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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 8  |  Issue : 2  |  Page : 124-128

Characteristics and patterns of surgical interventions in differentiated thyroid cancer with distant metastasis


Department of Head and Neck Surgery, Tata Medical Center, Kolkata, West Bengal, India

Date of Submission05-Nov-2020
Date of Decision07-Nov-2020
Date of Acceptance08-Nov-2020
Date of Web Publication8-Dec-2020

Correspondence Address:
Arun Pattatheyil
Department of Head and Neck Surgery, Tata Medical Center, Major Arterial Road, New Town, Kolkata - 700 156, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jhnps.jhnps_54_20

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  Abstract 


Objective: Unlike most head and neck cancers, the presence of distant metastasis (DM) does not preclude curative intent treatment and surgical interventions are common in metastatic disease. This research attempts to study the demographics, patterns of metastasis, and surgical interventions in patients of differentiated thyroid cancer (DTC) with DM. Materials and Methods: The retrospective cohort study of thirty-two patients of DTC with radiologically or histopathologically/cytopathologically confirmed DM who underwent surgery at a tertiary care center from August 2011 to December 2018. Results: The study population comprised of 59% of women and had a median age of 55 (19–79) years. Thorax was the most common site of metastasis, documented in 56% patients, while 53% of patients had bone metastases. Multiple DM were noted in 8 patients. Surgery for metastatic sites was possible in 14 patients (44%), with debulking and spine fixation being the most common surgical intervention for metastasis. The median dose of radioactive iodine (RAI) received by patients was 400 (25–749) mCi in one to four sessions (median-2 sessions). Three patients received conventional chemotherapy, while four received Sorafenib. Conclusion: Metastasectomy in DTC with DM is feasible in selected patients, and surgical interventions are most commonly performed on the spine to prevent neurological complications. RAI ablation is universally administered in this subset of patients and in very high doses, often distributed in multiple sessions. The role of chemotherapy and tyrosine kinase inhibitor is still restricted to palliative settings and cost constraints remain a detriment to more widespread use.

Keywords: Differentiated thyroid cancers, distant metastasis, patterns of surgical intervention, radioactive iodine


How to cite this article:
Kathar MA, Jain P, Manikantan K, Sharan R, Pattatheyil A. Characteristics and patterns of surgical interventions in differentiated thyroid cancer with distant metastasis. J Head Neck Physicians Surg 2020;8:124-8

How to cite this URL:
Kathar MA, Jain P, Manikantan K, Sharan R, Pattatheyil A. Characteristics and patterns of surgical interventions in differentiated thyroid cancer with distant metastasis. J Head Neck Physicians Surg [serial online] 2020 [cited 2021 Jan 18];8:124-8. Available from: https://www.jhnps.org/text.asp?2020/8/2/124/302636




  Introduction Top


Thyroid malignancy is the fifth most common in women worldwide and it is expected to become the second-most common malignancy in women and the ninth-most common in men by 2030.[1] The incidence of thyroid cancers has been rising over the past few decades. Distant metastasis (DM) has an adverse impact on survival and lends considerable morbidity to the patient. Based on the histopathology, thyroid cancers are divided into various subtypes, which include differentiated thyroid carcinoma (DTC), medullary, and anaplastic thyroid carcinomas. DTCs are derived from thyrocytes, express the sodium transporter and represent 90% of all thyroid cancers and the terminology encompasses papillary thyroid cancer (PTC), follicular carcinoma, and poorly differentiated thyroid cancers (DTCs).[2]

Genetic determinants of clinical behavior in DTC are being investigated and find applications in the assessment of the risk of malignancy in indeterminate thyroid nodules.[3] Notable among these markers has been the BRAFV600E mutation present in 45%–59% of PTC and associated with a higher incidence of extrathyroidal extension, nodal metastasis, refractoriness to radioactive iodine (RAI) treatment, and decreased survival.[4]

Four percent of all patients are diagnosed with or develop DM. Metastasis develops in 7%–15% of patients following thyroid surgery for DTC.[5] Poorly DTCs account for 5%–10% of all thyroid cancers and the mean survival after diagnosis is 3.2 years.[6] Bone metastasis has been observed to occur in 2%–13% of patients diagnosed with DTCs. In thyroid cancer, the overall 10-year survival had been declined to 13%–21% in the presence of bone metastasis.[7]

Skeletal survey with whole-body bone scan, computed tomography/magnetic resonance imaging (MRI) and whole-body MRI in patients with spinal cord involvement is warranted whenever there is a suspicion of metastasis. Biopsy from the metastatic site may be required to confirm the histology.[8]

I131 therapy is the first choice of treatment for papillary and follicular thyroid cancers with DM, unless they lose the ability to trap iodine.[9] RAI therapy has shown to be effective in improving the disease-free survival in patients diagnosed with locally advanced or metastatic diseases.[10]

According to the guidelines published by the American Thyroid Association, complete removal of bony metastasis has been seen to exert a beneficial effect on survival and it is recommended, particularly in younger patients with spinal metastases with neurological deficits.[11] Hence, resection of bony metastases should be attempted wherever feasible.[12] Lung metastases respond well to RAI therapy than any other organ metastases, but surgical resection of the lung is undertaken only in selected patients, especially with anatomically limited disease.[13]

Tyrosine kinase inhibitors are effective and promising drugs for the treatment of poorly DTCs.[14] Newer treatment options to treat the locally recurrent and metastatic progressive DTCs include small molecule oral multi-targeted kinase inhibitors, namely Vandetanib and Sorafenib. Sorafenib works on vascular endothelial growth factor 1, 2, and 3 and platelet-derived growth factor.

The role and administration of external beam radiation therapy (EBRT) are not well characterized in DTCs due to the lack of homogeneity of protocols and conflicting outcomes. A study done by Benker et al.,[15] showed that EBRT is not routinely recommended in PTC as there is no significant improvement in overall survival. In fact, the higher survival is observed in patients who did not receive EBRT. Despite these drawbacks, in some studies, the administration of EBRT has improved loco-regional control in invasive disease, unresectable/gross residual tumors and in disease resistant to RAI therapy.[16]

Unlike cancer at other head-and-neck sites, patients with metastatic DTC frequently undergo surgery during the course of their protracted treatment. There are no available data on the clinical characteristics and patterns of surgical care received by this rare subset of patients leading us to conduct this study.


  Materials and Methods Top


Data were abstracted from the maintained electronic records of 492 patients with thyroid cancer who were treated surgically at our hospital during the period from August 2011 to December 2018. Of these 492 patients, 381 were diagnosed with DTC and 32 patients diagnosed clinically with metastasis from DTC at presentation or who were detected to have metastasis on follow-up were included in our analysis. Patients with medullary and anaplastic carcinoma were excluded. The demographics, patterns of metastasis, and surgical interventions in this rare subgroup of patients with DTC were studied in this research.

Ethical considerations

This study was registered with our institution’s Clinical Audit department. Patient information was anonymized before data analysis.

Statistical analysis

Data were analyzed using SPSS version 17 (IBM, Chicago, IL, USA).


  Results Top


[Table 1] shows continuous variables of patient characteristics with metastatic DTCs.
Table 1: Continuous variables of patient characteristics with metastatic differentiated thyroid cancer

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Of the 32 patients with metastatic DTC available for final analysis, 59% were women (n = 19). The median age of the entire study population was 55 years (17–79 years).

Metastatic sites were identified in the thorax (lungs and mediastinum), bones (vertebra, femur, skull, clavicle, manubrium sterni, and iliac bones), and brain. Twenty-four patients (75%) had single-site metastasis. Metastases were detected at multiple sites in eight patients (25%). Lung and mediastinal metastases were seen in 56% and bone metastases were seen in 53% of patients either singly or in combination. One patient had brain metastasis.

Notably, a majority of patients (n = 20, 63%) had undergone some form of treatment before they were referred to the study center. Six patients were diagnosed with thyroid cancer after histopathology following surgery to the spine. Four patients had incomplete surgery on the thyroid with or without any intervention for the metastatic disease and one patient had complete surgery for the thyroid but was referred for the care of metastatic disease. The metastatic site was addressed by surgery (metastasectomy) in 44% (n =14). The most common intervention performed was debulking with fixation of the spine, which was carried out in 15% (n =5) of these patients. Metastasectomy was carried out in 14 patients, of which 5 had spinal metastasis debulking. In the remaining 18 patients, the thyroid was ablated with or without a neck dissection and metastatic disease was addressed using RAI. The majority of cases were diagnosed histologically as papillary thyroid carcinoma (62.5%, n =20).

[Table 2] shows the categorical variables of patient characteristics with metastatic DTCs.
Table 2: Categorical variables of patient characteristics with metastatic differentiated thyroid cancers

Click here to view


Radioactive iodine therapy

All patients, except one patient, received adjuvant RAI therapy in our hospital as one patient received RAI at the peripheral hospital (RAI). The study population received a maximum of four sessions of treatment with a median of two doses and a cumulative median dose of 400 mCi, ranging from 25 mCi to 749 mCi.

Systemic therapy

Three patients received conventional chemotherapy. One patient received cisplatin and doxorubicin in our hospital. Two patients received chemotherapy elsewhere and four patients received tyrosine kinase inhibitors. Though lenvatinib was recommended, all patients received sorafenib due to cost constraints.

Follow up

The median follow-up was 26.5 (range 1–69) months. During this period, there were five deaths in the study cohort. Survival analysis could not be performed due to the paucity of events during follow-up and is therefore not being reported.


  Discussion Top


DTC carries an excellent prognosis and the development of metastasis is a rare event in everyday head-and-neck oncology practice. In spite of the evolution of numerous protocols to guide practice, metastases from DTC are treated heterogeneously across treating centers. In our series, metastases were identified in 32 of 381 (8.4%) patients with DTC. The presentation of metastases from DTC is insidious in many cases. In our series, 19% (n = 6) of patients underwent treatment for conditions in the spine without being aware of primary thyroid pathology. The fact that metastatic workup is not recommended by all established guidelines and that thyroidectomy being a common ENT procedure performed even in low resource nonspecialty institutions results in many patients to undergo limited surgeries like hemithyroidectomy and who are subsequently diagnosed with metastases on referral to specialized services after the initial surgery. We had five such patients in our series (16%). The incidence of bone metastasis was 53% (n = 17), which is in concordance with published literature. Distant metastases are associated with poor prognosis in DTCs. The most common site of bone metastasis in DTCs is vertebrae, ribs, and hips. Tumor cell adhesive molecules bind the tumor cells to marrow stromal cells and bone matrix, allowing them to grow and produce angiogenic and bone-resorbing factors.

Metastasis of DTC has been treated with curative intent.[17] In a study done by Moneke et al., out of 43 patients who had undergone pulmonary metastasectomy predominantly for follicular carcinoma, showed an encouraging 10 years disease-free survival of 84% in patients who underwent complete resection. This significantly declined to 62% on incomplete resection (P = 0.013).[10]

In our study, the most common thyroid cancer histopathology was PTC followed by follicular cancer and poorly DTCs, respectively.

There is uniformity across protocols on the recommendation of RAI in patients with metastatic DTC in terms of a survival advantage. In a study done on 228 patients, 71 received iodine therapy with a cumulative dose of at least 600 mCi, This study reiterated that there seemed to be a better prognosis with greater cumulative doses of RAI but the disease-specific mortality was 60% over 10 years follow-up period when treated with higher cumulative doses.[11] In our study, all patients except one received RAI. The median dose of 400 mCi is in accordance with a study published by Pitoia et al., which showed that the patient treated with a mean effective cumulative RAI dose of 457.3 ± 29.7 mCi I131 (300–600 mCi) had a good response to treatment.[18]

It is imperative that young patients with metastatic DTC be warned of the adverse effects of high-dose radioiodine, most importantly xerostomia, pulmonary fibrosis, and infertility. The option of cryopreservation of semen or oocytes may be offered to potential recipients of high dose RAI.[19]

The role of conventional EBRT has been well established in the literature to allay pain, to improve neurological deficits and or to prevent pathological fractures. Four patients in our series received EBRT, all for the alleviation of pain. Rosenbluth et al. showed that of the twenty nonanaplastic thyroid cancers treated with intensity modulated radiotherapy, 54 Gy is required to treat low-risk microscopic disease, 59.5 Gy to the high-risk areas to 63–70 Gy for treating gross disease to achieve local control rates and the 2-year overall survival rate was 60%.[20] However, EBRT has been found to show a higher rate of local progression and pain relapse with long-term follow-up.[21] In our research, only four patients received EBRT to the metastatic site with a maximum of 54 Gy and a minimum of 30 Gy.


  Conclusion Top


Surgical interventions are common in patients with metastatic DTC. Procedures to the neck commonly include completion of thyroidectomy and clearance of nodes from the lateral neck. Procedures to the metastatic sites include debulking and fixation of the spine and metastasectomy. A high index of suspicion is needed while evaluating spinal lesions and the possibility of metastasis from the thyroid needs to be entertained. All patients receive RAI in conjunction with surgery in high doses with its attendant complications. Most patients receive a combination of therapies in varied sequences and the goal of treatment should be to mitigate complications and improve quality of life since most patients live long in spite of their advanced disease. The role of radiotherapy needs to be defined in large multicenter trials and more experience with targeted therapy is needed to formulate robust guidelines.

Limitations

This is a single-center experience and despite the collation of data over 7 years, we could collect information from only 32 patients. Large collaborative data sets would be necessary to throw light on this issue. The implications of various patterns of metastases on survival would have provided interesting insights, but we were constrained by the fact that even with a long period of follow-up, only five events were documented.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Disclosure

This material has never been published and is not currently under evaluation in any other peer reviewed publication.

Ethical approval

The permission was taken from Institutional Ethics Committee prior to starting the project. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.



 
  References Top

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Ullmann TM, Gray KD, Moore MD, Zarnegar R, Fahey TJ 3rd. Current controversies and future directions in the diagnosis and management of differentiated thyroid cancers. Gland Surg 2018;7:473-86.  Back to cited text no. 1
    
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Schmidbauer B, Menhart K, Hellwig D, Grosse J. Differentiated thyroid cancer-treatment: State of the art. Int J Mol Sci 2017;18: 1292.  Back to cited text no. 2
    
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McLeod DS. Current concepts and future directions in differentiated thyroid cancer. Clin Biochem Rev 2010;31:9-19.  Back to cited text no. 3
    
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Li F, Chen G, Sheng C, Gusdon AM, Huang Y, Lv Z, et al. BRAFV600E mutation in papillary thyroid microcarcinoma: A meta-analysis. Endocr Relat Cancer 2015;22:159-68.  Back to cited text no. 4
    
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Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin 2014;64:9-29.  Back to cited text no. 5
    
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Landa I, Ibrahimpasic T, Boucai L, Sinha R, Knauf JA, Shah RH, et al. Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers. J Clin Invest 2016;126:1052-66.  Back to cited text no. 6
    
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Elshafie OT, Hussein S, Al-Hamdani A, Bererhi H, Woodhouse NJ. Multiple bone metastases in a patient with differentiated thyroid cancer (DTC). Sultan Qaboos Univ Med J 2010;10:101-5.  Back to cited text no. 7
    
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Wexler JA. Approach to the thyroid cancer patient with bone metastases. J Clin Endocrinol Metab 2011;96:2296-307.  Back to cited text no. 8
    
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Lin JD, Kuo SF, Huang BY, Lin SF, Chen ST. The efficacy of radioactive iodine for the treatment of well-differentiated thyroid cancer with distant metastasis. Nucl Med Commun 2018;39:1091-6.  Back to cited text no. 9
    
10.
Moneke I, Kaifi JT, Kloeser R, Samson P, Haager B, Wiesemann S, et al. Pulmonary metastasectomy for thyroid cancer as salvage therapy for radioactive iodine-refractory metastases. Eur J Cardiothorac Surg. 2018 Mar 1;53:625-30.  Back to cited text no. 10
    
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Kato S, Murakami H, Demura S, Fujimaki Y, Yoshioka K, Yokogawa N, et al. The impact of complete surgical resection of spinal metastases on the survival of patients with thyroid cancer. Cancer Med 2016;5:2343-9.  Back to cited text no. 11
    
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Toshkezi G, Galgano M, Libohova S, Marawar S. Isolated Spinal Metastasis with Spinal Cord Compression Leads to a Diagnosis of a Follicular Thyroid Carcinoma. Cureus. 2015;7:e346.  Back to cited text no. 12
    
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Durante C, Haddy N, Baudin E, Leboulleux S, Hartl D, Travagli JP, et al. Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: Benefits and limits of radioiodine therapy. J Clin Endocrinol Metab 2006;91:2892-9.  Back to cited text no. 13
    
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Sherman SI. Early clinical studies of novel therapies for thyroid cancers. Endocrinol Metab Clin North Am 2008;37:511-24, xi.  Back to cited text no. 14
    
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Benker G, Olbricht T, Reinwein D, Reiners C, Sauerwein W, Krause U, et al. Survival rates in patients with differentiated thyroid carcinoma. Influence of postoperative external radiotherapy. Cancer 1990;65:1517-20.  Back to cited text no. 15
    
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Kiess AP, Agrawal N, Brierley JD, Duvvuri U, Ferris RL, Genden E, et al. External-beam radiotherapy for differentiated thyroid cancer locoregional control: A statement of the American Head and Neck Society. Head Neck 2016;38:493-8.  Back to cited text no. 16
    
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Treasure T, Internullo E, Utley M. Resection of pulmonary metastases: a growth industry. Cancer Imaging 2008;8:121-4.  Back to cited text no. 17
    
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Pitoia F, Bueno F, Cross G. Long-term survival and low effective cumulative radioiodine doses to achieve remission in patients with 131Iodine-avid lung metastasis from differentiated thyroid cancer. Clin Nucl Med 2014;39:784-90.  Back to cited text no. 18
    
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Rosenbluth BD, Serrano V, Happersett L, Shaha AR, Tuttle RM, et al. Intensity-modulated radiation therapy for the treatment of nonanaplastic thyroid cancer. Int J Radiat Oncol Biol Phys 2005;63: 1419-26.  Back to cited text no. 20
    
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Yarnold JR. 8 Gy single fraction radiotherapy for the treatment of metastatic skeletal pain: Randomised comparison with a multifraction schedule over 12 months of patient follow-upOn behalf of the Bone Pain Trial Working Party. Radiother Oncol 1999;52:111-21.  Back to cited text no. 21
    



 
 
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