|Year : 2020 | Volume
| Issue : 1 | Page : 17-22
Outcomes of incidental pulmonary nodules in head-and-neck squamous cell cancer patients treated with curative intent
Daniel Tani1, Rahul Ladwa2, Wen Xu2, Zarnie Lwin1, Karin Steinke1, Brett G M Hughes1
1 School of Medicine, University of Queensland; Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia
2 Princess Alexandra Hospital, Woolloongabba; School of Medicine, University of Queensland, Brisbane, QLD, Australia
|Date of Submission||19-Dec-2019|
|Date of Decision||23-Jan-2020|
|Date of Acceptance||14-May-2020|
|Date of Web Publication||18-Jun-2020|
Royal Brisbane and Women's Hospital, Brisbane, QLD 4006
Source of Support: None, Conflict of Interest: None
Introduction: Incidental pulmonary nodule(s) (IPNs) are a common finding during staging imaging for the head-and-neck squamous cell cancers (HNSCC) treated with curative intent. Currently, the incidence of metastasis or synchronous malignancies and outcomes for IPN in this population is unknown. Methods: All cases (n = 2489) reviewed at a tertiary Australian Institution's head and neck (H and N) multidisciplinary meeting, from January 2010 to December 2014, were included. Of these patients, 310 (12.5%) had an HNSCC with an IPN that had been detected during staging imaging. These patients were also to undergo treatment by curative intent. Clinicopathological characteristics, the incidence of malignancy, progression-free survival, and overall survival (OS) were collected retrospectively over 5 years. Results: The median age of patients with an IPN was 66 (range 25–95) years. Tissue diagnosis of IPN was attempted in 46 (14.8%) patients due to radiological suspicion of malignancy. Malignancy was confirmed in 33 (11.0%) patients. From these, 33 patients, 11 (30.3%) had histological diagnoses of nonsquamous cell lung cancers and hence are not due to metastatic spread from a primary HNSCC. Age, gender, previous malignancies, smoking status, p16 status, stage, or primary site did not predict for malignancy. The incidence of pulmonary metastasis in patients who did not undergo tissue biopsy due to low clinical and radiological suspicion of malignancy (n = 244) occurred in 10 patients (4.1%). At the time of analysis, 91 (29.4%) patients had died, and tumor recurrence had occurred in 82 (26.5%) patients. The mean OS was 48 months (95% confidence interval: 44–51). OS was significantly associated with greater age (hazards ratio [HR] 1.04, P < 0.001); immunosuppression (HR 2.15, P = 0.013); and biopsy being attempted (HR 1.78, P = 0.013). There was no biopsy related mortality. Discussion: Detection of an IPN in patients undergoing workup for H and N cancer is common. The risk of malignancy in these IPNs however, is low. We did not identify any clinicopathological parameters to predict malignancy in this setting. Advanced age, current smoking status, and history of immunosuppression predict for poor outcomes. Further work is being undertaken to analyze radiological features that may predict malignancy in an IPN found during the radiological staging of HNSCC.
Keywords: Head-and-neck cancer, outcomes, predictors, pulmonary nodule
|How to cite this article:|
Tani D, Ladwa R, Xu W, Lwin Z, Steinke K, M Hughes BG. Outcomes of incidental pulmonary nodules in head-and-neck squamous cell cancer patients treated with curative intent. J Head Neck Physicians Surg 2020;8:17-22
|How to cite this URL:|
Tani D, Ladwa R, Xu W, Lwin Z, Steinke K, M Hughes BG. Outcomes of incidental pulmonary nodules in head-and-neck squamous cell cancer patients treated with curative intent. J Head Neck Physicians Surg [serial online] 2020 [cited 2020 Jul 13];8:17-22. Available from: http://www.jhnps.org/text.asp?2020/8/1/17/287156
| Introduction|| |
Head-and-neck (H and N)cancers are a heterogeneous group of malignancies with an incidence of >500,000 cases annually worldwide. Incidental pulmonary nodules (IPN) are defined as a focal opacity on imaging measuring ≤3 cm in diameter and surrounded by aerated lung. Examples of IPNs from the study population are shown in [Figure 1], [Figure 2], [Figure 3]. The frequency of IPNs found during the comprehensive staging of H and N cancer is unknown. The incidence of IPNs in the National Lung Screening Trial (NLST), a population with similar risk factors, was approximately 30%, of which approximately 2%–5% had confirmed lung cancer. Despite some shared risk factors, the NLST patient population is likely to be different to the H and N cancer population with different risks for synchronous primary malignancy or metastatic disease.
|Figure 1: 9 mm solid pulmonary nodule (blue arrow), medial right lung base|
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|Figure 2: 30 mm pulmonary nodule in left lower lobe (blue arrow). Percutaneous tissue biopsy confirmed squamous cell cancer|
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|Figure 3: 22 mm ovoid, spiculated lesion on left upper lobe (blue arrow). Bronchoscopic tissue biopsy confirmed squamous cell cancer. Note presence of multiple calcified pleural plaques secondary to asbestos exposure|
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With the increasing availability and sophistication of medical imaging techniques, the detection of IPN is increasingly common in this population. The incidence is thought to be between 11% and 33% in high-risk patients. In clinical practice, the selection of patients undergoing biopsy of pulmonary nodules (IPNs) is largely based on radiological parameters. The aim of this study was to determine the incidence of IPN in a large cohort of H and N cancer patients, and the outcomes of those patients found to have IPN on workup for curative-intent treatment.
| Methods|| |
We conducted a retrospective study collecting data acquired over 5 years (January 2010 to December 2014) in a single tertiary care institution in Queensland, Australia. Out of 2489 patients discussed at the H and N multidisciplinary meeting (MDM), 480 were found to have an IPN in the absence of definitive metastatic disease through a retrospective chart review and confirmation of radiology report. The number of IPNs was not restricted. Of the 480 patients, 310 were included in our final data analysis following exclusions secondary to noncurative intent treatment offered (n = 78), benign H and N pathology (n = 18), non-H and N cancer primary (n = 6), nonsquamous cell H and N cancer, and missing data (n = 4). The American Joint Committee on Cancer 7th Edition was used for staging H and N cancers. IPNs were initially detected via diagnostic computed tomography (CT) or positron emission tomography (PET)/CT during staging at diagnosis. Fleischner Society recommendations on IPNs were used as a basis for the radiological features that were considered when assessing IPNs. These features include size, number of nodules, location, and morphology. The Fleischner Society recommendations were not designed for patients who have a known synchronous malignancy and thus were used only as a general guide to the identification of a suspicious nodule. These patients were then discussed in MDM, where both radiological and clinicopathological factors (e.g., performance status, co-morbidities, degree of underlying lung disease, risk of procedural pneumothorax, etc.) were taken into account before determining which patients to select for biopsy.
To test the association between categorical variables and various outcomes, Pearson's Chi-squared test statistic or Fisher's exact test were used, as appropriate. Unadjusted mean overall survival (OS) and disease-free survival (DFS) times were estimated using Kaplan-Meier survival analysis. OS was defined as the time from diagnosis to death, and DFS was defined as the time from diagnosis to event. Cox-proportional hazards models were used to model OS and progression-free survival. All analysis was performed in SPSS version 22 (IBM Corp., Armonk, NY).
Low-risk ethical approval HREC/15/QRBW/275 was granted for the study by the Royal Brisbane and Women's Hospital human research ethics committee.
| Results|| |
Baseline characteristics for the study population (n = 310) can be seen in [Table 1]. IPN were identified in 310 (12.5%) of all patients discussed in the H and N MDM over 5 years. The median age at diagnosis was 66 (range 26–95) years. The cohort consisted of predominantly male patients (80.3%) with an Eastern cooperative oncology group (ECOG) performance status of 0–1 in 93.2% and current smoking history in 28.7%. Advanced disease, defined as nonmetastatic stage III-IV, accounted for 64.9% of cases. Primary sites of malignancy included oral cavity (28.1%), oropharynx (24.5%), hypopharynx/larynx/nasopharynx/unknown primary (22.6%) and other sites, including skin, salivary gland, thyroid, and paranasal sinus malignancies (24.8%). Previous malignancies of any type were documented in 31.3%. Patients were considered immunosuppressed if they had a history of previous organ or bone marrow transplantation, Chronic Lymphocytic Leukaemia, HIV, or the use of immunosuppressive medications, including corticosteroids. The rate of immunosuppression was 6.5%. Surgery alone was used as a treatment in 19% of cases, surgery with postoperative radiotherapy or chemotherapy in 46.1%, and definitive radiotherapy or chemotherapy in 34.8%.
Attempts at tissue biopsy occurred in 46 (14.8%) patients due to radiological concerns of malignancy. Thirty-three (71.7%) were malignant, 10 (21.7%) were benign and 3 (6.5%) were nondiagnostic. These 3 patients underwent serial imaging, which did not reveal the progression of the IPN. Of these, two patients developed recurrent systemic metastatic H and N cancer over 12 months following treatment end date. Therefore, the IPN was thought unlikely to have been malignant. Age, gender, previous malignancies, smoking, stage, or primary site did not predict for malignancy in this setting [Table 2]. In patients found to have a confirmed histological diagnosis of malignancy on IPN, 57.6% (n = 19) were squamous cell lung cancer, 30.3% (n = 10) were nonsquamous cell lung cancer, and 12.1% (n = 4) were metastasis from other primaries based on clinicopathological features.
|Table 2: Clinical characteristics of patient with incidental pulmonary nodules and histological diagnosis|
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The remaining 264 (85.2%) patients did not have a biopsy taken, of which 244 (92.4%) were not thought to be clinically or radiologically suspicious; 10 (3.8%) had a poor performance status; and 10 (3.8%) for other reasons. Of the 244 patients in which the IPN was thought not to be clinically or radiologically suspicious, pulmonary metastases occurred in 10 patients (4.1%). In 6 of these patients, the DFS was <6 months, suggesting the IPN could have been a metastasis from the outset.
Recurrence of head-and-neck squamous cell cancer (HNSCC) occurred in 82 (26.5%) of our IPN cohort. Loco-regional recurrence occurred in 45 patients (54.9%), lung metastasis occurred in 30 patients (36.6%), and systemic metastasis without lung involvement occurred in 7 patients (8.5%). A total of 91 (29.4%) patients died with the cause of death secondary to progressive H and N cancer in 59.3% of patients, other malignancy in 13.2%, nonmalignant causes in 24.2%, and unknown in 3.3%.
The mean OS was 48 months (95% confidence interval [CI]: 44–51). Increased risk of mortality was associated with advanced age (hazards ratio [HR] 1.04 [1.02–1.06]; P < 0.001); and immunosuppression (HR 2.15 [1.18–3.95]; P = 0.013). The mean OS for patients histologically shown to have a malignant IPN was 16.7 months (95% CI: 12–21). Gender, primary site, history of previous malignancies, and histology did not affect OS.
ECOG performance status was a strong indicator of shorter OS rates [Figure 4] with ECOG grade 0 patients surviving on average 47 months (95% CI: 42–51) while ECOG grade 3 patients survive an average of 9 months (95% CI: 7–10).
| Discussion|| |
With the increasing availability and sophistication of medical imaging techniques such as high-resolution CT and fluorodeoxygenase PET-CT, the detection of IPN is increasingly common in patients undergoing staging for newly diagnosed cancer. HNSCC patients share similar risk factors (cigarette smoking) to those with primary lung cancer. While the incidence and outcomes for patients undergoing lung cancer screening is well known little is known in this specific HNSCC population. From a smaller study assessing 100 consecutive patients seen in a H and N MDM, 11% had IPNs on staging CT. In our study, 12.5% of all patients discussed in the H and N MDM were found to have an IPN suggesting that the incidence is relatively common in this select patient group. Ninety-seven of the 310 patients (31.3%) with IPN had a history of previous malignancy. Of these, 34 (35.1%) had previous skin SCCs or melanomas, which have a high incidence in the Australian population. Thirty (30.9%) had a recurrence of a H and N SCC, 10 (10.3%) had a previous hematological malignancy, and 23 (23.7%) had a previous malignancy from other primaries (colorectal, prostate, breast, bladder, cervical, or renal cell).
Despite the prevalence of IPN in H and N cancer patients, the incidence of malignancy in this select patient group remains unknown. In our study, of those 46 patients that had a radiologically suspicious IPN and tissue biopsy was attempted, the risk of a synchronous second malignancy or metastatic disease was high at 74%. The most common reason for not obtaining a tissue biopsy was that the IPN was not deemed clinically/radiologically suspicious (92%). Of these patients, metastatic lung recurrence was low (4.1%), suggesting a high negative predictive value and concordance with clinical judgment and evaluation in this single-institution setting.
Currently, there are no evidence-based guidelines to inform which of these patients with IPN need more regular imaging surveillance and follow-up, and which can be safely disregarded. In the MDM, treating teams rely on radiological parameters to assess which patients to select for biopsy and further management. Clinical and pathological predictors have not been studied in this select group previously. Of those patients who had a biopsy attempted, age, gender, previous malignancy, smoking status, history of immunosuppression, primary site, and clinical stage of disease did not predict for malignancy. Increasing age, active smoking, and a history of immunosuppression did predict a poorer prognosis.
This comprehensive retrospective study includes analysis from a large sample size of 2489 patients attending a busy multidisciplinary the H and N meeting in Brisbane, Australia. Limitations to our study include the retrospective nature of the analysis, the low incidence of biopsy-proven H and N malignancies from those patients who had an attempt at tissue diagnosis, and the subsequent statistical power to detect a difference in clinicopathological predictors was limited.
Our study demonstrates that IPN is a common phenomenon in H and N cancer patients undergoing staging of their cancer. The majority of IPN found in patients with primary H and N cancers are likely benign with an indolent outcome. The presence of nonsuspicious IPN should not unduly influence the otherwise curative intent of treatment for these patients. Further radiological evaluation of IPN characteristics to help better define more suspicious nodules in this patient population is currently underway and should help to better stratify both the diagnostic workup of IPN and overall patient management. A multidisciplinary approach to the evaluation of an IPN should occur on a case by case basis in this patient group. The low incidence of malignant IPN demonstrates a good negative predictive value for not sampling nodules predicted to be likely benign based on radiological and clinical factors in a H and N MDT assessment at this single-institution study.
Leesa Wockener-QIMR Berghofer Medical Research Institute– For assistance in statistical analysis.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
This material has never been published and is not currently under evaluation in any other peer reviewed publication.
The permission was taken from Institutional Ethics Committee prior to starting the project. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]