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Foreword T h y r o i d C a r c i n o m a a n d Ot h e r Thyroid Disorders
Derek LeRoith, MD, PhD Consulting Editor
We decided that an update on thyroid disorders would be appropriate since our last thyroid issue a number of years ago. In particular, it is clear that the incidence of thyroid cancer is increasing and there are a number of new modalities to therapy. In addition, there are a number of articles that cover considerations that have not been dealt with previously. Drs Mon and Hodak discuss the emerging technology of using molecular diagnostic tools in fine-needle aspirations of thyroid nodules. Since up to 40% of the cases remain indeterminate, it is hoped that these molecular tests would result in more definitive results. As they discuss, the specificity and sensitivity are as yet not 100% and therefore not always conclusive. Dr McLeod discusses how serum thyrotropin (TSH) levels have been associated with thyroid cancer, suggesting a potential causative relationship, although this has never been definitively proven. However, serum TSH levels remain important in the management of thyroid cancer. In particular, in detecting metastatic disease, traditionally thyroid suppression therapy was ceased to induce hypothyroidism and elevate TSH levels prior to isotope studies. Today, with the advent of recombinant TSH availability, it can be administered to elevate circulating levels, without cessation of the thyroid suppression and induction of hypothyroidism. Thyroid cancer, except in unusual situations, requires thyroid surgery. Drs Callender, Carling, Christison-Lagay, and Udelsman describe in their article that the diagnosis is commonly made on fine-needle aspiration of a nodule greater than 1 cm in diameter. Occasionally, the diagnosis may be made by detecting the BRAF V600E mutation in papillary thyroid cancer or rearranged during transfection (RET) protoncogene mutations in the case of multiple endocrine neoplasia, or familial medullary thyroid carcinoma. Small tumors may suffice with partial thyroidectomy, while those greater than 1 cm require total (or near total) thyroidectomy to reduce recurrence. Central lymph node dissection is critical if lymph nodes are involved or even the absence, if the tumor Endocrinol Metab Clin N Am - (2014) -–http://dx.doi.org/10.1016/j.ecl.2014.03.001 0889-8529/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
endo.theclinics.com
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Foreword
is large. These and other considerations require a team of thyroid cancer specialists and thus patients should be referred to large academic centers where possible, for the best considerations and care. Drs Duke and Terris describe alternative approaches to avoiding scarring of the neck following thyroidectomy. Numerous groups have perfected the minimally invasive anterior cervical approach that leaves a limited scar. Recently, the development of remote access approaches has been developed in an attempt to totally avoid the cervical scar. Unfortunately, these approaches from the chest, axilla, breast, and so on, while avoiding the scar, may be extremely problematic given the tissues they traverse and potential harm inflicted, as well as more prolonged postsurgery recovery; perhaps they should be avoided? Staging of disease in the situation of differentiated thyroid disease has been very useful to decide on appropriate therapy. However, as discussed by Drs Momesso and Tuttle, this staging needs to remain a dynamic process since incomplete responses are common and tumors may change their characteristics. The authors have devised an algorithm based on initial and ongoing outcomes and ranges from those with excellent responses to those with either biochemical or structural incomplete responses. Physicians are encouraged to consider these situations and treat appropriately. Drs Hu, Ying, and Jimenez describe the underlying oncogenic process in medullary thyroid cancer, an aggressive, often familial and fortunately rare form of thyroid cancer. The RET oncogene is the most common abnormality, due to either germline or somatic mutations that result in an activated RET. Other tyrosine kinase receptors have also been found to be overexpressed but whether they are primary or secondary to RET is unclear. Initial diagnosis is usually made with fine-needle aspiration, but chromogranin A and CEA levels are also useful. At present, there are tyrosine kinase–specific inhibitors that are available for therapeutic use and others in the pipeline. The prognosis in general is still much worse than that of PTC and FTC. Posttreatment fatigue in survivors of thyroid cancer is apparently a less well-recognized phenomenon. In the article by Sawka and colleagues, a description of the limited published data and their review of the literature are provided. Due to the paucity of data, the authors do not recommend specific interventions, but strongly support the idea of randomized controlled trials, a highly commendable suggestion. One could certainly extrapolate this to other endocrine conditions as well. Dr Rosenthal discusses, in her article, ethical issues in the management of thyroid diseases. These include informed consent prior to any form of thyroid ablation, whether radioablation or surgery. As she discusses, patients under severe stress or suffering from extremes of the disorders such as hypothyroidism or thyrotoxicosis may not totally comprehend the various therapeutic choices and it behooves the physician to be alert to these possibilities. In addition, there are ethical issues arising from genetic disorders of thyroid disease in terms of confidentiality and testing of family members. Clearly, the use of experimental drugs in clinical trials has its own issues that need addressing. While the article focuses on thyroid disorders, it is clearly important for all medical conditions that we as health care providers are involved in diagnosing and treating. Since thyroid hormone is critical for normal heart and cardiovascular system physiology, both overt thyroid dysfunction as well as subclinical disease may affect the cardiovascular system. Hyperthyroid-related cardiovascular effects are well known with both classic signs and symptoms, whereas hypothyroidism is associated with more subtle changes; the diagnosis is often established by elevated TSH levels. Of particular concern are the changes in lipid profiles. Drs Danzi and Klein also discuss the
Foreword
precautions needed when starting replacement therapies in the case of hypothyroidism, to avoid catastrophes, and further discuss the low T3 syndrome seen in chronic heart disease and amiodarone-induced thyroid dysfunction and how to deal with this problem. In a similar vein, Dr Samuels discusses the cognitive impairment and other psychological disturbances that are seen in hypothyroidism and thyrotoxic patients. These include anxiety and depression. They may be overt and more severe in classic hypothyroid and hyperthyroid patients, whereas they may be more subtle in subclinical forms of these disorders. Nevertheless, the good news is that there is usually significant improvement when the conditions are treated appropriately. Pregnancy affects thyroid physiology due to increased thyroid-binding globulin and human chorionic gonadotropin, as well as enhanced iodine metabolism. For these reasons, normal reference ranges for thyroid function tests are altered. As Drs Nathan and Sullivan discuss, pregnant women with overt hypothyroidism and those with subclinical hypothyroidism but thyroid peroxidase antibody-positive should be treated with levothyroxine to maintain thyroid function in the normal range, specific for each trimester. In regard to treating thyrotoxicosis in pregnancy, thionamides are still the treatment of choice. Radioisotope use is an important tool in the diagnosis and therapy of well-differentiated thyroid cancer and recurrence or distant metastases. Dr Esposito discusses how decisions are made regarding the dosage. In very low-risk patients with confined disease and no lymph node involvement nor distant metastases, a wait and watch approach is justified. In low-risk patients, those under 45 years of age with tumors between 1 and 2 cm, the American Thyroid Association suggests doses of 30 to 100 mCi. For intermediate-risk patients, tumors greater than 2 cm, using up to 100 mCi is suggested, whereas for high-risk patients, with residual tumor and lymph node involvement or distant metastases, using 150 to 200 mCi is suggested. While papillary thyroid carcinoma is usually associated with an excellent prognosis, its recurrence often requires additional management. Drs Goyal, Jonklass, and Burman discuss how, when cervical lymph nodes are detected after initial surgery as a recurrence, decisions are necessary as whether to use a surgical approach, radioactive iodine ablation, percutaneous ethanol injection, or simply observation. Drs Elisai, Viola, Matorne, Biagini, and Molinaro discuss the value of thyroglobulin (Tg) measurements, particularly in managing and treating recurrences in the case of differentiated thyroid cancer including papillary and follicular subtypes. Since these tumors synthesize and secrete Tg, a rising level can be an indication of remnant neck tumor or distant metastases. In follow-up management after surgery, TSH suppression by thyroid hormone often results in undetectable Tg. A rise in Tg suggests recurrence and requires the search and eradication of the remnant and metastases, usually by careful neck ultrasound and whole radioisotope scans, followed by radioisotope therapy. Clinical guidelines are developed by appropriate organizations to “guide” physicians in the best considered treatment plan for patients with certain disorders. In the case of Graves disease, the American Thyroid Association and the American Association of Clinical Endocrinologists jointly produced these guidelines. However, as detailed by Drs Muldoon, Mai, and Burch, there is a significant discrepancy between the guidelines and actual physician practice. For example, in diagnosing the condition, the guidelines do not recommend routine thyroid scan, uptake, or ultrasound, while between 40% and 50% of physicians still use these tests. Furthermore, thyroid receptor antibody, which is not recommended, is used by approximately 60%. In regard to antithyroid drugs, both guidelines suggest and physicians use methylmethimazole
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preferentially over propylthiouracil, due to potential side effects. Similarly, in regard to thyrotoxicosis and pregnancy, there were discrepancies, while in regard to Graves ophthalmopathy, most physicians followed the guidelines. I have thoroughly enjoyed reading the articles and hope the readers concur. The articles are written by the experts and cover basic and practical aspects that are important for our daily care of these common disorders. My appreciation to the issue editors, Dr Jonklaas and Burman, and the authors for this excellent compilation. Derek LeRoith, MD, PhD Division of Endocrinology, Metabolism, and Bone Diseases Department of Medicine Mount Sinai School of Medicine One Gustave L. Levy Place Box 1055, Altran 4-36 New York, NY 10029, USA E-mail address: [email protected]
Foreword T h y r o i d C a r c i n o m a a n d Ot h e r Thyroid Disorders
Derek LeRoith, MD, PhD Consulting Editor
We decided that an update on thyroid disorders would be appropriate since our last thyroid issue a number of years ago. In particular, it is clear that the incidence of thyroid cancer is increasing and there are a number of new modalities to therapy. In addition, there are a number of articles that cover considerations that have not been dealt with previously. Drs Mon and Hodak discuss the emerging technology of using molecular diagnostic tools in fine-needle aspirations of thyroid nodules. Since up to 40% of the cases remain indeterminate, it is hoped that these molecular tests would result in more definitive results. As they discuss, the specificity and sensitivity are as yet not 100% and therefore not always conclusive. Dr McLeod discusses how serum thyrotropin (TSH) levels have been associated with thyroid cancer, suggesting a potential causative relationship, although this has never been definitively proven. However, serum TSH levels remain important in the management of thyroid cancer. In particular, in detecting metastatic disease, traditionally thyroid suppression therapy was ceased to induce hypothyroidism and elevate TSH levels prior to isotope studies. Today, with the advent of recombinant TSH availability, it can be administered to elevate circulating levels, without cessation of the thyroid suppression and induction of hypothyroidism. Thyroid cancer, except in unusual situations, requires thyroid surgery. Drs Callender, Carling, Christison-Lagay, and Udelsman describe in their article that the diagnosis is commonly made on fine-needle aspiration of a nodule greater than 1 cm in diameter. Occasionally, the diagnosis may be made by detecting the BRAF V600E mutation in papillary thyroid cancer or rearranged during transfection (RET) protoncogene mutations in the case of multiple endocrine neoplasia, or familial medullary thyroid carcinoma. Small tumors may suffice with partial thyroidectomy, while those greater than 1 cm require total (or near total) thyroidectomy to reduce recurrence. Central lymph node dissection is critical if lymph nodes are involved or even the absence, if the tumor Endocrinol Metab Clin N Am - (2014) -–http://dx.doi.org/10.1016/j.ecl.2014.03.001 0889-8529/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
endo.theclinics.com
ii
Foreword
is large. These and other considerations require a team of thyroid cancer specialists and thus patients should be referred to large academic centers where possible, for the best considerations and care. Drs Duke and Terris describe alternative approaches to avoiding scarring of the neck following thyroidectomy. Numerous groups have perfected the minimally invasive anterior cervical approach that leaves a limited scar. Recently, the development of remote access approaches has been developed in an attempt to totally avoid the cervical scar. Unfortunately, these approaches from the chest, axilla, breast, and so on, while avoiding the scar, may be extremely problematic given the tissues they traverse and potential harm inflicted, as well as more prolonged postsurgery recovery; perhaps they should be avoided? Staging of disease in the situation of differentiated thyroid disease has been very useful to decide on appropriate therapy. However, as discussed by Drs Momesso and Tuttle, this staging needs to remain a dynamic process since incomplete responses are common and tumors may change their characteristics. The authors have devised an algorithm based on initial and ongoing outcomes and ranges from those with excellent responses to those with either biochemical or structural incomplete responses. Physicians are encouraged to consider these situations and treat appropriately. Drs Hu, Ying, and Jimenez describe the underlying oncogenic process in medullary thyroid cancer, an aggressive, often familial and fortunately rare form of thyroid cancer. The RET oncogene is the most common abnormality, due to either germline or somatic mutations that result in an activated RET. Other tyrosine kinase receptors have also been found to be overexpressed but whether they are primary or secondary to RET is unclear. Initial diagnosis is usually made with fine-needle aspiration, but chromogranin A and CEA levels are also useful. At present, there are tyrosine kinase–specific inhibitors that are available for therapeutic use and others in the pipeline. The prognosis in general is still much worse than that of PTC and FTC. Posttreatment fatigue in survivors of thyroid cancer is apparently a less well-recognized phenomenon. In the article by Sawka and colleagues, a description of the limited published data and their review of the literature are provided. Due to the paucity of data, the authors do not recommend specific interventions, but strongly support the idea of randomized controlled trials, a highly commendable suggestion. One could certainly extrapolate this to other endocrine conditions as well. Dr Rosenthal discusses, in her article, ethical issues in the management of thyroid diseases. These include informed consent prior to any form of thyroid ablation, whether radioablation or surgery. As she discusses, patients under severe stress or suffering from extremes of the disorders such as hypothyroidism or thyrotoxicosis may not totally comprehend the various therapeutic choices and it behooves the physician to be alert to these possibilities. In addition, there are ethical issues arising from genetic disorders of thyroid disease in terms of confidentiality and testing of family members. Clearly, the use of experimental drugs in clinical trials has its own issues that need addressing. While the article focuses on thyroid disorders, it is clearly important for all medical conditions that we as health care providers are involved in diagnosing and treating. Since thyroid hormone is critical for normal heart and cardiovascular system physiology, both overt thyroid dysfunction as well as subclinical disease may affect the cardiovascular system. Hyperthyroid-related cardiovascular effects are well known with both classic signs and symptoms, whereas hypothyroidism is associated with more subtle changes; the diagnosis is often established by elevated TSH levels. Of particular concern are the changes in lipid profiles. Drs Danzi and Klein also discuss the
Foreword
precautions needed when starting replacement therapies in the case of hypothyroidism, to avoid catastrophes, and further discuss the low T3 syndrome seen in chronic heart disease and amiodarone-induced thyroid dysfunction and how to deal with this problem. In a similar vein, Dr Samuels discusses the cognitive impairment and other psychological disturbances that are seen in hypothyroidism and thyrotoxic patients. These include anxiety and depression. They may be overt and more severe in classic hypothyroid and hyperthyroid patients, whereas they may be more subtle in subclinical forms of these disorders. Nevertheless, the good news is that there is usually significant improvement when the conditions are treated appropriately. Pregnancy affects thyroid physiology due to increased thyroid-binding globulin and human chorionic gonadotropin, as well as enhanced iodine metabolism. For these reasons, normal reference ranges for thyroid function tests are altered. As Drs Nathan and Sullivan discuss, pregnant women with overt hypothyroidism and those with subclinical hypothyroidism but thyroid peroxidase antibody-positive should be treated with levothyroxine to maintain thyroid function in the normal range, specific for each trimester. In regard to treating thyrotoxicosis in pregnancy, thionamides are still the treatment of choice. Radioisotope use is an important tool in the diagnosis and therapy of well-differentiated thyroid cancer and recurrence or distant metastases. Dr Esposito discusses how decisions are made regarding the dosage. In very low-risk patients with confined disease and no lymph node involvement nor distant metastases, a wait and watch approach is justified. In low-risk patients, those under 45 years of age with tumors between 1 and 2 cm, the American Thyroid Association suggests doses of 30 to 100 mCi. For intermediate-risk patients, tumors greater than 2 cm, using up to 100 mCi is suggested, whereas for high-risk patients, with residual tumor and lymph node involvement or distant metastases, using 150 to 200 mCi is suggested. While papillary thyroid carcinoma is usually associated with an excellent prognosis, its recurrence often requires additional management. Drs Goyal, Jonklass, and Burman discuss how, when cervical lymph nodes are detected after initial surgery as a recurrence, decisions are necessary as whether to use a surgical approach, radioactive iodine ablation, percutaneous ethanol injection, or simply observation. Drs Elisai, Viola, Matorne, Biagini, and Molinaro discuss the value of thyroglobulin (Tg) measurements, particularly in managing and treating recurrences in the case of differentiated thyroid cancer including papillary and follicular subtypes. Since these tumors synthesize and secrete Tg, a rising level can be an indication of remnant neck tumor or distant metastases. In follow-up management after surgery, TSH suppression by thyroid hormone often results in undetectable Tg. A rise in Tg suggests recurrence and requires the search and eradication of the remnant and metastases, usually by careful neck ultrasound and whole radioisotope scans, followed by radioisotope therapy. Clinical guidelines are developed by appropriate organizations to “guide” physicians in the best considered treatment plan for patients with certain disorders. In the case of Graves disease, the American Thyroid Association and the American Association of Clinical Endocrinologists jointly produced these guidelines. However, as detailed by Drs Muldoon, Mai, and Burch, there is a significant discrepancy between the guidelines and actual physician practice. For example, in diagnosing the condition, the guidelines do not recommend routine thyroid scan, uptake, or ultrasound, while between 40% and 50% of physicians still use these tests. Furthermore, thyroid receptor antibody, which is not recommended, is used by approximately 60%. In regard to antithyroid drugs, both guidelines suggest and physicians use methylmethimazole
iii
iv
Foreword
preferentially over propylthiouracil, due to potential side effects. Similarly, in regard to thyrotoxicosis and pregnancy, there were discrepancies, while in regard to Graves ophthalmopathy, most physicians followed the guidelines. I have thoroughly enjoyed reading the articles and hope the readers concur. The articles are written by the experts and cover basic and practical aspects that are important for our daily care of these common disorders. My appreciation to the issue editors, Dr Jonklaas and Burman, and the authors for this excellent compilation. Derek LeRoith, MD, PhD Division of Endocrinology, Metabolism, and Bone Diseases Department of Medicine Mount Sinai School of Medicine One Gustave L. Levy Place Box 1055, Altran 4-36 New York, NY 10029, USA E-mail address: [email protected]
