ORIGINAL ARTICLE

Effect of a second primary thyroid carcinoma on patients with head and neck squamous cell carcinoma Anthony M. Tolisano, MD,1* Christopher Klem, MD,1 Michael B. Lustik, MS,2 Joseph C. Sniezek, MD,3 J. Blake Golden, MD1 1

Department of Otolaryngology, Tripler Army Medical Center, Honolulu, Hawaii, 2Department of Clinical Investigations, Tripler Army Medical Center, Honolulu, Hawaii, 3Division of Head and Neck Surgery, Swedish Cancer Institute, Seattle, Washington.

Accepted 6 May 2015 Published online 15 July 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/hed.24121

ABSTRACT: Background. The purpose of this study was to characterize the timing, histology, and behavior of second primary thyroid carcinoma (SPTC) developing after a diagnosis of head and neck squamous cell carcinoma (HNSCC). Methods. We conducted a retrospective review of the Surveillance, Epidemiology, and End Results (SEER) 9 database. Results. Patients with HNSCC who develop SPTC die 1.6 times sooner than those without SPTC. This effect is only seen if SPTC presents >6 months after diagnosis of HNSCC. Models were adjusted for age, sex, year of diagnosis, and location of HNSCC. There was no effect of prior

radiation therapy on either mortality rates or time to development of thyroid cancer in patients with SPTC. The type of thyroid carcinoma that developed was similar between cohorts. Conclusion. The development of SPTC in patients with HNSCC results in C 2015 Wiley Periodicals, Inc. Head decreased overall length of survival. V Neck 38: E890–E894, 2016

INTRODUCTION

relationships,7–10 to our knowledge, no study has investigated the effect of a second primary thyroid carcinoma (SPTC) on patients with HNSCC. This relationship is important as the incidence of thyroid carcinoma is increasing. The National Cancer Institute estimates that there will be roughly 63,000 new cases of thyroid malignancy diagnosed in 2014, representing 3.8% of all new cancer cases in the United States.11 Risk factors for developing thyroid cancer include a family history of thyroid cancer and exposure to ionizing radiation.12 Survival rates are typically excellent for this disease, as 97.8% of patients are alive at 5 years.13 Nevertheless, it is unclear if patients who develop an SPTC after HNSCC have the same cross-section of “low-risk” thyroid carcinomas as that of the general population. This study, therefore, sought to characterize the timing, histology, and behavior of thyroid carcinoma developing after a diagnosis of HNSCC using the Surveillance, Epidemiology, and End Results (SEER) 9 database.

Cancer of the head and neck accounts for roughly 3% to 5% of human malignancies, of which squamous cell carcinoma is the most common.1,2 Mortality is stagedependent, and nodal metastasis represents the single most important prognostic factor.3 With improvements in detection, treatment, surveillance, and support, many individuals live long lives after receiving their initial diagnosis. In fact, survival rates for patients with head and neck squamous cell carcinoma (HNSCC) have steadily risen over the last several decades. Between 2001 and 2010, death rates from oral cavity and oropharyngeal cancer decreased by 1.3% per year, and death rates from laryngeal cancer decreased by 2.2% per year.4,5 As such, the impact on survival from developing a second primary carcinoma becomes increasingly important. The incidence of developing a second primary carcinoma after HNSCC is roughly 4% per year, with upper aerodigestive tract and lung cancers being most common.6 Although a number of studies have evaluated these

KEY WORDS: thyroid cancer, second primary malignancy, head and neck squamous cell carcinoma, Surveillance, Epidemiology, and End Results (SEER), survival

MATERIALS AND METHODS Database and patient selection

*Corresponding author: A. M. Tolisano, Department of Otolaryngology, Tripler Army Medical Center, 1 Jarrett White Road, Honolulu, HI 96859. E-mail: [email protected] Disclosure: The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the U.S. Government. This work was presented at the 2014 International Federation of Head and Neck Oncologic Societies 5th World Congress and American Head and Neck Society Annual Meeting, New York, New York, July 26–30, 2014.

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The SEER database is maintained by the National Cancer Institute and collects data on all cancer cases reported to its population-based cancer registries across the United States. The SEER-9 registry contains longitudinally collected data between the years 1973 and 2010 and covers 28% of the U.S. population. The Multiple Primary-Standardized Case listing session was queried to extract all patients with HNSCC who went

SECOND

PRIMARY THYROID CARCINOMA

TABLE 1. Demographics.

HNSCC/SPTC (n 5 117)

Race Black White Other/unknown Sex Male Female Age at HNSCC dx, y Age at thyroid cancer dx, y Time to SPTC dx, mo Minimum p25 Median p75 Maximum

Thyroid carcinoma only (n 5 62,539)

HNSCC only (n 5 95,556)

No. of patients

%

No. of patients

%

No. of patients

%

9 100 8

8 85 7

11,239 80,045 4272

12 84 4

3546 51,777 7216

6 83 12

80 37 Mean 59 62 36 1 4 13 40 386

68 32 SD 13 13 60 – – – – –

69,777 25,779 Mean 63 – – – – – – –

73 27 SD 12 – – – – – – –

15,311 47,228 Mean – 47 – – – – – –

24 76 SD – 16 – – – – – –

Abbreviations: HNSCC, head and neck squamous cell carcinoma; SPTC, second primary thyroid carcinoma; dx, diagnosis; p25, 25th percentile; p75, 75th percentile.

on to develop thyroid carcinoma. Patients who did not develop thyroid carcinoma were also collected for comparison. Only cases with malignant behavior and known age were included. Autopsy only and death certificate only cases were excluded from this analysis. Cohort selection criteria were as follows: first primary sites of “tongue,” “floor of mouth,” “gum and other mouth,” “tonsil,” “oropharynx,” “hypopharynx,” “other oral cavity and pharynx,” and “larynx”; squamous cell histologies (ICD-O-3 Hist/behav, malignant 8051–8078/3 and 8083– 8084/3); subsequent malignancy site of “thyroid.” For patients who developed >1 thyroid cancer after HNSCC, the first occurrence was used for analysis. The registry was then queried for all thyroid malignancies over this same time period. Selection criteria were as follows: site and morphology behavior recode “malignant”; site recode ICD-O-3/World Health Organization 2008 “thyroid.” For patients with multiple occurrences of thyroid cancer, the first occurrence was used for analysis. The data used in this study are public access and deidentified, and therefore this study was granted exemption from institutional review board oversight by Tripler Army Medical Center.

and diagnosis year. The effect of disease stage was examined, but this was only available for 16% of the cases. Post hoc analyses were conducted to assess the effect of SPTC stratified by time between HNSCC and SPTC diagnoses (6 months and >6 months). A significance level of 0.05 was used for all analyses, which were conducted using SAS software version 9.2 (SAS Institute, Cary, NC).

RESULTS Demographics Table 1 outlines the baseline characteristics of patients with HNSCC with and without SPTC, as well as those patients with thyroid carcinoma only. A total of 117 patients were identified with HNSCC and SPTC

Statistical analysis Cox proportional hazard models were performed to estimate hazard ratios (HRs) to evaluate the effect of SPTC on survival for patients with HNSCC and to assess the effect of prior HNSCC on survival for patients with thyroid cancer. Survival time was referenced to the date of diagnosis of the first tumor. Time to SPTC was treated as a time-dependent covariate for analysis and calculated as the date of SPTC diagnosis minus the date of HNSCC diagnosis. Survival times for patients alive at most recent contact were treated as censored observations for analysis. Models were adjusted for age, sex, location of HNSCC,

FIGURE 1. Time to onset of second primary thyroid carcinoma.

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FIGURE 2. All-cause mortality rates.

(HNSCC/SPTC), 95,556 had HNSCC only, and 62,539 patients had thyroid carcinoma only. Sex and race distributions were similar between the HNSCC/SPTC and HNSCC only groups, but patients who developed SPTC were 4 years younger on average when diagnosed with HNSCC than those who never developed SPTC (59 vs 63; p < .001). Compared to the thyroid carcinoma only group, patients with HNSCC were more likely to be men (roughly 7 in 10 patients with HNSCC were men, whereas nearly 8 in 10 thyroid carcinoma only patients were women) and were 16 years older on average when first diagnosed with cancer (63 vs 47; p < .001). For patients with HNSCC/SPTC, nearly one third of patients developed SPTC within 6 months of their HNSCC diagnosis (Figure 1), with a median time to diagnosis of 13 months (interquartile range, 4–40 months) and a maximum of 32 years. A much higher percentage of patients in the HNSCC subset died than in the thyroid carcinoma only subset. All-cause mortality was 76% for patients with HNSCC versus 18% for thyroid carcinoma only patients. Diseasespecific mortality for thyroid cancer was 4%. Of the 117 patients with HNSCC who developed SPTC, a total of 66 died (56%; Figure 2). Table 2 presents the cause of death in patients with HNSCC/SPTC. The most common cause of death was due to laryngeal cancer. Eight of the 66 deaths (12%) were due to thyroid cancer.

Histology The type of HNSCC that patients suffered from was similar between those patients who did and did not develop SPTC. Laryngeal cancer was the most common primary site, followed by tongue, gum, tonsil, and floor of mouth (Table 3). Table 4 outlines the type of thyroid cancer that patients developed. In both the SPTC and thyroid carcinoma only cohorts, papillary thyroid cancer was most common, followed by follicular, H€urthle cell, and medullary types. Chi-square analysis revealed a significant difference between the histology in the thyroid cohorts (p 5 .007), however, this was driven by variation in the “other” category (8.5% of SPTC vs 2.9% of thyroid carcinoma only). This “other” category included a broad cross-section of both generic diagnoses (eg, carcinoma, not otherwise specified; adenocarcinoma, not otherwise specified; E892

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neoplasm; and malignant) and rare histological subtypes (eg, nonencapsulated sclerosing carcinoma; spindle cell carcinoma; squamous cell carcinoma; and giant cell carcinoma).

Effect of radiation therapy Eighty-five of the 117 patients with HNSCC/SPTC (73%) received radiation therapy. No difference in mortality rates was noted (HR 5 1.51; 95% confidence interval [CI] 5 0.84–2.71; p 5 .17). Additionally, no difference in time to development of thyroid carcinoma was noted.

Mortality Based on a Cox proportional hazards survival analysis for patients with HNSCC, the all-cause mortality rate for patients with SPTC was about 1.6 times the rate for patients with HNSCC with no thyroid cancer (HR 5 1.58;

TABLE 2. Cause of death for patients with head and neck squamous cell carcinoma/second primary thyroid carcinoma. Cause of death

Larynx Miscellaneous malignant cancer Diseases of the heart Thyroid Lung and bronchus Other cause of death Tongue Cerebrovascular disease Gum and other mouth Anus, anal canal, and anorectum Chronic liver disease and cirrhosis Hypertension without heart disease Non-Hodgkin lymphoma Oropharynx Other infectious and parasitic disease Other oral cavity and pharynx Pancreas Prostate Stomach Stomach and duodenal ulcers Suicide and self-inflicted injury Total

No. of patients

%

13 10 8 8 4 4 3 2 2 1 1 1 1 1 1 1 1 1 1 1 1 66

19.7 15.2 12.1 12.1 6.1 6.1 4.5 3.0 3.0 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 100

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TABLE 3. Head and neck squamous cell carcinoma cancer site. HNSCC/SPTC Site

Larynx Tongue Gum Tonsil Floor of mouth Hypopharynx Oropharynx Other Total

PRIMARY THYROID CARCINOMA

TABLE 5. Hazard ratios for mortality.

HNSCC only

No. of patients

%

No. of patients

%

54 24 17 10 7 3 2 0 117

46 21 15 9 6 3 2 0 100

34,045 19,256 12,047 9866 8640 7326 2335 2041 95,556

36 20 13 10 9 8 2 2 100

All patients with HNSCC SPTC vs no SPTC Time to SPTC dx after HNSCC 6 mo >6 mo All thyroid patients Prior HNSCC vs no prior HNSCC

HR

95% LB

95% UB

p value

1.58

1.24

2.01

< .001

1.13 1.86

0.71 1.40

1.79 2.46

.616 < .001

3.46

2.71

4.41

< .001

Abbreviations: HNSCC, head and neck squamous cell carcinoma; HR, hazard ratio; UB, upper bound; LB, lower bound; SPTC, second primary thyroid carcinoma; dx, diagnosis. Abbreviations: HNSCC, head and neck squamous cell carcinoma; SPTC, second primary thyroid carcinoma.

DISCUSSION 95% CI 5 1.24–2.01; p < .001; Table 5). This result was adjusted for age at diagnosis, sex, HNSCC site, and diagnosis year. Further, when the data was analyzed by 10year intervals for year of diagnosis (1973–1985, 1986– 1998, and 1999–2010), the calculated HRs were not statistically significant (p 5 .2657). The result was no longer significant after also adjusting for disease stage (HR 5 1.38; 95% CI 5 0.80–2.38; p 5 .247), but this may be partly because only 16% of the cases had a reported disease stage, including only 38 patients who developed SPTC within 6 months of HNSCC/SPTC. For patients who developed SPTC within 6 months from their diagnosis of HNSCC, the all-cause mortality rate was not significantly higher than the rate for patients who did not develop thyroid cancer (HR 5 1.13; 95% CI 5 0.71–1.79; p 5 .616). In contrast, for patients who developed SPTC >6 months after their diagnosis of HNSCC, the all-cause mortality rate was nearly 1.9 times the rate for patients who did not develop thyroid cancer (HR 5 1.86; 95% CI 5 1.40–2.46; p < .001). Among all patients with thyroid cancer, the all-cause mortality rate for those who also had a prior history of HNSCC was roughly 3.5 times the rate for patients with thyroid carcinoma only (HR 5 3.46; 95% CI 5 2.71–4.41; p < .001; adjusted for age at diagnosis, sex, and diagnosis year). The HR increased to 4.41 (95% CI 5 2.60–4.49; p < .001) after also adjusting for disease stage for the thyroid cancer.

TABLE 4. Thyroid cancer histology. HNSCC/SPTC

Thyroid carcinoma only

Histology

No. of patients

%

No. of patients

%

Papillary Follicular Other H€urthle cell Medullary Anaplastic Total

68 33 10 5 1 0 117

58.1 28.2 8.5 4.3 0.9 0.0 100.0

37,277 19,808 1841 1701 1520 392 62,539

59.6 31.7 2.9 2.7 2.4 0.6 100.0

Abbreviations: HNSCC, head and neck squamous cell carcinoma; SPTC, second primary thyroid carcinoma. p 5 .007 based on chi-square.

Patients who live long lives with HNSCC have a higher risk of developing a second primary malignancy. In order to comprehensively treat patients with HNSCC, it is essential to consider the impact of second primary malignancies on patient survival. Second primary malignancies represent the most common cause of non-HNSCC death, and recent reviews have identified lung, esophagus, and colorectal cancer as the 3 most deadly.14,15 Of course, there are many other possible second primary malignancies. SPTC is of particular concern to the head and neck surgeon for several reasons. First, thyroid cancer is very commonly encountered and its incidence is increasing. Second, treatment for thyroid cancer is within the scope of practice for head and neck surgeons. Third, early identification and treatment of SPTC could potentially impact survival. Of course, most thyroid cancers are welldifferentiated with a comparatively low risk of death.16 The extent of management in these patients is already steeped in controversy.17,18 Despite this, there are several characteristics of patients with post-HNSCC that cause them to differ from the general population with respect to potential thyroid cancers. These patients undergo more frequent and vigorous physical examination of the head and neck in the years after HNSCC diagnosis. Surveillance imaging with CT, positron emission tomography/CT, MRI, and ultrasound have become more readily available, allowing earlier detection of thyroid nodules. Finally, treatment regimens for HNSCC often include neck irradiation, which is a wellknown risk factor for thyroid cancer development. Several questions arise, therefore, regarding a new diagnosis of thyroid cancer in patients with a history of HNSCC. To what extent does a second primary thyroid carcinoma affect survival? Do these thyroid cancers behave the same as those diagnosed in the absence of prior HNSCC? Ultimately, how does this affect treatment? This study revealed that the all-cause mortality rate for patients with HNSCC/SPTC was about 1.6 times the rate for patients with HNSCC with no thyroid cancer. Interestingly, this difference in mortality was only present in patients for whom SPTC developed >6 months after HNSCC. This cannot be explained by exposure to external beam radiation therapy in the treatment of HNSCC, as this effect was not shown to demonstrate a significant difference in this study. It is important to note, however, HEAD & NECK—DOI 10.1002/HED

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that the sample size was relatively small and, thus, may not have had sufficient power to detect a difference. Furthermore, the data were limited regarding radiation doses used in treatment, and this potentially important subgroup analysis was unable to be performed. On the other hand, differences in the type of thyroid cancer histology were shown, and this was due to a marked difference in the “other” category. As mentioned, the “other” category included a broad cross-section of both generic diagnoses and rare histological subtypes. It is possible that patients who develop SPTC after HNSCC are at risk for rarer forms of thyroid cancer. Another possibility is that squamous cell carcinoma attributed to the thyroid may actually have been a misdiagnosed level VI lymph node from the previous head and neck primary. Regardless, the database is incomplete with respect to thyroid pathology and therefore it is difficult to assess the effect of thyroid histology on overall outcomes. Furthermore, it should be noted that the database does not discriminate with respect to incidentally discovered thyroid cancers or micro cancers. There were several weaknesses in this study. As with all research that draws upon the SEER database, there were significant gaps in staging data. This limited more detailed analyses for both HNSCC and thyroid cancer. Detailed information on radiation dose and delivery was absent, as was chemotherapeutic data for the patients with HNSCC population. Additionally, as the data spans several decades, it is likely that the earliest record in our cohort (July 1973) received very different care than the most recent (May 2010). Over this time period, there have been significant advances in the treatment of head and neck cancer. Improved surgical techniques and instrumentation, more sophisticated imaging modalities, and increasingly elegant radiation delivery techniques have all contributed to the ongoing evolution of care for these patients. Despite this limitation, the calculated HRs were controlled for year of diagnosis. In conclusion, our study demonstrated that patients with HNSCC who develop SPTC die more quickly than

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patients with HNSCC with no thyroid cancer. This finding remains to be elucidated further with respect to its impact on surveillance and treatment of patients. Future prospective studies will be needed to clarify these important questions.

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Effect of a second primary thyroid carcinoma on patients with head and neck squamous cell carcinoma.

The purpose of this study was to characterize the timing, histology, and behavior of second primary thyroid carcinoma (SPTC) developing after a diagno...
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