Management of non-Hodgkin's lymphoma of the thyroid: the Royal Marsden Hospital experience.

A retrospective review was conducted of patients treated for thyroid non-Hodgkin's lymphoma (TNHL) at the Royal Marsden Hospital between 1936 and 1996 to determine the effect of radiotherapy (RT) on outcome. 91 patients were identified from the Thyroid Unit Database. There were 77 females and 14 males with a median age of 65 years (range 22-87 years). RT was delivered according to two separate policies: (1) involved field radiotherapy (IFRT) to the thyroid bed and cervical lymph nodes; (2) extended field radiotherapy (EFRT) covering the thyroid bed, cervical and mediastinal lymph nodes. 89 patients received RT as part of definitive treatment following surgery, to a dose of approximately 40 Gy. 25 patients received IFRT and 64 patients EFRT. 27 patients received cytotoxic chemotherapy. 18 patients (72%) treated with IFRT died of TNHL with a median relapse free survival (RFS) of 10 months and a median overall survival (OS) of 21 months. In contrast, only 29 patients (46%) treated with EFRT died of TNHL with a median RFS of 76 months (p = 0.01 for RFS with respect to IFRT and p = 0.04 for OS). Significantly more patients treated with IFRT relapsed locally (52% vs 27%). There was no difference in the rates of systemic relapse (20% vs 22%). EFRT alone for Stage I, but not for Stage II disease, yielded acceptable rates of local control and disease free survival with doses of at least 40 Gy. These historical data strongly support the addition of combination chemotherapy to the treatment regimen in all patients with Stage II disease. Indeed, in recent years this has become the standard of care for all cases of thyroid lymphoma unless the histology is of marginal zone type (mucosa associated lymphoma tissue (MALT) lymphoma).

Metastases to the thyroid gland: the Royal Marsden experience.

AIM: A review of patients seen at the Royal Marsden Hospital with metastases to the thyroid gland. METHOD: Experience reported on 15 patients that were seen at our institution between 1985 and 2002. RESULTS: The most common site of origin was the kidney (4/15). Ages ranged between 26 and 76 years. Twelve presented with a neck mass. Most had metastatic disease elsewhere at the time of presentation (9/15). Diagnosis was made by fine needle aspiration cytology (5), tru-cut biopsy (1), or surgery (9); surgery comprised total thyroidectomy (3), subtotal thyroidectomy (3) or lobectomy (3). Radiotherapy resulted in disease stabilisation in three patients. Chemotherapy was used to treat local recurrence in two patients post-operatively. The interval from diagnosis of the primary tumour to thyroid metastasis varied from 0 months to 15 years. Thyroid gland metastasis was the initial manifestation of metastatic disease in five patients. Five patients are alive, with one disease free 7 years following resection of the thyroid metastasis. CONCLUSIONS: Thyroid metastases are clinically rare, with the kidney the most common primary site of origin. They usually occur when there are metastases elsewhere, sometimes many years after diagnosis of the original primary tumour. Surgical resection of an isolated metastasis may result in prolonged disease-free survival. Radiotherapy and chemotherapy may be of value in specific situations.

The pharmacological treatment of aggressive fibromatosis: a systematic review.

BACKGROUND: Despite the use of surgery and radiotherapy, 20-35% of patients with aggressive fibromatosis (AF) will have local recurrence. The purpose of this review was to collect and analyze all available information regarding the role of non-cytotoxic and cytotoxic chemotherapy in AF that has been accumulated over the past few decades. PATIENTS AND METHODS: A systematic review of published clinical trials, studies and case series was carried out using the Medline Express Databases and the Cochrane Collaboration Database from 1970 to October 2000. RESULTS: Most studies published in the literature are in the form of successful case reports and single-arm series with small patient numbers. Most commonly used agents include hormonal agents, non-steroidal anti-inflammatory drugs (NSAIDs), interferons and cytotoxics. The literature data support the use of hormonal agents. Several questions, however, remain unresolved, such as which is the most suitable endocrine manipulation and what is the optimal dose and duration of treatment. NSAIDs and interferons have demonstrated activity against AF either alone or in combination with hormone therapy or chemotherapy but the precise mechanism of action is still unknown. Finally, there is growing evidence in the literature that chemotherapy is effective against AF with almost one in two patients being likely to respond. CONCLUSIONS: The evidence in the literature supports the opinion that both non-cytotoxic and cytotoxic chemotherapies are effective against AF. However, the lack of sufficient patient numbers and randomized trials compromises the validity of the reported results and mandates further investigation with properly designed prospective studies including larger patient numbers, with main end points to include not only tumor response rate and survival but also quality-of-life issues.

Prognosis for fertility and ovarian function after treatment with radioiodine for thyroid cancer.

The aim of this study was to review the outcome of ablative radioiodine treatment on ovarian function in young women treated for differentiated thyroid carcinoma. Of 1398 patients with differentiated thyroid cancer, 496 were women under the age of 40 at the time of diagnosis who had received radioiodine therapy. Of these, 322 received a single 3 GBq ablation dose of radioiodine while the remainder received subsequent treatment with (131)I with a cumulative activity of 8.5-59 GBq for residual, recurrent, or metastatic disease. Transient amenorrhoea or menstrual irregularities lasting up to 10 months were experienced in 83 patients (17%). No cases of permanent ovarian failure were recorded. There were 427 children born to 276 women; only one patient wishing to achieve a successful pregnancy outcome has been unsuccessful. Four premature births and 14 miscarriages occurred but no congenital abnormalities were reported. The risk of permanent damage to the ovaries after ablative radioiodine treatment appears to be low and patients can be reassured they can have normal pregnancies after this treatment.

Improvements in target coverage and reduced spinal cord irradiation using intensity-modulated radiotherapy (IMRT) in patients with carcinoma of the thyroid gland.

BACKGROUND AND PURPOSE: External beam radiotherapy for thyroid carcinoma poses a significant technical challenge as the target volume lies close to or surrounds the spinal cord. The potential of intensity-modulated radiotherapy (IMRT) to improve the dose distributions was investigated. MATERIALS AND METHODS: A planning study was performed on patients with thyroid carcinoma. Plans were generated to irradiate the thyroid bed alone or to treat the thyroid bed and the loco-regional lymph nodes in two phases. Conventional plans with minimal beam shaping were compared to three-dimensional conformal radiotherapy (3DCRT) and inverse-planned IMRT plans to assess target coverage and normal tissue sparing. IMRT techniques were optimized to find the minimum number of equispaced beams required to achieve the clinical benefit and a concomitant boost technique was explored. RESULTS: For the thyroid bed alone and the thyroid bed plus loco-regional lymph nodes, conventional and conformal techniques produced low minimum doses to the planning target volume (PTV) if spinal cord tolerance was respected. 3DCRT reduced the irradiated volume of normal tissue (P=0.01). IMRT plans achieved the goal dose to the PTV (P<0.01) and also reduced the spinal cord maximum dose (P<0.01). IMRT, using a concomitant boost technique, produced better target coverage than a two-phase technique. For both the two-phase and concomitant boost techniques, IMRT plans with seven and five equispaced fields produced similar dose distributions to nine fields, but three fields were significantly worse. CONCLUSIONS: 3DCRT reduced normal tissue irradiation compared to conventional techniques, but did not improve PTV or spinal cord doses. IMRT improved the PTV coverage and reduced the spinal cord dose. A simultaneous integrated boost technique with five equispaced fields produced the best dose distribution. IMRT should reduce the risk of myelopathy or may allow dose escalation in patients with thyroid cancer.

Thoracic metastasectomy in thyroid malignancies.

BACKGROUND: Relatively little evidence exists to guide the decision pathway regarding thoracic metastasectomy for thyroid malignancy. METHODS: Single-institution 10-year review. RESULTS: Sixteen patients had surgical treatment for intrathoracic metastatic thyroid malignancy: 12 men and 4 women, mean age 43.7 years (range 19 to 77). Histopathologic type was papillary in 6 cases, follicular in 4, Hurthle cell in 3, and medullary in 3. Indication was either "bulky" disease (8 patients) or poor response to radiotherapy (8 patients). We performed 11 sternotomies and five thoracotomies. Operative mortality was 6.25%. Operative morbidity was 6.25%. Mean survival was 39.5 months (0 to 144). Nine patients died during follow-up (mean survival of 41.2 months). Six patients survived, 4 free of disease (mean survival 70 months) and 2 with further relapse (mean survival 17 months). Five-year survival was 32.5%. CONCLUSIONS: The cohort studied is one of the largest in the literature on the topic. Surgical treatment achieved a reasonable survival in a small subgroup of patients where radiotherapy had failed or was deemed inappropriate because of the size or location of the tumor. Further follow-up and more observations will be required for evaluating these preliminary findings.

The role of radiotherapy in the management of elevated calcitonin after surgery for medullary thyroid cancer.

Among 139 patients with medullary thyroid cancer (MTC) treated at the Royal Marsden Hospital between 1957-1998, 51 had persistently elevated calcitonin levels after initial surgery in the absence of clinically or radiologically demonstrable residual disease. Of these, 24 were treated with radiotherapy because of advanced local disease at presentation; this resulted in normalization of calcitonin in only 1 patient, although 10 remained free of clinical recurrence. Surveillance alone was used in the remaining 27 patients, of whom 8 (30%) remained free of overt disease. Local relapse rate was significantly lower after radiotherapy (29% vs. 59%) but there was no significant difference in 10-year survival between the two groups (72% vs. 60%). In view of this favorable long-term survival of patients with elevated calcitonin on observation, we cannot recommend the routine use of radiotherapy. However, it does appear to have a role in those presenting with more advanced disease to reduce the incidence of loco-regional relapse.

False positive 131I whole body scans in thyroid cancer.

Well differentiated thyroid cancer is a rare disease in the UK. It is the only cancer which, having metastasized, remains curable by radioisotope therapy with 131I. The main indication for administering repeat doses of 131I is the appearance of abnormal uptake in a whole body scan following diagnostic or therapeutic 131I administration. False positive scans, showing the presence of 131I uptake in the absence of residual thyroid tissue or metastases can occur, although they are uncommon. Unless recognized as a false positive, 131I uptake may result in diagnostic error and lead to administration of an unnecessary therapy dose. We describe a series of nine patients in whom the scans showed false positive uptake of 131I, including cases where the cause of the uptake is still uncertain. We demonstrate the common sites of false positive uptake, discuss the underlying mechanisms and suggest a systematic approach to the interpretation of whole body scans in order to prevent unnecessary treatment with 131I.

Recurrent differentiated thyroid cancer without elevation of serum thyroglobulin.

Thyroglobulin (Tg) is a reliable tumor marker in patients with well-differentiated thyroid cancer (WDTC). We identified 11 patients who had undetectable serum Tg and no thyroglobulin antibody (TgAb) in the presence of clinical disease. Three had residual disease after ablation of the thyroid by surgery plus radioiodine and 8 relapsed after a disease-free interval. Histologic review confirmed that 7 of the tumors were papillary carcinomas and 4 were follicular carcinomas. Immunohistochemical staining for Tg was positive in 6 of 7 papillary and in 3 of 4 follicular carcinomas. There were no identifiable histologic or clinical features that could be used to predict further patients who may relapse with absence of this serum marker. Negative serum Tg did not appear to be an adverse prognostic feature. During follow-up, measurement of Tg and TgAb should be supplemented by radioiodine scanning and radiological imaging in patients in whom recurrence is likely or suspected.

Thyroid cancer in children: the Royal Marsden Hospital experience.

The first child with well-differentiated thyroid cancer treated at the Royal Marsden Hospital presented in 1917. Since that time 30 children under the age of 16 years have been treated over a period during which many new treatments have been introduced. We have reviewed their management and outcome. The median follow-up is 22.5 years (range: 1-66). The median time to recurrence was 7 years (range: 2-44). There were events up to 44 years after presentation. The risk of recurrence was higher in children aged 10 years or younger [HR 3.45, 95% CI (1.04-11.11) P = 0.03]. Thyroid stimulating hormone (TSH) suppression was the only intervention to be shown to reduce the recurrence rate [HR 11, 95% CI (2.27-50) P = 0.0003]. The median overall survival is 53 years. The only presenting feature predictive of poorer survival was the presence of metastases (HR 28.96, 95% CI 2.51-334, P < 0.001). Patients who developed recurrence had a higher risk of death (HR 9.90, 95% CI 0.98-100, P = 0.02) and a shorter median survival of 30 years. No therapeutic intervention could be shown statistically to impact on survival. Our recommendation for treatment is total or near-total thyroidectomy for all patients and radioiodine ablation for all except those with early T stage node-negative disease aged over 10 years. Modified neck dissection is recommended for children with clinically positive neck nodes and TSH suppression for all. Follow-up with serial thyroglobulin measurement should be lifelong.

Medullary thyroid cancer: multivariate analysis of prognostic factors influencing survival.

AIMS: The aims of this study were to assess the long-term results of treatment of medullary thyroid carcinoma (MTC) and to define prognostic factors. METHODS: Retrospective analysis of all patients diagnosed with MTC between 1949 and 1998 and treated in our unit was carried out. RESULTS: One hundred and sixty-two patients (87 females, 75 males) were identified; 52 patients (32%) had familial disease. Median follow-up was 9 years (2-20 years). The majority of patients (90%) presented with a thyroid mass or enlarged neck nodes. Total/subtotal thyroidectomy was performed in 129/18 patients respectively; 45 patients also underwent neck dissection while 52 had simple nodal excision. External beam radiotherapy (RT) was given to 76 patients with advanced disease at presentation. Overall survival was 72% at 5 years and 56% at 10 years; case-specific survival was very similar. In multivariate analysis the factors which were significant predictors of survival were age at diagnosis, extent of nodal disease, extent of surgery and metastases at presentation. RT significantly reduced local relapse in patients with ipsilateral nodal disease. CONCLUSIONS: MTC may be associated with prolonged survival; the best prognosis occurs in young patients undergoing total thyroidectomy and neck dissection. External beam RT significantly reduces local relapse in patients with limited nodal disease.

Squamous cell carcinoma of the thyroid: outcome of treatment in 16 patients.

AIMS AND METHODS: Squamous cell carcinoma of the thyroid is very rare and has a poor prognosis. Treatment and outcome were retrospectively analysed in a consecutive series of 16 patients treated at the Royal Marsden Hospital, with the aim of establishing guidelines for management. RESULTS: Twelve of the 16 patients had locoregional disease only at presentation and four had distant metastases. Eight of the 16 underwent surgery and four were given post-operative radiotherapy. Radiotherapy alone was used in six patients unsuitable for surgery. Median survival was 16 months. There were three long-term survivors; each had localized disease treated with surgery and post-operative radiotherapy. Patients treated with surgery alone all developed local recurrence. Two of six patients treated with radiotherapy alone had a partial response but all subsequently developed progressive local disease. Chemotherapy was used in two patients with no response. CONCLUSIONS: Long-term survival is possible if disease is diagnosed early and is completely resected. Surgery should be followed by radical dose radiotherapy.

Failure of TSH rise prior to radio-iodine therapy for thyroid cancer: implications for treatment.

We describe three patients with well-differentiated thyroid carcinoma in whom no rise in serum thyroid-stimulating hormone (TSH) was observed after the discontinuation of thyroid hormone. In one patient, TSH deficiency was due to panhypopituitarism secondary to the empty sella syndrome. This patient initially failed to respond to (131)I but was subsequently given purified porcine TSH prior to further (131)I therapy. This resulted in a significant fall in the thyroglobulin level. In two further patients, TSH levels were suppressed by functioning follicular thyroid cancer. There was an unexpectedly good (131)I uptake by metastases and they responded clinically. The failure of TSH levels to rise after thyroid hormone withdrawal should prompt investigation of the pituitary-thyroid axis. In patients with hypopituitarism, exogenous TSH is recommended, to increase the (131)I uptake. In contrast, when TSH is suppressed by functioning tumour, radio-iodine treatment may still be effective.

Good prognosis in thyroid cancer found incidentally at surgery for thyrotoxicosis.

An analysis of the outcome of thyroid carcinoma incidentally discovered in patients undergoing surgery for hyperthyroidism is presented. Among 986 patients with differentiated thyroid cancer, 23 had presented with symptoms and signs of hyperthyroidism. Graves' disease was diagnosed in 11, multinodular goitre in eight and toxic adenoma in four. Following thyroidectomy, histology revealed papillary (18), follicular (four) and Hurthle cell (one) carcinoma. Tumour size ranged from 4 mm to 5.5 cm, multifocality was detected in three patients, and lymph node involvement in one. Two patients (one with associated Graves' disease, one with multinodular goitre) relapsed locally and required further surgery; one developed distant metastases and died 7 years after initial presentation. Two patients died of unrelated causes; the remaining 20 patients are alive and well with a median follow-up of 16 (1-34) years. Differentiated thyroid cancer found incidentally at surgery for hyperthyroidism has a good prognosis.

Management of differentiated thyroid cancer diagnosed during pregnancy.

OBJECTIVE: To assess the outcome of thyroid cancer diagnosed during pregnancy. DESIGN: Retrospective analysis of patients diagnosed between 1949 and 1997 with thyroid cancer presenting during pregnancy. RESULTS: Nine women with a median age of 28 years were identified. A thyroid nodule was discovered by the clinician during routine antenatal examination in four cases, the remainder had noted a lump in the neck. In all patients, the nodule was reported to almost double in size during the pregnancy. One patient underwent subtotal thyroidectomy during the second trimester; eight were operated on within 3 to 10 months from delivery. Total thyroidectomy was performed in five and subtotal thyroidectomy in four. All tumours were well differentiated and ranged in size from 1 to 6 cm. OUTCOME: The median follow-up was 14 years (5-31 years). One patient relapsed locally requiring further surgery. One patient developed bone metastases dying 7 years after presentation; her planned treatment had been delayed because of an intervening pregnancy. Eight of the original cohort of patients are currently disease free. CONCLUSIONS: Differentiated thyroid cancer presenting in pregnancy generally has an excellent prognosis. When the disease is discovered early in pregnancy, surgery should be considered in the second trimester but radioiodine scans and treatment can be safely delayed until after delivery. In all cases, treatment should not be delayed for more than a year.

Radiotherapy planning techniques for thyroid cancer.

External beam radiotherapy has a role in each histological type of thyroid cancer. For treatment confined to the thyroid bed, an antero--oblique wedged pair of beams is simple to apply. More frequently, however, the volume needs to include both sides of the neck and adequate dose must be given down to the level of the suprasternal notch, precluding use of lateral fields. Thus, anterior and posterior fields are usually necessary, extending from the tips of the mastoid processes or hyoid down to the carina and laterally to include both sides of the neck and supraclavicular fossae. The mandible and infraclavicular portions of both lungs are shielded, but there is no midline lead in the phase one volume. A mid-plane dose of 46 Gy given in 23 daily fractions results in an acceptable early radiation reaction and will avoid late damage to the spinal cord. Because of considerable variation of interplanar distance along the length of the volume, a lateral simulator film should be taken to determine the maximum cord dose. For most patients, a three-dimensional CT planned phase two volume will be required and should be determined prior to completing phase one. The optimum beam arrangement, usually incorporating conformal beam shaping assisted by use of a multileaf collimator, should avoid further dose to the cord. If there is additional dose to the spinal cord, this phase can be introduced before 46 Gy is reached.

Thyroid cancer: a review of treatment and follow-up.

The importance of thyroid cancers far exceeds their frequency, since they are uncommon tumours accounting for only 1% of all malignancies and for even smaller proportion of cancer deaths (0.2%). A variety of distinct tumour types arise in the thyroid gland, with variable natural histories resulting from different rates of growth and biological aggressiveness. The long natural history of the majority of thyroid neoplasms imposes a commitment for long-term follow-up and stresses the importance of planning treatment so as to avoid delayed complications that impair the quality of life of patients. The management of thyroid cancer is multidisciplinary, requiring consultation and active intervention by surgeons, endocrinologists and radiotherapists. Surgery is of paramount importance in the successful eradication of the tumours while radioiodine offers a unique therapeutic approach. Treatment must be strongly influenced by consideration of prognostic variables.