Papillary, follicular, and anaplastic thyroid carcinoma and lymphoma
Introduction
Papillary and follicular thyroid carcinomas are the most frequent forms of thyroid cancers and are among the most curable cancers. However, some patients are at high risk of recurrence or even death from their cancer, and can be identified at the time of diagnosis using well-established prognostic indicators (1–3). The apparent increase in the incidence of thyroid carcinomas observed in recent years is mainly related to an increased detection of low risk small carcinomas in adults, which is attributed to an improvement in diagnostic techniques (4, 5). This leads to the treatment of an increasing number of low-risk patients for whom an optimal quality of life should be maintained. However, the number of high-risk patients remains unchanged and these patients require aggressive treatment and follow-up. The extent of initial treatment and follow-up should therefore be individualized according to recent guidelines and consensus (6, 7).
Diagnosis
Most differentiated thyroid carcinomas present as asymptomatic thyroid nodules, but occasionally the first signs of the disease are lymph node metastases and rarely lung or bone metastases. Hoarseness, dysphagia, cough, and dyspnoea are suggestive of advanced stages of the disease. At physical examination, the carcinoma, usually single, is firm, freely moveable during swallowing, and not easily distinguishable from a benign nodule. A thyroid nodule should be suspected of being a carcinoma when it is found in children or adolescents or in men above 60 years of age, when it is hard and irregular, when ipsilateral lymph nodes are enlarged or compressive symptoms are present, and when there is a history of progressive increase in size. Virtually all patients are clinically euthyroid and have normal serum thyrotropin concentrations.
Thyroid ultrasonography is useful for assessing the characteristics of the nodule and detecting other nodules and lymph node enlargement, and to guide the fine-needle biopsy. Suspicious ultrasonographic findings are taller than wide shape, marked hypoechogenicity, spiculated margins, microcalcifications and macrocalcifications, and hypervascularization; isoechogenicity of the nodule in conjunction with a spongiform appearance are reliable criteria for benign nodules (8). Whatever the presentation, fine-needle aspiration cytology is the best test for diagnosing a papillary thyroid carcinoma. Provided an adequate specimen is obtained (6, 7, 9), three cytological results are possible: benign, malignant, and indeterminate (or suspicious). Among indeterminate results, only 20% are from malignant nodules, reflecting the difficulty of differentiating benign follicular or oncocytic adenomas from their malignant counterparts.
Prognostic indicators
The overall 10-year survival rates for middle-aged adults with thyroid carcinomas are about 80–95% (Table 3.5.6.1). Five to 15% of patients have local or regional recurrences and 5–10% have distant metastases. Prognostic indicators of recurrence and of death are age at diagnosis, histological type, and extent of the tumour (1–3, 10).
Table 3.5.6.1 Proportion of various histotypes among malignant thyroid tumours, and overall 10-year survival rates for each histotype in the absence of distant metastases
Proportion (%) | Overall 10-year survival rates (%) | |
|---|---|---|
Differentiated thyroid cancer | 85 | |
Papillary | 65 | 95 |
Follicular | 20 | 90 |
Poorly differentiated | <10 | 50 |
Other thyroid tumours | 15 | |
Anaplastic | <5 | <20 |
Medullary | 5–10 | 65 |
Rare tumours | <5 |
There are many scoring systems for thyroid carcinoma, among which the pTNM staging system is the most widely accepted (Table 3.5.6.2) (11). Based on this system, 80–85% of patients are classified as being at low risk of cancer-specific mortality. Some patients have a higher risk of recurrences. They include young (<16 years) and older (>45 years) patients, and those with large tumours, extension of the tumour beyond the thyroid capsule, or lymph node metastases. Finally, patients with certain histological subtypes (tall cell, columnar cell, and diffuse-sclerosing variants), and those with poorly differentiated carcinoma (12, 13) may have a higher risk of both recurrence and tumour-related death.
Table 3.5.6.2 TNM staging system for papillary and follicular thyroid carcinoma
Stage | Age <45 years | Age >45 years |
|---|---|---|
I | Any T, Any N, M0 | T1, N0, M0 |
II | Any T, Any N, M1 | T2, N0, M0 |
III | T3, N0, M0 or any T1–3, N1a, M0 | |
IVA | T1–3, N1b, M0 or T4a, Any N, M0 N, M0 | |
IVB | T4b, Any N, M0 | |
IVC | Any T, Any N, M1 |
Primary tumour (T): T1, tumour ≤2 cm limited to the thyroid; T2, tumour >2 to ≤4 cm limited to the thyroid; T3, tumour >4 cm limited to the thyroid or any tumour with minimal extrathyroidal extension (e.g. extension to sternothyroid muscle or perithyroidal soft tissues); T4a, tumour of any size with extension beyond the thyroid capsule and invading any of the following: subcutaneous soft tissues, larynx, trachea, oesophagus, recurrent laryngeal nerve; T4b, tumour invading prevertebral fascia, mediastinal vessels, or encases carotid artery.
Lymph nodes (N): To classify as N0 or N1, at least six lymph nodes should be examined at histology. Otherwise, the tumour is classified as Nx. N0, no regional lymph node metastasis; N1a, metastases in pretracheal and paratracheal, including prelaryngeal and Delphian lymph nodes; N1b, metastases in other unilateral, bilateral, or contralateral cervical or upper mediastinal lymph nodes.
Distant metastases (M): M0, no distant metastasis; M1, distant metastasis.
Initial treatment
Surgery
The goal of surgery is to remove all neoplastic neck tissue. A neck ultrasonography is performed preoperatively, but can detect only one-half of metastatic lymph nodes. Total thyroidectomy is advocated for all patients with thyroid cancer (6, 7). It reduces the recurrence rate as compared with more limited surgery because many papillary carcinomas are multifocal and bilateral. Removal of most if not all of the thyroid gland facilitates total ablation with 131I. However, total thyroidectomy may increase the risk of recurrent laryngeal nerve injury and hypoparathyroidism, but morbidity remains low when performed by an experienced surgeon. A lobectomy may be appropriate only in patients with papillary carcinomas less than 1 cm in diameter, if unifocal and intralobar (6, 7, 14). In patients who underwent a lobectomy for a supposedly benign tumour that proves to be a follicular carcinoma, a completion thyroidectomy should be offered to those patients for whom a near-total or total thyroidectomy would have been recommended had the diagnosis been available before the initial surgery.
Lymph node dissection is routinely performed in patients with known lymph node involvement, as demonstrated pre- or peroperatively. It includes a dissection of the central compartment (level VI), defined as the removal of lymph nodes and soft tissue from the hyoid bone superiorly, to the great vessels inferiorly and to the jugular veins laterally and may also include a dissection of the supraclavicular area and the lower one-third of the jugulocarotid chain (levels III and IV). In the absence of demonstrated lymph node metastases, several arguments support its routine use in patients with large papillary carcinomas: (1) about two-thirds of patients have lymph node metastases, more than 80% of whom have involvement of the central compartment (15); (2) metastases are difficult to detect in lymph nodes located behind the vessels or in the paratracheal groove; and (3) it has improved the recurrence and survival rates in several series. In patients with small (T1–T2) papillary carcinomas, the indication for prophylactic lymph node dissection is controversial, but the knowledge of lymph node status will help to better define the indication for postoperative 131I therapy (16).
Iodine-131 therapy
Iodine-131 therapy is given postoperatively for three reasons: (1) it destroys normal thyroid remnants, thereby increasing the sensitivity and the specificity of serum thyroglobulin measurement for the detection of persistent or recurrent disease; (2) it may destroy occult microscopic carcinoma, thereby decreasing the long-term recurrence rate; and (3) it permits a postablative total body scan, a sensitive tool for the detection of persistent carcinoma (6, 7).
Iodine-131 therapy is administered 4–6 weeks after surgery, during which no thyroid hormone treatment is given to achieve a serum thyroid-stimulating hormone (TSH) level above 30 mU/l. As an alternative, thyroxine treatment may be given after surgery and recombinant human TSH (rhTSH) injected (0.9 mg intramuscularly on two consecutive days) and 131I given on the day after the second injection (17); this method avoids hypothyroidism, maintains the quality of life, reduces the body radiation exposure, and shortens the length of hospitalization (18–20). Patients should be instructed to avoid iodine-containing medications and iodine-rich foods, and urinary iodine should be measured in doubtful cases. Pregnancy must be excluded in women of childbearing age. Education of the patient with written documents is mandatory before any administration of radio-iodine. Total ablation (undetectable stimulated serum thyroglobulin with normal neck ultrasonography) is achieved 6–12 months later, after the administration of either 100 mCi (3700 MBq) or 30 mCi (1100 MBq) in almost all patients who had a total thyroidectomy (17, 21). Total ablation requires a dose of at least 300 Gy delivered to thyroid remnants, and a dosimetric study allows to estimate more precisely the activity of 131I to be administered (22).
A total body scan is carried out 3–7 days later, and thyroxine therapy is maintained or is initiated in case of withdrawal. This total body scan is informative for the detection of neoplastic uptake foci outside the thyroid bed when uptake in thyroid remnants is less than 1%. The fusion of scintigraphy images with anatomical CT images on a dedicated gamma camera improves both the sensitivity and the specificity of the technique (23).
Simple methods are used for minimizing body irradiation, improving the quality of scanning images, and reducing the risk of false-positive images: lemon juice decreases uptake in salivary glands, ingestion of large quantities of liquid decreases bladder and gonad irradiation, and laxative treatment decreases colon contamination. Furthermore, patients are invited to take a shower and to wear clean clothes before scanning. False-positive results are rare and are usually easily recognized. They may be related to skin contamination, axillary perspiration, to salivary glands, to the presence of radioactive saliva in the mouth and oesophagus, to thymus hypertrophy, or to various conditions such as pleuropericardial cyst or inflammatory processes.
A diagnostic total body scan with 2 mCi (74 MBq) 131I may be performed before 131I therapy only when less than a total thyroidectomy has been performed, in order to assess the size of thyroid remnants; however, it may induce stunning (24). A low or undetectable serum thyroglobulin level obtained on the day of 131I administration is predictive of a favourable outcome (25).
Postoperative 131I therapy should be used selectively (Table 3.5.6.3) (6, 7). In very low-risk patients, the long-term prognosis after surgery alone is so favourable that 131I ablation is usually not recommended. Patients who are at high risk of recurrence or in whom resection of the neoplastic tissue was incomplete, or who have known distant metastases are routinely treated with a high activity of 131I (100 mCi or more) following thyroid hormone treatment withdrawal, because 131I treatment improves the outcome. Finally, for the other patients, there is no firm evidence that 131I treatment may improve the outcome, and a high (100 mCi or more) or a low (30 mCi) 131I activity may be administered following either thyroid hormone treatment withdrawal or rhTSH.
Table 3.5.6.3 Indications for 131I ablative treatment in patients with thyroid carcinoma after initial surgery
Patient group | Tumour staging | Comments |
|---|---|---|
Very low risk patients | T <1 cm, unifocal, intrathyroidal, and N0 | No benefits, no indication |
High risk patients | T2–4, large or multiple N1, M1, persistent disease | Treatment with a high activity (100 mCi or more) following thyroid hormone withdrawal |
Low risk patients | All others | Controversial benefits. Ablation may be performed with either a low (30 mCi) or high (100 mCi) activity and following either thyroid hormone withdrawal or rhTSH |
External radiotherapy
External radiotherapy to the neck and mediastinum is indicated only in patients older than 45 years in whom surgical excision has been incomplete or impossible, and in whom the tumour tissue does not take up 131I (26).
Follow-up
The goals of follow-up after initial therapy are to maintain adequate thyroxine therapy and to detect persistent or recurrent thyroid carcinoma. Most recurrences occur during the first years of follow-up, but some occur late. Therefore, follow-up is necessary throughout the patient’s life.
Thyroxine treatment
Thyroxine is given to all patients with thyroid carcinoma to restore euthyroidism. Also, the growth of thyroid tumour cells is stimulated by thyrotropin (TSH) and inhibition of thyrotropin secretion with thyroxine improves the recurrence and survival rates, but only in high-risk patients. TSH suppression is achieved in such patients and in those with any evidence of disease; in low-risk patients with no evidence of disease, the risk of recurrence is so low that total suppression is not justified and serum TSH is maintained within the normal range (27). The initial daily dose is 2.2 μg/kg body weight in adults; children require higher doses. The adequacy of therapy is monitored by measuring serum TSH 3 months after it is begun, the initial goal being a serum TSH concentration of not more than 0.1 μU/ml and a serum free triiodothyronine concentration within the normal range to avoid overdosing.
Early detection of recurrent disease
Clinical and ultrasonographic examinations
Palpation and ultrasonography of the thyroid bed and lymph node areas are routinely performed. Lymph nodes that are small, thin, or oval, in the posterior neck chains, and decrease in size after an interval of 3 months are considered benign; suspicious findings are short axis more than 0.5 cm, round shape, loss of fatty hyperechoic hilum, hypoechogenicity, cystic appearance, hyperechoic punctuations, and peripheral vascularization (Table 3.5.6.4) (28). Serum thyroglobulin is undetectable in 20% of patients receiving thyroxine treatment who have isolated lymph node metastases, and undetectable serum thyroglobulin values do not exclude metastatic lymph node disease (29). Suspicious cases should be submitted to an ultrasound-guided node biopsy for cytology and thyroglobulin measurement in the fluid aspirate (30, 31).
Table 3.5.6.4 Ultrasound criteria of malignancy for cervical lymph nodes. These criteria may be difficult to interpret in small lymph nodes
Sensitivity (%) | Specificity (%) | |
|---|---|---|
Long axis (>1 cm) | 68 | 75 |
Short axis (>0.5 cm) | 61 | 96 |
Round shape | 46 | 64 |
Loss of fatty hyperechoic hilum | c.100 | 29 |
Hypoechogenicity | 32 | 21 |
Cystic appearance | 11 | 100 |
Hyperechoic punctuations | 46 | 100 |
Peripheral vascularization | 86 | 82 |
From Leboulleux S, Girard E, Rose M, Travagli JP, Sabbah N, Caillou B, et al. Ultrasound criteria of malignancy for cervical lymph nodes in patients followed for differentiated thyroid cancer. J Clin Endocrinol Metab, 2007; 92: 3590–4.
Serum thyroglobulin determinations
Thyroglobulin is a glycoprotein that is produced only by normal or neoplastic thyroid follicular cells. It should not be detectable in patients who have had total thyroid ablation, and its detection in them indicates persistent or recurrent disease. The production of thyroglobulin by both normal and neoplastic thyroid tissue is in part TSH dependent.
The functional sensitivity of first-generation thyroglobulin immunometric assays was 1 ng/ml. Because results of serum thyroglobulin determination may be different with various assays, the same assay should be used for the follow-up of a given patient. Serum antithyroglobulin antibodies that are found in about 15–25% of patients with thyroid carcinoma are always sought by a radioimmunoassay because they may induce falsely reduced or falsely negative serum thyroglobulin measurements (32, 33). In patients in complete remission after total thyroid ablation, serum antithyroglobulin antibodies decline with a median time of 3 years to low or undetectable values; their persistence or their reappearance during follow-up should be considered as suspicious for persistent or recurrent disease.
After total ablation in patients on thyroxine treatment, serum thyroglobulin is undetectable in 98% of individuals considered in complete remission. It is detectable in practically all patients with large metastases and often at high levels; however, in this context, about 20% of patients with isolated lymph node metastases and 5% of patients with small lung metastases have an undetectable serum thyroglobulin level. Following withdrawal of thyroid hormone treatment, thyroglobulin concentration will increase in most patients with neoplastic disease and will frequently reach high levels. In this situation, serum thyroglobulin will remain undetectable in less than 5% of patients with isolated lymph node metastases and in less than 1% of patients with small lung metastases. In contrast, serum thyroglobulin will remain undetectable in more than 90% of patients with no other evidence of disease (32, 34, 35). Intramuscular injection of rhTSH is an alternative to withdrawal (0.9 mg intramuscularly for two consecutive days and serum thyroglobulin determination 3 days after the second injection), because thyroxine treatment need not be discontinued and side effects are minimal. The efficacy of rhTSH for the detection of persistent and recurrent disease is similar to that of thyroid hormone withdrawal, and a major advantage of the use of rhTSH is that it avoids hypothyroidism and maintains the quality of life (19, 20, 36, 37). The serum thyroglobulin concentration is an excellent prognostic indicator, and recurrence rate after 12 years is 0.5% in patients with undetectable thyroglobulin following withdrawal or rhTSH stimulation (40, 41) (Box 3.5.6.1).
The availability of second-generation thyroglobulin assays with a functional sensitivity of 0.1 ng/ml or even less may reduce the need for routine rhTSH stimulation in low-risk patients with undetectable serum thyroglobulin on thyroxine treatment (38, 39). However, the significance of the frequently observed low but detectable serum thyroglobulin levels is currently unknown. Also, an undetectable serum thyroglobulin following rhTSH stimulation or thyroid hormone withdrawal allows to reassure the patient, to decrease the thyroxine dosage, and to avoid any other testing (Box 3.5.6.1), but whether this can also be done with an undetectable serum thyroglobulin obtained during thyroxine treatment with a second-generation assay has not yet been established.
Imaging modalities
Imaging modalities for the detection of persistent and recurrent disease are indicated only in selected patients. Control 131I total body scan with a diagnostic activity (2–5 mCi) may be performed in patients who had large thyroid remnants at the time of ablation and in whom the post-therapy total body scan was not informative. In patients with an informative post-therapy total body scan that is normal, a control total body scan is not beneficial and for this reason is not recommended on a routine basis (40, 41).
Iodine-131 total body scan is more sensitive for detecting neoplastic foci when it is performed with a high activity (100 mCi or more) than with a low activity (42, 43). It is performed after thyroid hormone withdrawal in patients with high and increasing serum thyroglobulin levels. The discovery of lesions with 131I uptake may indicate further 131I treatments. However, in the absence of such lesions no further 131I treatment should be given.
[18F]2-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET)/CT has a sensitivity of 50–100% for the localization of recurrent disease depending on tumour burden and histology subtype (44) (Box 3.5.6.2). Furthermore, treatment changes due to FDG-PET results occur in 20–38% of the cases. FDG-PET is particularly informative in patients with aggressive thyroid cancer such as tall cell, Hürthle cell, or poorly differentiated cancer. FDG-PET and neck–chest CT with contrast-medium injection are complementary, with FDG-PET being more sensitive for the detection of neck and mediastinum lymph nodes and bone metastases and chest CT being more sensitive for the detection of micronodular lung metastases. PET/CT with high-quality CT being performed with contrast-medium injection and respiratory gating will combine the advantages of the two methods. The drawback of FDG-PET is the risk of false-positive lesions that can occur in up to 17% of patients; neck inflammatory lymph nodes with low FDG uptake are frequently seen. FDG uptake increases following rhTSH stimulation, with rhTSH-stimulated FDG-PET showing more lesions than FDG-PET performed during thyroxine treatment (45). Whether rhTSH administration should be performed systematically before FDG-PET has, however, not yet been demonstrated.
Bone involvement is well visualized by MRI or CT and by FDG-PET in cases with FDG uptake. Because bone metastases are osteolytic, bone scintigraphy is usually poorly informative showing a decrease or a moderately increased uptake.
Follow-up strategy
If the total body scan performed after the administration of 131I to destroy the thyroid remnant does not show any uptake outside the thyroid bed, physical examination is performed and serum TSH, free triiodothyronine, and thyroglobulin are measured during thyroxine treatment 3 months later. Nine to 12 months after initial treatment, a determination of serum thyroglobulin following rhTSH stimulation and a neck ultrasonography are obtained (Fig. 3.5.6.1) (6, 7). The results of these two tests will guide the subsequent follow-up, and may allow to revise the initial prognostic assessment. If serum thyroglobulin following TSH stimulation is undetectable and neck ultrasonography is normal, the risk of recurrence is less than 0.5% at 12 years (40, 41). These low-risk patients are considered cured, and can be reassured; the dose of thyroxine is decreased to maintain serum TSH concentration around 0.5 mU/l. In higher risk patients, higher doses of thyroxine are given for 5 years, the goal being a low serum TSH concentration (around 0.1 mU/l). Clinical and biochemical evaluation is then performed annually; any other testing is unnecessary as long as the serum thyroglobulin concentration is undetectable, and repeating rhTSH stimulation is usually not necessary (46). In these patients, control 131I total body scan does not provide any benefits and is usually not performed (47–49).
If serum thyroglobulin is detectable following TSH stimulation at 9–12 months, another determination following rhTSH is obtained 6–18 months later, because with longer follow-up serum thyroglobulin became undetectable following rhTSH stimulation in two-thirds of these patients (50). In those with high and increasing serum thyroglobulin levels, imaging tests should be performed, including a CT of the neck and chest, the administration of a large activity of 131I (100 mCi (3700 MBq) or more) with a total body scan 3–5 days later, and an FDG-PET scan (42, 44). These imaging modalities are also performed during long-term follow-up in patients receiving thyroxine in whom serum thyroglobulin becomes detectable, and increases above 10 ng/ml after TSH stimulation.
In low-risk patients who have had a total thyroidectomy but who were not given 131I postoperatively, and in those who have had less than a total thyroidectomy, the follow-up protocol is based on thyroglobulin determinations and neck ultrasonography. Further treatment may be given for increasing serum thyroglobulin level with time or for any imaging abnormality.
Local and regional recurrences
Local or regional recurrences occur in 5–20% of patients with differentiated thyroid carcinomas. Some are related to incomplete initial treatment (in a thyroid remnant or in lymph nodes), and others indicate tumour aggressiveness (in the thyroid bed after total thyroidectomy or in soft tissues) and are often associated with distant metastases (51, 52).
A local or regional recurrence that is palpable or easily visualized with ultrasonography or CT scan should be resected. Total excision may be facilitated by total body scanning 4 days after administration of 100 mCi (3700 MBq) 131I, because additional tissue that should be excised may be identified. Surgery is performed 1 day later, preferably using an intraoperative probe. The completeness of resection is verified 1–2 days after surgery by another total body scan and was achieved in 92% of patients who underwent this protocol (53). Involvement of the trachea or oesophagus may indicate extensive surgery (54)
A local or regional recurrence that is small, less than 1 cm in diameter, may be treated with 131I alone. Indeed, 131I uptake will still be detectable in only 24% of patients after three 131I treatments, and depending on disease location these patients may then undergo surgery (55). Preoperative charcoal tattooing under ultrasonographic guidance may facilitate the peroperative detection of small lymph node metastases.
From a practical point of view, there is no evidence that treatment of small lymph nodes (<5 mm in diameter) may provide a better outcome than treatment of lymph nodes that are more than 7–10 mm in diameter; for this reason, there is no usually need to explore small abnormalities found at neck ultrasonography. External radiotherapy is indicated in patients with soft tissue recurrences that cannot be completely excised and that do not take up 131I.
Distant metastases
Distant metastases, mostly in the lungs and bones, occur in 5–10% of patients with differentiated thyroid carcinomas. Lung metastases are most frequent in young patients with papillary carcinoma. Bone metastases are more common in older patients and in those with follicular carcinoma. Other less common sites are the brain, liver, and skin (56–59).
Diagnosis
Clinical symptoms of lung involvement are uncommon. The pattern of lung involvement may vary from macronodular to diffuse infiltrates. The latter is usually diagnosed with 131I total body scan and may be confirmed by CT; enlarged mediastinal lymph nodes are often present in children with papillary carcinomas. Pain, swelling, or fractures occur in more than 80% of patients with bone metastases. Nearly all patients with distant metastases have a high serum thyroglobulin concentration and two-thirds of patients have 131I uptake in the metastases. 131I uptake is more frequently found in younger patients, in those with small metastases, and in those with a well-differentiated thyroid carcinoma. FDG uptake on PET scan is more frequently seen in older patients with poorly differentiated thyroid carcinoma and large metastases. High FDG uptake is an adverse prognostic indicator for survival and for response to 131I therapy (60, 61).
Treatment
Palliative surgery is required for bone metastases when there are neurological or orthopaedic complications or there is a high risk of such complications. Surgery may also be useful to debulk large tumour masses, and may be curative in patients with a single bone metastasis (62). Other local treatment modalities may include cement injection, radiofrequency, and external radiotherapy.
Patients with metastases that take up 131I are treated with 100–150 mCi (3700–5550 MBq) following thyroid hormone withdrawal every 4–6 months. The effective radiation dose, which depends on the effective half-life of 131I in the metastasis and on the ratio between total uptake and the mass of thyroid tissue, is correlated with the outcome of 131I therapy (63–65). This was the rationale to administer higher activities (200 mCi or more, or based on dosimetry), but no clinical benefits have been demonstrated over standard treatment. Lower activities (1 mCi/kg (37 MBq) body weight) are given to children. There is no limit to the cumulative activity of 131I that can be given to patients with distant metastases, although above a cumulative activity of 600 mCi (22 000 MBq) further 131I therapy usually has little benefit but the risk of leukaemia increases significantly (56).
Cytotoxic chemotherapy with an anthracycline or taxane regimen is poorly effective in patients with advanced or metastatic disease that is refractory to 131I treatment and is progressive (66). In these patients, treatment with drugs that are antiangiogenic and that interfere with the MAP kinase pathway provided significant benefits and are used as first-line treatment (67–70).
Treatment results
Complete responses have been obtained in 45% of patients with distant metastases with initial 131I uptake, more frequently in younger patients with well-differentiated tumours, and with metastases that are small when discovered and with no significant FDG uptake on PET (Box 3.5.6.3). Nearly all complete responses have been obtained with a cumulative activity of 600 mCi or less and nearly half with a cumulative activity of 200 mCi. Few relapses occurred after complete response, despite detectable serum thyroglobulin concentration in some patients (56).
Overall survival after the discovery of distant metastases is about 40% at 10 years. Young patients with well-differentiated tumours who have metastases that are small when discovered and that take up 131I and have no FDG uptake on PET scan have a more favourable outcome: the large majority of these patients are cured and their overall survival is excellent. In the other groups of patients with distant metastases, median survival after the discovery of the metastases is about 3 years in those with no initial 131I uptake, and about 5 years in those with initial 131I uptake but who are not cured with 131I treatment. When the tumour mass is considered, the location of the metastases, be it the lungs or bone, has no independent prognostic influence. The poor prognosis of bone metastases is linked to the bulkiness of their lesions and their clinical morbidity. Local treatment of bone lesions should be performed, even in the presence of 131I uptake, including surgery, radiofrequency, cement injection, or external radiation therapy.
Complications of treatment with 131I
Acute side effects
Acute side effects (nausea, sialadenitis, lost of taste) after treatment with 131I are common but are usually mild and resolve rapidly. Radiation thyroiditis is usually trivial, but, if the thyroid remnant is large, the patient may have enough pain to warrant corticosteroid therapy for a few days. Tumour in certain locations, brain, spinal cord, and paratracheal, may swell in response to TSH stimulation or after 131I therapy, causing compressive symptoms and may warrant corticosteroid therapy. Radiation fibrosis may develop in patients with diffuse lung metastases who have high 131I uptake, if high activities (>150 mCi (5550 MBq)) are administered at short intervals (<3 months). Xerostomia (71) and obstruction of the lachrymal duct (72) may occur after 131I treatment.
Genetic defects and infertility
Particular attention must be paid to avoid administration of 131I in pregnant women. After 131I treatment, in men spermatogenesis may be transiently depressed (73), and women may have transient ovarian failure (74). Pregnancy outcome is not affected by previous radio-iodine exposure (75, 76). Therefore, it is only recommended that conception be postponed for 6 months after treatment with 131I. There is no evidence that pregnancy affects tumour growth in women receiving adequate thyroxine therapy, which should be monitored carefully before conception and during pregnancy.
Carcinogenesis and leukaemogenesis
Mild pancytopenia may occur after repeated 131I therapy, especially in patients with bone metastases also treated with external radiotherapy. The overall relative risk of secondary carcinoma and of leukaemia was found to be increased in patients treated with a high cumulative activity of 131I (>500 mCi (18 500 MBq)) or in association with external radiotherapy (77).
Anaplastic thyroid carcinoma
Anaplastic carcinoma of the thyroid is one of the most aggressive cancers encountered in humans. In most cases, it represents the ultimate stage in the dedifferentiation of a follicular or papillary carcinoma. In fact, anaplastic cells do not produce thyroglobulin, they are not able to concentrate iodine, and thyrotropin receptors are not found in their plasma cell membranes. Anaplastic carcinomas represent less than 5% of all thyroid cancers. Nearly all patients affected are older people. The peak incidence is in the seventh decade of life and the male to female ratio is 1:3 (78).
Diagnosis
More than one-third of the patients with anaplastic carcinoma have a long-standing goitre. The most common mode of presentation is a rapidly enlarging fixed neck mass, with palpable lymph nodes. Invasion of adjacent organs and compressive symptoms are frequent. Twenty to 50% of patients have distant metastases, most commonly in lungs, bones, brain, and liver. Anaplastic carcinomas are solid masses. Fine-needle aspiration biopsy is an effective diagnostic method but the diagnosis should be established by biopsy or at surgery. Neck ultrasonography, CT scan or MRI, FDG-PET scan, and endoscopy will assess the local extent of the tumour and will search for distant metastases (79).
Pathology
The tumour is typically composed of varying proportions of spindle, polygonal, and giant cells, often harbouring squamous cells and sarcomatoid foci. Keratin is the most useful epithelial marker and is present in 40–100% of the tumours. Many anaplastic carcinomas have a well-differentiated component. Conversely, differentiated carcinomas with small undifferentiated foci should be considered as anaplastic.
Immunohistochemical studies indicate that most tumours previously classified as small cell undifferentiated carcinomas were in fact primary malignant lymphomas (positive for leucocyte common antigen) or less often medullary carcinomas (positive for calcitonin and carcinoembryonic antigen), poorly differentiated thyroid carcinomas, or a thyroid metastasis from another primary tumour. Some tumours do not react with any antibody; they are considered as anaplastic carcinomas and carry the same prognosis.
Treatment
Survival is not altered by treatment with surgery, radiotherapy, or chemotherapy alone. In most patients, death is caused by local tumour invasion. The median survival is 2–6 months, and few patients have survived more than 12 months.
Only combined multimodality treatment improved the local control rate, thus avoiding death from suffocation. This includes surgical resection of all tumour masses present in the neck, followed by a combination of systemic chemotherapy and external radiotherapy to the neck and mediastinum. Chemotherapy consists of either fractionated doses of doxorubicin, 10 mg/m2 per week, or a combination of doxorubicin, 60 mg/m2, and cisplatin, 90 mg/m2, every 3–4 weeks; a taxane regimen may also be used as first- or second-line treatment (80, 81).
External radiotherapy may be hyperfractionated and accelerated. This comprises fractions of 1.25 Gy given twice a day for 5 days a week to a total dose of 40–45 Gy. It is given either in combination with fractionated doxorubicin or between the second and third courses of the combination doxorubicin–cisplatin. Severe toxicity occurs in one-third of the patients. All protocols of combined multimodality treatment provide similar rates of local control and long-term survival: complete local control is obtained in 60–80% of patients, thus avoiding death from local invasion and suffocation; long-term survival is obtained in 20–30% of patients with most deaths being due to distant metastases.
Benefits are observed mostly in patients who had apparently complete surgery and in whom the anaplastic cancer component represented a small fraction of the thyroid tumour mass. No response was observed in patients with distant metastases. This underlines the need for treating these patients as soon as possible, before distant metastases appear.
Thyroid lymphoma
Primary non-Hodgkin’s lymphomas of the thyroid are rare tumours accounting for 2.5% of all non-Hodgkin’s lymphomas and less than 5% of all malignant thyroid tumours (82). Older people are predominantly affected with the peak incidence during the seventh decade of life and the male to female ratio is 1:3.
Pathology
Primary thyroid lymphoma almost always has a B-cell lineage. The majority are ‘mucosa-associated lymphoid tissue’ (MALT) lymphomas, and arise in patients with chronic autoimmune thyroiditis. These small cell lymphomas are characterized by a low grade of malignancy, a slow growth rate, and a tendency for recurrence at other MALT sites such as the gastrointestinal or respiratory tract, the thymus, or the salivary glands.
At diagnosis, diffuse large cell lymphomas account for about 70–80% of tumours, and a significant proportion of clinical cases arise from the transformation of low-grade MALT lymphoma to high-grade B-cell lymphoma.
Diagnosis
Thyroid lymphomas almost invariably present as a rapidly enlarging painless fixed neck mass with palpable lymph nodes. One-third of the patients have compressive symptoms. Clinically evident distant disease is uncommon. In patients with chronic autoimmune thyroiditis, the diagnosis of small cell lymphoma may be difficult and a lymphoma should be sought when the goitre increases in size, or when patients complain of neck discomfort, pain, or compressive symptoms.
The palpated mass is solid and hypoechoic on ultrasonography. A biopsy is needed for immunohistochemical staining to diagnose small cell lymphomas and the frequently associated chronic autoimmune thyroiditis. It is also needed to exclude an anaplastic carcinoma. Lymphocyte monoclonality for light chain immunoglobulin may be necessary to confirm malignant lymphoma.
Accurate staging is critical for treatment planning. Staging includes a physical examination, complete blood count, serum lactate dehydrogenase, liver function tests, bone marrow biopsy, CT scan or MRI of the neck, thorax, abdomen, and pelvis, FDG-PET scan, and appropriate biopsies at sites where tumour is suspected. Involvement of Waldeyer’s ring and of the gastrointestinal tract have been associated with thyroid lymphomas and therefore upper gastrointestinal tract endoscopy should be performed.
Treatment
Treatment is guided by the histological subtype, the extent of the disease, and in case of diffuse large B-cell lymphoma by the age-adjusted international prognostic index. Small tumours are often treated initially as primary thyroid carcinomas with surgery, and additional radiotherapy may be necessary in case of indolent lymphoma. Surgical debulking of thyroid lymphomas is neither feasible nor necessary.
For diffuse large B-cell lymphoma, or transformation of MALT lymphoma to high-grade B-cell lymphoma, chemotherapy combined with rituximab (chimeric human-mouse anti-CD20 monoclonal antibody) has become the standard treatment (83). The chemotherapy usually consists of 4–6 cycles of the CHOP regimen (cyclophosphamide, 750 mg/m2 on day 1, doxorubicin, 50 mg/m2 on day 1, vincristine, 1.4 mg/m2 on day 1 and prednisone, 40 mg/m2 per day on days 1–5) every 3 weeks. Radiotherapy alone for aggressive lymphoma should be used only for elderly patients who cannot receive medical treatment. In fact, about one-third of the patients with disease apparently confined to the neck and treated with external radiotherapy alone, develop a recurrence at distant sites.
For localized MALT lymphomas, total thyroidectomy (predicted overall survival and freedom-from-progression survival, 100% at 5 years) or involved-field radiation therapy alone, 2 Gy/fraction for 5 days a week up to a total dose of 30–40 Gy, (5-year overall survival 90%) may be adequate if disease is localized after accurate staging (84, 85). For disseminated MALT lymphoma, chemotherapy alone with a single agent such as chlorambucil or combined with local radiation therapy can be used.
Other unusual tumours of the thyroid
Histiocytosis X
Isolated cases of thyroid involvement have been reported in patients with the malignant form of histiocytosis X. Chemotherapy with an anthracycline-based regimen induces long-term remission in most of these patients.
Sinus histiocytosis with massive lymphadenopathy (Rosai–Dorfman disease)
S100 protein-positive histiocytes with strong plasma cell reactions are the main histological features. Most affected patients have irregular goitre and enlarged cervical lymph nodes that simulate chronic autoimmune thyroiditis or a malignant process. The majority of the cases resolve spontaneously, but the disease may progress and is potentially lethal. In these cases, chemotherapy with an anthracycline-based regimen can be effective.
Mesenchymal tumours of the thyroid
Benign mesenchymal tumours of the thyroid such as lipoma and haemangioma are extremely rare and are usually treated with surgery alone. Primary fibrosarcomas and angiosarcomas of the thyroid are also rare and the differential diagnosis with anaplastic carcinoma may be difficult. They should be treated in the same manner as patients with anaplastic thyroid carcinoma.
Teratoma of the thyroid gland
There are two different types of thyroid teratomas. In infants, teratomas are often congenital and are composed of mature cystic tissue; these benign lesions are treated by total thyroidectomy. Teratomas in children and adults are composed of neuroepithelial tissue and are highly malignant, metastasizing early to lymph nodes and lungs. They require combined treatment with surgery, external radiotherapy, and chemotherapy.
Other primary tumours
Ectopic parathyroid or thymic tissue and primary paraganglioma may be found inside the thyroid gland.
Thyroid metastases
Microscopic metastases to the thyroid are a regular feature of necroptic findings in patients with malignant tumours. A thyroid nodule is rarely the initial sign of a tumour arising in a contiguous structure. Such cases ordinarily do not complicate the diagnosis. However, the discovery of a squamous or a neuroendocrine tumour should dictate a complete work-up including neck CT scan and endoscopies. Frequently, a thyroid mass is discovered in a patient who has been treated for another neoplasm such as cancer of the kidney, breast, lung, colon, or a malignant melanoma. This is a frequent finding on FDG-PET scan. Many years may elapse between the diagnosis of the primary lesion and the appearance of the thyroid mass. Furthermore, the thyroid mass may be the only known metastatic site. In such cases, fine-needle aspiration biopsy may be a useful diagnostic tool, but surgery is usually performed. Diagnosis may be difficult and immunohistochemical studies are warranted. Negative immunostaining with antithyroglobulin and anticalcitonin antibodies is firm evidence for the metastatic origin of the thyroid tumour. Although detection of metastasis to the thyroid gland often signifies a poor prognosis, aggressive surgical and medical therapy may be effective in a small percentage of patients.
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