Guidelines for the management of thyroid cancer
2014; Wiley; Volume: 81; Issue: s1 Linguagem: Inglês
10.1111/cen.12515
ISSN1365-2265
AutoresPetros Perros, Kristien Boelaert, Steve Colley, Carol Evans, Rhodri Evans, Georgina Gerrard BA, Jackie Gilbert, Barney Harrison, Sarah J. Johnson, Thomas E. Giles, Laura Moss, Valerie Lewington, Kate Newbold, Judith Taylor, Rajesh V. Thakker, John Watkinson, Graham R. Williams,
Tópico(s)Thyroid and Parathyroid Surgery
ResumoIn spite of advances in diagnostic methods, surgical techniques and clinical care, there are differences in survival of patients with thyroid cancer in different countries, and the outcome in the UK prior to 1989 appeared to be worse than in other western European nations.1 The reasons for this are unclear and may be multifactorial. There is a sense that outcomes in the UK are improving, but only long term national registry data can confirm or refute this in future. However, it may not be unreasonable to speculate that the impact of previous editions of these guidelines, and recent changes in cancer services within the National Health Service may have contributed. These include mandatory specialist multidisciplinary team management of all cancers (http://www.mycancertreatment.nhs.uk/wp-content/themes/mct/uploads/2012/09/resources_measures_HeadNeck_Measures_April2011.pdf), regular mandatory national peer review, equity of access to specialist care, the cancer drug fund, national cancer research groups supporting trials, patient support groups, national audits by professional organisations, the cancer reform strategy and survivorship programme. It is hoped that the third edition of the national guidelines for thyroid cancer, and their implementation through local protocols of the NHS networks, will continue to facilitate this process and improve care and outcomes in the UK. The intention is to provide guidance for all those involved in the management of patients with differentiated thyroid cancer (DTC) and some of the rarer thyroid cancers. This document is not intended as guidelines for management of thyroid nodules, though the role of ultrasound (US) in assessing thyroid nodules is included. A summary of the key recommendations for the management of adult differentiated thyroid cancer, medullary thyroid cancer (MTC) and anaplastic thyroid cancer is provided (see previous section). Randomised trials are often not available in this setting. Therefore, evidence is based on large retrospective studies and the level of evidence is ascribed according to the Scottish Intercollegiate Guidelines Network 50 (A guideline developer's handbook (http://www.sign.ac.uk/pdf/sign50.pdf). These guidelines do not address thyroid lymphomas or metastases to the thyroid. In the period 1971–1995, the annual UK incidence was reported at 2.3 per 100 000 women and 0.9 per 100 000 men, with approximately 900 new cases and 250 deaths recorded in England and Wales due to thyroid cancer every year.2 In 2010, data from Cancer Research UK indicate 2654 new cases in the UK and 346 deaths. (http://www.cancerresearchuk.org/cancer-info/cancerstats/types/thyroid/uk-thyroid-cancer-statistics). Annual incidence data for the UK from 2008 show 5.1 per 100 000 women and 1.9 per 100 000 men (http://www.cancerresearchuk.org/cancer-info/cancerstats/types/thyroid/uk-thyroid-cancer-statistics). Thyroid cancer is the most common malignant endocrine tumour, but represents only about 1% of all malignancies.2 The incidence of thyroid cancer is increasing globally, mostly due to PTC,3 including in the paediatric population.4 The bulk of the increase is lower stage cancers and/or incidental micro-papillary thyroid cancers found when surgery is performed for thyroid diseases other than cancer.5, 6 Overall mortality from thyroid cancer has remained stable over many years.7 It has been suggested that the increase in incidence of thyroid cancer is due to better detection of incidental microcarcinomas.7, 8 This view has been challenged by studies which found that the incidence of thyroid cancers of all sizes has been increasing over time.3, 9 It seems plausible that factors other than increased detection, may underlie the rising incidence of thyroid cancer, and may include changing iodine status and exposure to radiation,10 but in most cases the cause is unknown. Nuclear fallout is a well recognised cause of an increase in the risk of thyroid cancer in children. Following the Chernobyl accident, the incidence of thyroid cancer rose several hundred times in children in the region. Therapeutic and diagnostic X-rays in childhood are also possible causes of thyroid cancer in adults; exposure to these sources should be limited whenever possible. In cases of populations or individuals being contaminated with 131I the thyroid can be protected by administering potassium iodide.11-13 At present there is no screening programme to detect thyroid cancer for the general population. Screening is possible for familial MTCs associated with specific oncogene mutations. The genetic basis of papillary, follicular and anaplastic thyroid cancer has been investigated and the roles and potential prognostic value of several genes, e.g. RET, TRK, RAS, BRAF, PPARG and p53, have been identified. Testing for these genes is not routinely available in clinical practice.14 Patients should be informed about and given the opportunity to consider participation in ongoing randomized clinical trials in cases where there is genuine clinical equipoise or lack of level 1 evidence (4, D). Key recommendation The long-term outcome of patients treated effectively for differentiated thyroid cancer (DTC) is usually favourable. The overall 10-year survival rate for middle-aged adults with DTC is 80–90%. However, 5–20% of patients develop local or regional recurrences and 10–15% distant metastases.1-3 Nine per cent of patients with a diagnosis of thyroid cancer die of their disease.4, 5 It is important to assess both risk of death from the disease and risk of recurrence in patients with DTC using a prognostic scoring system. This enables a more accurate prognosis to be given and the appropriate treatment decisions to be made. Several factors have been shown consistently to be important for predicting death and recurrence in multivariate analyses of large patient cohorts: Age at the time of diagnosis is one of the most consistent prognostic factors in patients with DTC. The risk of recurrence and death increases with age, particularly after the age of 40 years.6-11 Young children, under the age of 10 years, are at higher risk of recurrence than older children or adolescents.12-15 The male gender has been reported as an independent risk factor in some but not all studies.4, 9, 10, 14, 15 The prognosis of papillary thyroid carcinoma (PTC) is better than that of follicular thyroid cancer (FTC). However, if the confounding effects of age and extent of tumour at diagnosis are removed, survival rates are comparable.6, 9, 17-19 Within the PTC group, poorer prognosis is associated with specific histological types (e.g. tall cell, columnar cell)20-24 and the degree of cellular differentiation and vascular invasion.7, 25 'Widely invasive' and 'vascular invasion' are features of follicular cancers associated with a poorer prognosis.26 Poorly differentiated and oncocytic follicular (Hürthle-cell) carcinomas are also associated with a poorer outcome.9, 10, 27, 28, 14, 29 The risk of recurrence and mortality correlates with the size of the primary tumour.6, 8-11, 16, 27 Extra-thyroidal invasion,6, 8-11, 25, 30, 31 lymph node metastases,6, 9, 10, 27, 32 and distant metastases25, 33-35 are all important prognostic factors.14 Several staging systems have been proposed for DTC and continue to evolve.36, 37 Any of these systems can be used to assign patients to the high-risk or low-risk group (MACIS is used only for PTC), based on well-established prognostic factors (detailed below), but TNM and MACIS probably yield the most useful prognostic information.38, 39 The TNM classification is used extensively for registration and predicts mortality (Table 2.1) (for online calculator see: http://www.thyroid.org/thyroid-cancer-staging-calculator/). From the clinical standpoint, the objective is to tailor treatment to the individual so as to minimise the risk of death and recurrence. Equally important, is avoidance of unnecessary exposure of patients with a good prognosis to invasive therapies associated with long-term side effects, which may impact on quality of life. The principles of personalised medicine are increasingly being applied to the management of patients with thyroid cancer. Advances in molecular medicine and the development of prognostic nomograms40 will facilitate this process. However, for the foreseeable future, conventional clinical and histopathological parameters remain the principal tools on which management decisions have to be based. The scoring and prognostic systems described above are helpful in stratifying patients, though they have evolved not only for clinical management but also for design and analysis of clinical trials or retrospective clinical studies and for cancer registration purposes.41 Post-operative TNM staging predicts the risk of death from disease, and is a valuable indicator of overall prognosis (Table 2.1). However, it does not take into account individual responses to treatment, which may alter prognosis, and it does not predict recurrence. A three tier system adapted from the American Thyroid Association (ATA) guidelines48 may be used to assign risk for persistent or recurrent disease (Table 2.2). This is useful for determining whether patients should undergo radioiodine remnant ablation (RRA) (Chapter 9), and the intensity and method of follow up in the post-operative setting. For patients who have undergone total thyroidectomy with R0 resection and RRA, the 9–12 months post-RRA stimulated thyroglobulin (sTg), whole body scan (WBS) (if performed) and neck ultrasound (US), will allow potential modification of the initial static risk estimate based on the patient's response to RRA. Using a combination of clinicopathological factors with treatment response criteria allows a more personalised approach to treatment, follow up and prognostication49 (Table 2.3). This will facilitate follow up as the majority of patients will have achieved an excellent response and TSH suppression can be relaxed (Chapter 11), allowing the TSH concentration to rise to the low-normal range. Annual Tg assessment can be carried out without stimulation and follow up intervals can be extended (Chapter 13). The TNM classification (7th edition)47 (Table 2.1) is recommended38, 43-45 (4, D). Key recommendation The ATA post-operative risk stratification for risk of recurrence shown in Table 2.2 is recommended (adapted from48) (4, C). Key recommendation Allocation to one of three response groups after Dynamic Risk Stratification (Table 2.3) is recommended (2-, C). Key recommendation Clear recommendations for or against treatments are possible for specific patient groups, but in many cases there is uncertainty. Both clinicians and patients can feel uncomfortable dealing with uncertainty. However, if handled appropriately, this process can become a positive experience and increase confidence about making the right choice. To achieve this, patient and clinician need to have adequate time for discussion, the opportunity for relatives or other third parties to participate in the discussion should be given if desired by the patient, time to reflect should be allowed, good quality information about the implications of the different options should be made available, and the responsible clinician should lead and guide the patient' choice using his/her expert knowledge. When the evidence for or against a treatment is inconclusive and no well designed, peer reviewed randomised or prospective national or institutional studies are ongoing to address this issue or if available, declined by the patient, these guidelines recommend a personalised approach to decision making (Personalised Decision Making) (4, D). Key recommendation Personalised Decision Making involves clinicians and patients working together to find a solution, that best suits the circumstances of the individual patient. This process consists of: Examples of uncertainty in decision making where Personalised Decision Making may be applied are shown in Table 2.4. MicroPTC with any of the following (Chapter 8.2): PTC TR), or irregular overall shape are also relevant for solid/cystic nodules as a predictor of malignancy.23 The high sensitivity of US for the detection of papillary carcinoma can result in the finding of small (<1 cm) nodules that are suspicious for thyroid malignancy. In such cases extra thyroidal extension and associated metastatic lymphadenopathy will influence the decision as to whether or not to perform FNAC. When there is no evidence of extra thyroidal disease, or no associated high risk clinical history, the decision whether or not to perform FNAC will depend on the clinical picture, and the responsible clinician needs to make an appropriate judgment (supported by the MDT) about pursuing cytological confirmation, in order to avoid overtreatment of clinically insignificant micro-papillary thyroid carcinomas (microPTCs).24 US appearances that are indicative of a benign nodule (U1–U2) should be regarded as reassuring not requiring fine needle aspiration cytology (FNAC), unless the patient has a statistically high risk of malignancy (Chapter 3.7) (2++, B). Key Recommendation If the US appearances are equivocal, indeterminate or suspicious of malignancy (U3–U5), an US guided FNAC should follow10 (2++, B). Key Recommendation If a nodule is being assessed by US, the practitioner (be they a sonographer, surgeon, endocrinologist or radiologist) should be competent in identifying the characteristic signs that can allow a differentiation of thyroid nodules (i.e. either benign (U2), equivocal/indeterminate (U3), suspicious (U4) or malignant (U5) as outlined in the U classification, Fig. 4.1. Good Practice Point ☑ A report should identify the various characteristics and give appropriate measurements of significant thyroid nodules/masses and the U score. In multinodular thyroids, the score for the most suspicious nodule should be recorded. Good Practice Point ☑ Any retrosternal extension or tracheal deviation should be noted. Good Practice Point ☑ When a malignancy is suspected a full assessment of the remainder of the neck for associated lymph node metastases is mandatory. Good Practice Point ☑ The follow up of thyroid nodules should depend upon the initial US appearances and associated cytology (Fig. 4.2).25-28 Nodules with Thy2 cytology but indeterminate or suspicious US features should undergo repeat FNAC for confirmation. The rate of malignancy in this setting is significant, and evidence supports repeat cytological sampling28 (2++, B). Key Recommendation Atypical (Thy3a), follicular (Thy3f), suspicious (Thy4) and diagnostic (Thy5) cytology is discussed in Chapter 5. Nodules detected by PET-CT with focal FDG activity should be investigated with ultrasound and FNAC, unless disseminated disease is identified and the prognosis from an alternative malignancy would preclude further investigation (1++, A). Key Recommendation US assessment should be recorded with images captured on picture archiving and communications system (PACS), with a formal written report linked to the Radiology Information System.33 Good Practice Point ☑ Reporting should follow the diagnostic criteria as outlined in Table 4.3. Good Practice Point ☑ Such services should be managed in conjunction with Radiology allowing supervision/advice to be sought when necessary. Good Practice Point ☑ Training should follow the guidance outlined by the Royal College of Radiologists for other non-Radiology groups.33 Good Practice Point ☑ Fine needle aspiration cytology (FNAC) is a valuable and cost-effective pre-operative investigation for thyroid nodules in adults.1-3 The results can reassure that a nodule is benign, triage patients for diagnostic surgery, or provide a definite diagnosis of some thyroid malignancies enabling one-stage therapeutic surgery. FNAC does have drawbacks, however, especially the sometimes high rate of inadequate/unsatisfactory samples; the inability to distinguish between non-neoplastic, benign and malignant follicular lesions1, 4, 5 and the difficulty in detecting follicular variant of papillary thyroid carcinoma.6-12 It is essential that adequate material is obtained for diagnosis and that the microscopy is performed by pathologists experienced in thyroid disease.13, 14 A high quality service requires close co-operation between biomedical/healthcare scientists, pathologists, radiologists/sonographers and clinicians managing the patients so that appropriate procedures are set up, implemented and monitored.13 Aspiration should be performed by an appropriately trained individual with expertise and interest in thyroid disease. They should perform sufficient aspirates to maintain expertise and they should audit their results.15 FNAC samples taken with ultrasound (US) guidance (Chapter 4), have increased accuracy13, 16-18 and reduced rates of unsatisfactory samples.19-22 Immediate assessment of the sample for adequacy by biomedical scientists or pathologists at the time of aspiration can reduce the rate of unsatisfactory samples and be cost-effective especially if the underlying adequacy rate is low,23-27 and facilitate collection of material for ancillary tests. FNAC can also be used in the diagnosis of suspicious lymph nodes and the measurement of thyroglobulin in the washout can improve diagnostic accuracy (Appendix 1).28, 29 Molecular analysis (e.g. BRAF V600E mutation for PTC, alone or part of a panel) is an emerging field and may refine the prediction of both benignity and malignancy in thyroid cytology samples.30-51 All FNAC requests should include full clinical details including a description of the abnormality (diagrams are helpful). Good Practice Point ☑ A nominated pathologist should be a core member of the local thyroid cancer Multidisciplinary Team (MDT).53 National Cancer Peer Review Programme, measure 11-2I-114 Thyroid cytology should be reported by a cytopathologist with experience in such samples and with access to colleagues with additional experience for second opinions when appropriate. Such review increases accuracy of cytology13, 54, 55 (2+, C). Key recommendation There should be routine correlation between the cytological diagnosis and any subsequent histology. Good Practice Point ☑ The cytology report should contain a descriptive section interpreting the findings, followed by the Thy numerical category as defined by RCPath (Section 5.2). Good Practice Point ☑ Key recommendation Numerical categories increase accuracy,56 aid local audit, allow comparison with other centres including internationally, and can guide discussion on further management but are not a replacement for the descriptive interpretation. The clinical scenario should be taken into account when reporting the cytology.1 Good Practice Point ☑ Additional cases (e.g. Thy3 category cytology) can benefit from MDT discussion and this should be at the discretion of the local MDT. Good Practice Point ☑ As noted above (Section 5.1), the Thy numerical diagnostic categories should be used in addition to a full text report. The Royal College of Pathologists publication should be followed for the terminology, and is summarised below. For full explanation of the categories, see the original RCPath document and any subsequent revision.66 These UK categories now map exactly to the Bethesda categories used in the USA67, which facilitates comparison between the two systems. The likelihood of a malignancy on subsequent histology increases with increasing Thy category and should be 100% for Thy5, though rates of 98–99% are reported.68, 69 Suspicious cytology (Thy4) is associated with malignant histology in about 68–70%.69, 70 Follicular or indeterminate cytology (Thy3) is followed by malignant histology in around 9·5–43% of cases70, 9, 71-77, 69 the risk being highest with suspicious ultrasound features.75 There is a false negative rate for benign (Thy2) cytology results (usually <3%).62 Malignancy can be found in nodules with Thy1 cytology (4·5–8·5%22, 63), especially if the lesion is cystic (14·3%).89 There is interobserver variation in the interpretation of follicular-patterned lesions in both cytology and histology.78, 69, 79, 80 Subdivision of indeterminate cytology (Thy3) further stratifies the risk of malignancy.8, 81, 8, 82-84, 65, 85, 86 Immunocytochemical and molecular methods may also assist in stratification of risk.87-91 Patients with suspected thyroid cancer should normally be seen in accordance with the national target for urgent referrals (currently 2 weeks) (Chapter 3). Good Practice Point ☑ If there are progressive/severe respiratory problems associated with a thyroid mass, patients must be referred and seen without delay. Good Practice Point ☑ Patients with new onset of stridor and a thyroid mass must be assessed as emergency cases. Good Practice Point ☑ Decisions should be made promptly with respect to diagnosis and treatment (maximum 31 days from diagnosis to first treatment and 62 days from urgent referral to first treatment, Chapter 3, Fig. 3.1). Good Practice Point ☑ The following should be recorded in the medical records: Good Practice Point ☑ There is a strong case for patients with thyroid cancer to be operated on and treated by clinicians who have appropriate training and experience. Complication rates from thyroid surgery are lower when patients, adult and paediatric, are treated by 'high volume' surgeons.1-3 Membership of the British Association of Endocrine and Thyroid Surgeons (BAETS) mandates annual returns and provides comparative performance data on surgical numbers and outcome measures (http://baets.e-dendrite.com). The surgeon should have training and expertise in the management of thyroid cancer and be a core member of the multidisciplinary team (MDT) (Improving outcomes in Head and Neck Cancer http://www.nice.org.uk/nicemedia/live/10897/28851/28851.pdf) Key recommendation Surgeons who operate on patients with thyroid cancer should perform a minimum of 20 thyroidectomies per year National Cancer Peer Review Programme, measure 11-2I-149 Cervical lymph node dissection should be performed by MDT authorised surgeons National Cancer Peer Review Programme, measure 1
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