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Surgical Management of Appendicular Skeletal Metastases in Thyroid Carcinoma

Surgical Management of Appendicular Skeletal Metastases in Thyroid Carcinoma Hindawi Publishing Corporation International Journal of Surgical Oncology Volume 2012, Article ID 417086, 12 pages doi:10.1155/2012/417086 Clinical Study Surgical Management of Appendicular Skeletal Metastases in Thyroid Carcinoma 1 1 2 2 Robert L. Satcher, Patrick Lin, Nursat Harun, Lei Feng, 1 1 Bryan S. Moon, and Valerae O. Lewis Department of Orthopaedic Oncology, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, FCT10.5044, Unit 1448, Houston, TX 77030, USA Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Correspondence should be addressed to Robert L. Satcher, rlsatcher@mdanderson.org Received 25 July 2012; Revised 16 October 2012; Accepted 30 October 2012 Academic Editor: Masaki Mori Copyright © 2012 Robert L. Satcher et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Bone is a frequent site of metastasis from thyroid carcinoma, but prognostic factors for patients who have surgery for thyroid carcinoma bone metastases are poorly understood. Methods. A retrospective review at a single institution identified 41 patients that underwent surgery in the appendicular skeleton for thyroid carcinoma bone metastasis from 1988 to 2011. Results. Overall patient survival probability by Kaplan-Meier analysis after surgery for bone metastasis was 72% at 1 year, 29% at 5 years, and 20% at 8 years. Patients who had their tumor excised (P = 0.001) or presented with solitary bone involvement had a lower risk of death following surgery adjusting for age and gender. Disease progression at the surgery site occurred more frequently with a histological diagnosis of follicular carcinoma compared with other subtypes (P = 0.023). Multivariate analysis showed that tumor subtype, chemotherapy, and preoperative radiation treatment had no effect on survival after surgery. Patients treated with radio- active iodine had better survival following thyroidectomy, but not following surgery for bone metastases. Conclusions.For patients undergoing surgery for thyroid cancer bone metastasis, resection of the bone metastasis, if possible, has a survival benefit. 1. Introduction that frequently metastasize to bone, such as lung and renal cell carcinoma [3–5, 7, 13–15]. After synchronous or meta- Distant metastases are found at diagnosis or followup in chronous BMs from thyroid carcinoma, 5-year survival has 10%–15% of patients with differentiated thyroid cancer [1– been reported to be from 29% to 69% [2, 5, 7, 9, 13–15]. 4]. Bone is the second most common site of metastasis after Complete resection of the BM is thought to be associated lung [1, 2, 4]. Patients with bone metastases (BMs), whether with better overall survival and can be curative [1, 7, 9, 12, isolated or associated with lung metastases, have a poor 15]. Prognosis also may improve if BMs are detected earlier prognosis, with ten-year survival rates ranging from 13%– [4, 5, 13, 16]. A recent study showed that BMs detected by I 21% [1, 5]. Several studies have examined the prognostic scanning had excellent response to I therapy [5]. Repeated factors and treatment outcomes for bone metastases from I therapy can be effective in targeting not only visible thyroid cancer, but few have evaluated the effects of surgical metastases, but also those too small to be imaged [17]. In management [2, 6–8]. contrast, there are no effective therapies for patients with Many of the lesions in the appendicular skeleton can poorly disseminated carcinomas that progress despite I be effectively managed by external beam radiation therapy therapy [5, 13, 18, 19]. Some recent studies have shown that (EBRT) or radioactive iodine [7, 9–12]. Some, however, patients with both lung metastases and BMs have similar require surgical intervention due to their symptoms and frac- survival as those with BMs alone, in contrast to historical ture risk [6–8]. Patients with BMs from thyroid carcinoma beliefs [1, 20]. Their survival is better than patients with generally have better survival than some other carcinomas metastases to other organs, such as the liver [1, 9]. 2 International Journal of Surgical Oncology The options for limb salvage reconstructions following Table 1: Patient demographics. partial or complete bone resections have increased in the Characteristic Number (total n = 41) recent years [21–26]. Surgical guidelines continue to evolve Gender and are not standardized. The goal of surgical management Female 22 has continued to be to establish a durable construct that lasts Male 19 the lifetime of the individual and simultaneously optimizes the quality of life via pain relief, mechanical stability, and Age (years) preservation of mobility [25, 27–29]. Because there have Mean 59 been few studies that evaluate the outcome of the surgical Range 12–82 management of BMs, the criteria for deciding whether these Followup (months) patients are treated with partial or complete BM resection Median 60 remain subjective [6, 8, 15]. Range 10–102 The goal of the present study was to determine the length Surgery sites of survival and prognostic factors for patients with thyroid Upper extremity (n = 16) carcinoma BMs who had surgery, as well as the type and Scapula 1 the survival of the various means of surgical reconstruction. Proximal humerus 5 In particular, we wished to evaluate whether the surgical Shaft humerus 4 implants lasted for the life of the patient, without the need for revision. We also examined the specific impact of BM Distal humerus 3 resection and histologic subtype of thyroid carcinoma on Radius 2 survival. Metacarpal 1 Lower extremity (n = 25) Acetabulum 8 2. Materials and Methods Proximal femur 12 2.1. Study Design. We performed a retrospective review of Shaft femur 4 patients treated surgically for osseous lesions secondary to Distal femur 1 metastatic thyroid carcinoma at a single institution between Skeletal presentation stage 1988 and 2011. Patients were identified by interrogating the Solitary bone metastasis 12 Department of Orthopaedic Oncology Surgical Database. Multiple bone metastases 29 The study was performed with the approval and in accor- dance with guidelines by the institutional review board. Medical records, operative reports, radiographic studies, and pathology reports were reviewed. tissue. The remaining 29 patients presented with metastases involving multiple bones. The most common site of syn- chronous metastasis in these patients was the lung (Figure 1). 2.2. Patients. There were 8681 patients with thyroid cancer Bone, soft tissue, and lymph nodes were the most common identified from institutional records. Of these, 550 developed locations for metachronous metastasis. bone metastases and 43 required skeletal surgery. The study Patients were followed for a minimum of 10 months population wascomposedof22females and21males.The unless they died prior to 12 months. The median duration median age at thyroid cancer diagnosis was 54 years (mean of the followup was 60 months (10–102 range). At the time 53, range 12–82), and at surgery for BM the median age was of the last followup, 11 of 41 patients were alive. All deaths 62 years (mean 59, range 12–82). Forty-three patients were were secondary to disease progression. Date of patient death identified that underwent surgery for bone metastases. Two was determined from patient records and the Social Security patients with surgery for lesions of the spine or cranium were Death Index. excluded as they were performed by Neurosurgeons. Forty one patients underwent operative intervention by the Mus- culoskeletal Oncology Service at 10 different sites for disease 2.3. Surgery. The site and type of surgery are summarized in the pelvis or appendicular skeleton. Patient demographics in Table 2. The indications for surgery included diagnosis are summarized in Table 1. Twenty-five patients (61%) had (biopsy), pathologic fracture, impending pathologic frac- synchronous bone metastases at the time of thyroid cancer ture, and intractable pain. Thirty-four patients had a surgery diagnosis. Sixteen patients (39%) developed metachronous that included tumor removal (curettage or wide resection), bone metastasis after thyroidectomy for the primary tumor. and seven patients did not (biopsy and bone stabilizing Twelve patients presented with solitary bone metastasis procedures). The total number of patients presenting at our (only one bone involved). Six of 12 patients with single bone institution with bone metastasis is shown in Table 3.Of metastasis had no other metastastic distant organ involve- the 8681 patients presenting with thyroid carcinoma, 550 ment. Two of the patients with single bone involvement had patients developed bone metastases, and 41 required surgery lung metastasis with no other organ involvement. The in the appendicular skeleton. For the 41 surgical cases, the remaining 4 patients with single bone involvement had syn- histological diagnosis was follicular carcinoma for 21 (51%), chronous metastases in the lymph nodes, liver, and soft papillary carcinoma for 6 (15%), Hurthle cell carcinoma for International Journal of Surgical Oncology 3 35 Table 2: Types of surgery. Tumor Number Category Procedure removal (n = 41) Median 150 cc EBL Range 0–2500 cc No (7 cases) Nail (closed) 3 Plate 1 Biopsy 3 Median 775 cc EBL Range 0–19900 cc Nail + PMMA 9 Yes Curettage Plate + PMMA 1 (34 cases) (19 cases) 10 Pins+PMMA 4 THA 5 Wide Endoprosthesis 12 5 resection 10 2 No reconstruction 3 1 (15 cases) 3 3 0 0 2.4. Statistical Analysis. Patient overall survival and local progression (recurrence) free survival was determined by Kaplan-Meier analysis, and the log rank test was used to compare the survival curves for different groups. Cox pro- Postop portional hazards model were also fitted. Local progression Preop was assessed by imaging studies. Local recurrence was Figure 1: The distribution of other metastatic disease sites at the defined as the reappearance on imaging studies of osseous of time of surgical intervention for osseous metastasis is shown in soft tissue tumor after prior excision. The Student’s t-test the lower bars. After surgery, the sites of subsequent metastases was used to compare means. The association of blood loss formation are shown in the upper bars. The most common site volume with tumor excision was assessed using the Wilcoxon of metastatic disease prior to surgery was lung. Following surgery, rank-sum test. SAS version 9.3 and S-Plus version 8.0 were bone was the most common site of new metastatic disease. used to perform all analyses. Statistical significance was defined as P< 0.05. 10 (24%), medullary carcinoma for 2 (5%), and anaplastic 3. Results for 2 (5%). The most common surgical site was the femur, 3.1. Survival. Overall patient survival probability by Kaplan- followed by the humerus, pelvis, radius, and then scapula. Meier analysis after surgery for bone metastasis was 72% at Thirty-seven of the 41 surgical patients were treated with 1 year, 29% at 5 years, and 20% at 8 years. Median survival radioactive iodine ( I). At our institution, the standard from time of skeletal surgery was 1.9 years (range 1.2–4.2, treatment for patients that present without metastasis (Stage Figure 2(a)). At the time of the last followup, 11 patients were I disease) is thyroidectomy and lymph node dissection, fol- alive. Patients who had their tumor excised had a lower risk lowed by radioactive iodine for the initial treatment. Patients of death following surgery adjusting for age and gender (P = presenting with bone metastasis (or other distant organ 0.001, Figure 2(b)). Univariate analysis showed that radioac- involvement) also have thyroidectomy and then receive tive iodine treatment, tumor subtype, chemotherapy, and radioactive iodine if there is no prior history of treatment, preoperative radiation treatment had no effect on survival and/or iodine tracer uptake at metastatic sites. after skeletal surgery (Table 4). Patients with a solitary bone Seven of the 41 surgical patients had preoperative radia- metastasis at the time of presentation also showed a trend tion to the bone metastatic site. Four patients received che- for improved survival relative to those with multiple bone motherapy instead of I. Thirty-eight of the patients had metastases, although not statistically significant (P = 0.07). complete thyroidectomies (one patient had a partial thy- Tumor excision and age were also significant prognostic fac- roidectomy). Surgical treatment of bone metastases included tors by multivariate analysis (Table 5). excision in 34 cases (16 with en bloc resection and 18 with In comparison, median survival after thyroidectomy in curettage). In 7 cases, the tumor was not removed, and the the same patient group was 5 years (range 0.8–8.5). Overall bone was simply stabilized. survival probability was 62% at 5 years and 35% at 10 years Adrenal Bone Brain Kidney Liver Lungs Lymph nodes Soft tissue Skull Vascular 4 International Journal of Surgical Oncology Table 3: Thyroid cancer diagnosis subtypes, bone metastases, and bone surgery sites. Patients with bone Patients who had surgery on Other treatments Thyroid cancer Total number of metastases bone metastases (percentage of Surgery sites (patients treated/total subtype patients (percentage of total) pts with bone mets) getting surgery) XRT, chemo Anaplastic 264 22 (8.3) 2 (9.1) Femur (2) (2/2) Hand metacarpal (1), radius (1), XRT Follicular 637 96 (15.1) 21 (21.9) humerus (6), (2/21) pelvis (5), femur (8) Humerus (5), scapula (1), XRT, chemo Hurthle 342 44 (12.9) 10 (22.7) pelvis (2), (4/10) femur (2) Humerus (1), Chemo Medullary 866 134 (15.5) 2 (1.5) femur (1) (1/2) Radius (1), Papillary 6572 254 (3.9) 6 (2.4) humerus (1), None femur (4) Total 8681 550 (6.3) 41 (7.5) (Figure 2(c)). After thyroidectomy, patients treated with In all cases of local progression, additional surgery was radioactive iodine had better survival than those who did not performed with hardware revision to either intercalary pros- (P = 0.002, Figure 2(d)). thesis, endoprosthesis, or joint replacement. One patient who The majority of patients (n = 23) had BM at the time of was treated with an intramedullary nail for a humerus metas- diagnosis of thyroid cancer. The median time to metastasis tasis developed increasing pain, fracture, and progression for patients (n = 16) without distant disease at the time of of disease 4 years after surgery. The recurrent tumor was thyroid cancer diagnosis was 2.72 years (Figure 3(a)). In these resected, and the nail was converted to a total humerus endo- patients the time to metastasis had no dependence thyroid prosthesis (Figures 3(d)–3(g)). The patient was alive at the tumor subtype or treatment modality. last followup 2 years after surgery to resect the recurrence. Serum thyroglobulin (TGB) levels were measured both Thehazardratio forrecurrencefreesurvivalwas 0.28 (P = pre- and postoperatively in 26 of 41 patients. In 22 patients, 0.012, 95% C.I. from 0.11 to 0.75, Table 4) for patients who the serum TGB levels decreased following bone metastasis had bone metastasis tumor excision compared to patients surgery. Preoperative serum TGBs ranged from 100 to 13000; who did not. Kaplan-Meier analysis demonstrates worse with the percentage of decrease after bone metastasis surgery recurrence free survival for patients who did not have ranging from 9%–99%. In the 4 patients where there was surgical tumor excision for control of metastatic disease no TGB decrease, 3 had widely metastasis disease involving (Figure 4(a), P = 0.007), and for patients that presented with multiple bones, and the skeletal surgery only addressed one multiple sites of bone metastasis (Figure 4(b), P = 0.036). site of bone involvement. The one remaining patient with no decrease in TGB had a biopsy, wherein the bone metastasis 131 3.3. Radiation. Patients treated with radioactive iodine ( I) was not removed. had better survival following thyroidectomy (P = 0.002), but not following surgery for bone metastases (Figures 5(a)- 3.2. Local Recurrence. Eight of 41 cases were complicated 5(b)). by local recurrence. The local progression free survival was Seven patients failed prior to palliative external radiation 89% at 1 year (80%–100%, 95% C.I.), 60% at 5 years (37%– of osseous metastases and subsequently underwent surgical 96%, 95% C.I.), and 40% at 8 years (16%–100%, 95% C.I.) treatment. Preoperative external beam radiation to the (Figure 3(b)). All cases of recurrence occurred in patients affected bone had no significant effect on overall patient with a diagnosis of the follicular subtype of thyroid carci- survival after skeletal surgery (Table 4). There was a trend noma, which was statistically significant via Kaplan-Meier towards a higher risk of recurrence in patients who had pre- analysis, in comparison to papillary, medullary, anaplastic, operative radiation to the bone, although it did not achieve and Hurthle cell subtypes, where there were no recurrences statistical significance (P = 0.08). One of the seven patients (P = 0.016, Figure 3(c)). In contrast to overall survival, developed a local recurrence after surgery for the osseous whether the metastasis was excised had no significant effect lesion. This patient had excision of the recurrent lesion and on the probability of local recurrence. All cases of local prog- hardware revision to acetabular reconstruction with total hip ression occurred in patients who had tumor excision. arthroplasty. International Journal of Surgical Oncology 5 Table 4: Univariate Cox model. Overall survival Time to bone metastasis Survival after bone metastasis surgery Recurrence free survival Prognostic factors Hazard Hazard Hazard Hazard 95% CI P value 95% CI P value 95% CI P value 95% CI P value ratio ratio ratio ratio Age 1.06 1.02–1.09 0.001 1.06 1.005–1.116 0.032 1.002 0.975–1.03 0.864 1.012 0.98–1.04 0.41 Gender 1.19 0.55–2.38 0.66 0.63 0.21–1.83 0.39 1.63 0.76–3.50 0.21 1.795 0.87–3.7 0.113 FvM Follicular subtype 1.1 0.51–2.37 0.81 1.26 0.43–3.71 0.68 0.83 0.40–1.73 0.63 1.33 0.63–2.81 0.45 Radioactive iodine Y v N 0.18 0.05–0.61 0.006 0.07 0.005–1.186 0.066 0.54 0.18–1.62 0.27 0.504 0.16–1.53 0.23 Other treatment Y v N 1.51 0.63–3.62 0.36 1.721 0.55–5.34 0.35 0.95 0.40–2.25 0.91 0.72 0.29–1.78 0.48 Skeletal presentation 0.044 2.44 0.93–6.44 0.07 3.03 1.03–8.92 Multiple bone v single Preoperative radiation to 1.985 0.73–5.38 0.18 1.74 0.65–4.68 0.27 bone Y v N Tumor excised from bone 0.21 0.075–0.58 0.003 0.28 0.11–0.75 0.012 YvN 6 International Journal of Surgical Oncology Table 5: Multivariate Cox model. Overall survival Survival after bone metastasis surgery Recurrence free survival Prognostic factors Hazard ratio 95% CI P value Hazard ratio 95% CI P value Hazard ratio 95% CI P value Age 1.054 1.02–1.09 0.002 Radioactive iodine Y v N 0.164 0.041–0.654 0.0104 Follicular subtype 1.589 0.646–3.910 0.313 0.832 0.396–1.748 0.627 1.547 0.706–3.39 0.276 Skeletal presentation 2.102 0.783–5.643 0.141 3.097 1.008–9.521 0.0485 Multiple bone v single Tumor excised from bone 0.242 0.087–0.677 0.0068 0.336 0.125–0.903 0.0306 International Journal of Surgical Oncology 7 Overall survival following skeletal surgery Tumor excised P-value = 0.001 0.8 0.8 0.6 0.6 0.4 0.4 0.2 0.2 0 2 4 6 8 0 2 4 6 8 Years Time after skeletal surgery (years) No (event/N = 6/7) Yes (event/N = 24/34) (a) (b) Overall survival following thyroid cancer diagnosis Radioactive iodine and survival 0.8 0.8 P-value = 0.002 0.6 0.6 0.4 0.4 0.2 0.2 0 5 10 15 20 25 30 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Years Time after thyroid removal (years) No (event/N = 4/4) Yes (event/N = 25/35) (c) (d) Figure 2: Kaplan-Meier analysis of patient survival. (a) Following surgery for osseous metastases patient survival was 72% at 1 year (95% CI 59–87%), 29% at 5 years (95% CI 17–49%), and 20% at 8 years (95% CI 10–42%). (b) There was better survival for patients when the metastastic osseous tumor was excised versus not excised. The median survival time for patients with tumor excision was 2 years (95% CI 1.4–5 years), compared with 0.6 years (95% CI 0.1–1.8 years) for patients without tumor excision (P = 0.001). No patient without tumor excision survived beyond 1.8 years. (c) Following thyroidectomy at initial diagnosis of thyroid carcinoma patient survival was 62% at 5 years (95% CI 48–80%), 35% at 10 years (95% CI 21–58%), 17% at 20 years (95% CI 7–41%), and 9% at 30 years (95% CI 2–32%). (d) After thyroid removal, patients who received radioactive iodine treatment had better survival than those who did not (P = 0.002). 3.4. Surgical Complications. Two patients had immediate patient became hypoxic and tachycardic during a hemiarth- perioperative complications. One patient with a history roplasty of the contralateral hip which immediately followed of smoking had respiratory insufficiency requiring delayed intramedullary nailing of the opposite femur. The hemi- extubation. One other patient had atrial fibrillation. Both arthroplasty procedure was aborted, and the patient had subsequently recovered uneventfully. There were no super- an uneventful subsequent recovery. There were no deaths ficial or deep infections, nonunions, or perioperative deaths. related to intraoperative blood loss. The mean blood loss of 1014 mL (range 0–3900 mL) for the cases where the tumor was not removed (n = 7) did not differ significantly from cases where tumor was excised 4. Discussion (mean = 1640 mL, range 0–19900 mL, n = 34). One patient became hemodynamically unstable during the second of The results of this study suggest that metastatic thyroid can- bilateral procedures for skeletal metastases. Specifically, the cer in bone is rare, but behaves aggressively. Surgery for bone Probability Probability Probability Probability 8 International Journal of Surgical Oncology Thyroid cancer subtype and Local recurrence following skeletal recurrence Time to skeletal metastasis surgery P-value = 0.016 0.8 0.8 0.8 0.6 0.6 0.6 0.4 0.4 0.4 0.2 0.2 0.2 0 0 0 5 10 15 20 02468 02468 Years Years Years Follicular (event/N = 5/23) Other (event/N = 0/15) (a) (b) (c) (d) (e) (f) (g) Figure 3: Progression of disease in bone. (a) Kaplan-Meier analysis of time to formation of skeletal metastasis. The median time to formation of bone metastasis after thyroid removal was 3.44 years. (b) Kaplan-Meier analysis of time to recurrence. The probability of recurrence free survival was 89% at 1 year (95% CI 80–100%), 60% at 5 years (95% CI 37–96%), and 40% at 8 years (95% CI 16–100%). (c) A diagnosis of follicular thyroid carcinoma was associated with a higher risk of recurrence versus other diagnoses (papillary, medullary, anaplastic, and Hurthle cell) (P = 0.016). All recurrences following surgery for osseous metastasis were in patients with follicular thyroid carcinoma histo- logic diagnosis. (d) A patient with an impending fracture of the proximal humerus shaft from isolated metastasis from follicular thyroid carcinoma underwent open nailing with curettage and cementation. (e) Postoperative X-ray demonstrates a humeral nail and bone cement filling the defect created by curettage of the metastasis. (f) Follow-up X-ray 5 years after surgery showing increasing lytic changes in bone extending to the distal aspect of the humerus, consistent with local progression of disease. (g) Postoperative X-ray showing total humerus endoprosthesis. The humerus, intramedullary nail, and bone cement were resected en bloc. The total humerus endoprosthesis reconstruction has remained stable, and the patient remains alive with no sign of disease. metastasis in thyroid carcinoma has been infrequently stud- appropriate that patients who have limited expected lifespan ied [6–8]. In 23 years at our institution there were only 41 should receive conservative treatment, our study shows a patients that required surgery for appendicular skeleton survival advantage for patients who had undergone surgical metastases. During the same period, 8681 patients with thy- excision of metastatic disease from bone. roid carcinoma were registered at our institution. Thus only Thyroid cancer generally has an indolent nature, so that approximately 0.5% of the patients required surgery for patients requiring skeletal surgery presented with bone meta- metastatic lesions in the appendicular skeleton. This study stasis both in late stages after treatment (16 of 41 patients) also shows that after bone metastasis occurs, survival is dimi- and with initial presentation (25 of 41 patients). Our study nished, in agreement with published reports [1, 2, 7, 9, 10, corroborates findings that survival with metastatic thyroid 16]. Few patients survived more than 8 years after having cancer tends to be better than some other cancers that surgery for bone metastasis [1, 15]. While it may seem metastasize to bone, such as renal cell carcinoma and lung Probability Probability Probability International Journal of Surgical Oncology 9 Tumor excised Skeletal presentation stage 0.8 0.8 P-value = 0.036 P-value = 0.007 0.6 0.6 0.4 0.4 0.2 0.2 02 46 8 0 2 4 6 8 Time to recurrence or death following surgery at Time to recurrence or death following surgery at MDACC (years) MDACC (years) No (event/N = 6/7) Multiple (event/N = 26/29) Yes (event/N = 25/31) Single (event/N = 5/9) (a) (b) Figure 4: Kaplan-Meier analysis for recurrence free survival, as determined by the probability of no recurrence or death. (a) Patients had a higher probability of recurrence free survival if the osseous metastasis was excised versus no excision (P = 0.007). All patients that had surgeries where the metastasis were not excised died (n = 6) or were lost to followup (n = 1). (b) Patients had a higher probability of recurrence free survival if they presented with a single bone metastasis versus multiple bones (P = 0.036). Five of the 9 (56%) patients with single bone metastasis at presentation were alive at last followup, compared with 6 of 29 (21%) patients who presented with multiple bone metastasis. Radioactive iodine Radioactive iodine 0.8 0.8 P-value = 0.002 P-value = 0.261 0.6 0.6 0.4 0.4 0.2 0.2 0 0 0 2 4 6 8 1012141618202224262830 0 2 4 6 8 Survival after thyroid removal (years) Survival following skeletal surgery (years) No (event/N = 4/4) No (event/N = 4/4) Yes (event/N = 25/35) Yes (event/N = 26/37) (a) (b) Figure 5: Kaplan-Meier analysis of the effect of radioactive iodine treatment on survival. (a) After thyroidectomy, patients treated with radio- active iodine had more favorable survival than those who were not candidates for radioactive iodine (P = 0.002). No patients who were not treated with radioactive iodine survived more than 3 years. (b) After surgery for osseous metastasis, there was no significant difference in survival between patients treated with radioactive iodine and those who were not (P = 0.261). carcinoma [2, 6, 14]. Three patients in this series survived Despite the survival advantage afforded by more aggres- for more than 30 years after their initial diagnosis, despite sive tumor removal, whether a patient underwent tumor developing metastases in multiple bones and organs. The excision did not affect whether there was local progression median survival for patients in our series was 7.6 years for patients with follicular carcinoma subtype. There was, following initial diagnosis. however, considerable morbidity for patients who developed Probability Probability Probability Probability 10 International Journal of Surgical Oncology uncontrolled tumor growth at metastatic osseous sites. In patients, surgical extirpation of solitary bone metastases was our study, all of the patients with local recurrence required associated with improved survival. additional surgical procedures. Total thyroidectomy followed by radioactive iodine is the treatment most often recommended for patients with There was no survival advantage or disadvantage follow- synchronous distant metastases to bone. It has been argued ing thyroid cancer diagnosis or surgery for bone metastasis that I is the only opportunity to slow progression and to associated with subtype, although bone metastases are more prolong survival [5]. Our study shows that patients treated common with the follicular subtype. Follicular thyroid can- with radioactive iodine have a clear survival advantage fol- cer accounts for less than 15% of all differentiated thyroid lowing thyroidectomy, that is less clear and likely diminished cancers, but has a relatively high incidence of bone metas- following skeletal surgery (Figure 5). A possible explanation tases, ranging from 7% to 28% [7, 9]. In our study, 6% of all is that the patients undergoing skeletal surgery have devel- patients developed bone metastases, and 7% of all patients oped bone metastases despite receiving I and therefore had follicular carcinoma. Of the patients with follicular have more aggressive disease. A similar trend was observed carcinoma, 15% developed bone metastases. Of the patients in patients that failed palliative external radiation. The prog- with bone metastases, 8% required skeletal surgery, and nosis for these patients was worse, although it did not achieve 21/43 (50%) of these patients had follicular carcinoma. All statistical significance. Of the 7 patients that failed palliative of the local recurrences occurred in patients with follicular XRT, 5 were known to have died within 4 years of surgery, thyroid carcinoma BM. Thus, the follicular subtype was with the other 2 patients lost to followup. associated with increased probability for local recurrence The involvement of multiple bones precludes curative compared with other subtypes (Figure 3(c)). There was no resection of bony disease. Of the 24 patients who had excision selection bias for the surgical procedure used in patients of the bone metastasis, 10 had solitary bone involvement. with recurrence, as they were almost evenly divided between At the last followup 5 of the 10 were alive, 4 died, and one curettage (4) and wide resection (3). Therefore, the reasons was lost to followup. Others studies have reported similar for the aggressiveness of follicular thyroid carcinoma in bone outcomes, with a significant improvement in survival with are not identifiable from the limited patient cohort included complete resection of skeletal metastases [1, 6]. For patients in the current study but deserve further study. that presented with multiple synchronous bone metastases, Bone metastases are much less common in papillary thy- surgical intervention afforded palliation for symptomatic roid cancer, with a reported incidence from 1% to7% [14]. disease that failed nonoperative interventions. Palliative In our study, the incidence of papillary carcinoma was 3%. surgery partially removes bone tumor or completely resects One comparable study that focused exclusively on patients bone tumor but leaves residual tumor in other organs [7]. In with BM reported that in 96 patients, 17% had papillary accordance with this, there was poorer recurrence free sur- histological diagnosis, and 71% were follicular [1]. Our vival observed in patients with multiple bone involvement. study cohort had similar proportionality, with three times as In patients with multiple organ involvement, the role of many patients with BM from follicular thyroid cancer than metastectomy is less well understood. In this study, two papillary thyroid cancer. patients with solitary skeletal metastasis at presentation did Anaplastic thyroid carcinoma typically has a poor prog- not have surgical extirpation of the BM because of syn- nosis. It is known to be the most lethal among all thyroid chronous involvement in other organs. One of these patients cancers, with median life expectancies reported to be from had stabilization of a lesion in the radius with a plate, fol- 4to12months [30–34]. Our results are consistent with lowed by external radiation. This patient was alive at 2-year more recent reports of marginally improved survival with followup, but went on to develop additional bone lesions in multimodal treatment strategies [31, 32]. Both patients with the clavicle and scapula. The other patient had synchronous anaplastic thyroid carcinoma in our study received additional lesions in the lungs and liver and a solitary lesion in the femur chemotherapy (doxorubicin based) and external radiation. that was stabilized by intramedullary nail and treated with One patient died at 23 months and the other died at 27 external radiation postoperatively. The patient died 8 months months following diagnosis. after surgery. Studies show that more than 80% of bone metastases In one compendium of 13 studies, the rate of bone from all thyroid tumors are located in the axial skeleton metastasis was found to be 25% among 1231 patients [12]. A [2]. Correspondingly, 41 out of 43 patients (95%) in our more recent study showed that survival decreased by 14% in cohort had axial BMs. The propensity for the axial skeleton patients older than 40 years with lung metastases or multiple is thought to be secondary to blood flow distribution char- bone metastases compared with comparable cohorts [9]. acteristics, and the bone microenvironment, which includes Other studies suggest that patients older than 45 years have growth factors favorable for tumor growth [2]. a poorer prognosis for remission following treatment with There are few studies on survival following surgery for radioactive iodine [2]. Our findings are consistent with these bone metastasis [3, 10, 35]. Reports have shown that removal reports. of up to five bone metastases can be associated with improved survival and quality of life [1, 8, 15]. Therefore, some have 5. Conclusions strongly recommended surgical excision for accessible, soli- tary metastases. Our study results agree with this, especially In conclusion, the development of osseous metastases from for patients without extra-skeletal metastases. In these thyroid carcinoma is associated with poorer patient survival International Journal of Surgical Oncology 11 and prognosis. Patients with multiple bone metastases had [13] Y. Orita, I. Sugitani, M. Matsuura et al., “Prognostic factors and the therapeutic strategy for patients with bone metastasis poorer survival than those with solitary bone metastases. from differentiated thyroid carcinoma,” Surgery, vol. 147, no. While 28% of patients died within a year of surgery for bone 3, pp. 424–431, 2010. metastases, 20% remained alive at 8 years. Patients who res- [14] J. A. Wexler and J. 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Surgical Management of Appendicular Skeletal Metastases in Thyroid Carcinoma

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Hindawi Publishing Corporation
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Copyright © 2012 Robert L. Satcher et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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2090-1402
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2090-1410
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10.1155/2012/417086
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Hindawi Publishing Corporation International Journal of Surgical Oncology Volume 2012, Article ID 417086, 12 pages doi:10.1155/2012/417086 Clinical Study Surgical Management of Appendicular Skeletal Metastases in Thyroid Carcinoma 1 1 2 2 Robert L. Satcher, Patrick Lin, Nursat Harun, Lei Feng, 1 1 Bryan S. Moon, and Valerae O. Lewis Department of Orthopaedic Oncology, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, FCT10.5044, Unit 1448, Houston, TX 77030, USA Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Correspondence should be addressed to Robert L. Satcher, rlsatcher@mdanderson.org Received 25 July 2012; Revised 16 October 2012; Accepted 30 October 2012 Academic Editor: Masaki Mori Copyright © 2012 Robert L. Satcher et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Bone is a frequent site of metastasis from thyroid carcinoma, but prognostic factors for patients who have surgery for thyroid carcinoma bone metastases are poorly understood. Methods. A retrospective review at a single institution identified 41 patients that underwent surgery in the appendicular skeleton for thyroid carcinoma bone metastasis from 1988 to 2011. Results. Overall patient survival probability by Kaplan-Meier analysis after surgery for bone metastasis was 72% at 1 year, 29% at 5 years, and 20% at 8 years. Patients who had their tumor excised (P = 0.001) or presented with solitary bone involvement had a lower risk of death following surgery adjusting for age and gender. Disease progression at the surgery site occurred more frequently with a histological diagnosis of follicular carcinoma compared with other subtypes (P = 0.023). Multivariate analysis showed that tumor subtype, chemotherapy, and preoperative radiation treatment had no effect on survival after surgery. Patients treated with radio- active iodine had better survival following thyroidectomy, but not following surgery for bone metastases. Conclusions.For patients undergoing surgery for thyroid cancer bone metastasis, resection of the bone metastasis, if possible, has a survival benefit. 1. Introduction that frequently metastasize to bone, such as lung and renal cell carcinoma [3–5, 7, 13–15]. After synchronous or meta- Distant metastases are found at diagnosis or followup in chronous BMs from thyroid carcinoma, 5-year survival has 10%–15% of patients with differentiated thyroid cancer [1– been reported to be from 29% to 69% [2, 5, 7, 9, 13–15]. 4]. Bone is the second most common site of metastasis after Complete resection of the BM is thought to be associated lung [1, 2, 4]. Patients with bone metastases (BMs), whether with better overall survival and can be curative [1, 7, 9, 12, isolated or associated with lung metastases, have a poor 15]. Prognosis also may improve if BMs are detected earlier prognosis, with ten-year survival rates ranging from 13%– [4, 5, 13, 16]. A recent study showed that BMs detected by I 21% [1, 5]. Several studies have examined the prognostic scanning had excellent response to I therapy [5]. Repeated factors and treatment outcomes for bone metastases from I therapy can be effective in targeting not only visible thyroid cancer, but few have evaluated the effects of surgical metastases, but also those too small to be imaged [17]. In management [2, 6–8]. contrast, there are no effective therapies for patients with Many of the lesions in the appendicular skeleton can poorly disseminated carcinomas that progress despite I be effectively managed by external beam radiation therapy therapy [5, 13, 18, 19]. Some recent studies have shown that (EBRT) or radioactive iodine [7, 9–12]. Some, however, patients with both lung metastases and BMs have similar require surgical intervention due to their symptoms and frac- survival as those with BMs alone, in contrast to historical ture risk [6–8]. Patients with BMs from thyroid carcinoma beliefs [1, 20]. Their survival is better than patients with generally have better survival than some other carcinomas metastases to other organs, such as the liver [1, 9]. 2 International Journal of Surgical Oncology The options for limb salvage reconstructions following Table 1: Patient demographics. partial or complete bone resections have increased in the Characteristic Number (total n = 41) recent years [21–26]. Surgical guidelines continue to evolve Gender and are not standardized. The goal of surgical management Female 22 has continued to be to establish a durable construct that lasts Male 19 the lifetime of the individual and simultaneously optimizes the quality of life via pain relief, mechanical stability, and Age (years) preservation of mobility [25, 27–29]. Because there have Mean 59 been few studies that evaluate the outcome of the surgical Range 12–82 management of BMs, the criteria for deciding whether these Followup (months) patients are treated with partial or complete BM resection Median 60 remain subjective [6, 8, 15]. Range 10–102 The goal of the present study was to determine the length Surgery sites of survival and prognostic factors for patients with thyroid Upper extremity (n = 16) carcinoma BMs who had surgery, as well as the type and Scapula 1 the survival of the various means of surgical reconstruction. Proximal humerus 5 In particular, we wished to evaluate whether the surgical Shaft humerus 4 implants lasted for the life of the patient, without the need for revision. We also examined the specific impact of BM Distal humerus 3 resection and histologic subtype of thyroid carcinoma on Radius 2 survival. Metacarpal 1 Lower extremity (n = 25) Acetabulum 8 2. Materials and Methods Proximal femur 12 2.1. Study Design. We performed a retrospective review of Shaft femur 4 patients treated surgically for osseous lesions secondary to Distal femur 1 metastatic thyroid carcinoma at a single institution between Skeletal presentation stage 1988 and 2011. Patients were identified by interrogating the Solitary bone metastasis 12 Department of Orthopaedic Oncology Surgical Database. Multiple bone metastases 29 The study was performed with the approval and in accor- dance with guidelines by the institutional review board. Medical records, operative reports, radiographic studies, and pathology reports were reviewed. tissue. The remaining 29 patients presented with metastases involving multiple bones. The most common site of syn- chronous metastasis in these patients was the lung (Figure 1). 2.2. Patients. There were 8681 patients with thyroid cancer Bone, soft tissue, and lymph nodes were the most common identified from institutional records. Of these, 550 developed locations for metachronous metastasis. bone metastases and 43 required skeletal surgery. The study Patients were followed for a minimum of 10 months population wascomposedof22females and21males.The unless they died prior to 12 months. The median duration median age at thyroid cancer diagnosis was 54 years (mean of the followup was 60 months (10–102 range). At the time 53, range 12–82), and at surgery for BM the median age was of the last followup, 11 of 41 patients were alive. All deaths 62 years (mean 59, range 12–82). Forty-three patients were were secondary to disease progression. Date of patient death identified that underwent surgery for bone metastases. Two was determined from patient records and the Social Security patients with surgery for lesions of the spine or cranium were Death Index. excluded as they were performed by Neurosurgeons. Forty one patients underwent operative intervention by the Mus- culoskeletal Oncology Service at 10 different sites for disease 2.3. Surgery. The site and type of surgery are summarized in the pelvis or appendicular skeleton. Patient demographics in Table 2. The indications for surgery included diagnosis are summarized in Table 1. Twenty-five patients (61%) had (biopsy), pathologic fracture, impending pathologic frac- synchronous bone metastases at the time of thyroid cancer ture, and intractable pain. Thirty-four patients had a surgery diagnosis. Sixteen patients (39%) developed metachronous that included tumor removal (curettage or wide resection), bone metastasis after thyroidectomy for the primary tumor. and seven patients did not (biopsy and bone stabilizing Twelve patients presented with solitary bone metastasis procedures). The total number of patients presenting at our (only one bone involved). Six of 12 patients with single bone institution with bone metastasis is shown in Table 3.Of metastasis had no other metastastic distant organ involve- the 8681 patients presenting with thyroid carcinoma, 550 ment. Two of the patients with single bone involvement had patients developed bone metastases, and 41 required surgery lung metastasis with no other organ involvement. The in the appendicular skeleton. For the 41 surgical cases, the remaining 4 patients with single bone involvement had syn- histological diagnosis was follicular carcinoma for 21 (51%), chronous metastases in the lymph nodes, liver, and soft papillary carcinoma for 6 (15%), Hurthle cell carcinoma for International Journal of Surgical Oncology 3 35 Table 2: Types of surgery. Tumor Number Category Procedure removal (n = 41) Median 150 cc EBL Range 0–2500 cc No (7 cases) Nail (closed) 3 Plate 1 Biopsy 3 Median 775 cc EBL Range 0–19900 cc Nail + PMMA 9 Yes Curettage Plate + PMMA 1 (34 cases) (19 cases) 10 Pins+PMMA 4 THA 5 Wide Endoprosthesis 12 5 resection 10 2 No reconstruction 3 1 (15 cases) 3 3 0 0 2.4. Statistical Analysis. Patient overall survival and local progression (recurrence) free survival was determined by Kaplan-Meier analysis, and the log rank test was used to compare the survival curves for different groups. Cox pro- Postop portional hazards model were also fitted. Local progression Preop was assessed by imaging studies. Local recurrence was Figure 1: The distribution of other metastatic disease sites at the defined as the reappearance on imaging studies of osseous of time of surgical intervention for osseous metastasis is shown in soft tissue tumor after prior excision. The Student’s t-test the lower bars. After surgery, the sites of subsequent metastases was used to compare means. The association of blood loss formation are shown in the upper bars. The most common site volume with tumor excision was assessed using the Wilcoxon of metastatic disease prior to surgery was lung. Following surgery, rank-sum test. SAS version 9.3 and S-Plus version 8.0 were bone was the most common site of new metastatic disease. used to perform all analyses. Statistical significance was defined as P< 0.05. 10 (24%), medullary carcinoma for 2 (5%), and anaplastic 3. Results for 2 (5%). The most common surgical site was the femur, 3.1. Survival. Overall patient survival probability by Kaplan- followed by the humerus, pelvis, radius, and then scapula. Meier analysis after surgery for bone metastasis was 72% at Thirty-seven of the 41 surgical patients were treated with 1 year, 29% at 5 years, and 20% at 8 years. Median survival radioactive iodine ( I). At our institution, the standard from time of skeletal surgery was 1.9 years (range 1.2–4.2, treatment for patients that present without metastasis (Stage Figure 2(a)). At the time of the last followup, 11 patients were I disease) is thyroidectomy and lymph node dissection, fol- alive. Patients who had their tumor excised had a lower risk lowed by radioactive iodine for the initial treatment. Patients of death following surgery adjusting for age and gender (P = presenting with bone metastasis (or other distant organ 0.001, Figure 2(b)). Univariate analysis showed that radioac- involvement) also have thyroidectomy and then receive tive iodine treatment, tumor subtype, chemotherapy, and radioactive iodine if there is no prior history of treatment, preoperative radiation treatment had no effect on survival and/or iodine tracer uptake at metastatic sites. after skeletal surgery (Table 4). Patients with a solitary bone Seven of the 41 surgical patients had preoperative radia- metastasis at the time of presentation also showed a trend tion to the bone metastatic site. Four patients received che- for improved survival relative to those with multiple bone motherapy instead of I. Thirty-eight of the patients had metastases, although not statistically significant (P = 0.07). complete thyroidectomies (one patient had a partial thy- Tumor excision and age were also significant prognostic fac- roidectomy). Surgical treatment of bone metastases included tors by multivariate analysis (Table 5). excision in 34 cases (16 with en bloc resection and 18 with In comparison, median survival after thyroidectomy in curettage). In 7 cases, the tumor was not removed, and the the same patient group was 5 years (range 0.8–8.5). Overall bone was simply stabilized. survival probability was 62% at 5 years and 35% at 10 years Adrenal Bone Brain Kidney Liver Lungs Lymph nodes Soft tissue Skull Vascular 4 International Journal of Surgical Oncology Table 3: Thyroid cancer diagnosis subtypes, bone metastases, and bone surgery sites. Patients with bone Patients who had surgery on Other treatments Thyroid cancer Total number of metastases bone metastases (percentage of Surgery sites (patients treated/total subtype patients (percentage of total) pts with bone mets) getting surgery) XRT, chemo Anaplastic 264 22 (8.3) 2 (9.1) Femur (2) (2/2) Hand metacarpal (1), radius (1), XRT Follicular 637 96 (15.1) 21 (21.9) humerus (6), (2/21) pelvis (5), femur (8) Humerus (5), scapula (1), XRT, chemo Hurthle 342 44 (12.9) 10 (22.7) pelvis (2), (4/10) femur (2) Humerus (1), Chemo Medullary 866 134 (15.5) 2 (1.5) femur (1) (1/2) Radius (1), Papillary 6572 254 (3.9) 6 (2.4) humerus (1), None femur (4) Total 8681 550 (6.3) 41 (7.5) (Figure 2(c)). After thyroidectomy, patients treated with In all cases of local progression, additional surgery was radioactive iodine had better survival than those who did not performed with hardware revision to either intercalary pros- (P = 0.002, Figure 2(d)). thesis, endoprosthesis, or joint replacement. One patient who The majority of patients (n = 23) had BM at the time of was treated with an intramedullary nail for a humerus metas- diagnosis of thyroid cancer. The median time to metastasis tasis developed increasing pain, fracture, and progression for patients (n = 16) without distant disease at the time of of disease 4 years after surgery. The recurrent tumor was thyroid cancer diagnosis was 2.72 years (Figure 3(a)). In these resected, and the nail was converted to a total humerus endo- patients the time to metastasis had no dependence thyroid prosthesis (Figures 3(d)–3(g)). The patient was alive at the tumor subtype or treatment modality. last followup 2 years after surgery to resect the recurrence. Serum thyroglobulin (TGB) levels were measured both Thehazardratio forrecurrencefreesurvivalwas 0.28 (P = pre- and postoperatively in 26 of 41 patients. In 22 patients, 0.012, 95% C.I. from 0.11 to 0.75, Table 4) for patients who the serum TGB levels decreased following bone metastasis had bone metastasis tumor excision compared to patients surgery. Preoperative serum TGBs ranged from 100 to 13000; who did not. Kaplan-Meier analysis demonstrates worse with the percentage of decrease after bone metastasis surgery recurrence free survival for patients who did not have ranging from 9%–99%. In the 4 patients where there was surgical tumor excision for control of metastatic disease no TGB decrease, 3 had widely metastasis disease involving (Figure 4(a), P = 0.007), and for patients that presented with multiple bones, and the skeletal surgery only addressed one multiple sites of bone metastasis (Figure 4(b), P = 0.036). site of bone involvement. The one remaining patient with no decrease in TGB had a biopsy, wherein the bone metastasis 131 3.3. Radiation. Patients treated with radioactive iodine ( I) was not removed. had better survival following thyroidectomy (P = 0.002), but not following surgery for bone metastases (Figures 5(a)- 3.2. Local Recurrence. Eight of 41 cases were complicated 5(b)). by local recurrence. The local progression free survival was Seven patients failed prior to palliative external radiation 89% at 1 year (80%–100%, 95% C.I.), 60% at 5 years (37%– of osseous metastases and subsequently underwent surgical 96%, 95% C.I.), and 40% at 8 years (16%–100%, 95% C.I.) treatment. Preoperative external beam radiation to the (Figure 3(b)). All cases of recurrence occurred in patients affected bone had no significant effect on overall patient with a diagnosis of the follicular subtype of thyroid carci- survival after skeletal surgery (Table 4). There was a trend noma, which was statistically significant via Kaplan-Meier towards a higher risk of recurrence in patients who had pre- analysis, in comparison to papillary, medullary, anaplastic, operative radiation to the bone, although it did not achieve and Hurthle cell subtypes, where there were no recurrences statistical significance (P = 0.08). One of the seven patients (P = 0.016, Figure 3(c)). In contrast to overall survival, developed a local recurrence after surgery for the osseous whether the metastasis was excised had no significant effect lesion. This patient had excision of the recurrent lesion and on the probability of local recurrence. All cases of local prog- hardware revision to acetabular reconstruction with total hip ression occurred in patients who had tumor excision. arthroplasty. International Journal of Surgical Oncology 5 Table 4: Univariate Cox model. Overall survival Time to bone metastasis Survival after bone metastasis surgery Recurrence free survival Prognostic factors Hazard Hazard Hazard Hazard 95% CI P value 95% CI P value 95% CI P value 95% CI P value ratio ratio ratio ratio Age 1.06 1.02–1.09 0.001 1.06 1.005–1.116 0.032 1.002 0.975–1.03 0.864 1.012 0.98–1.04 0.41 Gender 1.19 0.55–2.38 0.66 0.63 0.21–1.83 0.39 1.63 0.76–3.50 0.21 1.795 0.87–3.7 0.113 FvM Follicular subtype 1.1 0.51–2.37 0.81 1.26 0.43–3.71 0.68 0.83 0.40–1.73 0.63 1.33 0.63–2.81 0.45 Radioactive iodine Y v N 0.18 0.05–0.61 0.006 0.07 0.005–1.186 0.066 0.54 0.18–1.62 0.27 0.504 0.16–1.53 0.23 Other treatment Y v N 1.51 0.63–3.62 0.36 1.721 0.55–5.34 0.35 0.95 0.40–2.25 0.91 0.72 0.29–1.78 0.48 Skeletal presentation 0.044 2.44 0.93–6.44 0.07 3.03 1.03–8.92 Multiple bone v single Preoperative radiation to 1.985 0.73–5.38 0.18 1.74 0.65–4.68 0.27 bone Y v N Tumor excised from bone 0.21 0.075–0.58 0.003 0.28 0.11–0.75 0.012 YvN 6 International Journal of Surgical Oncology Table 5: Multivariate Cox model. Overall survival Survival after bone metastasis surgery Recurrence free survival Prognostic factors Hazard ratio 95% CI P value Hazard ratio 95% CI P value Hazard ratio 95% CI P value Age 1.054 1.02–1.09 0.002 Radioactive iodine Y v N 0.164 0.041–0.654 0.0104 Follicular subtype 1.589 0.646–3.910 0.313 0.832 0.396–1.748 0.627 1.547 0.706–3.39 0.276 Skeletal presentation 2.102 0.783–5.643 0.141 3.097 1.008–9.521 0.0485 Multiple bone v single Tumor excised from bone 0.242 0.087–0.677 0.0068 0.336 0.125–0.903 0.0306 International Journal of Surgical Oncology 7 Overall survival following skeletal surgery Tumor excised P-value = 0.001 0.8 0.8 0.6 0.6 0.4 0.4 0.2 0.2 0 2 4 6 8 0 2 4 6 8 Years Time after skeletal surgery (years) No (event/N = 6/7) Yes (event/N = 24/34) (a) (b) Overall survival following thyroid cancer diagnosis Radioactive iodine and survival 0.8 0.8 P-value = 0.002 0.6 0.6 0.4 0.4 0.2 0.2 0 5 10 15 20 25 30 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Years Time after thyroid removal (years) No (event/N = 4/4) Yes (event/N = 25/35) (c) (d) Figure 2: Kaplan-Meier analysis of patient survival. (a) Following surgery for osseous metastases patient survival was 72% at 1 year (95% CI 59–87%), 29% at 5 years (95% CI 17–49%), and 20% at 8 years (95% CI 10–42%). (b) There was better survival for patients when the metastastic osseous tumor was excised versus not excised. The median survival time for patients with tumor excision was 2 years (95% CI 1.4–5 years), compared with 0.6 years (95% CI 0.1–1.8 years) for patients without tumor excision (P = 0.001). No patient without tumor excision survived beyond 1.8 years. (c) Following thyroidectomy at initial diagnosis of thyroid carcinoma patient survival was 62% at 5 years (95% CI 48–80%), 35% at 10 years (95% CI 21–58%), 17% at 20 years (95% CI 7–41%), and 9% at 30 years (95% CI 2–32%). (d) After thyroid removal, patients who received radioactive iodine treatment had better survival than those who did not (P = 0.002). 3.4. Surgical Complications. Two patients had immediate patient became hypoxic and tachycardic during a hemiarth- perioperative complications. One patient with a history roplasty of the contralateral hip which immediately followed of smoking had respiratory insufficiency requiring delayed intramedullary nailing of the opposite femur. The hemi- extubation. One other patient had atrial fibrillation. Both arthroplasty procedure was aborted, and the patient had subsequently recovered uneventfully. There were no super- an uneventful subsequent recovery. There were no deaths ficial or deep infections, nonunions, or perioperative deaths. related to intraoperative blood loss. The mean blood loss of 1014 mL (range 0–3900 mL) for the cases where the tumor was not removed (n = 7) did not differ significantly from cases where tumor was excised 4. Discussion (mean = 1640 mL, range 0–19900 mL, n = 34). One patient became hemodynamically unstable during the second of The results of this study suggest that metastatic thyroid can- bilateral procedures for skeletal metastases. Specifically, the cer in bone is rare, but behaves aggressively. Surgery for bone Probability Probability Probability Probability 8 International Journal of Surgical Oncology Thyroid cancer subtype and Local recurrence following skeletal recurrence Time to skeletal metastasis surgery P-value = 0.016 0.8 0.8 0.8 0.6 0.6 0.6 0.4 0.4 0.4 0.2 0.2 0.2 0 0 0 5 10 15 20 02468 02468 Years Years Years Follicular (event/N = 5/23) Other (event/N = 0/15) (a) (b) (c) (d) (e) (f) (g) Figure 3: Progression of disease in bone. (a) Kaplan-Meier analysis of time to formation of skeletal metastasis. The median time to formation of bone metastasis after thyroid removal was 3.44 years. (b) Kaplan-Meier analysis of time to recurrence. The probability of recurrence free survival was 89% at 1 year (95% CI 80–100%), 60% at 5 years (95% CI 37–96%), and 40% at 8 years (95% CI 16–100%). (c) A diagnosis of follicular thyroid carcinoma was associated with a higher risk of recurrence versus other diagnoses (papillary, medullary, anaplastic, and Hurthle cell) (P = 0.016). All recurrences following surgery for osseous metastasis were in patients with follicular thyroid carcinoma histo- logic diagnosis. (d) A patient with an impending fracture of the proximal humerus shaft from isolated metastasis from follicular thyroid carcinoma underwent open nailing with curettage and cementation. (e) Postoperative X-ray demonstrates a humeral nail and bone cement filling the defect created by curettage of the metastasis. (f) Follow-up X-ray 5 years after surgery showing increasing lytic changes in bone extending to the distal aspect of the humerus, consistent with local progression of disease. (g) Postoperative X-ray showing total humerus endoprosthesis. The humerus, intramedullary nail, and bone cement were resected en bloc. The total humerus endoprosthesis reconstruction has remained stable, and the patient remains alive with no sign of disease. metastasis in thyroid carcinoma has been infrequently stud- appropriate that patients who have limited expected lifespan ied [6–8]. In 23 years at our institution there were only 41 should receive conservative treatment, our study shows a patients that required surgery for appendicular skeleton survival advantage for patients who had undergone surgical metastases. During the same period, 8681 patients with thy- excision of metastatic disease from bone. roid carcinoma were registered at our institution. Thus only Thyroid cancer generally has an indolent nature, so that approximately 0.5% of the patients required surgery for patients requiring skeletal surgery presented with bone meta- metastatic lesions in the appendicular skeleton. This study stasis both in late stages after treatment (16 of 41 patients) also shows that after bone metastasis occurs, survival is dimi- and with initial presentation (25 of 41 patients). Our study nished, in agreement with published reports [1, 2, 7, 9, 10, corroborates findings that survival with metastatic thyroid 16]. Few patients survived more than 8 years after having cancer tends to be better than some other cancers that surgery for bone metastasis [1, 15]. While it may seem metastasize to bone, such as renal cell carcinoma and lung Probability Probability Probability International Journal of Surgical Oncology 9 Tumor excised Skeletal presentation stage 0.8 0.8 P-value = 0.036 P-value = 0.007 0.6 0.6 0.4 0.4 0.2 0.2 02 46 8 0 2 4 6 8 Time to recurrence or death following surgery at Time to recurrence or death following surgery at MDACC (years) MDACC (years) No (event/N = 6/7) Multiple (event/N = 26/29) Yes (event/N = 25/31) Single (event/N = 5/9) (a) (b) Figure 4: Kaplan-Meier analysis for recurrence free survival, as determined by the probability of no recurrence or death. (a) Patients had a higher probability of recurrence free survival if the osseous metastasis was excised versus no excision (P = 0.007). All patients that had surgeries where the metastasis were not excised died (n = 6) or were lost to followup (n = 1). (b) Patients had a higher probability of recurrence free survival if they presented with a single bone metastasis versus multiple bones (P = 0.036). Five of the 9 (56%) patients with single bone metastasis at presentation were alive at last followup, compared with 6 of 29 (21%) patients who presented with multiple bone metastasis. Radioactive iodine Radioactive iodine 0.8 0.8 P-value = 0.002 P-value = 0.261 0.6 0.6 0.4 0.4 0.2 0.2 0 0 0 2 4 6 8 1012141618202224262830 0 2 4 6 8 Survival after thyroid removal (years) Survival following skeletal surgery (years) No (event/N = 4/4) No (event/N = 4/4) Yes (event/N = 25/35) Yes (event/N = 26/37) (a) (b) Figure 5: Kaplan-Meier analysis of the effect of radioactive iodine treatment on survival. (a) After thyroidectomy, patients treated with radio- active iodine had more favorable survival than those who were not candidates for radioactive iodine (P = 0.002). No patients who were not treated with radioactive iodine survived more than 3 years. (b) After surgery for osseous metastasis, there was no significant difference in survival between patients treated with radioactive iodine and those who were not (P = 0.261). carcinoma [2, 6, 14]. Three patients in this series survived Despite the survival advantage afforded by more aggres- for more than 30 years after their initial diagnosis, despite sive tumor removal, whether a patient underwent tumor developing metastases in multiple bones and organs. The excision did not affect whether there was local progression median survival for patients in our series was 7.6 years for patients with follicular carcinoma subtype. There was, following initial diagnosis. however, considerable morbidity for patients who developed Probability Probability Probability Probability 10 International Journal of Surgical Oncology uncontrolled tumor growth at metastatic osseous sites. In patients, surgical extirpation of solitary bone metastases was our study, all of the patients with local recurrence required associated with improved survival. additional surgical procedures. Total thyroidectomy followed by radioactive iodine is the treatment most often recommended for patients with There was no survival advantage or disadvantage follow- synchronous distant metastases to bone. It has been argued ing thyroid cancer diagnosis or surgery for bone metastasis that I is the only opportunity to slow progression and to associated with subtype, although bone metastases are more prolong survival [5]. Our study shows that patients treated common with the follicular subtype. Follicular thyroid can- with radioactive iodine have a clear survival advantage fol- cer accounts for less than 15% of all differentiated thyroid lowing thyroidectomy, that is less clear and likely diminished cancers, but has a relatively high incidence of bone metas- following skeletal surgery (Figure 5). A possible explanation tases, ranging from 7% to 28% [7, 9]. In our study, 6% of all is that the patients undergoing skeletal surgery have devel- patients developed bone metastases, and 7% of all patients oped bone metastases despite receiving I and therefore had follicular carcinoma. Of the patients with follicular have more aggressive disease. A similar trend was observed carcinoma, 15% developed bone metastases. Of the patients in patients that failed palliative external radiation. The prog- with bone metastases, 8% required skeletal surgery, and nosis for these patients was worse, although it did not achieve 21/43 (50%) of these patients had follicular carcinoma. All statistical significance. Of the 7 patients that failed palliative of the local recurrences occurred in patients with follicular XRT, 5 were known to have died within 4 years of surgery, thyroid carcinoma BM. Thus, the follicular subtype was with the other 2 patients lost to followup. associated with increased probability for local recurrence The involvement of multiple bones precludes curative compared with other subtypes (Figure 3(c)). There was no resection of bony disease. Of the 24 patients who had excision selection bias for the surgical procedure used in patients of the bone metastasis, 10 had solitary bone involvement. with recurrence, as they were almost evenly divided between At the last followup 5 of the 10 were alive, 4 died, and one curettage (4) and wide resection (3). Therefore, the reasons was lost to followup. Others studies have reported similar for the aggressiveness of follicular thyroid carcinoma in bone outcomes, with a significant improvement in survival with are not identifiable from the limited patient cohort included complete resection of skeletal metastases [1, 6]. For patients in the current study but deserve further study. that presented with multiple synchronous bone metastases, Bone metastases are much less common in papillary thy- surgical intervention afforded palliation for symptomatic roid cancer, with a reported incidence from 1% to7% [14]. disease that failed nonoperative interventions. Palliative In our study, the incidence of papillary carcinoma was 3%. surgery partially removes bone tumor or completely resects One comparable study that focused exclusively on patients bone tumor but leaves residual tumor in other organs [7]. In with BM reported that in 96 patients, 17% had papillary accordance with this, there was poorer recurrence free sur- histological diagnosis, and 71% were follicular [1]. Our vival observed in patients with multiple bone involvement. study cohort had similar proportionality, with three times as In patients with multiple organ involvement, the role of many patients with BM from follicular thyroid cancer than metastectomy is less well understood. In this study, two papillary thyroid cancer. patients with solitary skeletal metastasis at presentation did Anaplastic thyroid carcinoma typically has a poor prog- not have surgical extirpation of the BM because of syn- nosis. It is known to be the most lethal among all thyroid chronous involvement in other organs. One of these patients cancers, with median life expectancies reported to be from had stabilization of a lesion in the radius with a plate, fol- 4to12months [30–34]. Our results are consistent with lowed by external radiation. This patient was alive at 2-year more recent reports of marginally improved survival with followup, but went on to develop additional bone lesions in multimodal treatment strategies [31, 32]. Both patients with the clavicle and scapula. The other patient had synchronous anaplastic thyroid carcinoma in our study received additional lesions in the lungs and liver and a solitary lesion in the femur chemotherapy (doxorubicin based) and external radiation. that was stabilized by intramedullary nail and treated with One patient died at 23 months and the other died at 27 external radiation postoperatively. The patient died 8 months months following diagnosis. after surgery. Studies show that more than 80% of bone metastases In one compendium of 13 studies, the rate of bone from all thyroid tumors are located in the axial skeleton metastasis was found to be 25% among 1231 patients [12]. A [2]. Correspondingly, 41 out of 43 patients (95%) in our more recent study showed that survival decreased by 14% in cohort had axial BMs. The propensity for the axial skeleton patients older than 40 years with lung metastases or multiple is thought to be secondary to blood flow distribution char- bone metastases compared with comparable cohorts [9]. acteristics, and the bone microenvironment, which includes Other studies suggest that patients older than 45 years have growth factors favorable for tumor growth [2]. a poorer prognosis for remission following treatment with There are few studies on survival following surgery for radioactive iodine [2]. Our findings are consistent with these bone metastasis [3, 10, 35]. Reports have shown that removal reports. of up to five bone metastases can be associated with improved survival and quality of life [1, 8, 15]. Therefore, some have 5. Conclusions strongly recommended surgical excision for accessible, soli- tary metastases. 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