Thyroid Cancer-A Multidisciplinary Approach

•头颈肿瘤专栏•

Thyroid Cancer-A Multidisciplinary Approach

Ashok R. Shaha, MD, FACS

INTRODUCTION

Thyroid cancer has generated considerable interest, debate and development of several guidelines around the world since the incidence of thyroid cancer is rapidly arising all over the world. This could be primarily related to incidental finding of small thyroid cancers. The incidence of thyroid cancer has almost quadrupled in the U.S. Approximately 8,000 new patients with thyroid cancer were seen in 1975 while today we see approximately 66,000 new patients with thyroid cancer and the number continues to rise continuously. This rise has been extremely evident in Korea over the last 10 years with the routine use of ultrasound of the neck. It is not uncommon to find a tiny nodule in the thyroid during routine ultrasound of the neck performed for other reasons such as neck pain, carotid evaluation, etc and find a tiny thyroid nodule a fine needle aspiration biopsy of which would reveal papillary carcinoma of the thyroid. Whether managing these patients at such early stage would make a major difference remains unclear at this time however the good aspect of this cancer is the majority of the new cancers we see today are micro carcinoma below 2cm with the overall survival exceeding 99%. Even though in the past thyroid cancer was considered as a surgical issue and surgeons were actively involved in the diagnostic evaluation and management of thyroid cancer, today it has truly become a multidisciplinary approach with involvement of the surgeons, endocrinologists, nuclear physicians, pathologists, diagnostic radiologists and epidemiologists.

INCIDENTALOMA OF THE THYROID

The majority of the thyroid cancers noted today are incidental findings. The classical incidentalomas are noted during routine clinical examination of the head and neck and other imaging studies. It is fairly common nowadays for the general practitioner or obstetrician to evaluate the neck for any neck complaints or fullness in the thyroid region. An ultrasound of the thyroid is routinely performed indicating a tiny thyroid nodule. The incidentalomas are also common during imaging studies such as CT scan of the chest, MRI of the neck and PET scan. The classical example is a car accident where MRI of the neck is performed for ruling out cervical problems and finding a tiny thyroid nodule. PET scan is common investigation in evaluation and follow up of other human cancers which may reveal a tiny hypermetabolic thyroid nodule. The PET incidentalomas need to be evaluated more carefully as the incidence of malignancy is approximately 30%～40% in focal PET incidentalomas. The diagnostic evaluation classically involves an ultrasound, ultrasound guided needle biopsy and close follow up. We recently described PET Associated Incidental Neoplasm(PAIN) in approximately 3%～4% of PET scans.

DIAGNOSTIC EVALUATION

Even though a variety of diagnostic studies are available for evaluation of the thyroid nodule, the classical evaluation still would be ultrasound and ultrasound guided needle biopsy of a nodule which is either suspicious or more than 1cm. Since the thyroid nodules are fairly common, there is considerable interest now not to perform a needle biopsy unless the nodule is more than lcm or there are suspicious findings on ultrasound. The classical suspicious findings on ultrasound of the thyroid include microcalcification, irregular borders and hypervascularity. The American Thyroid Association recently published their guidelines in management of thyroid nodules which is an excellent document for review and reference. The cytological interpretation of the thyroid nodule may raise considerable differences of opinion. Recently the cytologists standarized their reporting into Bethesda system with Bethesda Ⅵ being classical papillary thyroid carcinoma. However, the Bethesda Ⅲ and Ⅳ can generate considerable controversy as to the overall incidence of malignancy and further evaluation of the thyroid nodule. The overall incidence of malignancy in Bethesda Ⅲ is approximately 10%～15%. In an effort to get better interpretation of the cytology there has been considerable interest recently in molecular markers and a Genetic Expression Classifier(GEC). The Afirma has become quite popular in the United States and if the Afirma is reported to be suspicious the overall incidence of malignancy rises to approximately 40%. Niki forav et al from University of Pittsburgh have developed identification of several gene mutations indicating high risk of malignancy in BRAF and RAS mutation. These tests are fairly common in the United States however in the other parts of the world they may not be available or too expensive. If one of the RAS mutations is positive then generally we would consider surgical intervention.

OBSERVATION APPROACH TO MICRO CARCINOMA OF THYROID

Even though, the definite treatment of thyroid cancer includes appropriate thyroidectomy there has been considerable interest in the recent years in observation of incidentally noted papillary carcinoma of the thyroid which are below 1cm. Ito et al from Japan have been observing such micro carcinomas over the last two decades. Even though approximately 30% of these patients will come to surgical intervention, a large number of these patients can be easily observed. We have similar experience from Memorial Sloan Kettering Cancer Center with observation studies. These studies are parallel to the incidental finding of thyroid carcinoma. There is considerable discussion whether these tumors truly should be called carcinoma or they could be called papillary micro tumors or IDLE(Indolent Lesion of Epithelial Origin). Obviously, the patients who are being observed with a proven thyroid carcinoma require considerable understanding and close follow up. Any change in the size of the thyroid nodule or if there is an extrathyroidal extension, patient needs to be surgically treated.

SURGICAL TREATMENT OF THYROID CANCER

Surgery is most effective and best way of controlling and curing thyroid cancer. However there has been considerable debate over the last half century regarding the controversy about extent of thyroidectomy. There are strong proponents of total thyroidectomy and the first two guidelines of the American Thyroid Association definitely recommended total thyroidectomy in patients with papillary carcinoma measuring more than 1cm, however, the guidelines have shown a remarkable change recently indicating lobectomy as a definitive and effective treatment for tumors below 4cm which are encapsulated. Obviously, the decisions regarding extent of thyroidectomy are made based on the philosophy and judgment of the operating surgeon, institutional practices and the risks of complications. The complications of thyroid surgery are directly proportional to the extent of thyroidectomy and inversely proportional to the surgeon’s experience. The debate continues today in relation to management of neck nodes in thyroid cancer. Obviously, appropriate pre-operative evaluation with ultrasound is very important especially in a larger tumor. The central compartment nodes may be difficult to evaluate with ultrasound however the lateral neck nodes can be easily evaluated and if there is any suspicious lymph node, appropriate pre-operative ultrasound guided needle biopsy of the lymph node should be performed with cytological interpretation and/or thyroglobulin assay on the aspirant. If the lateral neck nodes are clinically palpable it would be important to consider a cross sectional imaging by CT scan with contrast. Whether the contrast material will delay the radioactive iodine treatment continues to be a debatable issue however the general consensus would be to get the appropriate imaging studies for better surgical intervention and to evaluate retrojugular, parapharyngeal and retropharyngeal lymph nodes for best surgical undertaking. There is some concern whether the contrast dye in the CT scan would delay the radioactive iodine treatment however generally the delay is not of major concern.

The debate continues as to the role of prophylactic central compartment nodal dissection. The first ATA guidelines published in 2006 recommended routine prophylactic central compartment dissection however it was recognized soon that there is a higher incidence of complications related to nerve injuries and temporary and permanent hypoparathyroidism with no definite benefit in the long-term outcome or disease free survival. The second edition of guidelines published in 2009 recommended prophylactic central compartment dissection only in high risk patients such as larger tumors, extra-thyroidal extension or aggressive histology. However, routine practice would be to evaluate the central compartment at the time of thyroid surgery very critically, get a frozen section if indicated and consider central compartment dissection only if there are suspicious or abnormal lymph nodes. We avoid routine central compartment dissection for fear of high incidence of complications. If the lateral neck nodes are enlarged or obviously enlarged and suspicious on the imaging studies a modified neck dissection or selective neck dissection should be performed preserving sternomastoid muscle, internal jugular vein and accessory nerve. The involvement of one level Ⅰ, Ⅱb and Va lymph nodes is uncommon and these areas can be easily spared in modified neck dissection unless there is a gross disease in these areas.

PROGNOSTIC FACTORS IN THYROID CANCER

Thyroid cancer is a unique human neoplasm. One cannot compare thyroid cancers to other human cancers such as pancreatic cancer, esophageal cancer or lung cancer. Those are generally considered to be deadly diseases. However, thyroid cancer may be considered as a friendly tumor if the patient belongs low risk group. Clearly in the high risk group the mortality is quite high from thyroid cancer. The risk group stratification is probably the most critical aspect of evaluation and management of thyroid cancer. The prognostic factors are extremely well defined in thyroid cancer. Age continues to be the most important prognostic factor with cut-off used as 45 years. Patients below the age of 45 are considered to be low risk in stage I and Ⅱ tumor while above the age of 45, the prognosis is not as good. Obviously, other prognostic factors are also very important. Recently in multi-national study the age cut-off was extended now to 55 which appears to be more logical especially in smaller tumors. The size of the tumor is very important and for tumors below 4cm, the outcome is excellent compared to tumors larger than 4cm. The nodal metastasis does not have a major impact especially in the low risk primary tumors however in older people, aggressive histology or bulky nodal metastasis the prognosis is not as good and the incidence of regional recurrence is fairly high. Probably one of the most important prognostic factors in the evaluation and management of thyroid cancer is extrathyroidal extension. When the tumor extends out of the thyroid gland involving surrounding structures such as strap muscles, recurrent laryngeal nerves, esophagus or trachea, the survival is much worse and the incidence of local recurrence is fairly high. Management of the local recurrence in these patients may be extremely complicated due to the involvement of the central compartment viscera and important organs such as trachea and esophagus. The most important clinical evaluation during surgery is to assess whether the tumor has come out of the thyroid gland involving surrounding structures and appropriate surgical resection of the involved structures is critical for best local control. R0 resection is probably the most important aspect of management of thyroid cancer.

TNM staging continues to be very important predictor of overall outcome, and recurrence. The decisions regarding adjuvant treatment are also based mainly on the prognostic factors of the primary tumor, nodal metastasis and aggressiveness of the histology. Thyroid cancer is a unique human neoplasm with a continuum of diseases. At one end of the spectrum there is a best human cancer papillary carcinoma of the thyroid with an overall survival exceeding 98% while at the other end of the spectrum there is anaplastic thyroid carcinoma with a mortality exceeding 98%. It is amazing that in the same human organ we have such a vast histological variation in thyroid cancer. The understanding of the aggressive thyroid tumors such as tall cell, insular, diffuse sclerosing variety, and poorly differentiated thyroid cancer is very important. It would be very important for the pathologist to re-review the slides in light of continuum of histological aggressiveness. The presence of poorly differentiated thyroid carcinoma is extremely important as these patients generally do not respond to radioactive iodine and appropriate surgical resection and close follow up is also very important. The radioactive iodine generally does not work in aggressive histology while the PET scan is more important. Follow up, imaging study for the local recurrence or regional and distant metastasis is very important. PET scan is very important in follow up of these patients.

POSTOPERATIVE MANAGEMENT

The usual knee jerk reflux in the United States for the management of thyroid cancer used to be total thyroidectomy and radioactive iodine ablation, Recently there seems to be considerable paradigm shift in appropriate use of radioactive iodine. For low risk thyroid cancer patients the role of radioactive iodine is questioned by several institutions and more importantly by American Thyroid Association guidelines. In the low risk thyroid cancer patient the radioactive iodine is rarely used and has not shown any major impact on the long-term outcome. There continues to be considerable debate as to the dose of radioactive iodine especially in the low risk thyroid cancer patients. In the high risk thyroid patients generally the initial dose of 100～150 mCi is considered quite satisfactory. Patients presenting with pulmonary metastasis or distant metastasis may even require a larger dose. One of the major advances in the management of thyroid cancer in the last decade has been the use of recombinant TSH. In the past the preparation of radioactive iodine ablation was to make patients hypothyroid for a period of 4～6 weeks which was a major concern especially in young women or in relation to their poor quality of life with severe hypothyroidism. However, with the use of recombinant TSH patients can continue with their thyroid medication which clearly maintains the best quality of life during those few weeks postoperatively.

TARGETED THERAPIES

In the last few years there has been considerable interest in understanding of the biology of thyroid cancer and molecular progression of thyroid cancer. Based on the genetic and molecular understanding, several drug therapies have been utilized in the management of thyroid cancer especially multiply recurrent and metastatic thyroid cancer. Several drugs have been tried such as Sorafenib, Vandetanib and Pazopanib. These targeted therapies have shown satisfactory response for controlling the progression of the tumor for a period of time. However, this would be important since there are no other therapeutic modalities available in these patients. The role of external radiation therapy continues to be a debatable issue. Generally it is used in patients with gross or residual tumor, aggressive histology or possibility of recurrent tumor in critical areas such as trachea or laryngeal structures which may require future laryngectomy. It would be most important to make individualized, personalized decision in use of these therapies. Multidisciplinary tumor groups discussion and decision is very important. Multidisciplinary team is extremely critical in these patients with recurrent thyroid cancer. Thyroglobulin levels and thyroglobulin doubling time is very important in the follow up of patients with thyroid cancer.

COMPLICATIONS OF THYROID SURGERY

Even though the complications of thyroid surgery are well known, the overall risk is quite small in the range of 2%～3%, however, the complication rate is much higher in patients with locally aggressive thyroid cancer, recurrent thyroid cancer or those undergoing neck dissection. The risks of complications is also high in patients with recurrent thyroid cancer in the central compartment. The major complications of routine thyroid surgery include hematoma, recurrent laryngeal nerve injury, superior laryngeal nerve injury and temporary or permanent hypoparathyroidism. The risks of these complications is much higher in the temporary manner. However permanent complications range between 2%～3%. The risk of hematoma is approximately 1%～2% however this can cause urgent emergency requiring either bedside evacuation and operating room exploration and more importantly maintaining the airway. The hematoma is generally noted within the first 6～8 hours of surgery however it can occur as late as 24～48 hours. The major reason behind the hematoma is violent cough and rupturing of a vessel. This requires prompt and appropriate attention of opening the wound, evacuating the hematoma and releasing the pressure leading to airway edema. The recurrent laryngeal nerve injury ranges between 1 to 2 percent. Whether the nerve monitor will change this number remains unclear however at present several studies have shown that the incidence still remains between 1 to 2 percent. The superior laryngeal nerve is very important for professionals such as singers, lawyers and teachers. The nerve can be identified in 50%～60% of the patients at the time of surgery and in remaining patients it is expected that the surgeon stays close to the upper portion of the thyroid and avoids injury to the superior laryngeal nerve. This nerve is extremely important in professional singers known as Amellita Galli-Curci nerve, the famous soprano who lost her singing voice after thyroid surgery in 1935.

The parathyroid problem is an enormous concern in thyroid surgery. The parathyroids may be damaged by devascularization, or maybe resected unknowingly when they are embedded in the thyroid substance. This is more common in patients with Hashimoto’s thyroiditis where the entire thyroid gland is diffusely enlarged and inflamed. It is also common in Graves’ disease. Utmost care should be taken to avoid injuring the parathyroid and separating them from the thyroid and maintaining their blood supply. These patients need close follow up in the postoperative period with a calcium check in 6 and 23 hours. If the calcium is considerably low they will require appropriate calcium, and vitamin D supplement. There is a considerable interest now in checking the parathyroid hormone levels 6～8 hours after surgery. The patients undergoing neck dissection have higher risk of complications related to chyle leak especially more so on the left side, and nerve injuries including accessory, ramus mandibularis, and the sympathetic chain leading to temporary or permanent Horner’s syndrome. The majority of the thyroid patients generally do not require a drain however patients undergoing extensive dissection, or large substernal goiter or neck dissection will require a drain for 24～48 hours. The majority of the thyroid patients can be discharged the next day of surgery. There is considerable interest to discharge the patients home the same day however this will depend upon the institutional practice, mainly for fear of hematoma in the postoperative period and acute emergency. In spite of these complications and issues, the statement by Halstead is very true—“Thyroid surgery is the supreme triumph of the Surgeon’s Art.”

IMPLICATIONS OF THE CURRENT ATA GUIDELINES IN THE MANAGEMENT OF THYROID CANCER

American Thyroid Association has published three sets of guidelines in the management of thyroid nodules and thyroid cancer. The first guidelines were published in 2006, the second in 2009 and the third one in 2015. The ATA guidelines committee had a large number of participants from different fields and truly represents a sincere effort to define multidisciplinary approach in the management of thyroid nodule and thyroid cancer. The major surgical difference between the first and second guidelines was related to prophylactic central compartment dissection. This generated a considerable debate, controversy and several publications and an attempt to consider randomized prospective studies. In 2006, elective prophylactic central compartment dissection was recommended however promptly it was realized that there is a higher risk of complications related to nerve injury and parathyroid and in 2009, second guidelines, the recommendation was made to consider elective prophylactic central compartment dissection in high risk patients with tumors larger than 4cm, gross extra- thyroidal extension or aggressive histology. The recent guidelines published in 2015 have several challenging issues addressed in the surgical management of thyroid cancer. There is a considerable emphasis on avoiding fine needle aspiration biopsy in sub centimeter thyroid nodules or those which are not radiologically suspicious. There is considerable interest in using molecular testing in indeterminate thyroid nodules with Afirma and Thyroseq. Whether this will have practical implications in the day-to-day management of thyroid nodule worldwide remains unclear at this time. The ultrasound is considered to be a very important investigation in the evaluation of the thyroid nodules and preoperative evaluation of the neck nodes. If there is any suspicious lymph node, a preoperative ultrasound guided needle biopsy is recommended. Preoperative vocal cord evaluation is a major addition in the current guidelines. This could be performed with mirror, rigid telescope or fiberoptic laryngoscope. However, documentation of the functionality of the vocal cord is very important in the preoperative preparation of patients with thyroid cancer. In patients with locally aggressive thyroid cancer, extra-thyroidal extension or vocal cord paralysis, a strong plea is made to perform a CT scan with contrast for cross sectional imaging. This helps the surgeons better in performing appropriate surgical procedure in patients presenting with aggressive thyroid cancer. It appears that the current guidelines have made a major change in the extent of thyroidectomy and lobectomy is quite acceptable for intrathyroidal up to 4cm thyroid nodules. This clearly is a major paradigm change in the management of patients with thyroid cancer. There appears to be considerable interest in using radioactive iodine in only selected patients such as intermediate or high risk thyroid cancer. The risk stratification is re-emphasized in patients with thyroid cancer including low, intermediate and high risk groups. There is an entire section in these guidelines on targeted therapies, as mentioned previously there appears to be considerable interest in using these targeted therapies, and TKI inhibitors in patients with recurrent or metastatic thyroid carcinoma. Clearly these guidelines are quite helpful in streamlining the current philosophy of management of thyroid cancer all around the world. The ATA committee on guidelines has done a remarkable job in compiling these guidelines where I am sure there were considerable controversies and debates.

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[20]Shaha AR. Training in head and neck surgery and oncology[J]. J Surg Oncol， 2008, 97(8): 717-720.

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2016- 03- 26

Ashok R. Shaha，纽约斯隆凯特琳纪念医院头颈外科医师，美国康奈尔医学院外科学教授，兼任美国多所大学、中国中山大学及印度圣托马斯大学客座教授。现任美国内分泌外科协会副主席，并在美国及世界多个重要学科组织任职，曾任美国头颈外科协会主席,纽约癌症协会主席,纽约外科学会主席等职。获美国耳鼻喉科头颈外科学会杰出贡献奖章。Journal of Surgical Oncology, Head and Neck, Annals of Surgical Oncology, Brazilian Journal of Surgery, and Journal of Clinical Oncology等杂志编委。长期致力于甲状腺癌的临床研究，发表论文140余篇，专注于甲状腺和甲状旁腺疾病的手术治疗，尤其擅长对累及气道等周围组织的复杂甲状腺癌行一期气管重建。

导读

近年来甲状腺癌发病率呈现急速上升的态势，新发病例中微小癌的比例明显提高，除遗传及环境因素影响外，还主要与超声、MRI和PET/CT等影像检查的发展和应用有关。过去单一的外科治疗被认为是甲状腺癌的主要治疗手段，而如今其诊治已演变为涉及外科、内分泌科、核医学科、病理科、影像科以及流行病学等多学科参与的疾病。不仅治疗方式上趋向以外科为主同时联合放射性碘消融和激素抑制治疗，而且在整个诊断、治疗、并发症处理和康复等过程中均涉及多种学科的参与和配合。Shaha教授在本文中以多学科综合治疗策略在甲状腺癌整个规范化治疗过程中多环节的渗透为主线，围绕甲状腺癌的诊断评估、微小癌处理、外科治疗相关热点问题、预后因素、术后管理、靶向治疗以及并发症处理等核心问题进行了全面阐述，并结合2015版ATA指南在甲状腺癌管理方面的建议，与过去两版指南进行对比，并结合自己的经验和视角进行了分析说明。Shaha教授希望甲状腺外科医师能够在不断提高自身技术的同时，更加注重诸如内分泌学等其他相关学科的学习，特别对于复发的复杂型病例应善于运用多学科联合的综合治疗策略，力争达到最佳的治疗效果。

(四川省肿瘤医院头颈外科 李 超)

E-mail: shahaa@mskcc.org

10.3969/j.issn.1674- 0904.2016.02.001

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