Primary Pulmonary Carcinoma in Patients With Idiopathic Pulmonary ...

Mayo Clin Proc, August 2002, Vol 77

Lung Cancer in UIP/IPF

763

Original Article

Primary Pulmonary Carcinoma in Patients With Idiopathic Pulmonary Fibrosis MARIE-CHRISTINE AUBRY, MD; JEFFREY L. MYERS, MD; WILLIAM W. DOUGLAS, MD; HENRY D. TAZELAAR, MD; TANYA L. WASHINGTON STEPHENS, MD; THOMAS E. HARTMAN, MD; CLAUDE DESCHAMPS, MD; AND V. SHANE PANKRATZ, PHD

• Objective: To identify distinguishing characteristics between patients with idiopathic pulmonary fibrosis (IPF) and primary lung carcinoma and patients with either IPF or carcinoma alone. • Patients and Methods: The study group consisted of 24 patients with histologically proven usual interstitial pneumonia and lung carcinoma identified through a search of the Rochester Mayo Clinic database for 1990 to 1998. Medical records, radiographs, and histological slides were reviewed. Several variables including survival were compared in 2 control groups, IPF only and carcinoma only, by using various statistical methods. • Results: Our study group included 21 men and 3 women (mean age, 72.3 years). Twenty-two were past or current smokers. Approximately half of the lung carcinomas were incidental findings. Of the 14 patients with preoperative computed tomographic scans, 12 had peripheral tumors situated in areas of fibrosis. Squamous cell carcinoma was the most common histological type, accounting for 16 cases. Almost all patients underwent surgical treatment; nearly 40% developed postoperative complications, and 3 died within 30 days of surgery. The ratio of men to women in patients with IPF and carcinoma was 7:1 compared with 1:1 in patients with IPF only (P=.003). Patients

with IPF and carcinoma were also older, with a mean age of 72.3 years compared with 64.4 years (P=.001), and were more often smokers (P=.002). Carcinomas involved the lower lobes in 42% of patients with IPF and carcinoma compared with 29% of patients with carcinoma only (P=.004) and were mainly composed of squamous cell carcinoma (P=.004). Mean survival in patients with IPF and lung carcinoma was 2.3 years after the diagnosis of IPF and 1.6 years after that of carcinoma. This finding did not differ significantly from survival of patients with either IPF or carcinoma alone. However, statistical power was limited. • Conclusion: Carcinoma in patients with IPF arises in older male smokers and usually presents as peripheral squamous cell carcinoma. The prognosis is poor. Mayo Clin Proc. 2002;77:763-770 CI = confidence interval; CT = computed tomography; DLCO = diffusing capacity; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; HRCT = highresolution computed tomography; IPF = idiopathic pulmonary fibrosis; PFT = pulmonary function test; SaO2 = arterial oxygen saturation; TLC = total lung capacity; UIP = usual interstitial pneumonia

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cal resections for lung carcinoma. All were male smokers, most older than 60 years, who developed peripheral carcinomas with a predilection for the upper lobes. These authors showed transition areas between atypical nonneoplastic epithelium and carcinoma and concluded that carcinomas arose from atypical hyperplasia within areas of honeycomb change. Most subsequent studies of carcinoma arising in association with idiopathic pulmonary fibrosis (IPF) have either lacked histological confirmation of usual interstitial pneumonia (UIP) or included patients with other underlying conditions, such as connective tissue disease or asbestosis.2-18 It is likely that these studies included patients with various fibrosing lung diseases. Rare reports have described lung carcinoma arising in histologically documented UIP but have focused on the pathologic findings.19-21 We reviewed the clinical, radiological, and pathologic findings in patients with primary lung carcinoma and IPF and compared them with findings in patients with lung

he association of pulmonary fibrosis and carcinoma has been recognized since 1939 when Friedrich first described peripheral carcinomas arising in focal scarring.1 Beaver and Spain subsequently suggested an association between bronchoalveolar carcinoma and diffuse interstitial fibrosis of various origins, speculating that the epithelial hyperplasia observed in areas of fibrosis may progress to lung carcinoma.1 Meyer and Liebow1 identified underlying honeycomb change in 32 (21%) of 153 consecutive surgiFrom the Department of Laboratory Medicine and Pathology (M.C.A., J.L.M., H.D.T.), Division of Pulmonary and Critical Care Medicine and Internal Medicine (W.W.D.), Department of Radiology (T.L.W.S., T.E.H.), Division of General Thoracic Surgery (C.D.), and Division of Biostatistics (V.S.P.), Mayo Clinic, Rochester, Minn. Dr Washington Stephens is now with The University of Texas M. D. Anderson Cancer Center, Houston. Address reprint requests and correspondence to Marie-Christine Aubry, MD, Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (e-mail: aubry [email protected]). Mayo Clin Proc. 2002;77:763-770

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© 2002 Mayo Foundation for Medical Education and Research

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carcinoma or IPF alone to identify distinguishing characteristics and differences in outcome. PATIENTS AND METHODS Our study group consisted of 24 patients with both histologically proven UIP and primary lung carcinoma. Patients were identified through a retrospective computerized search of the Rochester Mayo Clinic database for 1990 to 1998. Patients with connective tissue disease, asbestos exposure, previous radiation therapy, or metastatic disease to the lung were excluded. Patients taking drugs that could potentially induce pulmonary fibrosis were also excluded. Thus, study patients were considered to have IPF. Histological diagnosis of UIP was based on previously published criteria.22 Primary lung carcinoma included any form of bronchogenic carcinoma. Two control groups were identified. The first group consisted of 63 patients with histologically documented UIP in the clinical setting of IPF without lung cancer (IPF only). The clinical characteristics of the group have been published previously.23 This group was selected because the clinical information, including long-term follow-up, was readily available and the pathologic diagnosis had been confirmed by 2 of us (J.L.M., H.D.T.). Since this group and the study group were composed of a small number of patients, matching was not possible. The second group consisted of 532 patients with lung carcinoma without evidence of IPF (carcinoma only) identified from the Mayo Tumor Registry. These carcinoma-only controls represented a subset of the total with lung cancer in the Mayo Tumor Registry. This subset was selected by excluding all patients with lung cancer in the tumor registry whose ages were outside the age range of the cases, who received treatments that the cases did not receive, or whose cancers were at different stages than those of the cases. All other lung cancer cases from the tumor registry were retained as the lung cancer control group. Matching on this gross level was performed only after failed attempts to obtain more closely matched controls. Data Collection Medical records were reviewed for age, sex, smoking history, time of diagnosis of IPF, symptoms and signs of IPF, results of pulmonary function tests (PFTs), time of diagnosis of primary lung carcinoma, presenting symptoms of lung carcinoma, tumor location, treatment, complications, and outcome, including operative mortality. The time of diagnosis of IPF was defined as the date of diagnosis at Mayo Clinic, Rochester, Minn, based on clinical, radiological, and/or pathologic evidence. The time of diagnosis of lung carcinoma was defined as the date of histological or cytologic diagnosis. Operative mortality was defined as death occurring within 30 days of operation.


Chest radiographs, computed tomography (CT), and high-resolution computed tomography (HRCT) scans were reviewed. The results of CT or HRCT were classified as typical UIP, probable or possible UIP, or unlikely UIP. Typical UIP was defined as symmetrical bilateral reticular infiltrates with a predominant basilar distribution and associated architectural distortion, including honeycomb change. Usual interstitial pneumonia was considered probable or possible if the infiltrates were asymmetrical, lacked basal predominance, or lacked honeycomb change. Localized opacities corresponding to carcinoma were classified as central if originating in the mediastinum and hilum and peripheral if originating beyond the hilum. The presence of emphysematous changes was also noted. The association of carcinoma with areas of honeycomb change was evaluated grossly and histologically and described as present or absent. Transition from metaplastic and/or hyperplastic epithelium to carcinoma was defined as a continuous range of increasing epithelial atypia contiguous with invasive carcinoma. Carcinomas were subtyped according to the World Health Organization histological classification of lung tumors24 and staged according to the TNM classification in use at the time of diagnosis. Statistical Analysis The study group was compared with each of the control groups for a number of variables. Sex, age at IPF diagnosis, smoking status (never, past, current), pack-years, total lung capacity (TLC), forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), diffusing capacity (DLCO), resting arterial oxygen saturation (SaO2), and exercise SaO2 were compared between the study group and IPF-only controls. Sex, type of carcinoma, and curative surgery status (yes or no) were compared between the study group and the carcinoma-only group. Differences in discrete variables (sex, smoking status, type of carcinoma) were assessed with the χ2 test, Fisher exact test, or a randomization test25 when χ2 assumptions were not met. Differences in continuous measurements (age at diagnosis, pack-years, TLC) were assessed with the t test or the rank sum test when t test assumptions were not met. Kaplan-Meier survival curves were computed for each of the 3 groups. The log-rank test was used to compare the unadjusted survival rates of the study group and control groups. For comparison of survival between the cases and patients with IPF only, time zero for the cases was considered the point at which IPF was diagnosed. For comparison between the cases and patients with carcinoma only, time zero for the cases was considered the point at which carcinoma was diagnosed. Unadjusted survival rates of the cancer-only and the IPF-only control groups were also compared by using the log-rank test. Cox proportional hazards

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Table 1. Summary of Clinical Findings in 24 Patients With Idiopathic Pulmonary Fibrosis and Lung Carcinoma* Characteristics Sex, No. (%) (N=24) Male Female Age (y) (n=23) Median Mean ± SD Range Smoking status (N=24) Current Past Never Pack-years (N=24) Median Mean ± SD Range PFT pattern, No. (%) (n=23) Normal Restriction Obstruction Mixed DLCO (% predicted) (n=22) Median Mean ± SD Range SaO2 at rest (%) (n=20) Median Mean ± SD Range SaO2 with exercise (%) (n=17) Median Mean ± SD Range Carcinoma-related symptoms, No. (%) Incidental New complaints† Hemoptysis Fatigue Weight loss Chest pain Shortness of breath and cough only

Result 21 (88) 3 (12) 72.8 72.3±9.1 50-89 2 (8) 20 (83) 2 (8) 51 53.5±26.8 10-105 3 (13) 9 (39) 4 (17) 7 (30) 48.5 51.3±20.1 27-99 95 94±2.2 87-97 90 89.7±4.5 78-96

Characteristics Surgery, No. (%) Lobectomy Wedge or segmentectomies Bilobectomy Pneumonectomy Combined wall resection and lung resection Adjuvant therapy, No. (%) No treatment, No. (%) Postoperative complications,† No. (%) (n=23) Acute respiratory failure Prolonged mechanical ventilation Bronchopleural fistula Gastrointestinal hemorrhage Persistent pneumothorax Chest tube leak Multiple pulmonary embolisms Cerebrovascular accident Postoperative mortality, No. (%) Outcome, No. (%) (N=24) Alive Mean (range) duration of follow-up from diagnosis of IPF (y) Mean (range) duration of follow-up from diagnosis of carcinoma (y) Dead Mean (range) survival from diagnosis of IPF (y) Mean (range) survival from diagnosis of carcinoma (y) Lost to follow-up Recurrence or metastases Time to recurrence (y)

Result 22 (92) 13 5 1 1 2 2 (8) 1 (4) 9 (38) 3 2 1 1 1 1 1 1 3 (12) 7 (29) 2.2 (0.2-10.0) 1.2 (0.1-3.8) 16 (67) 2.3 (0.02-7.7) 1.6 (0.02-6.1) 1 (4) 8 (33) 1.7 (0.2-6.1)

10 (42) 11 (46) 4 3 3 3 3 (12)

*Sample sizes are the total number of patients for whom data were available. DLCO = diffusing capacity; IPF = idiopathic pulmonary fibrosis; PFT = pulmonary function test; SaO2 = arterial oxygen saturation. †Some patients had more than 1 complaint or complication.

regression models were used to further examine survival among the groups with IPF or carcinoma. In particular, proportional hazard models were used to assess associations between continuous variables and survival. They were also used to estimate hazard ratios and 95% confidence intervals (CIs) for predictors of interest. Multivariate survival analyses were not performed because of the small sample size of the IPF plus carcinoma group. Differences for each of these tests were considered statistically significant at P