Clinical significance of indeterminate pulmonary nodules in patients with locally advanced head and neck squamous cell carcinoma

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1 ORIGINAL ARTICLE Clinical significance of indeterminate pulmonary nodules in patients with locally advanced head and neck squamous cell carcinoma Raphael E. Alford, MD, MA, 1 David V. Fried, BS, 2 Benjamin Y. Huang, MD, 1 Mark Weissler, MD, 3 Carol Shores, MD, PhD, 3 William Shockley, MD, 3 Trevor Hackman, MD, 3 Adam Zanation, MD, 3 Neil Hayes, MD, MPH, 4 Jared Weiss, MD, 4 Juneko Grilley Olson, MD, 4 Valerie Jewells, DO, 1 Katherine Birchard, MD, 1 Bhishamjit S. Chera, MD 2 * 1 Department of Radiology, University of North Carolina Hospitals, Chapel Hill, North Carolina, 2 Department of Radiation Oncology, University of North Carolina Hospitals, Chapel Hill, North Carolina, 3 Otolaryngology/Head and Neck Surgery Chapel Hill, University of North Carolina Hospitals, Chapel Hill, North Carolina, 4 Division of Hematology and Oncology, University of North Carolina Hospitals, Chapel Hill, North Carolina. Accepted 29 January 2013 Published online 1 June 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed ABSTRACT: Background. The purpose of this study was to determine whether indeterminate pulmonary nodules (IPNs) at staging are predictive of lung metastasis, primary lung carcinoma, or survival in patients with advanced head and neck squamous cell carcinoma (HNSCC). Methods. One hundred ten patients with IPN at staging who had followup imaging and 100 patients without IPN were identified from an HNSCC database. The primary endpoints were lung progression-free survival (PFS) and overall survival (OS). Results. Two-year lung PFS for the IPN and No-IPN cohorts were 66% versus 61% (p ¼.92) and the OS for these cohorts were 71% versus 68% (p ¼.77). Within the IPN cohort, level IV/V lymph node involvement (odds ratio ¼ 4.34; p ¼.03), hypopharynx primary (odds ratio ¼ 21.5; p ¼.005), and race (odds ratio ¼ 9.29; p ¼.001) were independent predictors of developing lung malignancy. Conclusion. IPNs at staging in patients with HNSCC do not affect prognosis and should neither influence initial treatment planning nor the frequency of posttreatment surveillance. VC 2013 Wiley Periodicals, Inc. Head Neck 36: , 2014 KEY WORDS: solitary pulmonary nodule, multiple pulmonary nodules, squamous cell carcinoma of the head and neck, metastasis, surveillance INTRODUCTION The most common site of distant metastases for head and neck squamous cell carcinoma (HNSCC) is the lung. The National Comprehensive Cancer Network currently recommends chest imaging for all patients with HNSCC 1 with CT of the chest being the imaging modality of choice for evaluation of the lungs, having replaced chest radiograph. CT has a higher sensitivity for detection of lung metastases and primary lung carcinomas, 2,3 but its use has also resulted in the identification of many clinically indeterminate pulmonary nodules (IPNs), commonly defined as pulmonary densities 10 mm in diameter that may be benign or represent early malignancy. The clinical significance of IPN has been prospectively studied in populations at-risk for lung cancer (ie, individuals with significant tobacco use). In these screening trials, the majority of IPNs detected by chest CT have been observed to be benign. 4,5 Patients with HNSCC presumably are a higher risk population as most are at increased risk for *Corresponding author: B. S. Chera, Department of Radiation Oncology, University of North Carolina Hospitals, Room 1043, North Carolina Clinical Cancer Center, 101 Manning Drive, Chapel Hill, NC bchera@med.unc.edu both lung metastases as well as primary lung cancer (given the high prevalence of smoking in this group). As treatment decisions are based on the extent of disease, whether an IPN truly represents metastatic disease or a primary lung cancer in a patient with HNSCC, raises a significant clinical problem. At our institution, patients with HNSCC with IPNs are given the benefit of the doubt, treatment decisions are made based on the assumption that IPNs are not malignant and are followed with serial imaging. The clinical and prognostic significance of IPNs in patients with HNSCC, however, has yet to be defined. We therefore conducted a single-institution retrospective study to evaluate the natural history of IPNs and to determine whether the presence and imaging characteristics of IPNs at staging were predictive of the development of lung metastasis or primary lung carcinoma, or of survival in patients with local-regionally advanced (TNM stage III/IV) HNSCC. We hypothesize IPNs do not adversely affect the clinical outcomes of patients with HNSCC. MATERIALS AND METHODS Patient selection Approval for this study was obtained from the University of North Carolina Hospitals at Chapel Hill Institutional Review Board (Institutional Review Board # ), informed consent was not required and review was performed in compliance with Health Insurance Portability 334 HEAD & NECK DOI /HED MARCH 2014

2 INDETERMINATE PULMONARY NODULES IN HNSCC and Accountability Act. Study subjects were identified through a retrospective chart review of patients in our institutional Head and Neck Database. Criteria for inclusion in the IPN cohort were: (1) negative pretreatment staging chest CT or positron emission tomography (PET)/CT for metastatic disease below the clavicles with mention of at least 1 IPN in the radiologist report; (2) TNM stage III/IV disease (any T, any N, M0), 6 defined pathologically if surgery was performed and on a clinical basis if surgery was not; (3) history of definitive local-regional treatment; and (4) at least 1 posttreatment follow-up cross-sectional imaging study. Between October 2002 and April 2011, 818 patients were evaluated at our institution for a diagnosis of HNSCC, with 792 (96.8%) being initially classified as M0 and 26 (3.2%) classified as M1. From the former group, 110 patients were identified with IPNs and met inclusion criteria. Ninety-one percent of patients (100 of 110) received a staging chest CT and 9% (10 of 110) received a staging PET/CT. Seventythree percent (161 of 219) and 26% (58 of 219) of all follow-up scans were chest CTs and PET/CTs, respectively. From the same database and time period, 100 patients with TNM stage III/IV with negative staging chest CTs were also identified as nonmatched controls (no-ipn cohort). Chest CT was adopted as the preferred imaging modality for distant staging at University of North Carolina Hospitals at Chapel Hill in October Image analysis Chest CT examinations were performed with helical scanners from the thoracic inlet to the pulmonary bases, with 5-mm slice thickness, mas of , and kvp. One study was performed at 8-mm slice thickness. PET/CT images were obtained from the skull base to the mid-thighs approximately 1 hour after the administration of 10 to 15 mci of F-18 fluorodeoxyglucose, with CT slice thicknesses ranging from 3 to 5 mm. For the IPN cohort, all staging and follow-up images were reviewed(eitherbyb.h.,whoisaboardcertifiedradiologist, or R. A., who is a diagnostic radiology resident), with original dictations available. When multiple follow-up crosssectional imaging studies were present, imaging was only reviewed if it occurred at a minimum of 6 weeks from the previous examination. The largest 3 IPNs at staging were categorized as the index nodules, and their location (lung lobe), maximal diameter, and density (calcified, noncalcified) were recorded on the pretreatment staging study and followed throughout available follow-up imaging. Additionally, the numbers of new, resolved, and total nodules were recorded for all follow-up examinations. The presence of mediastinal/ hilar adenopathy was recorded for all examinations. Imaging was not reviewed for the no-ipn cohort. To evaluate interobserver variability, 40 staging studies were randomly selected to be evaluated separately by both readers. Nodule size, number, and presence or absence of calcified nodules for each of these patients was specifically compared. Statistical analysis The primary endpoints of this study were lung progression-free survival (PFS) and overall survival (OS). Lung PFS events were defined as the development of metastatic pulmonary disease by consensus of the radiologist and clinical team, the development of primary lung cancer, or death from any cause. All primary lung cancers were pathologically proven. Predictors of lung progression were calculated using univariate and multivariate logistic regression. The p values <.05 were treated as being statistically significant. Those factors demonstrating significance or marginal significance (p values <.10 and >.05) during univariate analysis were included in multivariate analysis. Univariate and multivariate regression analyses were performed on the IPN cohort as well as the total cohort of patients comprised of those with and without IPNs at staging. Rates of lung PFS and OS were calculated with the Kaplan Meier product limit method. Clinical follow-up duration was determined from first date of definitive treatment (surgery or radiation) until event. R version was used for all statistical calculations and plots. RESULTS Patient characteristics All patients in this analysis were treated from October 2002 to April The characteristics of our patient population are reported in Table 1. The median follow-up for all patients with IPN and living patients with IPN was 23.5 months and 27.1 months, respectively (range, 4 95 months). The median follow-up for patients living and all no-ipn was 22.9 and 25.9 months, respectively (range, 4 91 months). No significant differences in age, race, T TABLE 1. Variables Patient characteristics. IPN cohort (n ¼ 110) % No-IPN cohort (n ¼ 100) % p value Median age, y 58 NA 58 NA.48 Median pack-years 30 NA 25 NA.04* Smoking status.71 Never smokers Smokers Race.59 White African American Other T classification.91 T T T T T N classification.44 N N N N Primary site.62 Hypopharynx Larynx Nasopharynx Oral cavity Oropharynx Unknown Abbreviations: IPN, indeterminate pulmonary nodule; NA, not applicable. * p <.05. HEAD & NECK DOI /HED MARCH

3 ALFORD ET AL. FIGURE 1. (A) Bland Altman plot demonstrating the 2 observers were within the limits of agreement in the majority of cases on the number of nodules present per study. (B) There was a good correlation between observers on the number of nodules present per case. or N classifications, or the primary sites of HNSCC were identified. Patients with IPNs had a higher median packyear history (30 vs 25; p ¼.04). The IPN cohort was primarily (92%; 101 of 110) composed of patients with IPNs less than 10 mm in diameter. The other 9 patients had their largest IPN measure as 10 mm (6 patients), 12 mm (1 patient), 13 mm (1 patient), or 19 mm (1 patient). The patient with a 19 mm IPN was included because of the benign appearance, per the radiologist report (partially calcified). Patients with IPN had on average 2 posttreatment imaging scans reviewed (range, 1 8), with the first follow-up scan conducted at median interval of 5 months (range, months), and the second follow-up at a median of 11 months (range months) from date of definitive treatment. The median number of IPNs at staging was 3 (range, 1 10). Fifty-two percent of patients with IPN (57 of 110) had 3 or fewer nodules at staging and, thus, all of their nodules were followed. Interobserver variability Both readers evaluated 40 randomly selected staging studies for the number of nodules, the size of the largest nodule, and whether or not any nodules were calcified. A Bland Altman plot along with a plot of both observers results against one another for the number of nodules and the size of largest nodule are shown in Figures 1 and 2, respectively. For the number of nodules and size of the largest nodule, there were 3 and 1 observations outside the limits of agreement (mean 62* SD), respectively. No biases were seen between observers. Aside from a few outliers (1 3 per 40 observations), the variability was limited and, thus, we used observations from each physician interchangeably. The observations regarding the presence of any nodule calcifications are shown in Table 2. These results yielded a Cohen Kappa value of 0.71, indicating substantial agreement. 7 Clinical outcomes At 2 years, the lung PFS of the IPN and no-ipn cohorts were 66% and 61% (p ¼.92), respectively. The OS of patients with IPN was 71% versus 68% for no-ipn (p ¼.77). The Kaplan Meier curves for these estimates are shown in Figure 3. In the IPN cohort, 19 patients (17%) developed lung metastases, with 16 of them developing metastases by 2 years. Four of these patients developed malignancy from index nodules. Three patients in the IPN cohort developed primary lung cancers at 1, 37, and 65 months post-initial staging chest CT. Fourteen FIGURE 2. A) Bland Altman plot demonstrating the 2 observers were within the limits of agreement in the majority of cases on the size of nodules present per study. (B) There was a good correlation between observers on the size of nodules present per case. 336 HEAD & NECK DOI /HED MARCH 2014

4 INDETERMINATE PULMONARY NODULES IN HNSCC TABLE 2. Presence of any calcified nodules from both observers. Benjamin Huang Calcified Not calcified Raphael Alford Calcified 7 4 Not calcified 0 29 Regarding the presence or absence of any calcified pulmonary nodules, there was substantial agreement between the reviewers. patients with no-ipn developed pulmonary metastases (14%), 13 of which occurred by 2 years. No patients in the no-ipn cohort developed primary lung cancers. Analysis of lung progression Within the IPN cohort, the mean number of pulmonary nodules at staging was not significantly different between those that progressed in the lung and those that did not (p ¼.44). The mean size of the largest index nodule at staging was 5.9 mm in both those that progressed to malignancy and those that did not (p ¼.46). At first follow-up, the mean number of nodules in those patients who went on to develop malignancy increased significantly (3.8 to 7.2) as compared to the stable number of nodules (4.4 to 4.5) in those who did not (p ¼.007). An increase of 3 or more nodules at first follow-up was found to be significantly predictive (p <.0001) of the development of lung metastasis or primary lung carcinoma. The mean size of the largest nodule at first followup also increased significantly (5.9 to 11.4 mm) in those who went on to develop a metastasis or lung primary, but remained relatively stable (5.9 to 5.7 mm) in those who did not (p ¼.01). As seen in Table 3, univariate analysis within the IPN cohort demonstrated low cervical (level IV/V) node involvement (p ¼.015), having a hypopharyngeal primary (p ¼.005) or poor grade tumor (p ¼.035), and being African American (p ¼.001) as predictive of developing lung metastasis or primary lung carcinoma. After multivariate analysis, level IV/V lymph node involvement (odds ratio ¼ 4.34; p ¼.03), hypopharyngeal primary (odds ratio ¼ 21.5; p ¼.005), and race (odds ratio ¼ 9.29; p ¼.001) remained independent predictors of progression. On staging chest CT, the number of IPNs (p ¼.89), largest nodule size (>5 mm as compared to <5 mm; p ¼.28), pack-year history of 10 as compared to >10 (p ¼.59), and presence of hilar (p ¼.97) or mediastinal adenopathy (p ¼.31) were not predictive of development of lung primary or metastasis. Combined analysis of both IPN and no-ipn cohorts demonstrated the presence of IPN for all patients was not significant (p ¼.63) in univariate analysis (Table 4). In this analysis, the only factors that predicted for lung metastasis or primary lung carcinoma were level III, IV, or V lymph node involvement (odds ratio ¼ 2.85; p ¼.01). Advanced T classification (odds ratio ¼ 2.48; p ¼.057) and being African American (odds ratio ¼ 2.09; p ¼.08) trended toward statistical significance. DISCUSSION We conducted a single institution retrospective study to analyze the natural history and prognostic impact of IPNs identified on pretreatment staging chest CT and PET/CT scans in patients with locally advanced HNSCC. Our results indicate the presence of IPNs does not significantly influence either lung PFS or OS. Furthermore, radiographic characteristics of the IPNs were not predictive for the development of pulmonary malignancy (metastases or primary lung cancer). Although we found no predictive imaging characteristics, a few clinical characteristics were identified as significant. In grouped analysis, low lymph node levels were most predictive of future lung involvement, with advanced T classification and race marginally predictive. Within those patients with IPNs, having a hypopharyngeal primary and poor tumor differentiation was predictive of lung malignancy. Advanced T classification, poor grade, and low lymph node levels are well established risk factors in prior reports. 8,9 Advanced N classification, a commonly reported predictor of distant metastasis, was not significant in our population. In our population of patients with TNM stage III and IV, 56% (117 of 210) of whom were N2 classification, it is likely we were not able to FIGURE 3. A) Kaplan Meier curve demonstrating no significant difference in lung progression-free survival between patients with indeterminate pulmonary nodules (IPNs) and those without (NO IPN). (B) Kaplan Meier curve demonstrating no significant difference in overall survival between patients with indeterminate pulmonary nodules (IPNs) and those without (NO IPN). HEAD & NECK DOI /HED MARCH

5 ALFORD ET AL. TABLE 3. Logistic regression results for indeterminate pulmonary nodule cohort for lung progression-free survival. Univariate analysis Multivariate analysis Factor Odds ratio 95% CI p value Odds ratio 95% CI p value No. of nodules (1 2vs3 5) to NA NA NA No. of nodules (1 2vs6þ) to NA NA NA Maximum nodule size (5mmvs>5 mm) NA NA NA Enlarged hilar lymph node to NA NA NA Enlarged mediastinal lymph node NA NA NA Calcified hilar lymph node to NA NA NA Calcified mediastinal lymph node to NA NA NA T Classification (T0 T2 vs T3/T4) NA NA NA N Classification (N0/N1 vs N2/N3) to NA NA NA Lowest involved lymph node (I II vs III V) NA NA NA Lowest involved lymph node (I III vs IV V) * * African American * * Age, continuous NA NA NA Smoking pack-year history (>10 vs 10) NA NA NA Primary site (hypopharynx vs other) * * Tumor differentiation (poor vs moderate/well) * ** Any calcified nodules (yes vs no) NA NA NA Abbreviations: CI, confidence interval; NA, not applicable. * p <.05. ** p <.10. tease out this previously described difference in risk given that our analysis would have excluded a substantial number of patients with N0. Furthermore, we observed an increased risk for lung progression in African Americans with IPNs (odds ratio ¼ 9.3). It has been reported that African American patients with HNSCC present at a later stage and have a worse outcome. 10 Our data support this contention. The malignancy rate of IPNs in patients with HNSCC is not well defined. In patients at high risk for lung cancer, the Early Lung Cancer Action Project demonstrated IPNs in 15% of their population, of which 8% were determined to be malignant. 5 The recently published National Lung Screening Trial research team evaluated 26,723 high-risk individuals with CT scan, among which 24.2% of scans demonstrated a noncalcified nodule 4 mm. Although the authors did not publish the percentage of these that were <1 cm, 96% of the nodules identified on CT were classified as false-positive. 11 Studies of patients with known malignancy have also demonstrated numerous pulmonary nodules with widely varying reports on malignancy rates. In a study of patients with known pulmonary malignancy, Keogan et al 12 identified 16% of 551 patients had noncalcified pulmonary nodules between 4 mm and 12 mm in size, of which 12% were ultimately malignant. Evaluating pulmonary nodules in patients with extrathoracic malignancies, Hanamiya et al 13 demonstrated 5% of 111 nodules 10 mm were malignant. In 2 studies of the outcomes of patients with HNSCC with staging chest CTs, the malignancy rate of IPNs was less well defined, ranging from 9% to 66%. 14,15 Both of these studies had relatively low numbers of patients with IPNs, 32 and 15 patients, respectively. Notably, the former of these studies found zero of their index nodules ultimately TABLE 4. Logistic regression results of combined indeterminate pulmonary nodule and no-indeterminate pulmonary nodule cohorts for lung progressionfree survival. Univariate analysis Multivariate analysis Factor Odds ratio 95% CI p value Odds ratio 95% CI p-value T Classification (T0 T2 vs T3/T4) * * N Classification (N0/N1 vs N2/N3) NA NA NA Lowest involved lymph node (I II vs III V) ** ** Lowest involved lymph node (I III vs IV V) * NA NA NA African American ** * Age, continuous NA NA NA Smoking pack-year history (>10 vs 10) NA NA NA Primary site (hypopharynx vs other) * Tumor differentiation (poor vs moderate/well) NA NA NA Presence of IPNs (yes vs no) NA NA NA Abbreviations: CI, confidence interval; NA, not applicable; IPNs, indeterminate pulmonary nodules. * p <.10. ** p <.05.Note: In multivariate analysis, the lowest involved lymph node (I II vs III V) was included over lowest involved lymph node (I III vs IV V) because it was the only one that was statistically significant. Lowest involved lymph node (I II vs III V) was excluded as both factors are correlated and this factor was only marginally significant on univariate analysis. 338 HEAD & NECK DOI /HED MARCH 2014

6 INDETERMINATE PULMONARY NODULES IN HNSCC developed into pulmonary malignancy, similar to our results. Our data suggest the likelihood that IPNs ultimately represent metastatic disease is on the lower end of this spectrum, and is similar to those at high risk for lung cancer. For the multidisciplinary oncology team (head and neck surgeon, radiation oncologist, and medical oncologist), the identification of IPNs on a staging chest CT may influence treatment recommendations. Definitive treatment (ie, aggressive multimodality treatment for cure ) of HNSCC puts patients at risk for significant acute and late toxicities. Furthermore, it is commonly accepted that a patient with metastatic disease is ultimately incurable. Thus, accurate diagnosis of metastatic disease is necessary to avoid giving intensive multimodality treatment that will cause significant harm and not cure the patient. When a patient with HNSCC has IPNs at diagnosis, a decision must be made as to whether to consider these to be malignant or benign. Many oncologists would give a patient the benefit of the doubt (as we do at our institution) and omit IPNs from the decision-making process. An error of omission may be made if the IPNs are truly malignant (ie, the patient would endure toxic definitive treatment and would not be cured). Our data suggests that IPNs can be safely ignored by the clinical team when planning initial treatment. We are not arguing chest CTs should not be performed for staging with HNSCC or in follow-up, but instead submit that patients with IPNs should not be followed more frequently than patients without IPNs. At our institution, all patients with HNSCC receive a chest CT at diagnosis. If they do not have IPNs, they are followed after definitive treatment with plain chest X-rays every 6 months for 2 years and then yearly thereafter. Our data suggest that IPNs are not a negative prognostic factor and the natural history of both IPN and no-ipn cohorts for developing lung metastasis or primary lung carcinoma is similar, with both cohorts demonstrating the majority of lung progression within 1 year from diagnosis. The presence of an IPN should not require more frequent imaging than those without. We therefore recommend patients with IPNs receive a chest CT every 6 months for 2 years, and if radiographic findings are stable, switch to yearly plain chest X-rays thereafter for screening for HNSCC metastasis in nonsmokers. In light of the National Lung Screening Trial results, it would be reasonable to continue with annual low-dose chest CTs for patients with significant tobacco histories. Even in patients with heavy smoking history, given that very few nodules identified at staging ultimately represented disease, we see little cause to alter imaging intervals based on nodule characteristics defined as indeterminate by the radiologist. There are limitations to our study. First and foremost are the limitations associated with any retrospective study: selection bias and accuracy of the medical records. The association between HNSCC and human papillomavirus (HPV) has become clear over the past few years. We lacked HPV data for all but our most recent patients; preventing analysis of HPV-associated malignancy and IPNs. A second limitation we faced was interobserver variability. Given the diversity of IPN appearances, we believe that some interobserver variability in choosing the most worrisome nodules out of many is expected, and likely simulates current radiologic practice. 16 Another limitation is that the CT technique utilized at our institution may not be ideal for evaluating pulmonary nodules. Although 5-mm thick axial CT images of the thorax are in our standard practice, narrower slices may have increased sensitivity for tiny nodules, and 3-mm slice thickness is common in some practices. In conclusion, IPNs identified on staging chest CT in patients with HNSCC do not affect prognosis. Specifically, the presence of IPNs does not predict for the progression of lung malignancy or survival after definitive treatment. Thus, the presence of IPNs should not influence initial treatment planning. The frequency and time points of surveillance of patients with HNSCC with IPNs after treatment should not differ from those who do not have IPNs. 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