Hurthle cell carcinoma - Wiley Online Library

Original Article

Hurthle Cell Carcinoma A Population-Level Analysis of 3311 Patients Paolo Goffredo1; Sanziana A. Roman, MD2; and Julie A. Sosa, MD, MA2

BACKGROUND: Hurthle cell carcinoma (HCC) is an uncommon and more aggressive thyroid cancer. To date, there is a paucity of data at a population level. In this study, demographic, clinical, and pathologic characteristics of HCC were investigated and compared with other types of differentiated thyroid cancers (ODTCs). The authors also evaluated disease-specific survival and compliance with American Thyroid Association (ATA) management guidelines from 2009. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database from 1988 to 2009 was used to obtain data on patients with thyroid cancer. Data analyses were performed using chi-square tests, analysis of variance, Kaplan-Meier analysis, binary logistic regression, and Cox proportional hazards regression. RESULTS: In total, 3311 patients with HCC and 59,585 patients with ODTC were identified. Compared with ODTC, HCC was more common among men (31.1% vs 23.0% for ODTC; P < .001) and among older patients (mean age, 57.6 years vs 48.9 years for ODTC; P < .001). Patients with HCC presented with higher SEER disease stage (P < .001), and their tumors were larger (36.1 mm vs 20.2 mm for ODTC; P < .001). Fewer patients underwent total thyroidectomy (P ¼ .028). Both overall and disease-specific survival were lower for patients with HCC (P < .001), and neither improved over the last 2 decades (P ¼ .689). After adjustment, age 45 years, not undergoing surgery, and metastatic disease were strongly associated with a worse prognosis (hazard ratio >3.0). Compliance with recommended surgical treatment according to ATA guidelines was lower among patients with HCC aged 65 years (odds ratio [OR], 1.43; P ¼ .002) and among unmarried patients (OR, 1.29; P ¼ .004). Predictors of noncompliance with ATA guidelines for treatment with radioactive implants or radioisotopes were age 65 years (OR, 1.31; P ¼ .017), diagnosis between 1988 and 1997, no surgery, and partial thyroidectomy (OR, 1.81, 19.48, and 4.02, respectively; P < .001). CONCLUSIONS: HCC has more aggressive behavior and compromised survival compared with ODTC. The current results indicated that it may be important to consider a different staging system or C 2012 American Cancer Society. separate practice guidelines. Cancer 2013;119:504-11. V KEYWORDS: Hurthle cell carcinoma, differentiated thyroid cancer, Surveillance, Epidemiology, and End Results, survival, guidelines, compliance.

INTRODUCTION Hurthle cells, or oxyphilic cells, are large polygonal cells with distinct borders derived from thyroid follicular epithelium. They contain abundant granular cytoplasm because of an excess of mitochondria and a large nucleus with a prominent nucleolus.1 Hurthle cell carcinoma (HCC), also known as oncocytic or oxyphilic carcinoma, is defined as a thyroid malignancy consisting of at least 75% Hurthle cells and differs from its benign counterpart (Hurthle cell adenoma) by the presence of capsular and/or vascular invasion.2 HCC has been classified by the World Health Organization as a variant of follicular cancer and is treated as such according to the American Thyroid Association (ATA) management guidelines for patients with thyroid nodules and differentiated thyroid cancer.3,4 It has been noted that patients with HCC have a high propensity for lymph node and distant metastases, late recurrence, and a decreased avidity for I131, making it a more aggressive tumor than other differentiated thyroid cancers (ODTCs).2,5,6 HCC represents from 3% to 7% of all differentiated thyroid cancers.7 Most experience with HCC in the literature comes from a small number of single-institutional series; to our knowledge, the only large-scale studies on HCC are based on data that are more than a decade old.8,9 The objectives of our current study were to compare the outcomes between patients with HCC and patients with ODTC and to evaluate the prognostic factors associated with HCC survival at a population level. We hypothesized that HCC has a more aggressive course than ODTC and that it may warrant consideration for separate management guidelines. Corresponding author: Julie A. Sosa, MD, MA, 333 Cedar Street FMB 130B, Divisions of Endocrine Surgery and Surgical Oncology, Department of Surgery, Yale University School of Medicine, New Haven, CT 06520; Fax: (203) 785-2498; [email protected] 1

Milano-Bicocca University, Monza, Italy; 2Department of Surgery, Yale School of Medicine, New Haven, Connecticut.

All authors 3 authors contributed to 1) conception and design or analysis and interpretation of data, 2) drafting the article or revising it critically for important intellectual content, and 3) final approval of the version to be published. We acknowledge Risa Wong; Michael Sullivan, MD; and Hadiza Kazaure, MD, for statistical help. DOI: 10.1002/cncr.27770, Received: June 9, 2012; Revised: July 10, 2012; Accepted: July 11, 2012, Published online August 14, 2012 in Wiley Online Library (wileyonlinelibrary.com)

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Hurthle Cell Carcinoma/Goffredo et al

MATERIALS AND METHODS Data Sources and Study Patients

The Surveillance, Epidemiology, and End Results (SEER) database was used to identify patients who had a diagnosis of HCC and ODTC; ODTC was defined as papillary and follicular thyroid cancers.10 This database uses the International Classification of Diseases for Oncology, Third Edition (ICD-O-3) as the reference for histology coding (HCC, code 8290; papillary thyroid cancer, codes 8050, 8340-8344, and 8350; follicular thyroid cancer, codes 8330-8332, 8335, and 8337).11 Data were collected from 18 registries (San Francisco-Oakland, Connecticut, metropolitan Detroit, Hawaii, Iowa, New Mexico, Utah [from 1973], Seattle-Puget Sound [from 1974], metropolitan Atlanta [from 1975], Alaska, San Jose-Monterey, Los Angeles, rural Georgia [from 1992], greater California [excluding San Francisco, Los Angeles, and San Jose]; Kentucky, Louisiana, New Jersey, and greater Georgia [excluding Atlanta and Rural Georgia; from 2000]); collectively, these regions represent nearly 28% of the US population. The SEER population is comparable to that of the general United States with regard to poverty and education level, but it tends to be more urban and has a higher proportion of foreign-born individuals.12 Patients who were diagnosed with thyroid cancer between 1973 and 1987 were excluded because of a lack of data concerning surgical procedures and the use of radioactive implants or radioisotopes (RAI) use before 1988. Demographic variables included patient sex, age at diagnosis, race, marital status, year of diagnosis, and survival status as of December 31, 2009. Age at diagnosis was classified into 3 groups: ages 18 to 44 years, 45 to 64 years, and 65 years. Race was recoded into white, black, and other (American Indian, Alaska Native, Asian, Pacific Islander, and other unspecified); marital status was coded as married and domestic partner, single, divorced, widowed or separated, and unknown. Year of diagnosis was treated as a categorical variable divided into the following intervals: 1988 to 1997, 1998 to 2006, and 2007 to 2009; these intervals were chosen because of SEER coding changes between 1997 and 1998 and the first release of ATA guidelines for the management of thyroid nodules and differentiated thyroid cancer in 2006. Clinical variables of interest were the number of primary tumors, thyroid surgery, and radiation therapy. The number of primary tumors was grouped into 1, 2, and 3. Surgery was divided into 3 subcategories: no surgery, partial thyroidectomy (SEER codes 10-20 [1988-1997] and 20-30 [1998-2009]), and total thyroidectomy (SEER codes 30-70 [1998-1997] and 40-80 [1998-2009]). RadiCancer

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ation therapy was categorized into 5 groups: none, external-beam radiation therapy, RAI, a combination of external-beam radiation therapy and radioactive implants or radioisotopes (both), and other/unknown. RAI administration was binary: no (none, refused by patient, or external-beam radiation therapy only) and yes (including radioisotopes, radioactive implants, or both for survival analysis and ‘‘radiation recommended but unknown if administered’’ for compliance analysis). Pathologic information included SEER stage, tumor size, extent of tumor, and lymph nodes examined. The SEER staging system is based on 3 levels of invasion: The tumor is described as local if it is confined entirely to the thyroid, regional if it extends beyond the thyroid into surrounding tissues or has metastasized to regional lymph nodes, and distant if metastases to extracervical lymph nodes or organs are present. According to the American Joint Commission on Cancer (AJCC), tumor size was subdivided into 3 groups (2.0 cm, 2.1-4.0 cm, 4.1 cm); tumors >15.0 cm were excluded because of the possibility of coding error.12 Tumor extent was classified into intrathyroidal, extrathyroidal, and unknown. The number of lymph nodes examined was categorized as none (no lymph nodes were examined), negative (lymph nodes examined were all negative), or positive. American Thyroid Association Management Guidelines Recommendations

According to ATA management guidelines recommendation 26, all patients with differentiated thyroid cancer should undergo total or near total thyroidectomy unless there are contraindications to surgery.5 Lobectomy alone may be sufficient for small (