Sarcopenia Increases the Risk of Major Organ Invasion in Patients with Papillary Thyroid Cancer


 While sarcopenia is associated with poor overall survival and cancer-specific survival in solid cancer patients, the impact of sarcopenia on clinicopathologic features that can influence conventional papillary thyroid cancer (PTC) prognosis remains unclear. To investigate the impact of sarcopenia on aggressive clinicopathologic features in PTC patients, prospectively collected data on 305 patients who underwent surgery for PTC with preoperative staging ultrasonography and bioelectrical impedance analysis were retrospectively analyzed. Nine sarcopenia patients showed more patients aged 55 or older (p = 0.022), higher male proportion (p < 0.001), lower body-mass index (p = 0.015), higher incidence of major organ invasion (p = 0.001), higher T (p = 0.002) stage, higher TNM (p = 0.007) stage, and more tumor recurrence (p = 0.023) compared to the non-sarcopenia patients. Unadjusted and adjusted logistic regression analyses showed that sarcopenia (odds ratio (OR) 9.936, 95% confidence interval (CI) 2.052–48.111, p = 0.004), tumor size (OR 1.048, 95% CI 1.005–1.093, p = 0.027), and tumor multiplicity (OR 3.323, 95% CI 1.048–10.534, p = 0.041) significantly increased the risk of major organ invasion. Therefore, sarcopenia in PTC patients should raise suspicion for a more locally advanced disease and direct appropriate management.


Introduction
Sarcopenia is the age-related loss of skeletal muscle mass and function, which is associated with metabolic, physiologic, and functional impairments. 1,2 Clinically, sarcopenia is identi ed by low muscle strength as well as low muscle quantity and quality. 2 Such changes in body composition can impact an extensive variety of disease processes, such as cardiac disease, respiratory disease, as well as some malignancies. [3][4][5][6] In oncology, severe sarcopenia may occur in cancer patients with profound weight loss, particularly of the skeletal muscle. 7,8 A high prevalence of sarcopenia has been reported in gastric cancer (57%), advanced hepatocellular carcinoma (HCC) (27.5%), and in metastatic renal cell carcinoma (RCC) (29%). [9][10][11] Poor overall survival and poor cancer-speci c survival have been associated with sarcopenia in breast cancer, HCC, RCC, and gastrointestinal tract cancer, as well as increased chemotherapy toxicity and postoperative complications in various solid cancers. 4,12−14 However, sarcopenia has not been associated with poor survival in soft tissue sarcoma, 14 suggesting that these associations may vary according to the speci c cancer type.
In thyroid cancers, the DECISION trial showed a signi cant association between sorafenib and reduced muscle mass in advanced differentiated thyroid cancer. 15 However, past studies have not explained whether sarcopenia can act as an aggressive clinicopathologic feature that potentially affects the prognosis of conventional papillary thyroid cancer (PTC).
Therefore, this study aimed to investigate the potential implications of sarcopenia on aggressive clinicopathologic features in PTC patients.

Baseline characteristics
Baseline clinicopathologic characteristics of the 305 patients with conventional PTC are summarized in

Clinicopathologic features of PTC in the sarcopenia group
Compared to the non-sarcopenia group, the sarcopenia group showed more patients older than 55 years of age (p = 0.022), higher male proportion (p < 0.001), lower BMI (p = 0.015), and more tumor recurrence (p = 0.023) ( Table 2). The sarcopenia group showed more major organ invasion (p = 0.001), high T stage (p = 0.002), and high overall TNM stage (p = 0.007) than the non-sarcopenia group. There were no signi cant differences in LN metastasis and disease-free survival between the two groups.

Discussion
In this study, sarcopenia was a signi cant risk factor for major organ invasion in PTC, and consequently a signi cant risk factor for more locally advanced disease. Sarcopenia was not signi cantly associated with disease-free survival in PTC.
Although signi cant associations between sarcopenia and adverse cancer outcomes have been suggested, 4 published literature about the potential impact of sarcopenia on PTC is scarce. Our study showed that despite the higher risk of locally advanced disease in PTC patients with sarcopenia, sarcopenia by itself was not signi cantly associated with disease-free survival. This may be explained in part by advancements in surgical techniques that increase the rate of complete resection, even in advanced ETE. 16, 17 The low incidence of tumor recurrence in our study may also be a contributing factor.
Our results showed that sarcopenia was signi cantly associated with major organ invasion, but not with LN metastasis. The association between sarcopenia and potential LN metastasis in various types of cancers remains controversial. 18-21 Sarcopenia has been shown to increase the risk of LN metastasis in colorectal cancer and advanced urothelial carcinoma, while no signi cant association has been found with resectable bile duct cancer or recurrent pancreas adenocarcinoma. [18][19][20][21] As with the association between sarcopenia and adverse cancer outcomes, the association between sarcopenia and LN metastasis also seems to depend on the speci c type of cancer. Preoperative diagnosis of sarcopenia may raise the suspicion of the clinician, radiologist, as well as the surgeon, for a more locally advanced disease and direct prompt and appropriate management.
In our study, BMI was not signi cantly associated with major organ invasion in PTC. While a previous Korean study suggested BMI as a signi cant risk factor for microscopic ETE and higher TNM stage, 22 another Korean study suggested that higher BMI was a signi cant risk factor for tumor multiplicity, but not for higher T stage, positive LN metastasis, nor ETE. 23 In a United States study, higher BMI was signi cantly associated with higher incidence of PTC, but with less tumor invasion and LN metastasis. 24 Evidently, any potential association between BMI and aggressive clinicopathologic features of PTC is variable. Differences in ethnicity, culture, and lifestyle that may in uence body composition, 2 as well as the application of previous versions of American Joint Committee on Cancer (AJCC) staging criteria may be the cause for these discrepant results.
We utilized BIA to assess body composition and to determine sarcopenia using SMI. BIA estimates skeletal muscle mass using whole-body electrical conductivity, and incorporates an affordable, widely available, and portable instrument with reproducible results. 2,25 Unlike other malignancies in which abdomen and pelvic CT scans are often included during routine staging work-up, measuring SMI on CT scans to assess sarcopenia in thyroid cancer may unnecessarily burden patients with more radiation exposure. Alternatively, BIA may be an easier, more affordable tool to diagnose sarcopenia in PTC, as demonstrated in our study. In addition, the assessment of sarcopenia may be of importance in treatment decisions for advanced or refractory thyroid cancer because sarcopenia is considered a contraindication or discouraging factor in tyrosine kinase inhibitor treatment. 15,26 There are several limitations to this study. First, an inherent bias owing to the retrospective analysis of prospectively obtained data was inevitable. Second, the low incidence of sarcopenia in our study was a major limiting factor in statistical analysis. Last, body composition analysis by BIA may yield inconsistent or discrepant results depending on different instrument brands, as well as different population characteristics. 2 Our study utilized cutoff values previously obtained with identical equipment in young, healthy Korean subjects. 27 Therefore, the ndings of this study may be limited to Korean patients. Further research that includes patients from more diverse populations may help clarify the potential impact of sarcopenia on the outcomes and clinicopathologic features of PTC patients.
In conclusion, sarcopenia is signi cantly associated with a higher risk of major organ invasion in conventional PTC. Sarcopenia in PTC patients should raise clinical, radiological, and surgical suspicion for a more locally advanced disease and direct appropriate management.

Methods
This prospective study was approved by the institutional review board at Severance Hospital (4-2013-0833), and was conducted in accordance with the Declaration of Helsinki as revised in 2013. Informed consent was obtained from all patients enrolled in this study.

Study population
From February 2014 to October 2015, a total of 2,717 patients aged 19 years or older underwent preoperative staging ultrasonography (US) at our institution. Patients who did not undergo preoperative BIA (n = 1,284) or thyroid surgery (n = 283) were excluded. Patients with benign pathology (including diffuse hyperplasia, adenomatous hyperplasia, follicular adenoma, Hurthle cell adenoma, Hashimoto's thyroiditis, lymphocytic thyroiditis, Grave's disease, hyalinizing trabecular tumor and branchial cleft cyst anomaly type II) (n = 98), PTC variants (follicular variant, oncocytic variant, diffuse sclerosing variant, and solid variant PTC) (n = 68), follicular carcinoma (n = 4), medullary carcinoma (n = 1), neuroendocrine tumor (n = 1), metastatic adenocarcinoma (n = 2), as well as papillary microcarcinoma (n = 671) were excluded. A total of 305 patients with a pathologically con rmed diagnosis of conventional PTC were eligible for nal analysis (Fig. 1). Disease-free survival was de ned as the time interval from the date of diagnosis to the last follow-up visit or the date of tumor recurrence.

Preoperative staging ultrasonography (US)
Preoperative staging US was performed by one of 17 radiologists (12 fellows with 1 or 2 years of experience and 5 faculties with 6 to 18 years of experience in thyroid US) using a 5-12 MHz linear transducer (iU22, Philips Medical Systems, Bothell, WA). Primary tumor and cervical LNs were evaluated and reviewed based on the 8th AJCC TNM classi cation. 28 Any LN with at least one suspicious US feature (focal or diffuse hyperechogenicity, presence of internal calci cation, cystic change, round shape, and chaotic or peripheral vascularity on Doppler US) was considered pathologic and was subsequently con rmed by either US-FNA or surgery.
Bioelectrical impedance analysis (BIA) All included patients underwent preoperative BIA. Multifrequency bioimpedance data was measured using In-Body 720 (Biospace, Seoul, South Korea) in a standardized manner for all patients who underwent thyroid surgery. In-Body 720 employs a direct segmental multi-frequency bioelectrical impedance (MF-BIA) analysis method using a tetrapolar 8-point tactile electrode system with 30 impedance measurements taken at 6 frequencies (1 kHz, 5 kHz, 50 kHz, 250 kHz, 500 kHz, 1000 kHz) and reactance evaluated by 15 impedance measurements at 3 frequencies (5 kHz, 50 kHz, 250 kHz) for each of the 5 body segments (right arm, left arm, trunk, right leg, and left leg). All measurements were carried out prior to surgery in all patients. Body fat mass, body fat percentage, muscle mass, skeletal muscle mass, visceral fat surface, waist-hip ratio and basal metabolic rate were measured to assess body composition. Furthermore, the outer circumference and fat thickness of various body compartments (neck, chest, abdomen, hip, arm, and thigh) were measured. Finally, the SMI (skeletal muscle mass/height 2 ) and BMI of each patient was analyzed using the aforementioned parameters. Sarcopenia was diagnosed according to sex-speci c cutoff values (two standard deviations below the mean) for SMI that were suggested in a previous study of a healthy Korean population. 27 Obesity was categorized according to the BMI as follows: underweight (< 18.5 kg/m 2 ), normal weight (18.5 − 22.9 kg/m 2 ), overweight (23.0 − 24.9 kg/m 2 ), obesity (25.0 − 29.9 kg/m 2 ) and severe obesity (≥ 30 kg/m 2 ) according to the World Health Organization guidelines for Asians. 29 Thyroid surgery and pathologic diagnosis All total thyroidectomy at our institution routinely included bilateral central compartment LN dissection (CCND), which included the paratracheal, pretracheal, and prelaryngeal LNs. All hemithyroidectomy surgeries routinely included unilateral CCND. Selective lateral compartment LN dissection was performed only when lateral LN metastasis was suspected on either preoperative US and US-FNA, or during intraoperative observations. The lateral compartment included level II, III, IV, and V LNs. Pathologic tumor size, tumor multiplicity, ETE, and the presence of central and/or lateral LN metastasis on nal surgical pathology reports were reviewed for analysis. T staging was as follows: 1) T1, tumor size smaller than 20 mm in greatest dimension limited to the thyroid; 2) T2, tumor size larger than 20 mm but equal to or smaller than 40 mm in greatest dimension limited to the thyroid; 3) T3a, tumor size larger than 40 mm but limited to the thyroid; 4) T3b, tumor of any size with gross strap muscle invasion; 5) T4, tumor of any size with invasion of major neck structures such as the larynx, trachea, esophagus, recurrent laryngeal nerve, prevertebral fascia or encasing major vessels. N staging was as follow: 1) N0, no evidence of regional LN metastasis; 2) N1a, metastasis to level VI or VII (pretracheal, paratracheal, or prelaryngeal/Delphian, or upper mediastinal); 3) N1b, metastasis to unilateral, bilateral, or contralateral lateral neck LNs (levels I, II, III, IV, or V) or retropharyngeal LNs. T3 and T4 were considered high T stages, and the overall TNM stages III and IV were considered as high TNM stages.

Statistical analysis
All statistical analyses were performed with commercial software (IBM SPSS Statistics, version 25.0; IBM Corp., Armonk, NY). The independent t-test or Mann-Whitney U test was performed to compare clinical and pathological variables for parametric and non-parametric continuous variables, respectively. Categorical variables were compared using the chi square test or Fisher's exact test. Logistic regression analyses were performed to estimate unadjusted ORs with 95% CIs to elucidate the association between sarcopenia and aggressive tumor features (such as tumor multiplicity, ETE, LN metastasis, T stage, TNM stage, and tumor recurrence). Unadjusted logistic regression analysis was performed to explore the potential implications of sarcopenia on those aggressive tumor features. For variables that were signi cantly associated with sarcopenia on unadjusted analysis, a subsequent adjusted logistic regression analysis was performed that included the other clinicopathologic variables to obtain ORs and 95% CIs. A p-value of less than 0.05 was considered statistically signi cant.

Declarations Competing Interests Statement
The authors declare no competing interests.