Interstitial Lung Abnormalities in Patients With Locally Advanced Esophageal Cancer: Prevalence, Risk Factors, and Clinical Implications : Journal of Computer Assisted Tomography

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Chest Imaging

Interstitial Lung Abnormalities in Patients With Locally Advanced Esophageal Cancer: Prevalence, Risk Factors, and Clinical Implications

Tseng, Shu-Chi MD∗,†; Hino, Takuya MD; Hatabu, Hiroto MD, PhD; Park, Hyesun MD; Sanford, Nina N. MD; Lin, Gigin MD, PhD; Nishino, Mizuki MD, MPH; Mamon, Harvey MD, PhD§

Author Information
Journal of Computer Assisted Tomography 46(6):p 871-877, 11/12 2022. | DOI: 10.1097/RCT.0000000000001366
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Abstract

Esophageal cancer is one of the most common types of malignancy in the gastrointerstinal tract, with estimated 20,640 new cases and 16,410 deaths in the United States in 2022, representing the seventh leading cause of cancer death in men.1 The prognosis of esophageal cancer remains poor, with a 5-year survival rate of less than 20%.2 Several risk factors have been identified, including male sex, smoking, use of chewing tobacco, alcohol consumption, high body mass index, a diet low in fruits, and geographical location of Asia and sub-Saharan Africa.2,3 Factors for poor prognosis included male sex, squamous cell carcinoma histology, upper-midthoracic tumor location, incomplete resections, and stage III or IV disease.4,5 Early-stage patients may undergo endoscopic or surgical resection; however, many patients do not receive esophagectomy because of advanced disease at diagnosis.6 In patients with locally advanced tumors without distant metastasis, induction chemotherapy or chemoradiotherapy followed by surgical resection may be considered, which can achieve longer overall survival (OS) and higher possibility of complete (R0) resection.6–8 Given the association with smoking and the availability of baseline chest computed tomography (CT) scans, patients with esophageal cancer undergoing chemoradiotherapy provide a unique opportunity for the imaging evaluation of the underlying lung parenchyma, which is an underinvestigated topic.

Among the lung parenchymal findings evaluable on chest CT, the importance of interstitial lung abnormality (ILA) has been increasingly recognized in subjects with and without cancer.9–19 Interstitial lung abnormality is defined with the radiologic patterns demonstrating increased lung density on chest CT scans and is characterized by nondependent ground-glass or reticular abnormalities, nonemphysematous cysts, honeycombing, and traction bronchiectasis affecting more than 5% of any lung zone.16 The prevalence of ILA is 8% in a cohort with chronic obstructive pulmonary disease (COPD), and 7% in a general population in the Framingham Heart Study.11,12 In 4 prospective cohort studies including smokers and general populations, the presence of ILA was associated with all-cause mortality.16

The prevalence of ILA and its prognostic implication have been previously reported in patients with lung cancer.15,20,21 Interstitial lung abnormalities were observed in 4% to 14% of patients in the prior studies of NSCLC cohorts. The risk factors associated with ILA included older age, male sex, greater exposure to tobacco smoking,15,21 and squamous cell histology of NSCLC.15,20 Patients with ILA had shorter OS compared with those without ILA, both in stage I and stage IV NSCLC patients.15,20,21 However, the prevalence of ILA and its prognostic implication have not been systematically investigated in thoracic malignancies other than lung cancer. Of note, there have been no prior reports on baseline lung CT findings such as ILA, other interstitial lung disease (ILD), or pulmonary fibrosis in patients with esophageal cancer. The purposes of the study are to determine the prevalence of ILA on baseline chest CT in patients with esophageal cancer undergoing chemoradiotherapy and to identify the association between ILA versus clinical characteristics and OS in these patients.

MATERIALS AND METHODS

Patients

The study population included 208 patients (166 men, 42 women; median age, 65.6 years) with locally advanced esophageal cancer who were considered to be surgical candidates and were treated with chemoradiotherapy as a part of planned trimodality therapy at our institution between 2000 and 2017, who had a baseline chest CT before the initiation of chemoradiotherapy available for review in our system. The cohort included patients with known ILDs. Clinical record of the patients including demographics, clinical characteristics, and outcome as well as CT studies were retrospectively reviewed under the institutional review board approval with the waiver of the informed consent.

Interstitial Lung Abnormality Scoring on Chest CT

Computed tomography scan was performed using standard clinical chest CT protocols at our institution with iodinated intravenous contrast agent unless medically contraindicated, as described before.15,20,21 Retrospective imaging review was performed on baseline chest CT obtained at the time of diagnosis of esophageal cancer before the initiation of therapy, with the median time from baseline CT to the initiation of chemoradiotherapy of 4.8 weeks.

Visual CT scoring of ILA was performed by using a sequential reading method previously described.11,17 Interstitial lung abnormality was scored on CT using a 3-point scale: “0,” no evidence of ILA; “1,” equivocal for ILA; and “2,” ILA. Interstitial lung abnormality (score 2) was defined as: nondependent ground-glass abnormality affecting more than 5% of any lung zone, nondependent reticular abnormality, with ground-glass abnormality, honeycombing, traction bronchiectasis, nonemphysematous cysts, or architectural distortion, as before.15,20,21 Equivocal for ILA (score of 1) was defined as focal or unilateral ground-glass attenuation, focal or unilateral reticulation, and patchy ground-glass abnormality (less than 5% of the lung).15,20,21

In the sequential reading method, CT scans were reviewed by 3 board-certificate thoracic radiologists (S.T., T.H., H.H.). Reader 1 reviewed and scored all the CT studies of the cohort. Next, reader 2 reviewed all the CT studies reader 1 scored as 1 or 2 and randomly selected 20% of the studies that received score 0 by Reader 1. Reader 2 reviewed these studies independently blinded to the scores of the reader 1. If 2 readers gave concordant score, the case received the concordant score as the final ILA score. The studies with discordant scores by 2 readers were independently reviewed by reader 3, who was blinded to the scores by readers 1 and 2, and were assigned the final score with majority opinion as described previously.11,15,17,20,21

Statistical Analysis

Associations between ILA scores and disease characteristics and demographics were assessed using Fisher exact test and χ2 test for categorical variables and Kruskal-Wallis test for continuous variables. The ILA scores of 2 was considered to indicate the presence of ILA. Overall survival was defined as the time from the date of treatment initiation to the date of death of any cause. Patients who were still alive by the time of analyses were censored at the last known date of follow-up. The log-rank test was used to assess differences in the OS distributions between groups. Cox proportional hazards models were used to estimate hazard ratios (HRs), and multivariable analyses were performed using a stepwise regression, adjusting for demographics and clinical variables listed in Table 1. All P values are 2-sided, and tests were conducted at the 0.05 level.

TABLE 1 - Interstitial Lung Abnormalities Scores and Patient Characteristics
Clinical Characteristics ILA Score 2 (n = 14) ILA Score 0 or 1 (n = 194) Total (N = 208) P
Age, median (range) 69.0 (61.4–82.4) 65.0 (21.4–88.8) 65.6 (21.4–88.8) 0.011
Sex Male 11 155 166 1.00
Female 3 39 42
Race White 13 173 186 0.802
Asian 0 6 6
Black 0 7 7
Other 1 8 9
Smoking Never 4 66 70 0.637
Former 9 115 124
Current 1 10 11
Unknown 0 3 3
Histology Adeno 10 165 175 0.245
Squamous 4 29 33
Tumor location Upper 1 6 7 0.165
Middle 3 20 23
Lower* 10 168 178
T staging T1 2 5 7 0.011
T2 3 50 53
T3 7 125 132
T4 2 2 4
Tx 0 12 12
Radiotherapy 3D 7 109 116 0.782
IMRT 7 85 92
Surgery Yes 7 155 162 0.016
No 7 39 46
*Include one patient with the tumor at middle and lower esophagus.
IMRT indicates intensity-modulated radiation therapy.

RESULTS

The demographics and disease characteristics of the study cohort of 208 patients and their ILA scores on the baseline chest CT studied are summarized in Table 1. Sixty-five percent of the patients (135/205) were current/former smokers, 85% (175/208) had adenocarcinoma while 15% (33/208) had squamous cell carcinoma, and 78% (162/208) had surgery after chemoradiotherapy. Interstitial lung abnormality was present (score 2) in 14 patients (7%), while ILA scores were 0 or 1 in 194 patients (93%; score 1 in 46, score 0 in 148). In the sequential reading process, 15% of the cases (32/208) required the scoring by the third reader.

Interstitial Lung Abnormality Scores and Clinical Characteristics

The baseline chest CT scans were scored before treatment and dichotomized into ILA score 2 (presence of ILA) versus 0 or 1 (no evidence or equivocal of ILA). The patients with ILA on baseline chest CT were significantly older than patients without ILA (median age, 69 vs 65 years, respectively; P = 0.011; Figs. 1, 2). Categorical smoking history (never, former, and current at the time of diagnosis) was not associated with the presence of baseline ILA (P = 0.637). However, a higher number of pack-years of smoking was associated with baseline ILA (χ2 test P = 0.02 and χ2 trend test P = 0.05, for pack-year groups divided by increment of 30). Significant imbalances were noted in clinical T staging between patients with and without baseline ILA (P = 0.011). Of the 196 patients with known T staging, T4 disease was significantly associated with the presence of ILA on baseline CT (2/4, 50% vs 12/192, 6.25%; Fisher P = 0.026; Fig. 3). The presence of ILA on baseline was also associated with a lack of surgery after chemoradiotherapy (P = 0.016). Surgical resection was not performed in 50% of patients with ILA (7/14), compared with in 20% of patients without ILA (39/194) on baseline CT. There was no significant difference in sex, race, tumor histology, tumor location, and types of radiotherapy for esophageal cancer (3D or intensity-modulated radiation therapy) between patients with and without baseline ILA.

F1
FIGURE 1:
A 78-year-old man who is a former smoker with 60 pack-years, presenting with adenocarcinoma in the lower esophagus (A, arrow). The baseline chest CT before initiation of therapy demonstrated ILAs with subpleural interlobular septal thickening, traction bronchiectasis, and honeycombing in bilateral lungs predominantly in lower lobes (arrows, B, C).
F2
FIGURE 2:
A 72-year-old man who is a former smoker with 40 pack-years, presenting with locally advanced esophageal cancer with adenocarcinoma histology in the mid esophagus (arrow, A). The baseline chest CT before initiation of therapy ILA with subpleural interlobular septal thickening and traction bronchiectasis in bilateral lungs predominantly in lower lobes.
F3
FIGURE 3:
A 61-year-old man who is a never smoker, presenting with locally advanced squamous cell carcinoma in middle third esophagus. Tumor was noted as marked esophageal wall thickening (asterisks, A, B) with tumor extension into the periesophageal fat (arrows, A, B) indicative of T4 disease. Chest CT images in the lung window also showed subpleural ground-glass opacity and reticulation in both lungs, without definite honeycombing (arrows, C, D).

Interstitial Lung Abnormality Scores and OS

At the time of the survival analysis, 124 of the 208 patients had died. The median follow-up time was 79.0 months. There were no significant OS differences between patients with and without ILA (median OS, 49.1 vs 41.4 months, respectively; log-rank P = 0.75; Fig. 4). Current smokers had significantly shorter survival compared with former and never smokers (median OS, 24.2, 56.8, and 39.6 months, respectively; log-rank P = 0.018). The multivariable Cox model for OS was built including ILA, sex, smoking status (current vs former/never smoker), tumor histology, and whether the patient received surgery. The current smokers at the time of diagnosis had significantly increased the risk of death (HR = 2.56 P = 0.010), whereas squamous cell histology and undergoing surgical resection were associated with decreased hazards of death (squamous histology, HR = 0.52, P = 0.023; undergoing surgery, HR = 0.31, P < 0.001). The presence of baseline ILA was not associated with OS in the Cox model (P = 0.613).

F4
FIGURE 4:
Overall survival of patients with ILA (score 2) and those without ILA (score 0 or 1).

DISCUSSION

The present study demonstrated that ILA is present in 7% of patients with locally advanced esophageal cancer at baseline before chemoradiotherapy. Older age, higher number of pack-year of smoking, and T4 disease were associated with ILA. Patients with ILA less frequently underwent surgical resection after chemoradiotherapy. To our knowledge, this is the first study that evaluated the prevalence and risk factor for ILA and its clinical implication in patients with esophageal cancer.

Interstitial lung abnormality was present in 7% of patients at the time of diagnosis of esophageal cancer, which was within the similar ranges compared with the general population based (3%–7%), smokers (4%–9%), never smokers (2%–7%), and 3 lung cancer cohorts (4%–14%).11–16,20–22 The prevalence may be explained by the similar proportion of risk factors of ILA (including old age and tobacco smoke exposure) across these studies. In our study, the median age of esophageal cancer patients at diagnosis was 65.6 years, which was comparable to the general population (Framingham Heart Study), risk assessment of smoking and COPD (COPDGene study), lung cancer screening, and 3 lung cancer cohorts.11,12,15,20–22 Our result showed the proportion of ever-smokers was 65.8% (135/205), which was within the range of those in the Framingham Heart Study (53%) and in the 3 studies of patients with lung cancer (75.8%–84.8%).12,15,20,21

In patients with esophageal cancer, the presence of ILA was associated with older age and higher pack-years of smoking, which is consistent with the previous studies in the general population-based participants and in lung cancer patients.11,12,15,20,21 In the COPDGene study, the subjects with ILA were found to be older, and the number of pack-years of smoking was also significantly higher in those with ILA.11 In the Framingham Heart Study, the prevalence of ILA was 2% in those younger than 50 years but increased to 9% in those older than 50 years, and current or former smokers had higher odds of having ILA (odds ratio, 3.2).12 Compared with the earlier lung cancer studies, the median age of patients in stage IV NSCLC, current esophageal cancer, and stage I NSCLC studies were 62, 65.6, and 69 years old, the corresponding prevalence of ILA were 3.9%, 7%, and 9.5%, respectively. The ILA group were older than non-ILA group in the stage I and IV NSCLC cohorts (72 vs 67, and 69 vs 62 years, respectively).15,20

In the present study in esophageal cancer, T4 disease was found to be associated with the presence of ILA on baseline CT. Based on the eighth edition of the American Joint Committee on Cancer staging for esophageal cancer, T4 is defined as tumor that invades adjacent structures (eg, trachea, bronchus, pleura, lung, pericardium, and aorta). The association between invasive tumors and fibrotic lungs may be due to compression effect and digestive impairment from malignant gastrointestinal conditions. Makharia et al23 reported that parenchymal lung disease may be caused by extrinsic compression by the dilated esophagus and recurrent microaspiration in achalasia patients with tight esophagogastric junction. Malignancy in the distal esophagus and esophagogastric junction may present similar morphological features.24 In our study, 2 patients with T4 stage esophageal tumors had ILA (2/4, 50%), one located at esophagogastric junction and the other one at the middle esophagus. However, given the small number of patients with T4 tumors in our study, the results need to be carefully interpreted and validated in a larger cohort.

Esophageal tumor location was not associated with ILA in our study, which is somewhat counter-intuitive, especially given the fact that approximately 85% of our cases were adenocarcinomas (175/208) with a propensity to involve the lower esophagus or esophagogastric junction. Lee et al.25 previously described the association between idiopathic pulmonary fibrosis and gastroesophageal reflux, which is a presumed risk factor for microaspiration. Another study examined the impact of sarcopenia on patients with unresectable advanced esophageal cancer and reported that aspiration pneumonia may result from multiple factors, not only sarcopenic dysphagia but also malignant obstruction and recurrent nerve paralysis.26 Association between ILA and aspiration remains to be determined, and the topic of tumor location and ILA can also be revisited with a larger cohort focusing on GE junction tumors.

No previous studies have been conducted on the association between the presence of ILA and the decision to undergo surgical resection in patients with esophageal cancer. Treatment of esophageal cancer is dependent on the stage of esophageal cancer and operative risk. In general, locally advanced esophageal cancer with invasion of adjacent structures (aorta, vertebral body, trachea) or distant metastases are unresectable.27 Preoperative risk factors for 30-day and operative mortality may warrant additional consideration in patients undergoing esophagectomy, including older age, preoperative requirement of assistance with activity of daily living, weight loss of more than 10% within 6 months before surgery, history of smoking within 1 year before surgery, male sex, history of COPD before surgery, and presence of metastatic/relapsed cancer.28 In this study, esophageal cancer patients with the presence of ILAs had older age and a higher number of pack-years of smoking, which might explain the low frequency of surgeries in this group compared with non-ILA patients, although the decision for surgical resection is often multifactorial.

Interstitial lung abnormality at baseline was also associated with a lack of surgery after chemoradiotherapy in the present study, where surgical resection was not performed in 50% of patients with ILA (7/14), compared with in 20% of patients without ILA (39/194, P = 0.016). Surgical resection is the traditional curative treatment for esophageal cancer,29–31 and therefore, the results are indicative of an important role of recognition of ILA on baseline chest CT for optimal treatment decisions. In terms of the association between presence of ILA and undergoing tumor resection, Miyazaki et al32 showed the similar results in lung cancer patients with stage I–III NSCLC, where surgery was performed in 67.6% of patients with ILD versus 82.6% of patients without ILD.33 Postoperative acute exacerbations of the baseline ILD also contributed to the poor prognosis of lung cancer patients after surgical resection, although surgery may still provide survival prolongation in a selected subgroup of patients.33–35 To our knowledge, this is the first report that indicated an association between ILA and treatment selection in patients with esophageal cancer. Optimal selection of surgical candidates is a key component of management of patients with esophageal cancer, particularly given the emerging use of immune-checkpoint inhibitors for unresectable tumors,36 and if confirmed in larger studies, attention to ILA on pretreatment chest CT may help further optimize patient selection for surgical and nonsurgical treatment.

Interstitial lung abnormality was not significantly associated with OS in esophageal cancer patients in the current study. The results are different from the previous studies of ILA in patients with lung cancer. In treatment-naive advanced NSCLC patients with ILA, the median OS was significantly shorter compared with those without ILA (median OS, 7.2 vs 14.8 months; P = 0.002).21 Two other recent studies also supported that ILA is associated with shorter OS in patients with NSCLC, both for stage I (median OS, 46.2 vs 121.92 months; P < 0.0001) and stage IV (median OS, 9.95 vs 16.95 months; P = 0.0002) diseases.15,20 Moreover, the presence of ILA alone was a prognostic factor of postoperative pulmonary complications in lung cancer (adjusted odds ratio, 1.91; P = 0.004), which was the major cause of perioperative morbidity and mortality after lung resection.37 A lack of association between ILA and survival in patients with esophageal cancer in the present study may reflect different prognostic implications of ILA for tumors originating in the lung versus tumors originating in the gastrointestinal tract, although further mechanistic details remain to be studied. In addition, the absence of data regarding occupational and environmental air pollution in our study, which is an established major risk for esophageal squamous cell carcinoma and ILA, may potentially influence our findings regarding the association between ILA and survival in patients with esophageal cancer.3

On the other hand, smoking status at the time of diagnosis was a predictor of survival in patients with esophageal cancer, with current smokers having shorter survival than former or never smokers, which remained significant after adjusting for tumor histology (P = 0.023), surgical resection (P < 0.001), and ILA (P = 0.613). Smoking as a poor prognostic factor for esophageal cancer has been reported in prior studies but may depend on histologic subtypes. Shitara et al38 reported that smoking history is strongly associated with poor prognosis in patients with esophageal squamous cell carcinoma, especially those treated by chemoradiotherapy. On the other hand, recent research reported that smoking was not associated with a significant difference in survival of esophageal adenocarcinoma patients.39 In 2 studies of esophageal adenocarcinomas, the impact of cigarette smoking on cancer risk was highly variable.40,41

In a population-based cohort, smoking was identified as a risk of cancer death, and mortality was significantly elevated for current versus never-smokers in most cancer types, including lung, esophagus, liver, pancreas, and colorectal cancers.42 In genetic research, Xi et al43 demonstrated that cigarette smoke mediated the repression of miR-217, whereas knockdown of miR-217 increased the growth of esophageal adenocarcinoma cell in vitro and in vivo. The variation in the magnitude of smoking-related risk of mortality from esophageal cancer is multifactorial and may be associated with tumor histology, smoking patterns, and epigenetic alterations.

The limitations of the study include a retrospective design and a relatively small number of patients treated at a single institution, with a limited number of patients demonstrating baseline ILA. Studies with a larger number of patients and also in a cohort with distant metastases are needed to further investigate the relationship between ILA and esophageal cancer characteristics and outcome.

In conclusion, ILA was noted in 7% of patients with locally advanced esophageal cancer at baseline before chemoradiotherapy, and the factors associated with ILA included older age, higher number of pack-year of smoking, and T4 disease. The presence of ILA was strongly associated with a lack of surgical resection after chemoradiotherapy, suggesting an implication of ILA in treatment selection in these patients. Further studies are needed to validate the prevalence and risk factors in larger cohort and further evaluate the prognostic implication of ILA in patients with esophageal cancer.

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Keywords:

interstitial lung abnormalities; computed tomography; esophageal cancer; chemoradiotherapy; chest radiology

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