Disease Burden and Outcome in Children and Young Adults With Concurrent Graves Disease and Differentiated Thyroid Carcinoma

Disease Burden and Outcome in Children and Young Adults With Concurrent Graves Disease and... Abstract Context Adults with differentiated thyroid cancer (DTC) and Graves disease (GD) demonstrate a greater reported disease burden and aggressive DTC behavior. To date, no studies have examined the impact and long-term outcome of concurrent GD and DTC (GD-DTC) in children and young adults. Design Single institution, retrospective longitudinal cohort study between 1997 and 2016. Participants One hundred thirty-nine children and young adults with DTC, diagnosed at median age 15 (range, 5 to 23) years, compared with 12 patients with GD-DTC, median age 18 (range, 12 to 20) years. Major Outcome Measures Patient demographics, preoperative imaging, fine needle aspiration (FNA) cytology, operative and pathological reports, laboratory studies, treatment, and subsequent 2-year outcomes. Results Compared with DTC, patients with GD-DTC were significantly older at the time of DTC diagnosis (P < 0.01). Patients with GD-DTC were more likely to exhibit microcarcinoma (P < 0.01), and 2 of 12 (17%) demonstrated tall cell variant papillary thyroid cancer (PTC) vs 2 of 139 (2%) in patients who had DTC alone (P = 0.03). Although patients with DTC showed greater lymphovascular invasion (60% vs 25%; P = 0.03), no group differences were noted in extrathyroidal extension, regional lymph node, and distant or lung metastasis. There were no group differences in the 2-year outcome for remission, persistent disease, or recurrence. Conclusions Concurrent DTC in pediatric patients with GD is not associated with a greater disease burden at presentation and shows no significant difference in 2-year outcomes compared with DTC alone. Similar to adults, microcarcinoma and tall cell variant PTC is prevalent in pediatric patients with GD-DTC. For patients who have GD-DTC with an identified nodule on ultrasound imaging prior to definitive therapy, FNA biopsy is recommended to guide definitive treatment. Graves disease (GD) is the most common cause of hyperthyroidism in children and accounts for 10% to 15% of all pediatric thyroid disease (1, 2). Similar to adults, most pediatric patients with GD are initially treated with antithyroid medications with the hope of achieving remission; however, pediatric patients often demonstrate a lower likelihood of achieving remission compared with adults (30% vs 50%, respectively) (3), and for many children and adolescents with GD, remission remains unattainable. For this reason, most pediatric patients with GD will require definitive therapy with radioactive iodine (RAI) therapy or surgery (2–4). An increased risk of differentiated thyroid cancer (DTC) in patients with GD has been previously reported (5, 6). Adults with GD have an estimated 10-fold higher risk of DTC compared with the general population, with the highest risk within the first 3 years after GD diagnosis (7, 8). In a subgroup of patients with GD, DTC is incidentally discovered on pathology review after thyroidectomy, most often as papillary thyroid microcarcinoma without invasion (8). We previously reported the utility of thyroid ultrasound in patients with GD with gland asymmetry, a palpable nodule, and/or pathologic cervical adenopathy followed by fine needle aspiration (FNA) biopsy of identified suspicious thyroid nodules prior to definitive therapy, particularly as thyroid ultrasound is an easy and efficient tool for identifying and selecting patients who may benefit from thyroidectomy rather than RAI (9). There is continued debate whether DTC in the setting of GD follows a more aggressive course in adult patients, with overall concern for higher mortality rates and a threefold increased risk of metastatic disease (10, 11). However, most studies in adults with concurrent GD and DTC are limited by retrospective cross-sectional design (5–7). Identified factors predictive of worse outcome in adults with concurrent GD and DTC include tumor size (>10 mm), multiplicity, extracapsular invasion, and clinical symptoms of cancer (12). To date, no previous studies have examined the impact and long-term outcome of concurrent GD and DTC in pediatric patients. We conducted a longitudinal cohort study comparing children and young adult patients diagnosed and treated with DTC to children and young adults diagnosed and treated with concurrent GD and DTC at the Children’s Hospital of Philadelphia (CHOP) Thyroid Center, a multidisciplinary, tertiary center with a large referral base. Our objective was to assess the extent of DTC and metastatic burden at diagnosis and overall outcome in children and young adults with concurrent GD compared with patients with DTC alone. Subjects and Methods We conducted a single-institution, retrospective longitudinal cohort study of children and young adults (age 5 to 25 years) from 1997 to 2016 who received care at the CHOP Thyroid Center, a multidisciplinary center compromised of members from the Divisions of Endocrinology, Oncology, Surgery, Otolaryngology, Radiology, Pathology, Social Work, and Behavioral Health. The study was fully approved by the CHOP Institutional Review Board with parent and/or participant consent for data collection. Study participants’ race was defined according to the National Institutes of Health categories. Data sources Clinical records, including outpatient visits, operative reports, and pathology reports, were reviewed. Data elements abstracted included date of birth, demographics (sex, age, and race), outpatient office visit records (Divisions of Endocrinology, Oncology, and Surgery), thyroid function, and antibody laboratory values, radiographic findings (ultrasound, MRI, and nuclear medicine scans), pathology results (cytology and histology), date of hospital admission and discharge, surgical procedure and intraoperative findings, postoperative laboratory values, postsurgical RAI, and DTC outcome. Papillary thyroid cancer (PTC) samples were classified in accordance with the 7th edition of the American Joint Committee cancer staging manual (13). The size of the carcinoma was determined by its largest dimension based on review of the gross pathology for nodules ≥1 cm and by direct microscopic measurements on the slides for nodules <1 cm. Tumors <1 cm were classified as microcarcinoma. PTC found on postoperative histopathological examination of excised thyroid tissue for the definitive surgical treatment of GD was considered incidental if (1) it was not visualized on preoperative thyroid ultrasound, (2) it was <1 cm in size, and (3) it not associated with extrathyroidal extension or lymph node metastasis (14). Study patients GD was defined based on clinical signs and symptoms, and laboratory values including suppressed TSH, elevated T3/T4 ratio, and elevated thyroid stimulating Ig (TSI) antibody titer. A thyroid ultrasound was performed when a nodule was suspected on physical examination, and, since 2010, for all patients with GD as part of their evaluation for definitive therapy. Surgery was recommended as part of definitive therapy for GD patients <10 years of age, presence of Graves-associated ophthalmic disease, markedly enlarged thyroid gland (more than fourfold the normal size), or presence of thyroid nodules on ultrasound imaging with suspicious features for DTC. FNA was performed on nodules with suspicious features, as previously described (9, 15). DTC was diagnosed based on positive FNA biopsy of an identified thyroid nodule and confirmed on final surgical pathology. All study patients underwent total thyroidectomy with the addition of central and/or lateral neck lymph node dissection based on preoperative staging. The surgical approach for all pediatric patients with DTC at our Center includes total thyroidectomy or staged lobectomy based on preoperative Bethesda classification system for cytopathology of the FNA biopsy and associated risk for PTC or follicular thyroid cancer, respectively. An ipsilateral prophylactic nodal dissection of the central compartment is completed in patients with preoperative diagnosis of PTC. For patients who have PTC with diffuse or multifocal thyroid tumors on preoperative staging, a bilateral prophylactic nodal dissection of the central compartment is undertaken. Lateral surgical neck dissection for lymph node metastasis is performed for patients with FNA-confirmed biopsy of metastatic cervical PTC on preoperative staging ultrasound imaging. Ipsilateral prophylactic nodal dissection of the central compartment is not routinely performed for patients with tumors <1 cm that are classified as microcarcinoma. Outcomes definition All patients with a diagnosis of DTC underwent postoperative evaluation that included thyroid hormone withdrawal and a low-iodine diet for 2 weeks in preparation for a [123I] diagnostic whole-body scan (Dx-WBS). Stimulated thyroglobulin (Tg; ng/mL) was measured by ELISA, and for patients with positive antibody status to Tg, levels were measured by radioimmunoassay rather than immunometric assays (16). Remission was defined as Tg of <1 ng/mL (or below the lower detection limit for the Tg assay) and absence of structural or anatomic disease by either neck ultrasound or Dx-WBS imaging. Patients with detectable biochemical and/or anatomic disease confirmed by ultrasound, CT, MRI, or Dx-WBS imaging more than 6 months after treatment were considered to have persistent disease. DTC recurrence was defined as newly detectable biochemical and/or anatomical disease confirmed by imaging in a patient who had previously achieved successful remission status. Statistical analysis Sample size was based on a convenient sample of all diagnosed cases within the selected date range (1980 to 2016). Analyses were performed using Stata 14.0 (StataCorp, College Station, TX). A P value < 0.05 was considered statistically significant, and two-sided tests were used throughout. Standard descriptive summaries or frequency (relative frequency percentage) were used for baseline demographic information and core retrospective data. Continuous variables were expressed as mean ± SD or median (range) for skewed distributions. Group differences in DTC vs DTC and GD were tested using t tests for continuous parametric or Wilcoxon rank sum test for nonparametric variables. Proportion group differences in participants with DTC verses DTC and GD were assessed using Fisher’s exact test. Results A total of 151 patients were included in this analysis. Overall, 685 patients were diagnosed with and treated for GD during the study time period, and 79 (12%) completed total thyroidectomy as part of definitive therapy. Twelve patients (11 females) were diagnosed with concurrent GD and DTC (Table 1). The prevalence of DTC was 1.8% among all patients diagnosed and treated for GD at our Center. Median age at GD diagnosis was 15 (range, 5 to 18) years, and median age of DTC diagnosis was 15 (range, 5 to 23) years. Of the 10 (10 of 12; 83%) patients with GD and DTC who completed presurgical thyroid ultrasound evaluation (Fig. 1), 5 (50%) demonstrated a thyroid nodule (>0.5 cm) and 4 subsequently (80%) underwent FNA biopsy prior to definitive surgery. Three of nine patients with DTC without presurgical FNA were survivors of childhood malignancy with a previous history of thyroid radiation exposure, where families elected to proceed directly to thyroidectomy without diagnostic FNA biopsy. Patients with DTC, on average, were diagnosed at significantly younger age compared with patients with GD and DTC (P < 0.01). However, there was no significant difference in sex or race at DTC diagnosis in each group [P = not significant (NS)]. All patients with DTC completed a presurgical thyroid ultrasound with identified thyroid nodules, and 130 (94%) underwent FNA biopsy prior to surgery. Table 1. Patient Demographics, Imaging, and FNA Results GD Plus DTC (N = 12) DTC Alone (N = 139) Overall (N = 151) P Value Female sex, % 11 (92%) 117 (84%) 128 (85%) 0.5 Race  White 8 (67%) 97 (70%) 105 (70%)  Black 3 (25%) 9 (6%) 12 (8%)  Asian — 7 (5%) 7 (5%)  Other 1 (8%) 26 (19%) 27 (18%) Age at DTC diagnosis, y 18 (12–20) 15 (5–23) 15 (5–23) 0.01 Presurgical thyroid ultrasound 10 (83%) 139 (100%) 149 (99%) <0.01 Nodules on ultrasound 5 (50%) 139(100%) 144 (97%) <0.001 FNA biopsy 4 (80%) 130 (94%) 134 (93%) <0.001 FNA results N = 4 N = 130 N = 134  Negative — 4 (3%) 4 (3%)  FLUS/AUS — 9 (7%) 9 (7%)  Follicular neoplasm — 20 (15%) 20 (15%)  Suspicious for PTC malignancy — 17 (13%) 17 (13%)  Positive for PTC malignancy 4 (100%) 75 (58%) 79 (59%) 0.87  Other — 5 (4%) 5 (4%) GD Plus DTC (N = 12) DTC Alone (N = 139) Overall (N = 151) P Value Female sex, % 11 (92%) 117 (84%) 128 (85%) 0.5 Race  White 8 (67%) 97 (70%) 105 (70%)  Black 3 (25%) 9 (6%) 12 (8%)  Asian — 7 (5%) 7 (5%)  Other 1 (8%) 26 (19%) 27 (18%) Age at DTC diagnosis, y 18 (12–20) 15 (5–23) 15 (5–23) 0.01 Presurgical thyroid ultrasound 10 (83%) 139 (100%) 149 (99%) <0.01 Nodules on ultrasound 5 (50%) 139(100%) 144 (97%) <0.001 FNA biopsy 4 (80%) 130 (94%) 134 (93%) <0.001 FNA results N = 4 N = 130 N = 134  Negative — 4 (3%) 4 (3%)  FLUS/AUS — 9 (7%) 9 (7%)  Follicular neoplasm — 20 (15%) 20 (15%)  Suspicious for PTC malignancy — 17 (13%) 17 (13%)  Positive for PTC malignancy 4 (100%) 75 (58%) 79 (59%) 0.87  Other — 5 (4%) 5 (4%) Abbreviations: AUS, atypia of undetermined significance; FLUS, follicular lesion of undetermined significance. View Large Table 1. Patient Demographics, Imaging, and FNA Results GD Plus DTC (N = 12) DTC Alone (N = 139) Overall (N = 151) P Value Female sex, % 11 (92%) 117 (84%) 128 (85%) 0.5 Race  White 8 (67%) 97 (70%) 105 (70%)  Black 3 (25%) 9 (6%) 12 (8%)  Asian — 7 (5%) 7 (5%)  Other 1 (8%) 26 (19%) 27 (18%) Age at DTC diagnosis, y 18 (12–20) 15 (5–23) 15 (5–23) 0.01 Presurgical thyroid ultrasound 10 (83%) 139 (100%) 149 (99%) <0.01 Nodules on ultrasound 5 (50%) 139(100%) 144 (97%) <0.001 FNA biopsy 4 (80%) 130 (94%) 134 (93%) <0.001 FNA results N = 4 N = 130 N = 134  Negative — 4 (3%) 4 (3%)  FLUS/AUS — 9 (7%) 9 (7%)  Follicular neoplasm — 20 (15%) 20 (15%)  Suspicious for PTC malignancy — 17 (13%) 17 (13%)  Positive for PTC malignancy 4 (100%) 75 (58%) 79 (59%) 0.87  Other — 5 (4%) 5 (4%) GD Plus DTC (N = 12) DTC Alone (N = 139) Overall (N = 151) P Value Female sex, % 11 (92%) 117 (84%) 128 (85%) 0.5 Race  White 8 (67%) 97 (70%) 105 (70%)  Black 3 (25%) 9 (6%) 12 (8%)  Asian — 7 (5%) 7 (5%)  Other 1 (8%) 26 (19%) 27 (18%) Age at DTC diagnosis, y 18 (12–20) 15 (5–23) 15 (5–23) 0.01 Presurgical thyroid ultrasound 10 (83%) 139 (100%) 149 (99%) <0.01 Nodules on ultrasound 5 (50%) 139(100%) 144 (97%) <0.001 FNA biopsy 4 (80%) 130 (94%) 134 (93%) <0.001 FNA results N = 4 N = 130 N = 134  Negative — 4 (3%) 4 (3%)  FLUS/AUS — 9 (7%) 9 (7%)  Follicular neoplasm — 20 (15%) 20 (15%)  Suspicious for PTC malignancy — 17 (13%) 17 (13%)  Positive for PTC malignancy 4 (100%) 75 (58%) 79 (59%) 0.87  Other — 5 (4%) 5 (4%) Abbreviations: AUS, atypia of undetermined significance; FLUS, follicular lesion of undetermined significance. View Large Figure 1. View largeDownload slide Radiologic findings of DTC in GD. (A) [123I] thyroid uptake and scan. Quantitative uptake of the RAI was 78.6% at 2.4 hours and 95.5% of the administered dose at 24 h. The images show decreased radiotracer uptake in the right lower lobe (arrow) and left upper lobe (arrow). (B) Thyroid ultrasound shows a solid, 0.8 × 0.6-cm, slightly hyperechoic, nearly round nodule with smooth margins in the left upper lobe corresponding to the photopenic area in (A). Histology revealed an encapsulated follicular variant of PTC. (C and D) Thyroid ultrasound showing transverse (C) and longitudinal (D) imaging of a solid, 2.0 × 1.6-cm, hypoechoic nodule with smooth margins, slightly taller than wide appearance on transverse imaging (C), with several hyperechoic foci (D) (arrow). Histology revealed a partially encapsulated classic variant PTC. Figure 1. View largeDownload slide Radiologic findings of DTC in GD. (A) [123I] thyroid uptake and scan. Quantitative uptake of the RAI was 78.6% at 2.4 hours and 95.5% of the administered dose at 24 h. The images show decreased radiotracer uptake in the right lower lobe (arrow) and left upper lobe (arrow). (B) Thyroid ultrasound shows a solid, 0.8 × 0.6-cm, slightly hyperechoic, nearly round nodule with smooth margins in the left upper lobe corresponding to the photopenic area in (A). Histology revealed an encapsulated follicular variant of PTC. (C and D) Thyroid ultrasound showing transverse (C) and longitudinal (D) imaging of a solid, 2.0 × 1.6-cm, hypoechoic nodule with smooth margins, slightly taller than wide appearance on transverse imaging (C), with several hyperechoic foci (D) (arrow). Histology revealed a partially encapsulated classic variant PTC. Seven patients with concurrent GD and DTC (58%) were diagnosed with an incidental microcarcinoma (median size, 0.3 cm; range, 0.1 to 0.9 cm) on review of surgical histopathology following surgery for definitive therapy. These patients did not demonstrate an identified presurgical thyroid nodule for FNA biopsy on ultrasound imaging. The majority (71%) of these incidental microcarcinomas were unilateral and two (29%) were bilateral/multifocal. Histopathology review of maximal tumor diameter in the remaining five patients with GD and DTC revealed three (25%) with tumor diameter ≥1 but <2 cm and two (17%) with tumor diameter ≥2 cm. As shown in Table 1, overall, there was no significant difference in DTC clinical characteristics in GD patients with DTC compared with patients with DTC alone. The median interval from diagnosis of GD to DTC was 2.7 (range, 0.2 to 14.9) years. Presurgical medical treatment and laboratory data, including TSH and TSI in GD-DTC patients, were similar to other patients with GD followed at our Center. One patient with GD-DTC was diagnosed with rheumatoid arthritis, a coexisting immune disorder. In the DTC cohort, 28 (20%) had concurrent autoimmune hypothyroidism (defined by the presence of thyroid peroxidase and/or Tg antibodies), and one patient each with type 1 diabetes mellitus and vitiligo, respectively. Eight patients with DTC were survivors of childhood malignancy with prior history of thyroid radiation exposure (total body or craniospinal) as part of treatment of high-risk neuroblastoma, acute leukemia (allogeneic hematopoietic stem cell transplantation), and brain tumor. All childhood cancer survivors were in remission from primary cancer at the time of DTC diagnosis (secondary malignancy) and all achieved successful second remission from DTC. Furthermore, there were no significant differences in the burden of disease, including TNM staging, presence of cervical and/or pulmonary metastases at the time of DTC diagnosis between the two groups: cervical N1b [40 (29%) DTC vs 2 (17%) GD-DTC; P = NS] or distant M1 [17(12%) DTC vs 2 (17%) GD-DTC; P = NS]. Lastly, no significant differences were present with respect to surgical approach, postoperative hypocalcemia due to surgical hypoparathyroidism, or recurrent laryngeal nerve injury in each cohort. There were subtle pathological differences in DTC subtype between the patients with DTC with and without GD (Fig. 2). Specifically, there was a statistically significant increase in tall-cell (P = 0.03) and microcarcinoma variants (P = 0.002) in GD patients with PTC (Table 2). No patients in the GD cohort had diffuse sclerosing papillary thyroid carcinoma, one of the recognized aggressive subtypes of PTC. Patients with DTC alone demonstrated significantly higher lymphovascular invasion (P = 0.03), but no difference was noted in extrathyroidal extension between the two cohorts. Based on postsurgical evaluation with Dx-WBS, similar RAI activity was administered to pediatric patients with GD and DTC compared with DTC alone. None of the patients diagnosed with microcarcinoma PTC was treated with RAI, and all remained in remission at the last follow-up evaluation. Finally, we observed no significant difference in the 2-year outcomes between patients with and without GD with respect to remission, evidence of DTC recurrence (laboratory or imaging), need for repeat surgical resection, or repeat RAI administration. Three (25%) patients with GD-DTC have persistent DTC, and two underwent more than one surgical resection of bulk cervical lymph node for metastatic recurrence. Two of the patients presented with lateral neck lymphadenopathy at the time of GD diagnosis and the third patient presented with a thyroid nodule and lateral neck lymphadenopathy ∼1 year after GD diagnosis. All three patients demonstrated extensive lymphovascular invasion and extrathyroidal extension on initial pathology and were treated with repeat RAI administration (median, two time; range, two to three times) for a cumulative dose range of 235 to 408 mCi. Figure 2. View largeDownload slide Histologic findings of DTC in GD. (A) Hematoxylin and eosin (H&E) staining; original magnification, ×50. Thyroid with GD and a single focus of unencapsulated papillary thyroid microcarcinoma (0.3 cm). Typical nuclear findings such as clearing, membrane irregularity, grooves, and enlargement are present in the tumor (inset; original magnification, ×400). The background thyroid shows typical features of diffuse papillary hyperplasia with scalloped colloid and irregular follicles (lower right). (B) H&E staining; original magnification, ×25. Low-power image of 1.3-cm PTC, tall-cell variant showing papillary architecture and unencapsulated, infiltrative growth. (C) H&E staining; original magnification, ×400. High-power image or tumor in (B) showing tall-cell histology with cells three times taller than wide and eosinophilic cytoplasm. Typical nuclear features of PTC are present, including elongation, clearing, membrane irregularity, grooves, and overlapping. (D) H&E staining; original magnification, ×100. Background thyroid of the same patient showing diffuse papillary hyperplasia of GD and intralymphatic psammoma bodies (arrow). Figure 2. View largeDownload slide Histologic findings of DTC in GD. (A) Hematoxylin and eosin (H&E) staining; original magnification, ×50. Thyroid with GD and a single focus of unencapsulated papillary thyroid microcarcinoma (0.3 cm). Typical nuclear findings such as clearing, membrane irregularity, grooves, and enlargement are present in the tumor (inset; original magnification, ×400). The background thyroid shows typical features of diffuse papillary hyperplasia with scalloped colloid and irregular follicles (lower right). (B) H&E staining; original magnification, ×25. Low-power image of 1.3-cm PTC, tall-cell variant showing papillary architecture and unencapsulated, infiltrative growth. (C) H&E staining; original magnification, ×400. High-power image or tumor in (B) showing tall-cell histology with cells three times taller than wide and eosinophilic cytoplasm. Typical nuclear features of PTC are present, including elongation, clearing, membrane irregularity, grooves, and overlapping. (D) H&E staining; original magnification, ×100. Background thyroid of the same patient showing diffuse papillary hyperplasia of GD and intralymphatic psammoma bodies (arrow). Table 2. Surgical Approach, Pathological Results, Treatment, and Disease Outcome GD Plus DTC (N = 12) DTC Alone (N = 139) Overall (N = 151) Histology  Papillary 12 (100%) 131 (95%) 143 (95%)   Classic 3 (12%) 64 (49%) 67 (47%)   Follicular variant 0 32 (24%) 32 (22%)   Tall cell variant 2 (17%) 2 (2%) 4 (3%)   Diffuse sclerosing variant 0 14 (11%) 14 (10%)   Microcarcinomaa 7 (58%) 19 (15%) 26 (%18)  Follicular 0 8 (6%) 8 (5%)   Classic — 7 (88%) 7 (88%)   Diffuse — 1 (12%) 1 (2%)  Lymphovascular invasionb 3 (25%) 83 (60%) 86 (57%)  Extrathyroidal extension 4 (33%) 44 (32%) 48 (32%)  Staging (TNM)   Tumor T1 8 (67%) 54 (39%) 62 (41%)   T2 0 34 (24%) 34 (23%)   T3 4 (33%) 44 (32%) 48 (32%)   T4 0 6 (4%) 6 (4%)   Tx 0 1 (1%) 1 (1%)  Nodes   N0 4 (33%) 56 (40%) 60 (40%)   N1a 1 (8%) 39 (28%) 40 (26%)   N1b 2 (17%) 40 (29%) 42 (28%)   Nx 5 (42%) 4 (3%) 9 (6%)  Distant metastasis   M0 6 (50%) 116 (83%) 122 (81%)   M1 2 (17%) 17 (12%) 20 (13%)   Mx 4 33%) 6 (4%) 9 (6%) Nodules on final pathology  One 6 (50%) 87 (63%) 93 (62%)  Multiple 6 (50%) 52 (37%) 58 (38%) Surgical approach  Total thyroidectomy 12 (100%) 137 (99%) 149 (99%)  Central neck: unilateral 1 (8%) 59 (42%) 60 (40%)  Central neck: bilateral 3 (25%) 38 (27%) 41 (27%)  Lymph dissection: unilateral — 27 (19%) 27 (18%)  Lymph dissection: bilateral 2 (17%) 21 (15%) 22 (15%) Cervical metastasis 3 (25%) 76 (55%) 79 (52%) Pulmonary metastasis 2 (17%) 17 (12%) 19 (13%) RAI 5 (42%) 107 (77%) 112 (74%) Repeat RAI 2 (17%) 12 (9%) 14 (9%) Median (range) RAI dose 99.5 (0–263.4) 85.4 (0–279.4) 85.7 (0–279.4) Multiple surgeries 2 (17%) 30 (22%) 32 (21%)  Completion thyroidectomy 0 17 (12%) 17 (11%) Outcome  Remission 9 (75%) 119 (86%) 128 (85%)  Persistent disease 3 (25%) 17 (12%) 20 (13%)  Recurrence — 7 (5%) 7 (5%) GD Plus DTC (N = 12) DTC Alone (N = 139) Overall (N = 151) Histology  Papillary 12 (100%) 131 (95%) 143 (95%)   Classic 3 (12%) 64 (49%) 67 (47%)   Follicular variant 0 32 (24%) 32 (22%)   Tall cell variant 2 (17%) 2 (2%) 4 (3%)   Diffuse sclerosing variant 0 14 (11%) 14 (10%)   Microcarcinomaa 7 (58%) 19 (15%) 26 (%18)  Follicular 0 8 (6%) 8 (5%)   Classic — 7 (88%) 7 (88%)   Diffuse — 1 (12%) 1 (2%)  Lymphovascular invasionb 3 (25%) 83 (60%) 86 (57%)  Extrathyroidal extension 4 (33%) 44 (32%) 48 (32%)  Staging (TNM)   Tumor T1 8 (67%) 54 (39%) 62 (41%)   T2 0 34 (24%) 34 (23%)   T3 4 (33%) 44 (32%) 48 (32%)   T4 0 6 (4%) 6 (4%)   Tx 0 1 (1%) 1 (1%)  Nodes   N0 4 (33%) 56 (40%) 60 (40%)   N1a 1 (8%) 39 (28%) 40 (26%)   N1b 2 (17%) 40 (29%) 42 (28%)   Nx 5 (42%) 4 (3%) 9 (6%)  Distant metastasis   M0 6 (50%) 116 (83%) 122 (81%)   M1 2 (17%) 17 (12%) 20 (13%)   Mx 4 33%) 6 (4%) 9 (6%) Nodules on final pathology  One 6 (50%) 87 (63%) 93 (62%)  Multiple 6 (50%) 52 (37%) 58 (38%) Surgical approach  Total thyroidectomy 12 (100%) 137 (99%) 149 (99%)  Central neck: unilateral 1 (8%) 59 (42%) 60 (40%)  Central neck: bilateral 3 (25%) 38 (27%) 41 (27%)  Lymph dissection: unilateral — 27 (19%) 27 (18%)  Lymph dissection: bilateral 2 (17%) 21 (15%) 22 (15%) Cervical metastasis 3 (25%) 76 (55%) 79 (52%) Pulmonary metastasis 2 (17%) 17 (12%) 19 (13%) RAI 5 (42%) 107 (77%) 112 (74%) Repeat RAI 2 (17%) 12 (9%) 14 (9%) Median (range) RAI dose 99.5 (0–263.4) 85.4 (0–279.4) 85.7 (0–279.4) Multiple surgeries 2 (17%) 30 (22%) 32 (21%)  Completion thyroidectomy 0 17 (12%) 17 (11%) Outcome  Remission 9 (75%) 119 (86%) 128 (85%)  Persistent disease 3 (25%) 17 (12%) 20 (13%)  Recurrence — 7 (5%) 7 (5%) a P < 0.01. b P = 0.03. View Large Table 2. Surgical Approach, Pathological Results, Treatment, and Disease Outcome GD Plus DTC (N = 12) DTC Alone (N = 139) Overall (N = 151) Histology  Papillary 12 (100%) 131 (95%) 143 (95%)   Classic 3 (12%) 64 (49%) 67 (47%)   Follicular variant 0 32 (24%) 32 (22%)   Tall cell variant 2 (17%) 2 (2%) 4 (3%)   Diffuse sclerosing variant 0 14 (11%) 14 (10%)   Microcarcinomaa 7 (58%) 19 (15%) 26 (%18)  Follicular 0 8 (6%) 8 (5%)   Classic — 7 (88%) 7 (88%)   Diffuse — 1 (12%) 1 (2%)  Lymphovascular invasionb 3 (25%) 83 (60%) 86 (57%)  Extrathyroidal extension 4 (33%) 44 (32%) 48 (32%)  Staging (TNM)   Tumor T1 8 (67%) 54 (39%) 62 (41%)   T2 0 34 (24%) 34 (23%)   T3 4 (33%) 44 (32%) 48 (32%)   T4 0 6 (4%) 6 (4%)   Tx 0 1 (1%) 1 (1%)  Nodes   N0 4 (33%) 56 (40%) 60 (40%)   N1a 1 (8%) 39 (28%) 40 (26%)   N1b 2 (17%) 40 (29%) 42 (28%)   Nx 5 (42%) 4 (3%) 9 (6%)  Distant metastasis   M0 6 (50%) 116 (83%) 122 (81%)   M1 2 (17%) 17 (12%) 20 (13%)   Mx 4 33%) 6 (4%) 9 (6%) Nodules on final pathology  One 6 (50%) 87 (63%) 93 (62%)  Multiple 6 (50%) 52 (37%) 58 (38%) Surgical approach  Total thyroidectomy 12 (100%) 137 (99%) 149 (99%)  Central neck: unilateral 1 (8%) 59 (42%) 60 (40%)  Central neck: bilateral 3 (25%) 38 (27%) 41 (27%)  Lymph dissection: unilateral — 27 (19%) 27 (18%)  Lymph dissection: bilateral 2 (17%) 21 (15%) 22 (15%) Cervical metastasis 3 (25%) 76 (55%) 79 (52%) Pulmonary metastasis 2 (17%) 17 (12%) 19 (13%) RAI 5 (42%) 107 (77%) 112 (74%) Repeat RAI 2 (17%) 12 (9%) 14 (9%) Median (range) RAI dose 99.5 (0–263.4) 85.4 (0–279.4) 85.7 (0–279.4) Multiple surgeries 2 (17%) 30 (22%) 32 (21%)  Completion thyroidectomy 0 17 (12%) 17 (11%) Outcome  Remission 9 (75%) 119 (86%) 128 (85%)  Persistent disease 3 (25%) 17 (12%) 20 (13%)  Recurrence — 7 (5%) 7 (5%) GD Plus DTC (N = 12) DTC Alone (N = 139) Overall (N = 151) Histology  Papillary 12 (100%) 131 (95%) 143 (95%)   Classic 3 (12%) 64 (49%) 67 (47%)   Follicular variant 0 32 (24%) 32 (22%)   Tall cell variant 2 (17%) 2 (2%) 4 (3%)   Diffuse sclerosing variant 0 14 (11%) 14 (10%)   Microcarcinomaa 7 (58%) 19 (15%) 26 (%18)  Follicular 0 8 (6%) 8 (5%)   Classic — 7 (88%) 7 (88%)   Diffuse — 1 (12%) 1 (2%)  Lymphovascular invasionb 3 (25%) 83 (60%) 86 (57%)  Extrathyroidal extension 4 (33%) 44 (32%) 48 (32%)  Staging (TNM)   Tumor T1 8 (67%) 54 (39%) 62 (41%)   T2 0 34 (24%) 34 (23%)   T3 4 (33%) 44 (32%) 48 (32%)   T4 0 6 (4%) 6 (4%)   Tx 0 1 (1%) 1 (1%)  Nodes   N0 4 (33%) 56 (40%) 60 (40%)   N1a 1 (8%) 39 (28%) 40 (26%)   N1b 2 (17%) 40 (29%) 42 (28%)   Nx 5 (42%) 4 (3%) 9 (6%)  Distant metastasis   M0 6 (50%) 116 (83%) 122 (81%)   M1 2 (17%) 17 (12%) 20 (13%)   Mx 4 33%) 6 (4%) 9 (6%) Nodules on final pathology  One 6 (50%) 87 (63%) 93 (62%)  Multiple 6 (50%) 52 (37%) 58 (38%) Surgical approach  Total thyroidectomy 12 (100%) 137 (99%) 149 (99%)  Central neck: unilateral 1 (8%) 59 (42%) 60 (40%)  Central neck: bilateral 3 (25%) 38 (27%) 41 (27%)  Lymph dissection: unilateral — 27 (19%) 27 (18%)  Lymph dissection: bilateral 2 (17%) 21 (15%) 22 (15%) Cervical metastasis 3 (25%) 76 (55%) 79 (52%) Pulmonary metastasis 2 (17%) 17 (12%) 19 (13%) RAI 5 (42%) 107 (77%) 112 (74%) Repeat RAI 2 (17%) 12 (9%) 14 (9%) Median (range) RAI dose 99.5 (0–263.4) 85.4 (0–279.4) 85.7 (0–279.4) Multiple surgeries 2 (17%) 30 (22%) 32 (21%)  Completion thyroidectomy 0 17 (12%) 17 (11%) Outcome  Remission 9 (75%) 119 (86%) 128 (85%)  Persistent disease 3 (25%) 17 (12%) 20 (13%)  Recurrence — 7 (5%) 7 (5%) a P < 0.01. b P = 0.03. View Large Discussion Our study represents a cohort of children and young adults with concomitant GD and DTC compared with a comparable cohort diagnosed and followed with DTC. In our patient cohort, no significant differences were identified in clinical characteristics at the time of presentation in patients with and without GD. Specifically, patients with GD and DTC did not demonstrate a greater extent of metastases or higher burden of disease at the time of diagnosis when compared with pediatric patients with DTC alone. Although a higher percentage of patients with GD demonstrated tall-cell variant or microcarcinoma on histopathologic review, tumor histology did not correlate with overall or event-free survival. Furthermore, the long-term disease outcome remained similar in DTC patients with and without GD, suggesting that the presence of GD did not confer a more aggressive course with DTC in our pediatric cohort. The incidence of DTC in pediatric patients has increased during the last few decades (17), and DTC is the second most common malignancy, after Hodgkin lymphoma, in white, adolescent females, age 15 to 19 years (17). Importantly, there are notable clinical, molecular, and pathological differences in pediatric DTC when compared with adults, and children with DTC exhibit a more favorable progression-free survival compared with adults (18). Some of these important differences include: (1) a higher risk of malignancy (22% to 26% vs 5% to 10%) in an identified thyroid nodule in children compared with adults (19–21); (2) higher regional lymph node metastasis (22–24), extrathyroidal extension, and pulmonary metastasis even after controlling for histology and tumor size in pediatrics compared with adults (25); and (3) reduced long-term, cause-specific mortality in children with DTC (<2%) despite extensive disease at clinical presentation (26–28). Additionally, many children with DTC and pulmonary metastasis develop persistent yet stable disease, with continued clinical response as evident by a sustained decline in Tg levels following RAI treatment (29). In adults, a clear difference in the presentation as well as prognosis of patients with concomitant GD and DTC remains unclear, as these identified studies are limited by small sample size, cross-sectional retrospective design, and selection bias. Although several retrospective cross-sectional studies in adults have reported a higher disease burden in patients with GD compared with patients with sporadic DTC (7, 30), it remains uncertain whether adult patients with GD truly present with a higher DTC disease burden or demonstrate a different prognosis compared with DTC patients diagnosed with biochemical euthyroidism. In a study by Pellegriti et al. (11) where patients with GD and DTC were matched to euthyroid DTC controls, patients with concomitant GD and DTC demonstrated a higher metastatic burden at the time of DTC diagnosis, an increased rate of recurrence, and a higher overall mortality. In contrast, in two additional adult studies assessing patients with euthyroid nodules compared with GD with nodules, the DTC incidence and disease burden at diagnosis remained equal (30, 31). Similar to previous adult reports (8, 30, 32), our study demonstrated significantly higher incidence of carcinoma measuring less than <1 cm (microcarcinoma) in GD. These identified cases with low-risk papillary thyroid microcarcinomas were without lymph node metastasis, lymphovascular invasion, or extrathyroidal extension. Hence, these incidental microcarcinomas did not require radioiodine therapy or subsequent TSH suppressive therapies. Although GD is characterized by a marked decrease in the TSH, the TSI detected in GD demonstrates strong agonistic activity to the TSH receptor (33). Similar to normal thyroid cells, DTC neoplastic cells also express functional receptors for TSH, and the TSI-mediated overstimulation of the thyroid follicular cells may serve as a potential explanation for the higher incidence of DTC and papillary thyroid microcarcinomas found in GD patients (8). The tall-cell variant PTC histology accounts for 1.3% to 12% of all PTCs in pediatric and adult patients, respectively, and is usually associated with aggressive clinical features (34). Two previous adult studies reported a higher prevalence of tall-cell variant PTC in patients with GD (34, 35). In our study, 17% of patients with GD and PTC had features of tall-cell variant PTC compared with 2% of patients with PTC alone (Table 2), although the overall number of patients was small. The presence of nodular lesions in patients with GD is a recognized risk factor for DTC as compared with patients undergoing thyroidectomy for causes other than definitive therapy for GD (8, 9, 30). Other identified risk factors for concomitant disease in adult patients with GD and DTC include increased age, larger tumor burden at the time of diagnosis, and clinical signs (cervical lymphadenopathy or hoarseness due to laryngeal nerve infiltration) suspicious for DTC on examination (11). Thyroidectomy or RAI are both effective definitive treatment options for patients with GD (2, 36). Our data demonstrated that the widely accepted and used [131I] is safe; however, the high incidence of DTC in patients with GD suggests that this risk should be taken into account when deciding between definitive treatment options. Thyroid ultrasound imaging is a low-risk modality, and if a nodule with high risk features (15, 37) is identified, FNA should be performed prior to finalizing a decision on which definitive treatment option is best for an individual patient. The retrospective nature of our report, small sample of subjects with both GD and PTC, and selection bias from a large referral, tertiary center, may limit our ability to make unequivocal, generalizable conclusions about the prevalence and behavior of concurrent DTC in pediatric patients with GD compared with pediatric patients with DTC alone. However, to our knowledge, the comprehensive data collection for this study resulted in minimal missing information and did not affect our analysis. Despite these limitations, our study has several strengths. Importantly, to our knowledge, this is the first pediatric study to assess the impact of concurrent GD and DTC disease burden at the time of diagnosis and long-term prognosis in children and young adults. The results of this study also highlight the absence of increased metastatic burden at the time of DTC diagnosis in GD along with similar, excellent, long-term clinical course compared with pediatric patients with DTC alone. We think that thyroid ultrasound is a useful clinical tool for identifying pediatric patients with GD and abnormal thyroid nodules prior to definitive therapy. Predefinitive therapy thyroid ultrasound in GD patients allows for identifying patients with thyroid nodules that may harbor clinically significant DTC. For patients found to have a thyroid nodule with concerning features (15), FNA biopsy allows for optimal surgical planning and complete resection of disease. Although this approach may result in more FNAs, it is a procedure associated with a low risk of complications and high diagnostic accuracy (24). Additionally, FNA procedures are more cost-effective in the long run, given the cost of treatment delay from identifying a nodule on thyroid scintigraphy as well as the risk of incomplete surgery in the absence of complete preoperative ultrasound screening. Conclusions DTC in pediatric patients with GD exhibits a similar pattern of disease burden, metastasis, and, overall, demonstrates an excellent prognosis compared with pediatric patients with DTC alone. Preoperative thyroid ultrasound is an effective modality to identify abnormal nodular disease and to evaluate for presurgical thyroid carcinoma. Incidental papillary thyroid microcarcinomas are common in pediatric patients with underlying GD and are not associated with a risk of extrathyroidal extension or lymph node metastasis. Abbreviations: Abbreviations: CHOP Children’s Hospital of Philadelphia DTC differentiated thyroid cancer Dx-WBS diagnostic whole-body scan FNA fine needle aspiration GD Graves disease NS not significant PTC papillary thyroid cancer RAI radioactive iodine Tg thyroglobulin TSI thyroid stimulating Ig Acknowledgments Financial Support: This work was supported by National Institutes of Health Grants K07 CA166177 (to S.M.-M.) and K12 CA076931 (to S.P.M.). Author Contributions: S.P.M., A.J.B., J.N., and S.M.-M. designed the study. S.M.-M, J.N., and A.J.B. collected and assembled the data. S.M.-M and J.N. analyzed data and performed statistical analyses. S.M.-M, A.J.B., S.P.M., L.F.S., J.N., and N.S.A. interpreted the results. S.P.M and S.M.M. wrote the paper. S.P.M., A.J.B, N.S.A, L.F.S., J.N., K.K., and S.M.-M. reviewed and critiqued the manuscript and contributed to revisions. All authors approved the final manuscript. Disclosure Summary: The authors have nothing to disclose. References 1. 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Google Scholar CrossRef Search ADS PubMed Copyright © 2018 Endocrine Society http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Clinical Endocrinology and Metabolism Oxford University Press

Disease Burden and Outcome in Children and Young Adults With Concurrent Graves Disease and Differentiated Thyroid Carcinoma

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Endocrine Society
Copyright
Copyright © 2018 Endocrine Society
ISSN
0021-972X
eISSN
1945-7197
D.O.I.
10.1210/jc.2018-00026
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Abstract

Abstract Context Adults with differentiated thyroid cancer (DTC) and Graves disease (GD) demonstrate a greater reported disease burden and aggressive DTC behavior. To date, no studies have examined the impact and long-term outcome of concurrent GD and DTC (GD-DTC) in children and young adults. Design Single institution, retrospective longitudinal cohort study between 1997 and 2016. Participants One hundred thirty-nine children and young adults with DTC, diagnosed at median age 15 (range, 5 to 23) years, compared with 12 patients with GD-DTC, median age 18 (range, 12 to 20) years. Major Outcome Measures Patient demographics, preoperative imaging, fine needle aspiration (FNA) cytology, operative and pathological reports, laboratory studies, treatment, and subsequent 2-year outcomes. Results Compared with DTC, patients with GD-DTC were significantly older at the time of DTC diagnosis (P < 0.01). Patients with GD-DTC were more likely to exhibit microcarcinoma (P < 0.01), and 2 of 12 (17%) demonstrated tall cell variant papillary thyroid cancer (PTC) vs 2 of 139 (2%) in patients who had DTC alone (P = 0.03). Although patients with DTC showed greater lymphovascular invasion (60% vs 25%; P = 0.03), no group differences were noted in extrathyroidal extension, regional lymph node, and distant or lung metastasis. There were no group differences in the 2-year outcome for remission, persistent disease, or recurrence. Conclusions Concurrent DTC in pediatric patients with GD is not associated with a greater disease burden at presentation and shows no significant difference in 2-year outcomes compared with DTC alone. Similar to adults, microcarcinoma and tall cell variant PTC is prevalent in pediatric patients with GD-DTC. For patients who have GD-DTC with an identified nodule on ultrasound imaging prior to definitive therapy, FNA biopsy is recommended to guide definitive treatment. Graves disease (GD) is the most common cause of hyperthyroidism in children and accounts for 10% to 15% of all pediatric thyroid disease (1, 2). Similar to adults, most pediatric patients with GD are initially treated with antithyroid medications with the hope of achieving remission; however, pediatric patients often demonstrate a lower likelihood of achieving remission compared with adults (30% vs 50%, respectively) (3), and for many children and adolescents with GD, remission remains unattainable. For this reason, most pediatric patients with GD will require definitive therapy with radioactive iodine (RAI) therapy or surgery (2–4). An increased risk of differentiated thyroid cancer (DTC) in patients with GD has been previously reported (5, 6). Adults with GD have an estimated 10-fold higher risk of DTC compared with the general population, with the highest risk within the first 3 years after GD diagnosis (7, 8). In a subgroup of patients with GD, DTC is incidentally discovered on pathology review after thyroidectomy, most often as papillary thyroid microcarcinoma without invasion (8). We previously reported the utility of thyroid ultrasound in patients with GD with gland asymmetry, a palpable nodule, and/or pathologic cervical adenopathy followed by fine needle aspiration (FNA) biopsy of identified suspicious thyroid nodules prior to definitive therapy, particularly as thyroid ultrasound is an easy and efficient tool for identifying and selecting patients who may benefit from thyroidectomy rather than RAI (9). There is continued debate whether DTC in the setting of GD follows a more aggressive course in adult patients, with overall concern for higher mortality rates and a threefold increased risk of metastatic disease (10, 11). However, most studies in adults with concurrent GD and DTC are limited by retrospective cross-sectional design (5–7). Identified factors predictive of worse outcome in adults with concurrent GD and DTC include tumor size (>10 mm), multiplicity, extracapsular invasion, and clinical symptoms of cancer (12). To date, no previous studies have examined the impact and long-term outcome of concurrent GD and DTC in pediatric patients. We conducted a longitudinal cohort study comparing children and young adult patients diagnosed and treated with DTC to children and young adults diagnosed and treated with concurrent GD and DTC at the Children’s Hospital of Philadelphia (CHOP) Thyroid Center, a multidisciplinary, tertiary center with a large referral base. Our objective was to assess the extent of DTC and metastatic burden at diagnosis and overall outcome in children and young adults with concurrent GD compared with patients with DTC alone. Subjects and Methods We conducted a single-institution, retrospective longitudinal cohort study of children and young adults (age 5 to 25 years) from 1997 to 2016 who received care at the CHOP Thyroid Center, a multidisciplinary center compromised of members from the Divisions of Endocrinology, Oncology, Surgery, Otolaryngology, Radiology, Pathology, Social Work, and Behavioral Health. The study was fully approved by the CHOP Institutional Review Board with parent and/or participant consent for data collection. Study participants’ race was defined according to the National Institutes of Health categories. Data sources Clinical records, including outpatient visits, operative reports, and pathology reports, were reviewed. Data elements abstracted included date of birth, demographics (sex, age, and race), outpatient office visit records (Divisions of Endocrinology, Oncology, and Surgery), thyroid function, and antibody laboratory values, radiographic findings (ultrasound, MRI, and nuclear medicine scans), pathology results (cytology and histology), date of hospital admission and discharge, surgical procedure and intraoperative findings, postoperative laboratory values, postsurgical RAI, and DTC outcome. Papillary thyroid cancer (PTC) samples were classified in accordance with the 7th edition of the American Joint Committee cancer staging manual (13). The size of the carcinoma was determined by its largest dimension based on review of the gross pathology for nodules ≥1 cm and by direct microscopic measurements on the slides for nodules <1 cm. Tumors <1 cm were classified as microcarcinoma. PTC found on postoperative histopathological examination of excised thyroid tissue for the definitive surgical treatment of GD was considered incidental if (1) it was not visualized on preoperative thyroid ultrasound, (2) it was <1 cm in size, and (3) it not associated with extrathyroidal extension or lymph node metastasis (14). Study patients GD was defined based on clinical signs and symptoms, and laboratory values including suppressed TSH, elevated T3/T4 ratio, and elevated thyroid stimulating Ig (TSI) antibody titer. A thyroid ultrasound was performed when a nodule was suspected on physical examination, and, since 2010, for all patients with GD as part of their evaluation for definitive therapy. Surgery was recommended as part of definitive therapy for GD patients <10 years of age, presence of Graves-associated ophthalmic disease, markedly enlarged thyroid gland (more than fourfold the normal size), or presence of thyroid nodules on ultrasound imaging with suspicious features for DTC. FNA was performed on nodules with suspicious features, as previously described (9, 15). DTC was diagnosed based on positive FNA biopsy of an identified thyroid nodule and confirmed on final surgical pathology. All study patients underwent total thyroidectomy with the addition of central and/or lateral neck lymph node dissection based on preoperative staging. The surgical approach for all pediatric patients with DTC at our Center includes total thyroidectomy or staged lobectomy based on preoperative Bethesda classification system for cytopathology of the FNA biopsy and associated risk for PTC or follicular thyroid cancer, respectively. An ipsilateral prophylactic nodal dissection of the central compartment is completed in patients with preoperative diagnosis of PTC. For patients who have PTC with diffuse or multifocal thyroid tumors on preoperative staging, a bilateral prophylactic nodal dissection of the central compartment is undertaken. Lateral surgical neck dissection for lymph node metastasis is performed for patients with FNA-confirmed biopsy of metastatic cervical PTC on preoperative staging ultrasound imaging. Ipsilateral prophylactic nodal dissection of the central compartment is not routinely performed for patients with tumors <1 cm that are classified as microcarcinoma. Outcomes definition All patients with a diagnosis of DTC underwent postoperative evaluation that included thyroid hormone withdrawal and a low-iodine diet for 2 weeks in preparation for a [123I] diagnostic whole-body scan (Dx-WBS). Stimulated thyroglobulin (Tg; ng/mL) was measured by ELISA, and for patients with positive antibody status to Tg, levels were measured by radioimmunoassay rather than immunometric assays (16). Remission was defined as Tg of <1 ng/mL (or below the lower detection limit for the Tg assay) and absence of structural or anatomic disease by either neck ultrasound or Dx-WBS imaging. Patients with detectable biochemical and/or anatomic disease confirmed by ultrasound, CT, MRI, or Dx-WBS imaging more than 6 months after treatment were considered to have persistent disease. DTC recurrence was defined as newly detectable biochemical and/or anatomical disease confirmed by imaging in a patient who had previously achieved successful remission status. Statistical analysis Sample size was based on a convenient sample of all diagnosed cases within the selected date range (1980 to 2016). Analyses were performed using Stata 14.0 (StataCorp, College Station, TX). A P value < 0.05 was considered statistically significant, and two-sided tests were used throughout. Standard descriptive summaries or frequency (relative frequency percentage) were used for baseline demographic information and core retrospective data. Continuous variables were expressed as mean ± SD or median (range) for skewed distributions. Group differences in DTC vs DTC and GD were tested using t tests for continuous parametric or Wilcoxon rank sum test for nonparametric variables. Proportion group differences in participants with DTC verses DTC and GD were assessed using Fisher’s exact test. Results A total of 151 patients were included in this analysis. Overall, 685 patients were diagnosed with and treated for GD during the study time period, and 79 (12%) completed total thyroidectomy as part of definitive therapy. Twelve patients (11 females) were diagnosed with concurrent GD and DTC (Table 1). The prevalence of DTC was 1.8% among all patients diagnosed and treated for GD at our Center. Median age at GD diagnosis was 15 (range, 5 to 18) years, and median age of DTC diagnosis was 15 (range, 5 to 23) years. Of the 10 (10 of 12; 83%) patients with GD and DTC who completed presurgical thyroid ultrasound evaluation (Fig. 1), 5 (50%) demonstrated a thyroid nodule (>0.5 cm) and 4 subsequently (80%) underwent FNA biopsy prior to definitive surgery. Three of nine patients with DTC without presurgical FNA were survivors of childhood malignancy with a previous history of thyroid radiation exposure, where families elected to proceed directly to thyroidectomy without diagnostic FNA biopsy. Patients with DTC, on average, were diagnosed at significantly younger age compared with patients with GD and DTC (P < 0.01). However, there was no significant difference in sex or race at DTC diagnosis in each group [P = not significant (NS)]. All patients with DTC completed a presurgical thyroid ultrasound with identified thyroid nodules, and 130 (94%) underwent FNA biopsy prior to surgery. Table 1. Patient Demographics, Imaging, and FNA Results GD Plus DTC (N = 12) DTC Alone (N = 139) Overall (N = 151) P Value Female sex, % 11 (92%) 117 (84%) 128 (85%) 0.5 Race  White 8 (67%) 97 (70%) 105 (70%)  Black 3 (25%) 9 (6%) 12 (8%)  Asian — 7 (5%) 7 (5%)  Other 1 (8%) 26 (19%) 27 (18%) Age at DTC diagnosis, y 18 (12–20) 15 (5–23) 15 (5–23) 0.01 Presurgical thyroid ultrasound 10 (83%) 139 (100%) 149 (99%) <0.01 Nodules on ultrasound 5 (50%) 139(100%) 144 (97%) <0.001 FNA biopsy 4 (80%) 130 (94%) 134 (93%) <0.001 FNA results N = 4 N = 130 N = 134  Negative — 4 (3%) 4 (3%)  FLUS/AUS — 9 (7%) 9 (7%)  Follicular neoplasm — 20 (15%) 20 (15%)  Suspicious for PTC malignancy — 17 (13%) 17 (13%)  Positive for PTC malignancy 4 (100%) 75 (58%) 79 (59%) 0.87  Other — 5 (4%) 5 (4%) GD Plus DTC (N = 12) DTC Alone (N = 139) Overall (N = 151) P Value Female sex, % 11 (92%) 117 (84%) 128 (85%) 0.5 Race  White 8 (67%) 97 (70%) 105 (70%)  Black 3 (25%) 9 (6%) 12 (8%)  Asian — 7 (5%) 7 (5%)  Other 1 (8%) 26 (19%) 27 (18%) Age at DTC diagnosis, y 18 (12–20) 15 (5–23) 15 (5–23) 0.01 Presurgical thyroid ultrasound 10 (83%) 139 (100%) 149 (99%) <0.01 Nodules on ultrasound 5 (50%) 139(100%) 144 (97%) <0.001 FNA biopsy 4 (80%) 130 (94%) 134 (93%) <0.001 FNA results N = 4 N = 130 N = 134  Negative — 4 (3%) 4 (3%)  FLUS/AUS — 9 (7%) 9 (7%)  Follicular neoplasm — 20 (15%) 20 (15%)  Suspicious for PTC malignancy — 17 (13%) 17 (13%)  Positive for PTC malignancy 4 (100%) 75 (58%) 79 (59%) 0.87  Other — 5 (4%) 5 (4%) Abbreviations: AUS, atypia of undetermined significance; FLUS, follicular lesion of undetermined significance. View Large Table 1. Patient Demographics, Imaging, and FNA Results GD Plus DTC (N = 12) DTC Alone (N = 139) Overall (N = 151) P Value Female sex, % 11 (92%) 117 (84%) 128 (85%) 0.5 Race  White 8 (67%) 97 (70%) 105 (70%)  Black 3 (25%) 9 (6%) 12 (8%)  Asian — 7 (5%) 7 (5%)  Other 1 (8%) 26 (19%) 27 (18%) Age at DTC diagnosis, y 18 (12–20) 15 (5–23) 15 (5–23) 0.01 Presurgical thyroid ultrasound 10 (83%) 139 (100%) 149 (99%) <0.01 Nodules on ultrasound 5 (50%) 139(100%) 144 (97%) <0.001 FNA biopsy 4 (80%) 130 (94%) 134 (93%) <0.001 FNA results N = 4 N = 130 N = 134  Negative — 4 (3%) 4 (3%)  FLUS/AUS — 9 (7%) 9 (7%)  Follicular neoplasm — 20 (15%) 20 (15%)  Suspicious for PTC malignancy — 17 (13%) 17 (13%)  Positive for PTC malignancy 4 (100%) 75 (58%) 79 (59%) 0.87  Other — 5 (4%) 5 (4%) GD Plus DTC (N = 12) DTC Alone (N = 139) Overall (N = 151) P Value Female sex, % 11 (92%) 117 (84%) 128 (85%) 0.5 Race  White 8 (67%) 97 (70%) 105 (70%)  Black 3 (25%) 9 (6%) 12 (8%)  Asian — 7 (5%) 7 (5%)  Other 1 (8%) 26 (19%) 27 (18%) Age at DTC diagnosis, y 18 (12–20) 15 (5–23) 15 (5–23) 0.01 Presurgical thyroid ultrasound 10 (83%) 139 (100%) 149 (99%) <0.01 Nodules on ultrasound 5 (50%) 139(100%) 144 (97%) <0.001 FNA biopsy 4 (80%) 130 (94%) 134 (93%) <0.001 FNA results N = 4 N = 130 N = 134  Negative — 4 (3%) 4 (3%)  FLUS/AUS — 9 (7%) 9 (7%)  Follicular neoplasm — 20 (15%) 20 (15%)  Suspicious for PTC malignancy — 17 (13%) 17 (13%)  Positive for PTC malignancy 4 (100%) 75 (58%) 79 (59%) 0.87  Other — 5 (4%) 5 (4%) Abbreviations: AUS, atypia of undetermined significance; FLUS, follicular lesion of undetermined significance. View Large Figure 1. View largeDownload slide Radiologic findings of DTC in GD. (A) [123I] thyroid uptake and scan. Quantitative uptake of the RAI was 78.6% at 2.4 hours and 95.5% of the administered dose at 24 h. The images show decreased radiotracer uptake in the right lower lobe (arrow) and left upper lobe (arrow). (B) Thyroid ultrasound shows a solid, 0.8 × 0.6-cm, slightly hyperechoic, nearly round nodule with smooth margins in the left upper lobe corresponding to the photopenic area in (A). Histology revealed an encapsulated follicular variant of PTC. (C and D) Thyroid ultrasound showing transverse (C) and longitudinal (D) imaging of a solid, 2.0 × 1.6-cm, hypoechoic nodule with smooth margins, slightly taller than wide appearance on transverse imaging (C), with several hyperechoic foci (D) (arrow). Histology revealed a partially encapsulated classic variant PTC. Figure 1. View largeDownload slide Radiologic findings of DTC in GD. (A) [123I] thyroid uptake and scan. Quantitative uptake of the RAI was 78.6% at 2.4 hours and 95.5% of the administered dose at 24 h. The images show decreased radiotracer uptake in the right lower lobe (arrow) and left upper lobe (arrow). (B) Thyroid ultrasound shows a solid, 0.8 × 0.6-cm, slightly hyperechoic, nearly round nodule with smooth margins in the left upper lobe corresponding to the photopenic area in (A). Histology revealed an encapsulated follicular variant of PTC. (C and D) Thyroid ultrasound showing transverse (C) and longitudinal (D) imaging of a solid, 2.0 × 1.6-cm, hypoechoic nodule with smooth margins, slightly taller than wide appearance on transverse imaging (C), with several hyperechoic foci (D) (arrow). Histology revealed a partially encapsulated classic variant PTC. Seven patients with concurrent GD and DTC (58%) were diagnosed with an incidental microcarcinoma (median size, 0.3 cm; range, 0.1 to 0.9 cm) on review of surgical histopathology following surgery for definitive therapy. These patients did not demonstrate an identified presurgical thyroid nodule for FNA biopsy on ultrasound imaging. The majority (71%) of these incidental microcarcinomas were unilateral and two (29%) were bilateral/multifocal. Histopathology review of maximal tumor diameter in the remaining five patients with GD and DTC revealed three (25%) with tumor diameter ≥1 but <2 cm and two (17%) with tumor diameter ≥2 cm. As shown in Table 1, overall, there was no significant difference in DTC clinical characteristics in GD patients with DTC compared with patients with DTC alone. The median interval from diagnosis of GD to DTC was 2.7 (range, 0.2 to 14.9) years. Presurgical medical treatment and laboratory data, including TSH and TSI in GD-DTC patients, were similar to other patients with GD followed at our Center. One patient with GD-DTC was diagnosed with rheumatoid arthritis, a coexisting immune disorder. In the DTC cohort, 28 (20%) had concurrent autoimmune hypothyroidism (defined by the presence of thyroid peroxidase and/or Tg antibodies), and one patient each with type 1 diabetes mellitus and vitiligo, respectively. Eight patients with DTC were survivors of childhood malignancy with prior history of thyroid radiation exposure (total body or craniospinal) as part of treatment of high-risk neuroblastoma, acute leukemia (allogeneic hematopoietic stem cell transplantation), and brain tumor. All childhood cancer survivors were in remission from primary cancer at the time of DTC diagnosis (secondary malignancy) and all achieved successful second remission from DTC. Furthermore, there were no significant differences in the burden of disease, including TNM staging, presence of cervical and/or pulmonary metastases at the time of DTC diagnosis between the two groups: cervical N1b [40 (29%) DTC vs 2 (17%) GD-DTC; P = NS] or distant M1 [17(12%) DTC vs 2 (17%) GD-DTC; P = NS]. Lastly, no significant differences were present with respect to surgical approach, postoperative hypocalcemia due to surgical hypoparathyroidism, or recurrent laryngeal nerve injury in each cohort. There were subtle pathological differences in DTC subtype between the patients with DTC with and without GD (Fig. 2). Specifically, there was a statistically significant increase in tall-cell (P = 0.03) and microcarcinoma variants (P = 0.002) in GD patients with PTC (Table 2). No patients in the GD cohort had diffuse sclerosing papillary thyroid carcinoma, one of the recognized aggressive subtypes of PTC. Patients with DTC alone demonstrated significantly higher lymphovascular invasion (P = 0.03), but no difference was noted in extrathyroidal extension between the two cohorts. Based on postsurgical evaluation with Dx-WBS, similar RAI activity was administered to pediatric patients with GD and DTC compared with DTC alone. None of the patients diagnosed with microcarcinoma PTC was treated with RAI, and all remained in remission at the last follow-up evaluation. Finally, we observed no significant difference in the 2-year outcomes between patients with and without GD with respect to remission, evidence of DTC recurrence (laboratory or imaging), need for repeat surgical resection, or repeat RAI administration. Three (25%) patients with GD-DTC have persistent DTC, and two underwent more than one surgical resection of bulk cervical lymph node for metastatic recurrence. Two of the patients presented with lateral neck lymphadenopathy at the time of GD diagnosis and the third patient presented with a thyroid nodule and lateral neck lymphadenopathy ∼1 year after GD diagnosis. All three patients demonstrated extensive lymphovascular invasion and extrathyroidal extension on initial pathology and were treated with repeat RAI administration (median, two time; range, two to three times) for a cumulative dose range of 235 to 408 mCi. Figure 2. View largeDownload slide Histologic findings of DTC in GD. (A) Hematoxylin and eosin (H&E) staining; original magnification, ×50. Thyroid with GD and a single focus of unencapsulated papillary thyroid microcarcinoma (0.3 cm). Typical nuclear findings such as clearing, membrane irregularity, grooves, and enlargement are present in the tumor (inset; original magnification, ×400). The background thyroid shows typical features of diffuse papillary hyperplasia with scalloped colloid and irregular follicles (lower right). (B) H&E staining; original magnification, ×25. Low-power image of 1.3-cm PTC, tall-cell variant showing papillary architecture and unencapsulated, infiltrative growth. (C) H&E staining; original magnification, ×400. High-power image or tumor in (B) showing tall-cell histology with cells three times taller than wide and eosinophilic cytoplasm. Typical nuclear features of PTC are present, including elongation, clearing, membrane irregularity, grooves, and overlapping. (D) H&E staining; original magnification, ×100. Background thyroid of the same patient showing diffuse papillary hyperplasia of GD and intralymphatic psammoma bodies (arrow). Figure 2. View largeDownload slide Histologic findings of DTC in GD. (A) Hematoxylin and eosin (H&E) staining; original magnification, ×50. Thyroid with GD and a single focus of unencapsulated papillary thyroid microcarcinoma (0.3 cm). Typical nuclear findings such as clearing, membrane irregularity, grooves, and enlargement are present in the tumor (inset; original magnification, ×400). The background thyroid shows typical features of diffuse papillary hyperplasia with scalloped colloid and irregular follicles (lower right). (B) H&E staining; original magnification, ×25. Low-power image of 1.3-cm PTC, tall-cell variant showing papillary architecture and unencapsulated, infiltrative growth. (C) H&E staining; original magnification, ×400. High-power image or tumor in (B) showing tall-cell histology with cells three times taller than wide and eosinophilic cytoplasm. Typical nuclear features of PTC are present, including elongation, clearing, membrane irregularity, grooves, and overlapping. (D) H&E staining; original magnification, ×100. Background thyroid of the same patient showing diffuse papillary hyperplasia of GD and intralymphatic psammoma bodies (arrow). Table 2. Surgical Approach, Pathological Results, Treatment, and Disease Outcome GD Plus DTC (N = 12) DTC Alone (N = 139) Overall (N = 151) Histology  Papillary 12 (100%) 131 (95%) 143 (95%)   Classic 3 (12%) 64 (49%) 67 (47%)   Follicular variant 0 32 (24%) 32 (22%)   Tall cell variant 2 (17%) 2 (2%) 4 (3%)   Diffuse sclerosing variant 0 14 (11%) 14 (10%)   Microcarcinomaa 7 (58%) 19 (15%) 26 (%18)  Follicular 0 8 (6%) 8 (5%)   Classic — 7 (88%) 7 (88%)   Diffuse — 1 (12%) 1 (2%)  Lymphovascular invasionb 3 (25%) 83 (60%) 86 (57%)  Extrathyroidal extension 4 (33%) 44 (32%) 48 (32%)  Staging (TNM)   Tumor T1 8 (67%) 54 (39%) 62 (41%)   T2 0 34 (24%) 34 (23%)   T3 4 (33%) 44 (32%) 48 (32%)   T4 0 6 (4%) 6 (4%)   Tx 0 1 (1%) 1 (1%)  Nodes   N0 4 (33%) 56 (40%) 60 (40%)   N1a 1 (8%) 39 (28%) 40 (26%)   N1b 2 (17%) 40 (29%) 42 (28%)   Nx 5 (42%) 4 (3%) 9 (6%)  Distant metastasis   M0 6 (50%) 116 (83%) 122 (81%)   M1 2 (17%) 17 (12%) 20 (13%)   Mx 4 33%) 6 (4%) 9 (6%) Nodules on final pathology  One 6 (50%) 87 (63%) 93 (62%)  Multiple 6 (50%) 52 (37%) 58 (38%) Surgical approach  Total thyroidectomy 12 (100%) 137 (99%) 149 (99%)  Central neck: unilateral 1 (8%) 59 (42%) 60 (40%)  Central neck: bilateral 3 (25%) 38 (27%) 41 (27%)  Lymph dissection: unilateral — 27 (19%) 27 (18%)  Lymph dissection: bilateral 2 (17%) 21 (15%) 22 (15%) Cervical metastasis 3 (25%) 76 (55%) 79 (52%) Pulmonary metastasis 2 (17%) 17 (12%) 19 (13%) RAI 5 (42%) 107 (77%) 112 (74%) Repeat RAI 2 (17%) 12 (9%) 14 (9%) Median (range) RAI dose 99.5 (0–263.4) 85.4 (0–279.4) 85.7 (0–279.4) Multiple surgeries 2 (17%) 30 (22%) 32 (21%)  Completion thyroidectomy 0 17 (12%) 17 (11%) Outcome  Remission 9 (75%) 119 (86%) 128 (85%)  Persistent disease 3 (25%) 17 (12%) 20 (13%)  Recurrence — 7 (5%) 7 (5%) GD Plus DTC (N = 12) DTC Alone (N = 139) Overall (N = 151) Histology  Papillary 12 (100%) 131 (95%) 143 (95%)   Classic 3 (12%) 64 (49%) 67 (47%)   Follicular variant 0 32 (24%) 32 (22%)   Tall cell variant 2 (17%) 2 (2%) 4 (3%)   Diffuse sclerosing variant 0 14 (11%) 14 (10%)   Microcarcinomaa 7 (58%) 19 (15%) 26 (%18)  Follicular 0 8 (6%) 8 (5%)   Classic — 7 (88%) 7 (88%)   Diffuse — 1 (12%) 1 (2%)  Lymphovascular invasionb 3 (25%) 83 (60%) 86 (57%)  Extrathyroidal extension 4 (33%) 44 (32%) 48 (32%)  Staging (TNM)   Tumor T1 8 (67%) 54 (39%) 62 (41%)   T2 0 34 (24%) 34 (23%)   T3 4 (33%) 44 (32%) 48 (32%)   T4 0 6 (4%) 6 (4%)   Tx 0 1 (1%) 1 (1%)  Nodes   N0 4 (33%) 56 (40%) 60 (40%)   N1a 1 (8%) 39 (28%) 40 (26%)   N1b 2 (17%) 40 (29%) 42 (28%)   Nx 5 (42%) 4 (3%) 9 (6%)  Distant metastasis   M0 6 (50%) 116 (83%) 122 (81%)   M1 2 (17%) 17 (12%) 20 (13%)   Mx 4 33%) 6 (4%) 9 (6%) Nodules on final pathology  One 6 (50%) 87 (63%) 93 (62%)  Multiple 6 (50%) 52 (37%) 58 (38%) Surgical approach  Total thyroidectomy 12 (100%) 137 (99%) 149 (99%)  Central neck: unilateral 1 (8%) 59 (42%) 60 (40%)  Central neck: bilateral 3 (25%) 38 (27%) 41 (27%)  Lymph dissection: unilateral — 27 (19%) 27 (18%)  Lymph dissection: bilateral 2 (17%) 21 (15%) 22 (15%) Cervical metastasis 3 (25%) 76 (55%) 79 (52%) Pulmonary metastasis 2 (17%) 17 (12%) 19 (13%) RAI 5 (42%) 107 (77%) 112 (74%) Repeat RAI 2 (17%) 12 (9%) 14 (9%) Median (range) RAI dose 99.5 (0–263.4) 85.4 (0–279.4) 85.7 (0–279.4) Multiple surgeries 2 (17%) 30 (22%) 32 (21%)  Completion thyroidectomy 0 17 (12%) 17 (11%) Outcome  Remission 9 (75%) 119 (86%) 128 (85%)  Persistent disease 3 (25%) 17 (12%) 20 (13%)  Recurrence — 7 (5%) 7 (5%) a P < 0.01. b P = 0.03. View Large Table 2. Surgical Approach, Pathological Results, Treatment, and Disease Outcome GD Plus DTC (N = 12) DTC Alone (N = 139) Overall (N = 151) Histology  Papillary 12 (100%) 131 (95%) 143 (95%)   Classic 3 (12%) 64 (49%) 67 (47%)   Follicular variant 0 32 (24%) 32 (22%)   Tall cell variant 2 (17%) 2 (2%) 4 (3%)   Diffuse sclerosing variant 0 14 (11%) 14 (10%)   Microcarcinomaa 7 (58%) 19 (15%) 26 (%18)  Follicular 0 8 (6%) 8 (5%)   Classic — 7 (88%) 7 (88%)   Diffuse — 1 (12%) 1 (2%)  Lymphovascular invasionb 3 (25%) 83 (60%) 86 (57%)  Extrathyroidal extension 4 (33%) 44 (32%) 48 (32%)  Staging (TNM)   Tumor T1 8 (67%) 54 (39%) 62 (41%)   T2 0 34 (24%) 34 (23%)   T3 4 (33%) 44 (32%) 48 (32%)   T4 0 6 (4%) 6 (4%)   Tx 0 1 (1%) 1 (1%)  Nodes   N0 4 (33%) 56 (40%) 60 (40%)   N1a 1 (8%) 39 (28%) 40 (26%)   N1b 2 (17%) 40 (29%) 42 (28%)   Nx 5 (42%) 4 (3%) 9 (6%)  Distant metastasis   M0 6 (50%) 116 (83%) 122 (81%)   M1 2 (17%) 17 (12%) 20 (13%)   Mx 4 33%) 6 (4%) 9 (6%) Nodules on final pathology  One 6 (50%) 87 (63%) 93 (62%)  Multiple 6 (50%) 52 (37%) 58 (38%) Surgical approach  Total thyroidectomy 12 (100%) 137 (99%) 149 (99%)  Central neck: unilateral 1 (8%) 59 (42%) 60 (40%)  Central neck: bilateral 3 (25%) 38 (27%) 41 (27%)  Lymph dissection: unilateral — 27 (19%) 27 (18%)  Lymph dissection: bilateral 2 (17%) 21 (15%) 22 (15%) Cervical metastasis 3 (25%) 76 (55%) 79 (52%) Pulmonary metastasis 2 (17%) 17 (12%) 19 (13%) RAI 5 (42%) 107 (77%) 112 (74%) Repeat RAI 2 (17%) 12 (9%) 14 (9%) Median (range) RAI dose 99.5 (0–263.4) 85.4 (0–279.4) 85.7 (0–279.4) Multiple surgeries 2 (17%) 30 (22%) 32 (21%)  Completion thyroidectomy 0 17 (12%) 17 (11%) Outcome  Remission 9 (75%) 119 (86%) 128 (85%)  Persistent disease 3 (25%) 17 (12%) 20 (13%)  Recurrence — 7 (5%) 7 (5%) GD Plus DTC (N = 12) DTC Alone (N = 139) Overall (N = 151) Histology  Papillary 12 (100%) 131 (95%) 143 (95%)   Classic 3 (12%) 64 (49%) 67 (47%)   Follicular variant 0 32 (24%) 32 (22%)   Tall cell variant 2 (17%) 2 (2%) 4 (3%)   Diffuse sclerosing variant 0 14 (11%) 14 (10%)   Microcarcinomaa 7 (58%) 19 (15%) 26 (%18)  Follicular 0 8 (6%) 8 (5%)   Classic — 7 (88%) 7 (88%)   Diffuse — 1 (12%) 1 (2%)  Lymphovascular invasionb 3 (25%) 83 (60%) 86 (57%)  Extrathyroidal extension 4 (33%) 44 (32%) 48 (32%)  Staging (TNM)   Tumor T1 8 (67%) 54 (39%) 62 (41%)   T2 0 34 (24%) 34 (23%)   T3 4 (33%) 44 (32%) 48 (32%)   T4 0 6 (4%) 6 (4%)   Tx 0 1 (1%) 1 (1%)  Nodes   N0 4 (33%) 56 (40%) 60 (40%)   N1a 1 (8%) 39 (28%) 40 (26%)   N1b 2 (17%) 40 (29%) 42 (28%)   Nx 5 (42%) 4 (3%) 9 (6%)  Distant metastasis   M0 6 (50%) 116 (83%) 122 (81%)   M1 2 (17%) 17 (12%) 20 (13%)   Mx 4 33%) 6 (4%) 9 (6%) Nodules on final pathology  One 6 (50%) 87 (63%) 93 (62%)  Multiple 6 (50%) 52 (37%) 58 (38%) Surgical approach  Total thyroidectomy 12 (100%) 137 (99%) 149 (99%)  Central neck: unilateral 1 (8%) 59 (42%) 60 (40%)  Central neck: bilateral 3 (25%) 38 (27%) 41 (27%)  Lymph dissection: unilateral — 27 (19%) 27 (18%)  Lymph dissection: bilateral 2 (17%) 21 (15%) 22 (15%) Cervical metastasis 3 (25%) 76 (55%) 79 (52%) Pulmonary metastasis 2 (17%) 17 (12%) 19 (13%) RAI 5 (42%) 107 (77%) 112 (74%) Repeat RAI 2 (17%) 12 (9%) 14 (9%) Median (range) RAI dose 99.5 (0–263.4) 85.4 (0–279.4) 85.7 (0–279.4) Multiple surgeries 2 (17%) 30 (22%) 32 (21%)  Completion thyroidectomy 0 17 (12%) 17 (11%) Outcome  Remission 9 (75%) 119 (86%) 128 (85%)  Persistent disease 3 (25%) 17 (12%) 20 (13%)  Recurrence — 7 (5%) 7 (5%) a P < 0.01. b P = 0.03. View Large Discussion Our study represents a cohort of children and young adults with concomitant GD and DTC compared with a comparable cohort diagnosed and followed with DTC. In our patient cohort, no significant differences were identified in clinical characteristics at the time of presentation in patients with and without GD. Specifically, patients with GD and DTC did not demonstrate a greater extent of metastases or higher burden of disease at the time of diagnosis when compared with pediatric patients with DTC alone. Although a higher percentage of patients with GD demonstrated tall-cell variant or microcarcinoma on histopathologic review, tumor histology did not correlate with overall or event-free survival. Furthermore, the long-term disease outcome remained similar in DTC patients with and without GD, suggesting that the presence of GD did not confer a more aggressive course with DTC in our pediatric cohort. The incidence of DTC in pediatric patients has increased during the last few decades (17), and DTC is the second most common malignancy, after Hodgkin lymphoma, in white, adolescent females, age 15 to 19 years (17). Importantly, there are notable clinical, molecular, and pathological differences in pediatric DTC when compared with adults, and children with DTC exhibit a more favorable progression-free survival compared with adults (18). Some of these important differences include: (1) a higher risk of malignancy (22% to 26% vs 5% to 10%) in an identified thyroid nodule in children compared with adults (19–21); (2) higher regional lymph node metastasis (22–24), extrathyroidal extension, and pulmonary metastasis even after controlling for histology and tumor size in pediatrics compared with adults (25); and (3) reduced long-term, cause-specific mortality in children with DTC (<2%) despite extensive disease at clinical presentation (26–28). Additionally, many children with DTC and pulmonary metastasis develop persistent yet stable disease, with continued clinical response as evident by a sustained decline in Tg levels following RAI treatment (29). In adults, a clear difference in the presentation as well as prognosis of patients with concomitant GD and DTC remains unclear, as these identified studies are limited by small sample size, cross-sectional retrospective design, and selection bias. Although several retrospective cross-sectional studies in adults have reported a higher disease burden in patients with GD compared with patients with sporadic DTC (7, 30), it remains uncertain whether adult patients with GD truly present with a higher DTC disease burden or demonstrate a different prognosis compared with DTC patients diagnosed with biochemical euthyroidism. In a study by Pellegriti et al. (11) where patients with GD and DTC were matched to euthyroid DTC controls, patients with concomitant GD and DTC demonstrated a higher metastatic burden at the time of DTC diagnosis, an increased rate of recurrence, and a higher overall mortality. In contrast, in two additional adult studies assessing patients with euthyroid nodules compared with GD with nodules, the DTC incidence and disease burden at diagnosis remained equal (30, 31). Similar to previous adult reports (8, 30, 32), our study demonstrated significantly higher incidence of carcinoma measuring less than <1 cm (microcarcinoma) in GD. These identified cases with low-risk papillary thyroid microcarcinomas were without lymph node metastasis, lymphovascular invasion, or extrathyroidal extension. Hence, these incidental microcarcinomas did not require radioiodine therapy or subsequent TSH suppressive therapies. Although GD is characterized by a marked decrease in the TSH, the TSI detected in GD demonstrates strong agonistic activity to the TSH receptor (33). Similar to normal thyroid cells, DTC neoplastic cells also express functional receptors for TSH, and the TSI-mediated overstimulation of the thyroid follicular cells may serve as a potential explanation for the higher incidence of DTC and papillary thyroid microcarcinomas found in GD patients (8). The tall-cell variant PTC histology accounts for 1.3% to 12% of all PTCs in pediatric and adult patients, respectively, and is usually associated with aggressive clinical features (34). Two previous adult studies reported a higher prevalence of tall-cell variant PTC in patients with GD (34, 35). In our study, 17% of patients with GD and PTC had features of tall-cell variant PTC compared with 2% of patients with PTC alone (Table 2), although the overall number of patients was small. The presence of nodular lesions in patients with GD is a recognized risk factor for DTC as compared with patients undergoing thyroidectomy for causes other than definitive therapy for GD (8, 9, 30). Other identified risk factors for concomitant disease in adult patients with GD and DTC include increased age, larger tumor burden at the time of diagnosis, and clinical signs (cervical lymphadenopathy or hoarseness due to laryngeal nerve infiltration) suspicious for DTC on examination (11). Thyroidectomy or RAI are both effective definitive treatment options for patients with GD (2, 36). Our data demonstrated that the widely accepted and used [131I] is safe; however, the high incidence of DTC in patients with GD suggests that this risk should be taken into account when deciding between definitive treatment options. Thyroid ultrasound imaging is a low-risk modality, and if a nodule with high risk features (15, 37) is identified, FNA should be performed prior to finalizing a decision on which definitive treatment option is best for an individual patient. The retrospective nature of our report, small sample of subjects with both GD and PTC, and selection bias from a large referral, tertiary center, may limit our ability to make unequivocal, generalizable conclusions about the prevalence and behavior of concurrent DTC in pediatric patients with GD compared with pediatric patients with DTC alone. However, to our knowledge, the comprehensive data collection for this study resulted in minimal missing information and did not affect our analysis. Despite these limitations, our study has several strengths. Importantly, to our knowledge, this is the first pediatric study to assess the impact of concurrent GD and DTC disease burden at the time of diagnosis and long-term prognosis in children and young adults. The results of this study also highlight the absence of increased metastatic burden at the time of DTC diagnosis in GD along with similar, excellent, long-term clinical course compared with pediatric patients with DTC alone. We think that thyroid ultrasound is a useful clinical tool for identifying pediatric patients with GD and abnormal thyroid nodules prior to definitive therapy. Predefinitive therapy thyroid ultrasound in GD patients allows for identifying patients with thyroid nodules that may harbor clinically significant DTC. For patients found to have a thyroid nodule with concerning features (15), FNA biopsy allows for optimal surgical planning and complete resection of disease. Although this approach may result in more FNAs, it is a procedure associated with a low risk of complications and high diagnostic accuracy (24). Additionally, FNA procedures are more cost-effective in the long run, given the cost of treatment delay from identifying a nodule on thyroid scintigraphy as well as the risk of incomplete surgery in the absence of complete preoperative ultrasound screening. Conclusions DTC in pediatric patients with GD exhibits a similar pattern of disease burden, metastasis, and, overall, demonstrates an excellent prognosis compared with pediatric patients with DTC alone. Preoperative thyroid ultrasound is an effective modality to identify abnormal nodular disease and to evaluate for presurgical thyroid carcinoma. Incidental papillary thyroid microcarcinomas are common in pediatric patients with underlying GD and are not associated with a risk of extrathyroidal extension or lymph node metastasis. Abbreviations: Abbreviations: CHOP Children’s Hospital of Philadelphia DTC differentiated thyroid cancer Dx-WBS diagnostic whole-body scan FNA fine needle aspiration GD Graves disease NS not significant PTC papillary thyroid cancer RAI radioactive iodine Tg thyroglobulin TSI thyroid stimulating Ig Acknowledgments Financial Support: This work was supported by National Institutes of Health Grants K07 CA166177 (to S.M.-M.) and K12 CA076931 (to S.P.M.). Author Contributions: S.P.M., A.J.B., J.N., and S.M.-M. designed the study. S.M.-M, J.N., and A.J.B. collected and assembled the data. S.M.-M and J.N. analyzed data and performed statistical analyses. S.M.-M, A.J.B., S.P.M., L.F.S., J.N., and N.S.A. interpreted the results. S.P.M and S.M.M. wrote the paper. S.P.M., A.J.B, N.S.A, L.F.S., J.N., K.K., and S.M.-M. reviewed and critiqued the manuscript and contributed to revisions. All authors approved the final manuscript. Disclosure Summary: The authors have nothing to disclose. References 1. 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Journal of Clinical Endocrinology and MetabolismOxford University Press

Published: Aug 1, 2018

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