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Journal of Thoracic Oncology:
doi: 10.1097/JTO.0000000000000209
Original Articles

Lung Cancer in Combined Pulmonary Fibrosis and Emphysema: A Series of 47 Western Patients

Girard, Nicolas MD, PhD*; Marchand-Adam, Sylvain MD, PhD; Naccache, Jean-Marc MD; Borie, Raphael MD§; Urban, Thierry MD; Jouneau, Stéphane MD, PhD; Marchand, Eric MD, PhD#; Ravel, Anne-Claire MD**; Kiakouama, Lize MD*; Etienne-Mastroianni, Bénédicte MD*; Cadranel, Jacques MD, PhD; Cottin, Vincent MD, PhD*; Cordier, Jean-François MD*; for the Groupe d’Etudes et de Recherche sur les Maladies “Orphelines Pulmonaires (GERMOP)

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Author Information

*Department of Respiratory Medicine, National Reference Center for rare pulmonary diseases, Hôpital Louis Pradel, Hospices Civils de Lyon; Université Claude Bernard Lyon 1, Lyon; Department of Respiratory Medicine, CHRU Tours, Université François Rabelais, INSERM UMR 1100, Tours; Chest Department, Expert Center of Thoracic Oncology, Regional Reference Center for rare pulmonary diseases, Hôpital Tenon, Assistance Publique Hôpitaux de Paris; Université Pierre et Marie Curie; §Department of Respiratory Medicine, Competence Center for Rare Pulmonary Diseases, Hôpital Bichat, Assistance Publique Hôpitaux de Paris, Paris; Department of Respiratory Medicine, CHU Angers, Angers; Department of Respiratory Medicine, Competence Center for rare pulmonary diseases, Hôpital Pontchaillou, IRSET UMR 1085, Université de Rennes 1, Rennes, France; #Department of Respiratory Medicine, CHU Mont-Godine, Université Catholique de Louvain, Yvoir, Belgium; and **Pulmonology Service, Hôpital de Bourgoin-Jallieu, Bourgoin-Jallieu, France.

Contributors (to be listed on PubMed): Ms Raphaële GUELMINGER, MSc (Lyon).

Disclosure: The authors declare no conflict of interest.

Address for correspondence: Nicolas Girard, MD, PhD, Service de Pneumologie, Hôpital Louis Pradel. 28 avenue doyen Lépine. 69677 Lyon (Bron) cedex, France. E-mail: nicolas.girard@chu-lyon.fr

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Abstract

Introduction: The syndrome of combined pulmonary fibrosis and emphysema (CPFE) is characterized by imaging features consisting of the association of centrilobular and/or paraseptal emphysema and pulmonary fibrosis. Virtually all patients are smokers and thus at high risk of developing lung cancer.

Methods: This retrospective multicentre study was conducted by the Groupe d’Etudes et de Recherche sur les Maladies “Orphelines” Pulmonaires (GERM”O”P).

Results: A total of 47 patients presenting with lung cancer and CPFE syndrome were identified. All patients were smokers, with a mean of 47 pack-years. A pathological diagnosis of lung cancer was obtained for 38 (81%) patients. Histological type was squamous cell carcinoma in 17 (36%) patients, adenocarcinoma in 14 (30%), non–small-cell lung cancer not otherwise specified in three (6%), small-cell lung cancer in three (6%), and sarcomatoid carcinoma in one (2%). Overall, 20 of the 47 patients could not receive standard-of-care treatment for lung cancer, as per international recommendations or guidelines; this limitation was considered to be directly related to the CPFE syndrome in eight (40%) cases.

Conclusion: Lung cancer in patients with CPFE syndrome represents a specific entity with a poor prognosis, that further represents the most characteristic and severe model of tobacco-related disease.

Combined pulmonary fibrosis and emphysema (CPFE) is an uncommon entity, consisting of the association at high-resolution computed tomography (CT) scan, of centrilobular and/or paraseptal emphysema mainly in the upper lobes, with pulmonary fibrosis - predominantly in the lower lobes.1–3 We described CPFE as a syndrome characterized by the above imaging features associated with subnormal spirometry, contrasting with severely disrupted gas exchange as demonstrated by strongly decreased carbon monoxide diffusing capacity and a high level of oxygen desaturation at exercise.2 Survival in CPFE is hampered by chronic respiratory failure and pulmonary hypertension, which is more frequent than in patients with either isolated emphysema or idiopathic pulmonary fibrosis.1,4,5

Virtually all patients presenting with CPFE are smokers.1,6,7 Although the pathophysiology of CPFE syndrome remains to be elucidated, it is noteworthy that both emphysema and pulmonary fibrosis are tobacco-related diseases.7,8 In this setting, patients with CPFE may be at high risk of developing lung cancer. However, only limited data are currently available on such association, mostly from Japanese cohorts.9,10 Lung cancer occurred in 47% of patients in a retrospective study of 47 patients with CPFE syndrome.10 Another study based on the radiology reports of 1143 patients with lung cancer found that pulmonary fibrosis and emphysema coexisted in 101 (8.9%) cases. The median survival of these patients was 10.8 months, significantly lower than that of 623 and 404 patients without underlying parenchymal disease (53.0 months) or with emphysema alone (21.9 months), respectively.9 These data suggest that lung cancer occurring in CPFE might be frequent with peculiar features.

Here, we took advantage of the background of the Groupe d’Etudes et de Recherche sur les Maladies “Orphelines” Pulmonaires (GERM”O”P) in the study of CPFE syndrome, to describe the clinical, pathological, imaging features, and the outcome of lung cancer occurring in patients with CPFE syndrome in Western countries.

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MATERIAL AND METHODS

Study Design

This retrospective multicentre study was conducted by the Groupe d’Etudes et de Recherche sur les Maladies “Orphelines” Pulmonaires (GERM”O”P), a collaborative group of approximately 200 French-speaking physicians, mostly from France, dedicated to the study of rare, mainly non-neoplastic, pulmonary diseases. Following previous studies on CPFE syndrome,1,5,11 all participating physicians were asked to report all cases of lung cancer associated with CPFE syndrome to the GERM”O”P registry. Clinical data for cases meeting the inclusion criteria were collected retrospectively. Data collection ended in February 2013.

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Study Population

Inclusion criteria were the following: (1) CPFE syndrome, as defined by the presence at CT scan of (a) emphysema, defined as well-demarcated areas of decreased attenuation in comparison with contiguous normal lung and marginated by a very thin (<1 mm) or no wall, and/or multiple bullae (>1 cm) with upper zone predominance and (b) the presence of a diffuse parenchymal lung disease with significant features of pulmonary fibrosis, defined as reticular opacities with peripheral and basal predominance, honeycombing, architectural distortion and/retraction, bronchiectasis, or bronchiolectasis1; focal ground-glass opacities and/or areas of alveolar consolidation might be associated but should not be prominent. Only cases for which a CT scan was available for review were included. (2) Pathologically or cytologically proven primary lung cancer, classified as per the World Health classification,12 or clinical radiological diagnosis of lung tumor when histologic proof could not be obtained, especially because of severe functional impairment. The absence of histological diagnosis may happen in the context of CPFE syndrome, and the criteria then used to make the diagnosis of lung cancer were collected from treating physicians, such as growing lesion on CT scan, hypermetabolism at 18-fluorodesoxyglucose (FDG) positron emission tomography (PET) scan, or resistance to antibiotics.

Patients presenting with isolated emphysema, or with a diagnosis of other interstitial lung disease (such as drug-induced interstitial lung disease, pneumoconiosis, hypersensitivity pneumonitis, and sarcoidosis), and for whom no follow-up information was available, were excluded.

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Clinical Review

The clinical history of eligible patients was retrospectively reviewed. According to French laws, the anonymous retrospective collection of data does not require the approval of an Institutional Review Board. However, the study was formally approved by the Institutional Review Board of the French learned society for respiratory medicine -Société de Pneumologie de Langue Française. We also called individually all the patients who were alive, or alternatively, if possible, the families of deceased patients, to obtain their consent for the study. A questionnaire was designed to collect clinical data, physical examination, fiberoptic bronchoscopy results, pulmonary function tests and cardiac echography reports, results from imaging investigations (e.g., chest radiography and CT scan), brain CT or magnetic resonance imaging, abdomen ultrasound or CT, 18-FDG-PET scan, and bone scintigraphy when performed), pathological reports, and blood tests results.

Patients were categorized as never smokers (<100 lifetime cigarettes), former smokers (quit >1 year ago), or current smokers (quit <1 year ago). Pulmonary function tests were performed according to the European Respiratory Society guidelines.13 Pulmonary hypertension was defined by a systolic arterial pulmonary pressure above 45 mmHg as estimated by the tricuspid regurgitant flow on Doppler-echocardiography. Performance status was evaluated according to the Eastern Cooperative Oncology Group scale.

Radiological data were collected for emphysema characteristics and the main interstitial abnormalities, as defined elsewhere.14 Clinical tumor stage was assessed using the 7th Tumor, Node, Metastasis system.15 Best response to chemotherapy was evaluated according to the RECIST v1.1 criteria.16 Toxicities were assessed using the National Cancer Institute grading system.17 Overall survival was defined as the time elapsed from the date of diagnosis of lung cancer until death (all causes). Surviving patients were censored at the last follow-up date.

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Statistical Analysis

All patients were included in the statistical analysis. Follow-up was obtained in all cases, and was censored on June 1, 2013. Categorical variables were compared using the χ2 or the Fisher ‘s exact test and continuous variables by the Student’s or Mann-Whitney nonparametric test. Survival was assessed using the Kaplan-Meier method. Results were considered significant at the 0.05 level (two-tailed test). Statistical analyses were performed using the SPSS software program (Chicago, IL), version 17.0.

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RESULTS

Population Characteristics
Clinical features

A total of 47 patients presenting with lung cancer and a syndrome of CPFE between January 2003 and December 2012 were identified in seven French Hospitals and one Belgian hospital. During the same period, a total of 322 patients with CPFE had been registered in the GERM”O”P registry; incidence of lung cancer was then 1.5% per year.

Patients’ characteristics at the time of cancer diagnosis are presented in Table 1. All patients but one was men, with a mean age of 68 (standard deviation [SD]: ± 8.6 years). All patients were smokers, with a mean total tobacco-smoking consumption of 47 (SD: ±21) pack-years. Cardiovascular atheromatous comorbidities were reported in 21 (45%) patients, including coronary artery disease with history of myocardial infarction in seven (15%) patients, peripheral vascular disease in seven (15%) patients, and history of cerebrovascular accident in seven (15%) patients; seven (17%) patients had diabetes mellitus, and three (7%) patients suffered from autoimmune disorders. Two (9%) patients had pulmonary hypertension at echocardiography. Nine (19%) patients had a previous history of cancer, the most frequent primary sites being the colon and the bladder.

Table 1
Table 1
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CPFE features

The CPFE syndrome had been diagnosed before lung cancer in 20 (43%) patients, with a median time interval of 2.1 years (range, 0.6–11.2 years), and was diagnosed synchronously with lung cancer in 27 (57%) patients. Dyspnea was severe (NYHA functional class III–IV) in 22 (47%) patients. According to the definition of CPFE, imaging features included emphysema in the upper lobes in all cases, and fibrotic lung disease in all cases, with honeycombing and reticular opacities of the lower lobes and the subpleural areas in 83% and 85% of patients, respectively. Pulmonary function tests showed a mean forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) ratio of 78%; FEV1 was higher than 80% of predicted in 27 (57%) patients. FEV1/FVC ratio was lower than 70% in 17 (36%) patients. Mean transfer factor for carbon monoxide (TLCO) was 44 (SD: ±16%) of predicted in the 36 patients tested. Overall, volume and flow values were within normal limits at spirometry in 16 (34%) patients, whereas TLCO was lower than 80% of predicted in all tested patients. Two patients had chronic respiratory failure requiring long-term oxygenotherapy. Eleven (23%) patients had previously received a treatment for CPFE syndrome, including oral steroids (nine patients), N-acetyl-cysteine (nine patients), and/or immunosuppressive agents (nine patients).

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Lung cancer

As shown in Table 2, 22 (47%) patients had no cancer-related symptoms; lung cancer was then detected on a routine imaging procedure. 25 (53%) patients presented with symptoms, mostly consisting of an increase in chronic dyspnea (13 patients) or cough (10 patients). The tumor was visible at chest radiography in 37 (79%) cases, with a mean largest diameter of 43 mm. Many patients had an early stage, i.e., stage I–II, tumor (55% of cases) at time of diagnosis (Table 3).

Table 2
Table 2
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Table 3
Table 3
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Histopathological Features

A pathological diagnosis of lung cancer was obtained in 38 (81%) patients (Table 2). The pathological diagnosis was made on surgical resection specimens in 15 (32%) patients. A preoperative pathological diagnosis was obtained in only five patients by fiberoptic bronchoscopy, mostly because of the peripheral location of the tumor. Five patients underwent preoperative percutaneous biopsy, which failed to provide tumor cells in four cases; one patient presented with post-biopsy pneumothorax.

In the 23 (49%) patients who ultimately did not undergo surgical treatment, the pathological diagnosis was made at cytologic/pathologic specimens obtained by fiberoptic bronchoscopy in 13 cases, and percutaneous biopsy in nine cases; video-assisted thoracoscopy was required in one case.

The time interval from the first finding of the lesion identified at imaging to the pathological diagnosis was longer than 60 days in 19 (40%) patients. As per the referring physician, this delay was exclusively because of the presence of the CPFE syndrome in five patients, either because of the need for an extensive functional assessment or the occurrence of a complication of diagnostic procedures. No significant relation was found between tumor histology and its location—anatomic lobe or emphysema versus fibrosis areas—in the lung parenchyma (p = 0.32).

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Cases Without Pathologic Diagnosis

The diagnosis of lung cancer could not be pathologically confirmed in nine (19%) patients. This was explained by pulmonary function alteration precluding fiberoptic bronchoscopy or percutaneous procedures to be conducted safely (seven patients), failure or complication of a diagnostic procedure (three patients), and/or too poor general medical condition leading to patient refusal of further procedures (two patients). The criteria then used to make the diagnosis of lung cancer in the absence of histopathological confirmation included the presence of a persistent spiculated or heterogeneous mass in the lung parenchyma (all nine cases), the growth of the lesion within a short period of follow-up (for nine cases), and a strong hypermetabolism of the lesion at 18-FDG-PET-scan (observed in nine cases), along with best attempts to rule out infection—all patients underwent sputum microbiology and/or bronchoalveolar lavage, which were sterile is all cases—and/or systematic antibiotic therapy (Supplementary Table 1, SDC 1, http://links.lww.com/JTO/A597). Ultimately, all the patients had a probability of lung cancer higher than 85%, as estimated by the Mayo Clinic Model integrating FDG-PET scan data (Supplementary Table 1, SDC 1, http://links.lww.com/JTO/A597).

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Treatment
Pathologically confirmed cases

The therapeutic management for the 38 patients with pathologically confirmed lung cancer is presented in Table 4. Among the 23 patients with clinical stage I–II tumor, a surgical resection was performed in 14 cases. Other treatments in nine patients with severe pulmonary function impairment, poor general condition, or comorbidities precluding surgery, consisted in chemotherapy in five patients, exclusive stereotactic radiotherapy in two patients, endoscopic Argon plasma coagulation in one patient (who had in situ carcinoma), and best supportive care in one patient. Among the five patients with stage III tumor, one was operated on, two received exclusive chemotherapy, one received chemoradiation (Fig. 2), and one had best supportive care. The 10 patients with metastatic lung cancer received exclusive chemotherapy in six cases, and best supportive care in four cases.

Figure 2
Figure 2
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Table 4
Table 4
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For the 15 patients who underwent surgical resection of the tumor, the procedure consisted of lobectomy in 14 cases, and segmentectomy in one case. Postoperative complications were pulmonary embolism in one patient, bronchopleural fistula in one patient, prolonged thoracic drainage in one patient; two patients developed acute exacerbation of pulmonary fibrosis, as defined by increasing dyspnea and hypoxemia, development of diffuse ground-glass abnormalities at CT scan, without evidence of infection and alternative causes (left heart failure, pulmonary embolism) of acute lung injury; one exacerbation was ultimately fatal. Five patients received perioperative chemotherapy, and two patients postoperative radiotherapy. After a median follow-up of 19.3 months, 10 patients had experienced tumor recurrence. Two patients were treated with radiotherapy (one stereotactic, one standard), both of whom experienced grade V radiation-induced pneumonitis despite state-of-the-art procedures and accurate dose constraints for non-tumoral tissues, especially the lungs. Three patients received chemotherapy, one patient had a second surgical resection, and four patients received best supportive care.

Treatment regimens in the 14 patients who received exclusive chemotherapy mostly consisted of platinum-based doublets: carboplatin-paclitaxel in five patients, cisplatine-pemetrexed in five patients (including one in combination with bevacizumab), carboplatin-vepeside in two patients, carboplatin-gemcitabine in one patient, and oral vinorelbine in one patient; only one patient received second-line treatment. Six patients experienced grade III–IV hematological and/or infectious toxicities. Two patients died from severe sepsis in the context of grade IV chemotherapy-induced neutropenia.

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Cases without pathological diagnosis.

For the nine patients with clinical diagnosis of lung cancer, treatment consisted of best supportive care in eight cases, mostly because of poor performance status (five cases), and/or advanced age (four patients), and/or CPFE-related hypoxemia (two cases). One patient received stereotactic radiotherapy (Fig. 1). All these patients ultimately developed systemic metastases during follow-up (Supplementary Table 1, SDC 1, http://links.lww.com/JTO/A597).

Figure 1
Figure 1
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Overall, 20 of the 47 patients could not receive standard-of-care treatment for lung cancer as per international recommendations and guidelines; this limitation was considered to be directly related to the CPFE syndrome in eight cases.

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Outcome

At time of data cutoff—median follow-up of 19.3 months—, 35 patients were dead, and 12 patients were alive. Causes of death included locoregional or systemic tumor progression in five (14%) and 17 (49%) patients, respectively, respiratory failure/hypoxemia in eight (23%) patients, treatment-induced toxicity in four (11%) patients, and postoperative exacerbation of pulmonary fibrosis in one (3%) patient. The estimated overall survival of the 47 patients was 26.6 (95% confidence interval [CI]: 17.7–35.5) months from the diagnosis of CPFE syndrome, and 7.6 (95% CI: 2.9–12.4) months, from the diagnosis of lung cancer (Fig. 3). There was no significant difference in the survival of patients with or without a pathological confirmation of lung cancer (7.6 (95% CI: 2.3–13.0) versus 7.1 (95% CI: 4.5–9.4) months, respectively; p = 0.354).

Figure 3
Figure 3
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DISCUSSION

Here we report the first series on the clinical, radiological, diagnostic and outcome features of 47 patients with lung cancer and underlying CPFE syndrome in a Western country. Our results highlight the specificities of this unique disease combination: very strong association with tobacco-smoking, characteristic histological-radiological presentation, and poor prognosis because of major limitations and risks of conducting standard-of-care diagnosis and therapeutic interventions in a significant proportion of patients.

In the 38 patients with pathologically confirmed lung cancer in this study, the most frequent histologic type of the tumor was squamous cell carcinoma, accounting for 45% of cases, whereas adenocarcinoma was diagnosed in 37% of cases. In the overall French lung cancer population, adenocarcinoma is the most frequent histologic type, accounting for 47% of cases, with squamous cell carcinoma diagnosed only in 27% of cases.18 The higher proportion of squamous cell carcinoma in CPFE syndrome may be related to the fact that virtually all patients are heavy smokers, as this histology has been reported to be more significantly associated with tobacco smoking than adenocarcinoma.19 Similarly, in two series of Japanese patients with lung cancer and CPFE, adenocarcinoma and squamous cell carcinoma collectively accounted for 43% and 35% of cases, respectively,9,10 whereas in the global lung cancer patients population in Japan, they represent about 60% and 30% of the cases, respectively.20 Small-cell carcinoma occurred in only three (6%) patients in our cohort, but represented 17% of cases in other series of patients with CPFE9,10; of note, the nine lung cancers that could not be confirmed pathologically had a clinical-radiological presentation typical for non–small-cell lung cancer, as shown in Supplementary Table 1, SDC 1, http://links.lww.com/JTO/A597. Our data are in line with those reported in pulmonary fibrosis, where the risk of lung cancer has been reported to be increased, with the most frequent histology being squamous cell carcinoma.21–23 In emphysema, data are sparse, as many patients with lung cancer do present with some degree of emphysema.

Of the 47 patients included in our study, a pathological diagnosis could not be obtained for nine (19%). The CPFE syndrome notably hampers the standard pretreatment workup of lung cancer to be performed. Especially, the risk of transthoracic needle biopsy, regarding hemorrhage and pneumothorax, is likely increased given the parenchymal changes, especially emphysema.24

Spirometry is often used as a first step to assess functional fitness for surgery before lung resection. It should be emphasized that, as patients present with normal or subnormal spirometry—mean FEV1 was 74 ± 19% of predicted in our cohort, similar to that reported in our original report on CPFE2—whereas TLCO is severely decreased (44 ± 16% of predicted), calculations methods based on predicted postoperative FEV1 may underevaluate the functional severity of the disease, and the risk of surgery in these patients.25 This could not be formally assessed in our cohort in the 15 patients undergoing surgery. One recommendation would be to systematically perform cardiopulmonary exercise testing, after careful assessment for pulmonary hypertension in CPFE patients who are candidates for lung resection.25,26

However, the most frequent treatment-induced toxicity in our cohort was acute exacerbation of pulmonary fibrosis (AEPF), which occurred in four patients—two after surgery, two after radiotherapy for tumor recurrence. AEPF was previously reported to occur in as many as 20% of patients with CPFE syndrome and lung cancer9 and is a well-known risk in patients with interstitial lung disease and lung cancer, both after surgical resection of the tumor27 or radiotherapy.28 In the later situation, AEPF, which is characterized at CT scan by diffuse bilateral ground-glass opacities, strongly differs from classical radiation pneumonitis, which presents with interstitial opacities that progressively form patchy and/or nonuniform consolidation starting in the radiation field. In this setting, lower TLCO and FVC values, and a higher amount of fibrosis at imaging were identified as significant predictors of acute respiratory distress syndrome after surgery.29,30 Besides dosimetric variables, emphysema and fibrosis-related decrease in FEV1 and TLCO are well-recognized risk factors of radiation-induced pneumonitis.30 Stereotactic radiotherapy may represent an adequate treatment in case of CPFE syndrome, as a pathological confirmation of the tumor may not be required in high-risk patients presenting with a growing and hypermetabolic mass in the lung,31 as per the experience of the Amsterdam VU group.32 However, AEPF remains largely unpredictable; in our study, the two patients who were treated with radiotherapy—stereotactic or conformal—for postoperative tumor recurrence developed grade V AEPF, whereas such procedure seems to be safe in patients without underlying lung disease.33 Of note, chemotherapy-induced AEPF has also been reported in up to 23% of patients with interstitial lung disease, mostly in Asian cohorts of patients with lung cancer,34 but this was not observed in our series. In the present cohort, infectious complications were also frequent in patients receiving chemotherapy; this high risk of infection has been reported in patients with chronic obstructive disease or emphysema.33

Ultimately, CPFE syndrome was estimated to directly hamper the management of lung cancer in 40% of the 20 patients for whom standard-of-care could not be conducted; other reasons are actually related to the clinical characteristics of patients, including poor general condition—25% of patients had a performance status more than two—and advanced age—mean age of patients with CPFE syndrome was 68 ± 8.6 years—as reported previously.1

Tobacco smoking represents the major common denominator between lung cancer, emphysema, and pulmonary fibrosis.7 Epidemiological evidence of a higher risk of lung cancer in patients with emphysema35 and pulmonary fibrosis21 has long been known. The molecular mechanisms underlying the carcinogenesis of lung epithelial cells in patients with CPFE syndrome are yet to be fully determined. The existence of a common genetic susceptibility to emphysema, fibrosis, and lung cancer may be hypothesized as the same germline polymorphisms have been identified for two or three of these conditions, occurring in various genes, including the alpha-nicotinic acetylcholine receptor gene,36 also associated with tobacco-dependence, the telomerase reverse transcriptase gene,37 the fragile histidine triad gene,38 the serpin B4 gene,39 the alpha-1-antitrypsin gene,40 and the surfactant protein A2 gene.41 At the somatic level, tobacco smoking induces numerous molecular alterations in the airway epithelium, both at the expression and genomic level.42,43 Further molecular links may exist between fibrosis, emphysema, and cancer.44

Before such molecular characterization is performed, the difficulties encountered to optimally diagnose and treat patients with lung cancer and CPFE syndrome, and the high risk of treatment-induced toxicities, lead to consider individual low-dose CT scan-based screening for lung cancer in this population. Given the virtually constant history of high tobacco consumption in patients with CPFE,1,6 most patients are actually likely to be eligible for such screening, which is now being recommended by major oncology societies.45–49 In our cohort, cancer was detected on a routine imaging procedure in up to 47% of cases. Tumor was diagnosed at an early stage in 52% of cases, which is a prerequisite to consider screening. However, a survival benefit of screening in CPFE patient remains uncertain, given the high morbidity associated with diagnostic and treatment procedures, and the high number of patients who are not eligible for standard-of-care treatment, which represent major determinants of the efficacy of screening. Conversely, CT scan screening may represent a unique opportunity to diagnose other conditions such as pulmonary fibrosis or CPFE syndrome in the process of screening for lung cancer in smokers.7,50

In conclusion, our data indicate that lung cancer occurring in patients with underlying CPFE harbors specific characteristics, with a poor prognosis related to major limitations and risks to conduct standard-of-care diagnosis and therapeutic interventions in a significant proportion of patients. Lung cancer represents, together with pulmonary hypertension, a major complication of the CPFE syndrome, with similarly poor prognosis. Further studies are needed to better understand the underlying biology of this entity, which constitutes a model of tobacco-smoking related lung disease.

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ACKNOWLEDGMENT

We thank Ms. Raphaële GUELMINGER, MSc for contribution to data extraction and analysis.

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Combined pulmonary fibrosis and emphysema syndrome; Lung cancer; Orphan disease; Tobacco smoking

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