 and focally for CK7.
86
A. Tavares e Castro et al. / Lung Cancer 93 (2016) 82–87
Fig. 2. (Continued).
SCLC biology is notably related to smoking. In fact, the decreasing incidence of this histologic subtype of lung cancer has been coupled to the decreasing smoking habits and the change to low-tar filter cigarettes resulting in lower carcinogen exposure in the central airways and deeper penetration of smoke into the lung [3]. Lung cancer in never-smokers has a distinct natural history and profile of oncogenic mutations [5]. Despite its rarity, interest in this subset of patients has revived, particularly because of new therapeutic approaches that target specific mutations more commonly found in this subset of patients [5,8]. However, despite promising results, no targeted therapy has yet been approved for use in SCLC [9,16,18]. In conclusion, our study aimed to supplement data on the rare association between never-smokers and SCLC and contribute to the better understanding of non-smoking-associated lung cancer.
Conflict of interest The authors have no conflict of interests to declare.
Acknowledgments To Dr. Tiago Alfaro, for his guidance and support. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.lungcan.2016.01. 006. References [1] A. Jemal, R. Siegel, J. Xu, E. Ward, Cancer statistics, CA Cancer J. Clin. 60 (5) (2010) 277–300, http://dx.doi.org/10.3322/caac.20073. [2] W.J. Scott, J. Howington, S. Feigenberg, B. Movsas, K. Pisters, Treatment of non-small cell lung cancer stage I and stage II: ACCP evidence-based clinical practice guidelines (2nd edition), Chest 132 (Suppl. 3) (2007) 234S–242S, http://dx.doi.org/10.1378/chest.07-1378. [3] R. Govindan, N. Page, D. Morgensztern, 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. 24 (28) (2006) 4539–4544, http://dx.doi.org/10.1200/JCO.2005.04.4859. [4] M.J. Thun, S.J. Henley, D. Burns, A. Jemal, T.G. Shanks, E.E. Calle, Lung cancer death rates in lifelong nonsmokers, J. Natl. Cancer Inst. 98 (10) (2006) 691–699, http://dx.doi.org/10.1093/jnci/djj187.
A. Tavares e Castro et al. / Lung Cancer 93 (2016) 82–87 [5] W.J. McCarthy, R. Meza, J. Jeon, S.H. Moolgavkar, Lung cancer in never smokers: epidemiology and risk prediction models, Risk Anal. 32 (Suppl. 1) (2012) S69–S84, http://dx.doi.org/10.1111/j.1539-6924.2012.01768.x (Chapter 6). [6] S. Sun, J.H. Schiller, A.F. Gazdar, Lung cancer in never smokers—a different disease, Nat. Rev. Cancer 7 (10) (2007) 778–790, http://dx.doi.org/10.1038/ nrc2190. [7] Y. Kurahara, T. Kawaguchi, K. Tachibana, 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 13 (1) (2012) 75–79, http:// dx.doi.org/10.1016/j.cllc.2011.04.001. [8] I. Okamoto, J. Araki, R. Suto, M. Shimada, K. Nakagawa, M. Fukuoka, EGFR mutation in gefitinib-responsive small-cell lung cancer, Ann. Oncol. 17 (6) (2006) 1028–1029, http://dx.doi.org/10.1093/annonc/mdj114. [9] M.F. Zakowski, M. Ladanyi, M.G. Kris, EGFR mutations in small-cell lung cancers in patients who have never smoked, N. Engl. J. Med. 355 (2) (2006) 213–215, http://dx.doi.org/10.1056/NEJMc053610. [10] N. Alam, K.S. Gustafson, M. Ladanyi, et al., Small-cell carcinoma with an epidermal growth factor receptor mutation in a never-smoker with gefitinib-responsive adenocarcinoma of the lung, Clin. Lung Cancer (2010) E1–E4 (accessed 30.12.13) http://www.sciencedirect.com/science/article/pii/ S1525730411700729. [11] T.-H. Shiao, Y.-L. Chang, C.-J. Yu, et al., Epidermal growth factor receptor mutations in small cell lung cancer: a brief report, J. Thorac. Oncol. 6 (1) (2011) 195–198, http://dx.doi.org/10.1097/JTO.0b013e3181f94abb.
87
[12] G.K. Antony, E. Bertino, M. Franklin, G.A. Otterson, A.Z. Dudek, Small cell lung cancer in never smokers: report of two cases, J. Thorac. Oncol. 5 (5) (2010) 747–748, http://dx.doi.org/10.1097/JTO.0b013e3181d6e124. [13] A.G. Pallis, K.N. Syrigos, Lung cancer in never smokers: disease characteristics and risk factors, Crit. Rev. Oncol. Hematol. 88 (3) (2013) 494–503, http://dx. doi.org/10.1016/j.critrevonc.2013.06.011. [14] T. Yano, A. Haro, Y. Shikada, R. Maruyama, Y. Maehara, Non-small cell lung cancer in never smokers as a representative non-smoking-associated lung cancer: epidemiology and clinical features, Int. J. Clin. Oncol. 16 (4) (2011) 287–293, http://dx.doi.org/10.1007/s10147-010-0160-8. [15] T. Kawaguchi, M. Ando, A. Kubo, et al., Long exposure of environmental tobacco smoke associated with activating EGFR mutations in never-smokers with non-small cell lung cancer, Clin. Cancer Res. 17 (1) (2011) 39–45, http:// dx.doi.org/10.1158/1078-0432, CCR-10-1773. [16] A. Tatematsu, J. Shimizu, Y. Murakami, et al., Epidermal growth factor receptor mutations in small cell lung cancer, Clin. Cancer Res. 14 (19) (2008) 6092–6096, http://dx.doi.org/10.1158/1078-0432, CCR-08-0332. [17] L.P. Stabile, A.L.G. Davis, C.T. Gubish, et al., Human non-small cell lung tumors and cells derived from normal lung express both estrogen receptor alpha and beta and show biological responses to estrogen, Cancer Res. 62 (7) (2002) 2141–2150 (accessed 25.4.14) http://www.ncbi.nlm.nih.gov/pubmed/ 11929836. [18] Y. Zhang, J. He, The development of targeted therapy in small cell lung cancer, J. Thorac. Dis. 5 (4) (2016) 538–548 (accessed 23.4.14) http://www.jthoracdis. com/article/view/1441/html.
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Small-cell lung cancer in never-smokers: A case series Ana Tavares e Castro a,∗ , Joana Clemente a , L. Carvalho b , Sara Freitas a , Jessica Cemlyn-Jones a a b
Pulmonology Unit, Hospitais da Universidade de Coimbra, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal Pathology Unit, Hospitais da Universidade de Coimbra, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
a r t i c l e
i n f o
Article history: Received 23 May 2014 Received in revised form 4 January 2016 Accepted 7 January 2016 Keywords: Small-cell lung cancer Never-smoker Women
a b s t r a c t 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. © 2016 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Lung cancer is the leading cause of cancer-related death and the second most commonly diagnosed cancer in women [1]. Smallcell 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 [1,4–6], it is very rare to find reports describing SCLC in never-smoking patients [7–12]. 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].
∗ Corresponding author at: Hospitais da Universidade de Coimbra, Praceta Prof. Mota Pinto, 3000-075 Coimbra, Portugal. E-mail address: [email protected] (A. Tavares e Castro). http://dx.doi.org/10.1016/j.lungcan.2016.01.006 0169-5002/© 2016 Elsevier Ireland Ltd. All rights reserved.
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.
A. Tavares e Castro et al. / Lung Cancer 93 (2016) 82–87
83
2. Case reports
2.2. Case 2
2.1. Case 1
A 40-year-old female with no relevant comorbidities was admitted to our Unit for chronic complaints of non-productive cough, bilateral chest pain, exertional dyspnoea, anorexia and weight loss of 10 kg. She had been medicated with antibiotics but there was no significant improvement. CT scan revealed a left hilar mass causing collapse of the left upper lobe, and obliteration of the left pulmonary artery and main bronchus. The lesion had no cleavage plane with the aortic arch and the proximal segment of the left superior pulmonary vein. Transbronchial biopsies in the upper left bronchus diagnosed SCLC: tumoral cells were small with scant cytoplasm and predominantly fibroblastic stroma; CK7, CD56, CGA, synaptophysin and nuclear TTF1 were expressed; there was focal positivity for Vimentin while negativity was seen for CGA, CK5/6, p63 and CD45. Ki-67 staining was inconclusive. It was an extended-disease due to bone metastasis. After chemotherapy with carboplatin and etoposide there was disease progression with liver and adrenal metastases. She was also treated for malignant superior vena cava
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 synaptophysin; chromogranin A (CGA) was focally positive while cluster of differentiation (CD) 56, CD45, CK5/6, p63 and Vimentin were negative. Ki-67 was positive in 90 to 100% of the cells. Staging revealed extended-disease due to multiple liver and brain metastases. She achieved partial remission of the pulmonary lesion after chemotherapy with carboplatin and etoposide, and holocranial radiotherapy. She died 17 months after the diagnosis (Fig. 1).
Fig. 1. Case 1 (Images 1a–e). (1a) Chest computed-tomography shows a nodular lesion of about 2.7 cm in the left upper lobe, invading the upper and lower lobar arteries, and causing collapse of the lobe and occlusion of the corresponding bronchus. (1b) No hilar or mediastinal lymphadenopathy were observed. (1c–e) Fragments of bronchial biopsy showed small cells arranged in cords with scant cytoplasm and hyperchromatic round nuclei, expressing AE1 + AE3, CD45, TTF1 and synaptophysin and negative for CD45. Case 2 (Images 2a–e). (2a) Chest CT-scan showing a left hilar mass measuring 5 × 3.9 cm causing stenosis of the left pulmonary artery and left main bronchus, and partial collapse of the upper left lobe. (2b) Chest CT-scan showing the pulmonary mass invading the aorto-pulmonary window and the anterior mediastinum. The lesion has no cleavage plane with the aortic arch and the proximal segment of the left superior pulmonary vein. (2c–e) Bronchial biopsy collected small pieces of tumoral tissue of round and elongated cells with scares cytoplasm, expressing CK7 and CD56 with nuclear TTF1.
84
A. Tavares e Castro et al. / Lung Cancer 93 (2016) 82–87
Fig. 1. (Continued).
syndrome with endovascular stent insertion. She died 20 months after the diagnosis (Fig. 1).
our Unit due to disorientation and incoherent speech resulting from extensive brain metastasis and died from the disease 11 months after the diagnosis (Fig. 2).
2.3. Case 3 A 67-year-old female was referred to our hospital by her family doctor due to clinical and radiological worsening of bilateral pneumonia despite empiric antibiotherapy. She also suffered from anorexia and had lost 5 kg in the previous five months. She had arterial hypertension, dyslipidaemia and asthma. CT scan revealed a right hilar mass extending to the right lower lobe and to the mediastinum, and invading the right main bronchus and the right pulmonary artery. There was no cleavage plane with the left atrium, the left pulmonary artery, the pulmonary vein or the ascending aorta. SCLC was diagnosed through bronchial biopsy from the right intermediate bronchus, corresponding to sheets of small cells in desmoplastic stroma, with nuclear crushing phenomena. Immunohistochemistry stains revealed positivity for CD56, synaptophysin and CGA; there was focal positivity for p63 and negativity for CK7, CK5/6, Vimentin and TTF1. The proliferation index determined by Ki67 was 100%. The disease was locally advanced and progressed after chemotherapy with carboplatin and etoposide. While on second-line chemotherapy with topotecan she was admitted to
2.4. Case 4 A 70-year-old female was admitted to our Unit for further study on a chest CT showing a mass in the upper left lobe of the lung, bilateral nodules and ipsilateral hilar and mediastinal lymphadenopathy. She had a 9-month history of non-productive cough, fatigue and significant weight loss. Her comorbidities were arterial hypertension, dyslipidaemia, epilepsy and a stoke 10 years ago. Chest CT showed a left hilar mass invading the left pulmonary artery. Bronchial biopsy from the upper left bronchus diagnosed SCLC after revealing sheets of tumoral cells with hyperchromatic nuclei, crushing phenomena focally and scarce vascular stroma. There was positivity for CK7, CD56 and synaptophysin; negativity for CGA, CK5/6, p63, Vimentin and TTF1. The proliferation index determined by Ki67 was 75%. Due to super vena cava syndrome an endovascular stent was placed. There was a partial response to chemotherapy with carboplatin and etoposide but she died 15 months after the diagnosis (Fig. 2).
A. Tavares e Castro et al. / Lung Cancer 93 (2016) 82–87
3. 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 published case reports have not provided information about ETS or have included passive smokers, and in these circumstances, secondhand smoke exposure was likely to have been responsible for lung cancer [7–10,12,16]. We also excluded additional occupational carcinogen exposure which suggests that other aspects involved in carcinogenesis, such as genetic, hormonal and viral factors, ought
85
to be considered in the development of lung cancer in patients without known risk factors. All patients in our study were female like most of the cases of lung cancer in never-smokers reported so far [7–10,12,13,16]. In fact, although SCLC is a predominantly male disease, the proportion of female patients has considerably increased [3]. Some studies have suggested that female hormones may play a pivotal role leading to lung cancer but no definite conclusions can be drawn [17]. Our study had some limitations. First, the number of cases found was small but it mirrors the low incidence of lung cancer in neversmokers as well as its higher frequency in female patients. A second limitation was that we did not provide data concerning other risk factors, including diet, family history of lung cancer and oncogenic viral diseases, but their role in lung cancer are still under review.
Fig. 2. Case 3 (Images 3a–e). (3a) Chest CT-scan showing a large lung mass, occupying the right lower lobe and extending to the mediastinum, and a parenchymal densification in the posterior segment of the right upper lobe. (3b) Chest CT-scan showing the mass invading and bronchus and the esophagus, and incarcerating the right pulmonary artery and its branches, the right pulmonary vein. (3c–e) Bronchial biopsy collected small pieces of small cell carcinoma with crushing phenomena and clusters of small round cells with large nuclei expressing Ki67 80%. Cytoplasmic expression of chromogranin A and CD56 was observed in over 50% of cells. CK7, TTF1 and CD5/6 were negative. Case 4 (Images 4a–e). (4a) Chest CT-scan showing a right hilar mass involving the left hilar arteries and main bronchus. (4b) The mass invades the mediastinum and the terminal portion of the trachea. (4c–e) Small fragments of bronchial mucosae with lamina propria occupied by malignant cells with large nuclei expressing Ki67 75% and scarse cytoplasm with positivity for CD56 and focally for CK7.
86
A. Tavares e Castro et al. / Lung Cancer 93 (2016) 82–87
Fig. 2. (Continued).
SCLC biology is notably related to smoking. In fact, the decreasing incidence of this histologic subtype of lung cancer has been coupled to the decreasing smoking habits and the change to low-tar filter cigarettes resulting in lower carcinogen exposure in the central airways and deeper penetration of smoke into the lung [3]. Lung cancer in never-smokers has a distinct natural history and profile of oncogenic mutations [5]. Despite its rarity, interest in this subset of patients has revived, particularly because of new therapeutic approaches that target specific mutations more commonly found in this subset of patients [5,8]. However, despite promising results, no targeted therapy has yet been approved for use in SCLC [9,16,18]. In conclusion, our study aimed to supplement data on the rare association between never-smokers and SCLC and contribute to the better understanding of non-smoking-associated lung cancer.
Conflict of interest The authors have no conflict of interests to declare.
Acknowledgments To Dr. Tiago Alfaro, for his guidance and support. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.lungcan.2016.01. 006. References [1] A. Jemal, R. Siegel, J. Xu, E. Ward, Cancer statistics, CA Cancer J. Clin. 60 (5) (2010) 277–300, http://dx.doi.org/10.3322/caac.20073. [2] W.J. Scott, J. Howington, S. Feigenberg, B. Movsas, K. Pisters, Treatment of non-small cell lung cancer stage I and stage II: ACCP evidence-based clinical practice guidelines (2nd edition), Chest 132 (Suppl. 3) (2007) 234S–242S, http://dx.doi.org/10.1378/chest.07-1378. [3] R. Govindan, N. Page, D. Morgensztern, 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. 24 (28) (2006) 4539–4544, http://dx.doi.org/10.1200/JCO.2005.04.4859. [4] M.J. Thun, S.J. Henley, D. Burns, A. Jemal, T.G. Shanks, E.E. Calle, Lung cancer death rates in lifelong nonsmokers, J. Natl. Cancer Inst. 98 (10) (2006) 691–699, http://dx.doi.org/10.1093/jnci/djj187.
A. Tavares e Castro et al. / Lung Cancer 93 (2016) 82–87 [5] W.J. McCarthy, R. Meza, J. Jeon, S.H. Moolgavkar, Lung cancer in never smokers: epidemiology and risk prediction models, Risk Anal. 32 (Suppl. 1) (2012) S69–S84, http://dx.doi.org/10.1111/j.1539-6924.2012.01768.x (Chapter 6). [6] S. Sun, J.H. Schiller, A.F. Gazdar, Lung cancer in never smokers—a different disease, Nat. Rev. Cancer 7 (10) (2007) 778–790, http://dx.doi.org/10.1038/ nrc2190. [7] Y. Kurahara, T. Kawaguchi, K. Tachibana, 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 13 (1) (2012) 75–79, http:// dx.doi.org/10.1016/j.cllc.2011.04.001. [8] I. Okamoto, J. Araki, R. Suto, M. Shimada, K. Nakagawa, M. Fukuoka, EGFR mutation in gefitinib-responsive small-cell lung cancer, Ann. Oncol. 17 (6) (2006) 1028–1029, http://dx.doi.org/10.1093/annonc/mdj114. [9] M.F. Zakowski, M. Ladanyi, M.G. Kris, EGFR mutations in small-cell lung cancers in patients who have never smoked, N. Engl. J. Med. 355 (2) (2006) 213–215, http://dx.doi.org/10.1056/NEJMc053610. [10] N. Alam, K.S. Gustafson, M. Ladanyi, et al., Small-cell carcinoma with an epidermal growth factor receptor mutation in a never-smoker with gefitinib-responsive adenocarcinoma of the lung, Clin. Lung Cancer (2010) E1–E4 (accessed 30.12.13) http://www.sciencedirect.com/science/article/pii/ S1525730411700729. [11] T.-H. Shiao, Y.-L. Chang, C.-J. Yu, et al., Epidermal growth factor receptor mutations in small cell lung cancer: a brief report, J. Thorac. Oncol. 6 (1) (2011) 195–198, http://dx.doi.org/10.1097/JTO.0b013e3181f94abb.
87
[12] G.K. Antony, E. Bertino, M. Franklin, G.A. Otterson, A.Z. Dudek, Small cell lung cancer in never smokers: report of two cases, J. Thorac. Oncol. 5 (5) (2010) 747–748, http://dx.doi.org/10.1097/JTO.0b013e3181d6e124. [13] A.G. Pallis, K.N. Syrigos, Lung cancer in never smokers: disease characteristics and risk factors, Crit. Rev. Oncol. Hematol. 88 (3) (2013) 494–503, http://dx. doi.org/10.1016/j.critrevonc.2013.06.011. [14] T. Yano, A. Haro, Y. Shikada, R. Maruyama, Y. Maehara, Non-small cell lung cancer in never smokers as a representative non-smoking-associated lung cancer: epidemiology and clinical features, Int. J. Clin. Oncol. 16 (4) (2011) 287–293, http://dx.doi.org/10.1007/s10147-010-0160-8. [15] T. Kawaguchi, M. Ando, A. Kubo, et al., Long exposure of environmental tobacco smoke associated with activating EGFR mutations in never-smokers with non-small cell lung cancer, Clin. Cancer Res. 17 (1) (2011) 39–45, http:// dx.doi.org/10.1158/1078-0432, CCR-10-1773. [16] A. Tatematsu, J. Shimizu, Y. Murakami, et al., Epidermal growth factor receptor mutations in small cell lung cancer, Clin. Cancer Res. 14 (19) (2008) 6092–6096, http://dx.doi.org/10.1158/1078-0432, CCR-08-0332. [17] L.P. Stabile, A.L.G. Davis, C.T. Gubish, et al., Human non-small cell lung tumors and cells derived from normal lung express both estrogen receptor alpha and beta and show biological responses to estrogen, Cancer Res. 62 (7) (2002) 2141–2150 (accessed 25.4.14) http://www.ncbi.nlm.nih.gov/pubmed/ 11929836. [18] Y. Zhang, J. He, The development of targeted therapy in small cell lung cancer, J. Thorac. Dis. 5 (4) (2016) 538–548 (accessed 23.4.14) http://www.jthoracdis. com/article/view/1441/html.