IAEA-TECDOC-1608 Nuclear Medicine in Thyroid Cancer Management: A Practical Approach March 2009
Nuclear Medicine in Thyroid Cancer Management: A Practical Approach
Jan 30, 2023
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IAEA-TECDOC-1608A Practical Approach
A Practical Approach
The originating Section of this publication in the IAEA was:
Nuclear Medicine Section International Atomic Energy Agency
Wagramer Strasse 5 P.O. Box 100
A-1400 Vienna, Austria
ISSN 1011–4289 © IAEA, 2009
Printed by the IAEA in Austria March 2009
FOREWORD
Thyroid cancers are now being diagnosed at an earlier stage and treatments together with follow-up strategies are more effective. However this is not consistent throughout the world. The practice does differ considerably from country to country and region to region. Many International Atomic Energy Agency (IAEA) Members States can benefit from the lessons learned and improve overall patient management of thyroid cancers.
The IAEA has significantly enhanced the capabilities of many Member States in the field of nuclear medicine. Functional imaging using nuclear medicine procedures has become an indispensable tool for the diagnosis, treatment planning and management of patients. In terms of treatment, the use of radioiodine (131I) has been central to thyroid cancer and has been successfully used for over six decades. Over the years the IAEA has also assisted many Member States to develop indigenous manufacturing of radioiodine therefore reducing the barriers for the care of patients.
This publication is a culmination of efforts by more than twenty international experts in the field to produce a global perspective on the subject. Views expressed are those of individual experts involved and are intended to assist national or regional authorities in decisions regarding the frameworks for effective treatment of thyroid cancer.
The IAEA is grateful to all the contributors and reviewers. The IAEA officers responsible for this publication were, in chronological order, A.K. Padhy, M. Dondi and K.K. Solanki. The IAEA officer responsible for revising and finalizing this publication was K.K. Solanki of the Division of Human Health.
EDITORIAL NOTE
The use of particular designations of countries or territories does not imply any judgement by the publisher, the IAEA, as to the legal status of such countries or territories, of their authorities and institutions or of the delimitation of their boundaries.
The mention of names of specific companies or products (whether or not indicated as registered) does not imply any intention to infringe proprietary rights, nor should it be construed as an endorsement or recommendation on the part of the IAEA.
CONTENTS
1.1. Background......................................................................................................... 1 1.1.1. Objective................................................................................................. 1 1.1.2. Scope....................................................................................................... 1 1.1.3. Structure.................................................................................................. 1
REFERENCES TO SECTION 1................................................................................................ 7
REFERENCES TO SECTION 2.............................................................................................. 16
3.3.1. Findings due to loco-regional spread.................................................... 21 3.3.2. Findings due to distant metastasis ........................................................ 21 3.3.3. Iatrogenic features................................................................................. 22 3.3.4. Others.................................................................................................... 22 3.3.5. Past history............................................................................................ 23 3.3.6. Family history ....................................................................................... 23
3.4. Conclusion ........................................................................................................ 24
4.1. Serum thyroglobulin measurements and its limitations ................................... 27 4.1.1. Variability of reagents .......................................................................... 27 4.1.2. Hook effect ........................................................................................... 28 4.1.3. Interference from thyroglobulin autoantibodies ................................... 28 4.1.4. Critical level for discerning the disease................................................ 29
4.2. Normal serum thyroglobulin concentrations .................................................... 29 4.3. Role of thyroglobulin in thyroid cancer ........................................................... 30
4.3.1. In primary diagnosis ............................................................................. 30 4.3.2. In post-surgical management ................................................................ 30 4.3.3. In follow-up .......................................................................................... 31
4.4. Comparison during and after withdrawal of thyroid hormone therapy or after rhTSH injection ........................................................................................ 31
4.5. Comparison of thyroglobulin with whole body radioiodine scan .................... 33 4.6. Conclusions ...................................................................................................... 34
REFERENCES TO SECTION 4.............................................................................................. 35
REFERENCES TO SECTION 6.............................................................................................. 55
7.1. Indications ........................................................................................................ 57 7.2. Contraindications.............................................................................................. 57
7.3. Complications................................................................................................... 57 7.4. Technique ......................................................................................................... 58
7.4.1. Equipment ............................................................................................. 58 7.4.2. Patient preparation ................................................................................ 58 7.4.3. The procedure ....................................................................................... 58 7.4.4. Making the smears ................................................................................ 59
7.5. Specimen adequacy .......................................................................................... 59 7.6. Reporting and clinical correlation .................................................................... 60 7.7. Accuracy........................................................................................................... 60
REFERENCES TO SECTION 7.............................................................................................. 61
8. PROGNOSTIC FACTORS AND RISK GROUP ANALYSES IN DIFFERENTIATED THYROID CARCINOMA .......................................................... 63
8.1. Prognostic factors in DTC ................................................................................ 63 8.2. Clinico-pathological prognostic factors............................................................ 63
8.2.1. Age........................................................................................................ 63 8.2.2. Gender................................................................................................... 63 8.2.3. Size........................................................................................................ 64 8.2.4. Multifocality ......................................................................................... 64 8.2.5. Vascular invasion.................................................................................. 64 8.2.6. Extrathyroidal extension ....................................................................... 64 8.2.7. Degree of tumour differentiation .......................................................... 64 8.2.8. Metastases............................................................................................. 64 8.2.9. Treatment .............................................................................................. 65 8.2.10. Tumour markers.................................................................................... 65 8.2.11. Tumour subtype .................................................................................... 65 8.2.12. Autoimmune thyroid disease ................................................................ 67 8.2.13. DNA ploidy........................................................................................... 67
9.7.2. Detection of pulmonary metastatic disease .......................................... 82 9.8. Treatment strategies.......................................................................................... 82
9.8.1. Surgical procedures in management of childhood disease ................... 82 9.8.2. Surgery for primary thyroid carcinoma ................................................ 82 9.8.3. Surgery for nodal metastases ................................................................ 85 9.8.4. Surgical morbidity ................................................................................ 85
9.9. Radioiodine treatment....................................................................................... 85 9.9.1. Residual thyroid tissue.......................................................................... 85 9.9.2. Nodal metastases................................................................................... 86 9.9.3. Pulmonary metastases........................................................................... 87 9.9.4. Tumour response to radioiodine therapy and possible adverse
10. SURGICAL MANAGEMENT....................................................................................... 96
10.1. Introduction ...................................................................................................... 96 10.2. Pre-operative evaluation ................................................................................... 96 10.3. Thyroid surgery ................................................................................................ 97 10.4. Risk groups in differentiated thyroid cancer .................................................... 98 10.5. Surgical management of differentiated thyroid cancers: total vs. near total
thyroidectomy................................................................................................... 99 10.6. Medullary thyroid cancer................................................................................ 101 10.7. Anaplastic cancer............................................................................................ 102 10.8. Postoperative complications ........................................................................... 102 10.9. Postoperative treatment .................................................................................. 102 10.10. Summary......................................................................................................... 103
thyroid with radioiodine...................................................................... 110 11.3. Optimisation of radiation dose and dose rate for ablation of remnant
11.5. Calculated dose ablation................................................................................. 116 11.6. Radioiodine treatment for thyroid cancer ....................................................... 119
11.7. Radioiodine therapy for patients with negative diagnostic scans and elevated thyroglobulin levels.......................................................................... 124
11.8. Conclusion ...................................................................................................... 124
12. PRACTICAL ASPECTS OF RADIOIODINE THERAPY ......................................... 129
12.1. Introduction .................................................................................................... 129 12.2. Selection of a therapeutic radionuclide for thyroid cancer treatment............. 129
12.2.1. Half-life............................................................................................... 129 12.2.2. Locally absorbed radiations ................................................................ 129 12.2.3. Specific activity and chemical form ................................................... 129
12.10. Long term advice ............................................................................................ 152 12.10.1. Future pregnancy ........................................................................... 152 12.10.2. Carcinogenesis............................................................................... 152 12.10.3. Other complications....................................................................... 153
REFERENCES TO SECTION 12.......................................................................................... 157
13.1. Radiotherapy................................................................................................... 159 13.2. Differentiated thyroid cancer.......................................................................... 160
15. POST SURGICAL IMAGING EVALUATION.......................................................... 171
15.1. Imaging with 131I ............................................................................................ 171 15.2. Limitations of 131I WBS ................................................................................. 171
15.2.1. Low sensitivity.................................................................................... 171 15.2.2. Low specificity ................................................................................... 172 15.2.3. Stunning .............................................................................................. 173 15.2.4. De-differentiation of DTC .................................................................. 173
15.3. Alternative imaging to 131I.............................................................................. 174 15.4. Summary......................................................................................................... 177
REFERENCES TO SECTION 15.......................................................................................... 177
16.1. Recurrence of papillary thyroid cancer........................................................... 180 16.1.1. Multiple episodes of recurrence.......................................................... 182 16.1.2. Survival............................................................................................... 182
16.5. Problems of overdosage of thyroxine............................................................. 194 16.6. Diagnosis and management of residual, recurrent and metastatic MTC........ 194
16.6.3. Survival............................................................................................... 197 16.6.4. Summary............................................................................................. 197
REFERENCES TO SECTION 18.......................................................................................... 249
19. EMERGING STRATEGIES ........................................................................................ 254
19.1. Introduction .................................................................................................... 254 19.2. Use of rhTSH in the diagnostic evaluation of differentiated thyroid
cancer.............................................................................................................. 255 19.3. Novel diagnostic and therapeutic strategies for poorly differentiated
ANNEX II. SAMPLE PATIENT INFORMATION SHEET ............................................ 266
ANNEX III. SAMPLE DOSE ADMINISTRATION RECORD ........................................ 268
CONTRIBUTORS TO DRAFTING AND REVIEW ........................................................... 271
1. EPIDEMIOLOGY AND AETIOLOGY
1.1. Background
This book is based on series of IAEA technical consultations mainly in the early part of this millennium. These technical consultations were than pooled together into a single IAEA publication with additional sections added to reflect current practice such as the use of thyroglobulin monitoring with the aid and services of international consultants. It provides views and practices from an international perspective, and the views expressed are those of individual experts involved. The publication is of directed at nuclear physicians, radiologists, oncologists, surgeons (general and head and neck surgeons), endocrinologists, medical physicists, medical technologists, radiopharmacists, radiotherapists, laboratory medicine scientists and researchers.
1.1.1. Objective
The prime objective of this book is to provide views and practices from an international perspective, thus an overview of thyroid cancer from series of technical consultations on nuclear medicine practices.
1.1.2. Scope
This publication can support essential discussion aimed at assisting the process of standardization and harmonization of clinical practice. This publication assists with the process of review and decision-making. It provides suggestions on improving numerous protocols leading to better patient management.
1.1.3. Structure
The structure takes the reader from primary care interventions, to diagnostic strategies, to widespread use of fine-needle aspiration biopsy, to surgery and to treatment options. It discusses clinical evaluation, management and long term follow-up of thyroid cancer patients. It provides specific information on the main goal of long term follow-up and detection of recurrent disease. It also deals with the combined use of thyroglobulin monitoring and recombinant human thyroid stimulating hormones (rhTSH) in modern day practices.
1.2. Epidemiology of thyroid cancer: global scenario
Although thyroid nodules are common, thyroid cancer is relatively rare. The overall incidence of cancer in a cold nodule is 5% to 15%, but it is higher in patients at the extremes of age. Clinically detectable thyroid carcinomas constitute less than 1 per cent of all human cancers.
The annual incidence rate in various parts of the world ranges from 0.5 to 10 cases per 100 000 population [1.1-1.6]. Hawaii, has the highest rate for thyroid cancer in both sexes. Globally, the lowest rate reported was from Barshi, India where the rate was 0.2/100 000 for females. Among males, in 174 out of 183 populations examined, the annual incidence rates were below 3 per 100 000 and among females the rates were below 5 per 100 000 in 123 out of 183 population groups [1.2].
1
2
FIG. 1.3. Incidence and mortality — thyroid cancers.
Age standardised rate (ASR) in females were always higher than in males in all countries as depicted in ‘Gobocan 2002’ (Figs 1.1, 1.2, 1.3). The rates in females were more than twice the rates in males in most of the population studied [1.1]. In Europe, France (11.06), Romania (9.09), Italy (9.3) and Iceland (9.80) have the highest rates in females. A high incidence of thyroid cancer has been observed in Iceland and in native Alaskan women also. Among men the highest rate was seen in Iceland (6.06) followed by Filipinos in Hawaii 5.08, and the Non Kuwaitis in Kuwait (4.79). Filipino men also have rates higher than most other groups [1.6].
An increasing trend in incidence has been observed especially in females in the United States of America (USA), Japan, Finland and Singapore and Chinese populations, whereas in India and the United Kingdom (UK) the rates have remained steady over the past 30 years. However, the analysis of incidence data from Connecticut, USA between 1935-1939 and 1990-1992 indicated that the increase in the incidence was due to cohort effect. The increase was observed in the cohort born between 1915 and 1945. For those born after 1945 the incidence declined. This was attributed to the practice of ionising radiation treatment for benign childhood conditions such as acne, parasitic infections of the scalp, and cervical adenitis. [1.3].
Cancer of thyroid in children has been observed and reported from all over the world. Though its incidence is low throughout the world, it has provided a base to study the aetiology of this disease. Parkin, et al. [1.4] have collected data on children from both population based registries and from established hospitals in the world in a book on childhood cancer where over 50 countries which includes regions from Africa, North America (USA and Canada), South America (Brazil, Columbia, Cuba, Jamaica, Puerto Rico), Asia (15 countries), Europe (22 countries) and Oceania (Australia, New Zealand and Fiji) were analysed. The highest ASR's for thyroid cancer in children among females were reported from African Americans in Los Angeles, USA with a rate of 2.8 per million and among males from the non Jewish population in Israel at 2.3 per million. Further the ASR’s were higher in females than in
3
males. It was observed in 33 out of the 65 populations where the rate in females was about one to five times higher than that in males.
Religious and ethnic differences in the incidence of thyroid cancer have also been reported in the literature [1.5-1.9]. In USA the rates in both sexes amongst non-African Americans were higher than that among African Americans population. In Israel, all the Jewish population had higher rates for thyroid cancer than other religious groups and the differences did not relate to their place of birth. Singaporean Malays have a higher incidence rate of thyroid cancer (males = 2.7, females = 5.0) than Singaporean Chinese (males = 1.5, females = 4.3) and the Singaporean Indian population (males = 0.7, females = 1.1). There have been very little differences in the incidence of thyroid cancer in the Japanese and Chinese who migrated to the USA, except for those who settled in Hawaiian island, where there was an increase in the incidence of thyroid cancer in both sexes as compared to the population of the country of origin [1.6]. The highest age adjusted incidence rate (AAR) of thyroid cancer was seen among Filipino women in Hawaii (ASR 25.46/100 000) followed by women residing in French Polynesia (15.9/100 000). Almost all communities living in Hawaii have rates higher than that seen in other areas of the world. This is seen both among males and females. However, women living in Manila, have incidence rates (8.7/100 000) one third of the rates seen in Filipinos of Hawaii. Similarly Chinese women in China have very low rates, between 0.5 and 2.96 but in Hawaii, Chinese women have an incidence rate of 9.42 [1.9]. Though many cancers are known to differ according to urban/rural status, there has not been any study to indicate this in the case of thyroid cancer.
1.3. Aetiology and risk factors
A risk factor is anything that increases a person's chance of getting a disease such as cancer. Different cancers have different risk factors. For example, unprotected exposure to strong sunlight is a risk factor for skin cancer, and smoking is a risk factor for cancers of the lungs, mouth, throat, oesophagus, bladder, and several other organs. Several authors have found a few risk factors that make a person more likely to develop thyroid cancer. However, even if a patient with thyroid cancer has one or more risk factors, it is impossible to know exactly how much that risk factor may have contributed to causing the cancer.
Of the few factors that are suspected as high risk for thyroid cancer are (a) exposure to radiation, (b) iodine intake and (c) certain diets. Of these, radiation exposure has been regarded as consistent with a causal role for thyroid cancer. Therapeutic radiation, radiation fall out from nuclear weapon testing and radiations from nuclear accidents have been observed as risk factors.
1.3.1. Radiation related risk factors
Natural high background radiation, Radiation exposures due to diagnostic, therapeutic, or accidental exposures
Low-level radiation like the high natural background radiation has not yet been shown as a high risk factor. An early study of resected specimens of thyroid nodules from people residing in the high natural radiation area of Kerala, India and a comparable control series did not indicate an increased frequency of thyroid cancer [1.12]. A study from the high natural radiation area in China has also shown similar results [1.13]. Natural high background radiation has been observed in the Karunagapally area of Quilon District in Kerala, India. The place is known for its monazite deposit, which emits gamma radiation varying from
4
3.8 mGy/a to 35 mGy/a [1.14]. Data indicates a high incidence of thyroid cancer in this area compared to others in India. However in the city of Thiruvananthapuram, 100 km away from Karunagappally, there is higher incidence of thyroid cancer in both sexes. Therefore, the association between risk for cancer and geographic variations in natural background radiation remains equivocal.
Exposure of the head and neck to radiation in early childhood increases the frequency of benign and malignant lesions. It is the only established etiological factor for thyroid cancer. The effect of radiation is more marked in the younger age group, as evident by the increased incidence in children three years after the nuclear accident in Belarus [1.15,1.16].
As a result of the accident at the Chernobyl Nuclear Power Plant on 26 April 1986, millions of Curies of short lived radioiodine isotopes were released in the fallout. The absorption of radioiodine through ingestion of contaminated food and water and inhalation led to an exposure of the thyroid gland that was 3-10 times higher in children than in adults. The risk of thyroid cancer was inversely correlated with the distance of residence from the source of contamination and age at the time of exposure. In children exposed to therapeutic radiation the incidence (33-37%) has been higher than that in non-exposed children [1.17-1.18].
A post Chernobyl rise in thyroid cancer was observed in far off places like Connecticut, in children as well as in adults, 4-7 years after the accident. This phenomenon was seen in other states like Iowa and Utah [1.20]. More details on the effect of radiation releases after Chernobyl accident is being described under various links from IAEA web site on Chernobyl forum.
1.3.2. Genetic factors
The mechanism by which radiation induces thyroid cancer at a low dose is not clear. It may be because of rearrangement of ret protooncogene due to the aberrant expression of the tyrosine kinase domain of the receptor involved in thyroid carcinogenesis [1.21]. However, the ret oncogene rearrangement is also found in tumours from non-irradiated children. Radiation may cause DNA strand break, which if not repaired can remain dormant and may express later if triggered by ‘modifier genes’ or other tumour promoting agents such as environmental factors, free radicals or hitherto other unknown factor(s) [1.22-1.25]. Analysis of thyroid cancer data from the Ukraine after Chernobyl using a two-mutation carcinogenesis model indicated that the absolute excess radiation risk per unit dose for children is about the same as or a little lower than that for adults [1.25]. Details on the genetic effects on thyroid cancer are presented in another section.
1.3.3. Hereditary conditions
People with certain inherited medical conditions are also at higher risk of thyroid cancer. Higher rates of the disease occur among people with conditions called Gardner's syndrome and familial polyposis. These conditions cause a very high risk of colorectal cancer and a slightly increased risk of cancers in some other organs. Also linked to an increased risk of thyroid cancer is Cowden's disease, a rare genetic condition. About 20% of medullary thyroid carcinomas result from inheriting an abnormal gene. These cases are known as familial medullary carcinoma. The combination of familial medullary thyroid carcinoma and tumours of other endocrine glands is called multiple endocrine neoplasia type 2 (MEN 2).
5
1.3.4. Iodine intake in diet
The role of iodine intake in preventing or promoting thyroid cancer has not been adequately demonstrated [1.26-1.29]. There is speculation of the role of dietary iodine in the increased incidence of thyroid cancer in Hawaiian populations where seafood is a predominant dietary constituent. However, there are reports that populations with iodine deficiency developed goitre and that such populations are seen to have more of the follicular type of thyroid cancer [1.27]. Iodine rich areas and iodine supplementation have shown an increase of papillary cancer (PC). In the coastal areas of Kerala, like Hawaii consumption of seafood is high and this could be a factor in the predominance of the PC in these areas as compared to the increase of follicular cancer (FC) in the areas remote from the coastal areas. A recent analysis relating iodine intake and thyroid cancer amongst women in a multiethnic population in the San Francisco Bay area study found that increased iodine intake was associated with a decreased risk of papillary thyroid cancer in low risk women but was slightly increased in high risk group of women with a history of goitre, nodules, family history of proliferative thyroid disease and those with history of radiation given to the head and neck. [1.30]. Another study from USA of a pooled analysis of the effect of fish and shell-fish consumption concluded that high consumption of fish did not increase the risk of developing thyroid cancer [1.31]. A review of available data from epidemiological studies, animal experiments and basic gene transfection studies indicated the relationship of iodine intake and cancer was…
A Practical Approach
The originating Section of this publication in the IAEA was:
Nuclear Medicine Section International Atomic Energy Agency
Wagramer Strasse 5 P.O. Box 100
A-1400 Vienna, Austria
ISSN 1011–4289 © IAEA, 2009
Printed by the IAEA in Austria March 2009
FOREWORD
Thyroid cancers are now being diagnosed at an earlier stage and treatments together with follow-up strategies are more effective. However this is not consistent throughout the world. The practice does differ considerably from country to country and region to region. Many International Atomic Energy Agency (IAEA) Members States can benefit from the lessons learned and improve overall patient management of thyroid cancers.
The IAEA has significantly enhanced the capabilities of many Member States in the field of nuclear medicine. Functional imaging using nuclear medicine procedures has become an indispensable tool for the diagnosis, treatment planning and management of patients. In terms of treatment, the use of radioiodine (131I) has been central to thyroid cancer and has been successfully used for over six decades. Over the years the IAEA has also assisted many Member States to develop indigenous manufacturing of radioiodine therefore reducing the barriers for the care of patients.
This publication is a culmination of efforts by more than twenty international experts in the field to produce a global perspective on the subject. Views expressed are those of individual experts involved and are intended to assist national or regional authorities in decisions regarding the frameworks for effective treatment of thyroid cancer.
The IAEA is grateful to all the contributors and reviewers. The IAEA officers responsible for this publication were, in chronological order, A.K. Padhy, M. Dondi and K.K. Solanki. The IAEA officer responsible for revising and finalizing this publication was K.K. Solanki of the Division of Human Health.
EDITORIAL NOTE
The use of particular designations of countries or territories does not imply any judgement by the publisher, the IAEA, as to the legal status of such countries or territories, of their authorities and institutions or of the delimitation of their boundaries.
The mention of names of specific companies or products (whether or not indicated as registered) does not imply any intention to infringe proprietary rights, nor should it be construed as an endorsement or recommendation on the part of the IAEA.
CONTENTS
1.1. Background......................................................................................................... 1 1.1.1. Objective................................................................................................. 1 1.1.2. Scope....................................................................................................... 1 1.1.3. Structure.................................................................................................. 1
REFERENCES TO SECTION 1................................................................................................ 7
REFERENCES TO SECTION 2.............................................................................................. 16
3.3.1. Findings due to loco-regional spread.................................................... 21 3.3.2. Findings due to distant metastasis ........................................................ 21 3.3.3. Iatrogenic features................................................................................. 22 3.3.4. Others.................................................................................................... 22 3.3.5. Past history............................................................................................ 23 3.3.6. Family history ....................................................................................... 23
3.4. Conclusion ........................................................................................................ 24
4.1. Serum thyroglobulin measurements and its limitations ................................... 27 4.1.1. Variability of reagents .......................................................................... 27 4.1.2. Hook effect ........................................................................................... 28 4.1.3. Interference from thyroglobulin autoantibodies ................................... 28 4.1.4. Critical level for discerning the disease................................................ 29
4.2. Normal serum thyroglobulin concentrations .................................................... 29 4.3. Role of thyroglobulin in thyroid cancer ........................................................... 30
4.3.1. In primary diagnosis ............................................................................. 30 4.3.2. In post-surgical management ................................................................ 30 4.3.3. In follow-up .......................................................................................... 31
4.4. Comparison during and after withdrawal of thyroid hormone therapy or after rhTSH injection ........................................................................................ 31
4.5. Comparison of thyroglobulin with whole body radioiodine scan .................... 33 4.6. Conclusions ...................................................................................................... 34
REFERENCES TO SECTION 4.............................................................................................. 35
REFERENCES TO SECTION 6.............................................................................................. 55
7.1. Indications ........................................................................................................ 57 7.2. Contraindications.............................................................................................. 57
7.3. Complications................................................................................................... 57 7.4. Technique ......................................................................................................... 58
7.4.1. Equipment ............................................................................................. 58 7.4.2. Patient preparation ................................................................................ 58 7.4.3. The procedure ....................................................................................... 58 7.4.4. Making the smears ................................................................................ 59
7.5. Specimen adequacy .......................................................................................... 59 7.6. Reporting and clinical correlation .................................................................... 60 7.7. Accuracy........................................................................................................... 60
REFERENCES TO SECTION 7.............................................................................................. 61
8. PROGNOSTIC FACTORS AND RISK GROUP ANALYSES IN DIFFERENTIATED THYROID CARCINOMA .......................................................... 63
8.1. Prognostic factors in DTC ................................................................................ 63 8.2. Clinico-pathological prognostic factors............................................................ 63
8.2.1. Age........................................................................................................ 63 8.2.2. Gender................................................................................................... 63 8.2.3. Size........................................................................................................ 64 8.2.4. Multifocality ......................................................................................... 64 8.2.5. Vascular invasion.................................................................................. 64 8.2.6. Extrathyroidal extension ....................................................................... 64 8.2.7. Degree of tumour differentiation .......................................................... 64 8.2.8. Metastases............................................................................................. 64 8.2.9. Treatment .............................................................................................. 65 8.2.10. Tumour markers.................................................................................... 65 8.2.11. Tumour subtype .................................................................................... 65 8.2.12. Autoimmune thyroid disease ................................................................ 67 8.2.13. DNA ploidy........................................................................................... 67
9.7.2. Detection of pulmonary metastatic disease .......................................... 82 9.8. Treatment strategies.......................................................................................... 82
9.8.1. Surgical procedures in management of childhood disease ................... 82 9.8.2. Surgery for primary thyroid carcinoma ................................................ 82 9.8.3. Surgery for nodal metastases ................................................................ 85 9.8.4. Surgical morbidity ................................................................................ 85
9.9. Radioiodine treatment....................................................................................... 85 9.9.1. Residual thyroid tissue.......................................................................... 85 9.9.2. Nodal metastases................................................................................... 86 9.9.3. Pulmonary metastases........................................................................... 87 9.9.4. Tumour response to radioiodine therapy and possible adverse
10. SURGICAL MANAGEMENT....................................................................................... 96
10.1. Introduction ...................................................................................................... 96 10.2. Pre-operative evaluation ................................................................................... 96 10.3. Thyroid surgery ................................................................................................ 97 10.4. Risk groups in differentiated thyroid cancer .................................................... 98 10.5. Surgical management of differentiated thyroid cancers: total vs. near total
thyroidectomy................................................................................................... 99 10.6. Medullary thyroid cancer................................................................................ 101 10.7. Anaplastic cancer............................................................................................ 102 10.8. Postoperative complications ........................................................................... 102 10.9. Postoperative treatment .................................................................................. 102 10.10. Summary......................................................................................................... 103
thyroid with radioiodine...................................................................... 110 11.3. Optimisation of radiation dose and dose rate for ablation of remnant
11.5. Calculated dose ablation................................................................................. 116 11.6. Radioiodine treatment for thyroid cancer ....................................................... 119
11.7. Radioiodine therapy for patients with negative diagnostic scans and elevated thyroglobulin levels.......................................................................... 124
11.8. Conclusion ...................................................................................................... 124
12. PRACTICAL ASPECTS OF RADIOIODINE THERAPY ......................................... 129
12.1. Introduction .................................................................................................... 129 12.2. Selection of a therapeutic radionuclide for thyroid cancer treatment............. 129
12.2.1. Half-life............................................................................................... 129 12.2.2. Locally absorbed radiations ................................................................ 129 12.2.3. Specific activity and chemical form ................................................... 129
12.10. Long term advice ............................................................................................ 152 12.10.1. Future pregnancy ........................................................................... 152 12.10.2. Carcinogenesis............................................................................... 152 12.10.3. Other complications....................................................................... 153
REFERENCES TO SECTION 12.......................................................................................... 157
13.1. Radiotherapy................................................................................................... 159 13.2. Differentiated thyroid cancer.......................................................................... 160
15. POST SURGICAL IMAGING EVALUATION.......................................................... 171
15.1. Imaging with 131I ............................................................................................ 171 15.2. Limitations of 131I WBS ................................................................................. 171
15.2.1. Low sensitivity.................................................................................... 171 15.2.2. Low specificity ................................................................................... 172 15.2.3. Stunning .............................................................................................. 173 15.2.4. De-differentiation of DTC .................................................................. 173
15.3. Alternative imaging to 131I.............................................................................. 174 15.4. Summary......................................................................................................... 177
REFERENCES TO SECTION 15.......................................................................................... 177
16.1. Recurrence of papillary thyroid cancer........................................................... 180 16.1.1. Multiple episodes of recurrence.......................................................... 182 16.1.2. Survival............................................................................................... 182
16.5. Problems of overdosage of thyroxine............................................................. 194 16.6. Diagnosis and management of residual, recurrent and metastatic MTC........ 194
16.6.3. Survival............................................................................................... 197 16.6.4. Summary............................................................................................. 197
REFERENCES TO SECTION 18.......................................................................................... 249
19. EMERGING STRATEGIES ........................................................................................ 254
19.1. Introduction .................................................................................................... 254 19.2. Use of rhTSH in the diagnostic evaluation of differentiated thyroid
cancer.............................................................................................................. 255 19.3. Novel diagnostic and therapeutic strategies for poorly differentiated
ANNEX II. SAMPLE PATIENT INFORMATION SHEET ............................................ 266
ANNEX III. SAMPLE DOSE ADMINISTRATION RECORD ........................................ 268
CONTRIBUTORS TO DRAFTING AND REVIEW ........................................................... 271
1. EPIDEMIOLOGY AND AETIOLOGY
1.1. Background
This book is based on series of IAEA technical consultations mainly in the early part of this millennium. These technical consultations were than pooled together into a single IAEA publication with additional sections added to reflect current practice such as the use of thyroglobulin monitoring with the aid and services of international consultants. It provides views and practices from an international perspective, and the views expressed are those of individual experts involved. The publication is of directed at nuclear physicians, radiologists, oncologists, surgeons (general and head and neck surgeons), endocrinologists, medical physicists, medical technologists, radiopharmacists, radiotherapists, laboratory medicine scientists and researchers.
1.1.1. Objective
The prime objective of this book is to provide views and practices from an international perspective, thus an overview of thyroid cancer from series of technical consultations on nuclear medicine practices.
1.1.2. Scope
This publication can support essential discussion aimed at assisting the process of standardization and harmonization of clinical practice. This publication assists with the process of review and decision-making. It provides suggestions on improving numerous protocols leading to better patient management.
1.1.3. Structure
The structure takes the reader from primary care interventions, to diagnostic strategies, to widespread use of fine-needle aspiration biopsy, to surgery and to treatment options. It discusses clinical evaluation, management and long term follow-up of thyroid cancer patients. It provides specific information on the main goal of long term follow-up and detection of recurrent disease. It also deals with the combined use of thyroglobulin monitoring and recombinant human thyroid stimulating hormones (rhTSH) in modern day practices.
1.2. Epidemiology of thyroid cancer: global scenario
Although thyroid nodules are common, thyroid cancer is relatively rare. The overall incidence of cancer in a cold nodule is 5% to 15%, but it is higher in patients at the extremes of age. Clinically detectable thyroid carcinomas constitute less than 1 per cent of all human cancers.
The annual incidence rate in various parts of the world ranges from 0.5 to 10 cases per 100 000 population [1.1-1.6]. Hawaii, has the highest rate for thyroid cancer in both sexes. Globally, the lowest rate reported was from Barshi, India where the rate was 0.2/100 000 for females. Among males, in 174 out of 183 populations examined, the annual incidence rates were below 3 per 100 000 and among females the rates were below 5 per 100 000 in 123 out of 183 population groups [1.2].
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FIG. 1.3. Incidence and mortality — thyroid cancers.
Age standardised rate (ASR) in females were always higher than in males in all countries as depicted in ‘Gobocan 2002’ (Figs 1.1, 1.2, 1.3). The rates in females were more than twice the rates in males in most of the population studied [1.1]. In Europe, France (11.06), Romania (9.09), Italy (9.3) and Iceland (9.80) have the highest rates in females. A high incidence of thyroid cancer has been observed in Iceland and in native Alaskan women also. Among men the highest rate was seen in Iceland (6.06) followed by Filipinos in Hawaii 5.08, and the Non Kuwaitis in Kuwait (4.79). Filipino men also have rates higher than most other groups [1.6].
An increasing trend in incidence has been observed especially in females in the United States of America (USA), Japan, Finland and Singapore and Chinese populations, whereas in India and the United Kingdom (UK) the rates have remained steady over the past 30 years. However, the analysis of incidence data from Connecticut, USA between 1935-1939 and 1990-1992 indicated that the increase in the incidence was due to cohort effect. The increase was observed in the cohort born between 1915 and 1945. For those born after 1945 the incidence declined. This was attributed to the practice of ionising radiation treatment for benign childhood conditions such as acne, parasitic infections of the scalp, and cervical adenitis. [1.3].
Cancer of thyroid in children has been observed and reported from all over the world. Though its incidence is low throughout the world, it has provided a base to study the aetiology of this disease. Parkin, et al. [1.4] have collected data on children from both population based registries and from established hospitals in the world in a book on childhood cancer where over 50 countries which includes regions from Africa, North America (USA and Canada), South America (Brazil, Columbia, Cuba, Jamaica, Puerto Rico), Asia (15 countries), Europe (22 countries) and Oceania (Australia, New Zealand and Fiji) were analysed. The highest ASR's for thyroid cancer in children among females were reported from African Americans in Los Angeles, USA with a rate of 2.8 per million and among males from the non Jewish population in Israel at 2.3 per million. Further the ASR’s were higher in females than in
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males. It was observed in 33 out of the 65 populations where the rate in females was about one to five times higher than that in males.
Religious and ethnic differences in the incidence of thyroid cancer have also been reported in the literature [1.5-1.9]. In USA the rates in both sexes amongst non-African Americans were higher than that among African Americans population. In Israel, all the Jewish population had higher rates for thyroid cancer than other religious groups and the differences did not relate to their place of birth. Singaporean Malays have a higher incidence rate of thyroid cancer (males = 2.7, females = 5.0) than Singaporean Chinese (males = 1.5, females = 4.3) and the Singaporean Indian population (males = 0.7, females = 1.1). There have been very little differences in the incidence of thyroid cancer in the Japanese and Chinese who migrated to the USA, except for those who settled in Hawaiian island, where there was an increase in the incidence of thyroid cancer in both sexes as compared to the population of the country of origin [1.6]. The highest age adjusted incidence rate (AAR) of thyroid cancer was seen among Filipino women in Hawaii (ASR 25.46/100 000) followed by women residing in French Polynesia (15.9/100 000). Almost all communities living in Hawaii have rates higher than that seen in other areas of the world. This is seen both among males and females. However, women living in Manila, have incidence rates (8.7/100 000) one third of the rates seen in Filipinos of Hawaii. Similarly Chinese women in China have very low rates, between 0.5 and 2.96 but in Hawaii, Chinese women have an incidence rate of 9.42 [1.9]. Though many cancers are known to differ according to urban/rural status, there has not been any study to indicate this in the case of thyroid cancer.
1.3. Aetiology and risk factors
A risk factor is anything that increases a person's chance of getting a disease such as cancer. Different cancers have different risk factors. For example, unprotected exposure to strong sunlight is a risk factor for skin cancer, and smoking is a risk factor for cancers of the lungs, mouth, throat, oesophagus, bladder, and several other organs. Several authors have found a few risk factors that make a person more likely to develop thyroid cancer. However, even if a patient with thyroid cancer has one or more risk factors, it is impossible to know exactly how much that risk factor may have contributed to causing the cancer.
Of the few factors that are suspected as high risk for thyroid cancer are (a) exposure to radiation, (b) iodine intake and (c) certain diets. Of these, radiation exposure has been regarded as consistent with a causal role for thyroid cancer. Therapeutic radiation, radiation fall out from nuclear weapon testing and radiations from nuclear accidents have been observed as risk factors.
1.3.1. Radiation related risk factors
Natural high background radiation, Radiation exposures due to diagnostic, therapeutic, or accidental exposures
Low-level radiation like the high natural background radiation has not yet been shown as a high risk factor. An early study of resected specimens of thyroid nodules from people residing in the high natural radiation area of Kerala, India and a comparable control series did not indicate an increased frequency of thyroid cancer [1.12]. A study from the high natural radiation area in China has also shown similar results [1.13]. Natural high background radiation has been observed in the Karunagapally area of Quilon District in Kerala, India. The place is known for its monazite deposit, which emits gamma radiation varying from
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3.8 mGy/a to 35 mGy/a [1.14]. Data indicates a high incidence of thyroid cancer in this area compared to others in India. However in the city of Thiruvananthapuram, 100 km away from Karunagappally, there is higher incidence of thyroid cancer in both sexes. Therefore, the association between risk for cancer and geographic variations in natural background radiation remains equivocal.
Exposure of the head and neck to radiation in early childhood increases the frequency of benign and malignant lesions. It is the only established etiological factor for thyroid cancer. The effect of radiation is more marked in the younger age group, as evident by the increased incidence in children three years after the nuclear accident in Belarus [1.15,1.16].
As a result of the accident at the Chernobyl Nuclear Power Plant on 26 April 1986, millions of Curies of short lived radioiodine isotopes were released in the fallout. The absorption of radioiodine through ingestion of contaminated food and water and inhalation led to an exposure of the thyroid gland that was 3-10 times higher in children than in adults. The risk of thyroid cancer was inversely correlated with the distance of residence from the source of contamination and age at the time of exposure. In children exposed to therapeutic radiation the incidence (33-37%) has been higher than that in non-exposed children [1.17-1.18].
A post Chernobyl rise in thyroid cancer was observed in far off places like Connecticut, in children as well as in adults, 4-7 years after the accident. This phenomenon was seen in other states like Iowa and Utah [1.20]. More details on the effect of radiation releases after Chernobyl accident is being described under various links from IAEA web site on Chernobyl forum.
1.3.2. Genetic factors
The mechanism by which radiation induces thyroid cancer at a low dose is not clear. It may be because of rearrangement of ret protooncogene due to the aberrant expression of the tyrosine kinase domain of the receptor involved in thyroid carcinogenesis [1.21]. However, the ret oncogene rearrangement is also found in tumours from non-irradiated children. Radiation may cause DNA strand break, which if not repaired can remain dormant and may express later if triggered by ‘modifier genes’ or other tumour promoting agents such as environmental factors, free radicals or hitherto other unknown factor(s) [1.22-1.25]. Analysis of thyroid cancer data from the Ukraine after Chernobyl using a two-mutation carcinogenesis model indicated that the absolute excess radiation risk per unit dose for children is about the same as or a little lower than that for adults [1.25]. Details on the genetic effects on thyroid cancer are presented in another section.
1.3.3. Hereditary conditions
People with certain inherited medical conditions are also at higher risk of thyroid cancer. Higher rates of the disease occur among people with conditions called Gardner's syndrome and familial polyposis. These conditions cause a very high risk of colorectal cancer and a slightly increased risk of cancers in some other organs. Also linked to an increased risk of thyroid cancer is Cowden's disease, a rare genetic condition. About 20% of medullary thyroid carcinomas result from inheriting an abnormal gene. These cases are known as familial medullary carcinoma. The combination of familial medullary thyroid carcinoma and tumours of other endocrine glands is called multiple endocrine neoplasia type 2 (MEN 2).
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1.3.4. Iodine intake in diet
The role of iodine intake in preventing or promoting thyroid cancer has not been adequately demonstrated [1.26-1.29]. There is speculation of the role of dietary iodine in the increased incidence of thyroid cancer in Hawaiian populations where seafood is a predominant dietary constituent. However, there are reports that populations with iodine deficiency developed goitre and that such populations are seen to have more of the follicular type of thyroid cancer [1.27]. Iodine rich areas and iodine supplementation have shown an increase of papillary cancer (PC). In the coastal areas of Kerala, like Hawaii consumption of seafood is high and this could be a factor in the predominance of the PC in these areas as compared to the increase of follicular cancer (FC) in the areas remote from the coastal areas. A recent analysis relating iodine intake and thyroid cancer amongst women in a multiethnic population in the San Francisco Bay area study found that increased iodine intake was associated with a decreased risk of papillary thyroid cancer in low risk women but was slightly increased in high risk group of women with a history of goitre, nodules, family history of proliferative thyroid disease and those with history of radiation given to the head and neck. [1.30]. Another study from USA of a pooled analysis of the effect of fish and shell-fish consumption concluded that high consumption of fish did not increase the risk of developing thyroid cancer [1.31]. A review of available data from epidemiological studies, animal experiments and basic gene transfection studies indicated the relationship of iodine intake and cancer was…
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