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).

One stage treatment of parathyroid cancer.

AIM: To review the methods of treating parathyroid cancer in our series and report successful use of intraoperative frozen section to enable one stage surgical management. METHOD: Seven cases of parathyroid cancer presented from 1991-2002. The presenting features, diagnosis and treatment are presented. They are separated into two groups based on method of referral and treatment. RESULTS: Patients presented with symptoms of hypercalcaemia. Median corrected calcium was 3.49 mmol/l. Parathyroid hormone levels were raised in seven of eight cases, range 14.5-495 pmol/l. A high index of pre-operative suspicion and use of frozen section enabled a one step surgical procedure. Recurrence was impossible to treat successfully. Radiotherapy appeared successful for residual disease. CONCLUSION: A high pre-operative index of suspicion for parathyroid carcinoma with use of frozen section at time of operation permits an optimal one step surgical procedure by en bloc resection followed by central lymph node excision. In cases where diagnosis has been made post-operatively radiotherapy may be beneficial.

Value of protein-bound radioactive iodine measurements in the management of differentiated thyroid cancer treated with (131)I.

Measurement of the protein-bound radioactive iodine level (PBI(131)) in the plasma of patients following (131)I-iodide administration for thyroid cancer has been re-examined in a retrospective study of 171 patient episodes. It is shown that whereas the previously used threshold value for the measurement at 6 days does not correlate well with the 3-day whole body scan, there is good agreement between the scan and the temporal changes in PBI(131) from 1-6 days: an increasing PBI(131) correlates with a positive scan, and a decreasing PBI(131) with a negative scan. The area under the curve (AUC) for the PBI(131)-time curve is related to the absorbed dose for the tumour. For a small group of 11 patients, dosimetry estimates were made from serial scans, quantified with phantoms; these absorbed doses correlated with the AUC and the 6-day PBI(131). Therefore, it is suggested that these parameters may be useful in predicting absorbed radiation dose in these patients.

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.

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.

Aggressive fibromatosis: evidence for a stable phase.

Purpose. Aggressive fibromatosis (AF) is an uncommon locally infiltrating benign disease of soft tissue for which treatment comprises complete surgical resection. Radiotherapy can be given postoperatively if the margin is incompletely resected. If the tumour is inoperable radiotherapy provides an alternative treatment. Hormone therapy and cytotoxic chemotherapy have also been used for unresectable or recurrent disease. All treatment modalities carry an associated morbidity. We believe that the natural history of aggressive fibromatosis may include a period of stable disease without progression, during which time, treatment is not always necessary.Patients and methods. We present a retrospective review of 42 patients referred to the Royal Marsden Hospital between 1988 and 1995 with aggressive fibromatosis. Evidence of periods of stable disease and the relationship to delivered treatment was obtained from the case notes, including the natural history prior to referral to our institution. Stable disease was defined as a period of no objective progression for 6 months or longer.Results. Seventeen patients could be assessed for stable disease and all (100%) experienced at least one episode of stable disease, eight of whom whilst receiving hormonal or cytotoxic therapy. Of the 23 patients who could not be assessed for stable disease, as they underwent surgery at presentation or recurrence of disease, only 2 had persisting disease at last follow-up. Both of these patients had had positive surgical resection margins.Discussion. This study demonstrates the variable natural history of AF, which can include a substantial period of stable disease in a significant number of patients. A less aggressive approach to the management of AF may therefore be appropriate, particularly if a subgroup of patients who are likely to experience a period of stable disease can be identified.

Ewing's sarcoma and primitive neuroectodermal tumor in adults: are they different from Ewing's sarcoma and primitive neuroectodermal tumor in children?

PURPOSE: To determine whether age at diagnosis influences the behavior of Ewing's sarcoma and primitive neuroectodermal tumor (PNET). PATIENTS AND METHODS: We reviewed the clinical features, treatment, and outcome of 59 consecutive patients with Ewing's sarcoma and PNET treated on the Adult Sarcoma Unit at our institution from 1980 to 1995. RESULTS: The 37 male and 22 female patients had a median age of 24 years. Lower limb was the most common primary tumor site. Fifteen patients had nonmetastatic tumor less than 100-mL volume, 27 had nonmetastatic disease greater than 100-mL volume, and 17 had evidence of metastatic disease at presentation. The origin of the primary tumor was soft tissue in 28 cases, bone in 30, and uncertain in one. The Kaplan-Meier estimate of 5-year overall survival (OS) in all patients was 38% and of progression-free survival (PFS), 27%. When patients with metastatic disease at presentation were excluded, these figures increased to 52% and 34%, respectively. Bulk of disease at presentation and response to primary treatment were statistically highly significant predictors of both PFS and OS. Age and tissue of origin of the tumor did not influence outcome. CONCLUSION: The behavior of Ewing's sarcoma and PNET in adults is no different from its behavior in children. We feel the way forward in the treatment of adults with Ewing's sarcoma and PNET is for them to be included in the current multicenter trials of multidisciplinary treatment directed at children.

The Impact of Radiotherapy Dose on Local Control of Ewing's Sarcoma of Bone.

Purpose. Improvements in the systemic management of Ewing's sarcoma of bone over the last 20 years have led to a dramatic improvement in survival. The corollary is that treatment of the primary disease requires re-evaluation, since a significant number of patients still suffer local relapse.Patients. The effect of radiation dose on local control was reviewed in a series of 96 patients treated between 1967 and 1986. Seventy-four had no metastases at presentation (M0), 22 had metastases (M1). The 5-year survival of all patients was 28%, and of M0 patients alone 37%. Although these figures are poor by today's standards, they are consistent with published studies whose patients were enrolled during the same calendar period. Although most deaths occurred by 5 years, survival continued to fall beyond 10 years, which has implications for follow-up in future studies.Results. The local control (LC) rate at 5 years was 56% for all patients and for M0 patients analyzed separately. There was no difference in either LC or survival between the first and second decades of the study. Primary site was a significant determinant of survival and local control, with better outcome for limb tumours compared to pelvic primaries. Chemotherapy also had a major effect on LC. Radiotherapy improved the probability of LC. Omission of radiotherapy, or a dose <40 Gy, was ineffective. In the dose range 40-66 Gy, there was no evidence of a dose-response relationship.

Thyroid volume measurement in thyrotoxic patients: comparison between ultrasonography and iodine-124 positron emission tomography.

The aim of this paper was to compare ultrasound (US) assessment of thyroid volume with that obtained by positron emission tomography (PET), in patients scheduled for adaptive radioiodine therapy, in which 50 Gy was prescribed to the functional PET volume. Firstly a pilot study was performed to ascertain the optimum method for US assessment of thyroid volume. Then 17 comparative measurements of thyroid volume by US and PET were made on 15 patients (two male and thirteen female, ages 28-73 years) with suspected Graves' disease. This comparison showed that in normal sized and enlarged thyroid glands (n=13), the ratio of functional PET to anatomical US volume was approximately 2:3. However, using the same ellipsoid model, PET and US assessment of anatomical volume agreed within the measurement errors. Owing to the presence of nodules and non-uniform distribution of radioiodine, the functional PET volume and anatomical US volume are often not equivalent. If high-resolution emission tomography (e.g. PET) is unavailable, the comparative data presented in this paper could be used to derive the functional volume from the US volume for calculating functional thyroid dose in hyperthyroid patients undergoing radioiodine therapy.

The use of paediatric chemotherapy protocols at full dose is both a rational and feasible treatment strategy in adults with Ewing's family tumours.

BACKGROUND: Ewing's sarcoma and primitive neuroectodermal tumour (ES/PNET) are rare, limiting opportunities for therapy studies in adults. Chemotherapy regimens adapted from paediatric studies are often used for adults but concerns about poor outcome and treatment toxicity may adversely affect drug dose intensity. We present our experience using a paediatric protocol at full dose. PATIENTS AND METHODS: Records of 34 patients with ES/PNET who received the IVAD chemotherapy regimens were reviewed. Received drug dose intensity, toxicity and survival data were collected. RESULTS: Received dose intensity in 30 evaluable patients was 0.92 compared to the standard IVAD schedule. Myelosuppression was the major toxicity, 83% of patients experienced grade 4 neutropenia. There was no major renal or cardiac toxicity. In patients without metastases at presentation, five-year overall survival was 63% and progression free survival was 39%. Tumour burden at presentation was statistically significantly associated with survival (P = 0.002). The five-year survival rate of 80% in patients presenting with low volume non metastatic disease was equivalent to published paediatric series. CONCLUSIONS: Although the IVAD chemotherapy regimens are myelotoxic in adults, they can be given safely. We recommend that adults with ES/PNET should be included in current multicentre, multidisciplinary treatment studies directed at children.

Medullary thyroid cancer: the role of radiotherapy in local control.

Fifty-one patients were treated with radiotherapy for loco-regional medullary thyroid cancer between 1960-1992. The actuarial overall survival at 5, 10 and 20 years was 69%, 52% and 30%, respectively. Patients were classified according to clinical stage (node-positive or -negative), post-operative histological residual disease status (none, microscopic or macroscopic) and dose of radiotherapy received. By univariate analysis, loco-regional recurrence-free survival was significantly longer for node-negative patients (P = 0.03). Patients who received at least 60 Gy over 6 weeks showed a trend towards improved local control (P = 0.23). The only significant variable by multivariate analysis for local recurrence-free survival was post-operative residual disease status (P=0.0005). The local control rate at 5 years was 100% for patients with no residual disease, 65% for those with microscopic tumour, and 24% for those with macroscopic residual disease. We conclude that there is a valuable role for radiotherapy in the management of patients with residual microscopic or macroscopic disease following surgery, as well as in those with inoperable disease.

Radiotherapy in the management of thyroid cancer.

Surgery is the definitive and potentially curative treatment for the slow growing well-differentiated papillary and follicular carcinomas. Total (or near-total) thyroidectomy is required, together with excision of adjacent lymph nodes when involved, or a modified block dissection if there is extensive lymphatic involvement. Ablation of residual normal thyroid with radioactive iodine usually follows as this will permit subsequent whole-body I-131 scanning to exclude the presence of residual or metastatic disease. Normally such patients have an excellent prognosis and can be followed simply with serum thyroglobulin estimations. Occasionally therapeutic radioactive iodine is necessary to eradicate metastatic disease. The anaplastic carcinomas grow and metastasise with explosive rapidity. They are typically inoperable at presentation and have no ability to concentrate iodine. Prognosis is appalling with external beam radiotherapy providing only palliation. Medullary carcinoma is different again as it arises from the parafollicular or C-cells. Total thyroidectomy must be undertaken as these tumours may be multifocal; a central compartment neck resection is ideally undertaken at the same time, together with a formal block dissection if lymph node disease is found to be present. External beam radiotherapy is often required. These tumours can be inherited and produce the tumour marker calcitonin. The rarest group of thyroid cancer is the lymphomas. Like the anaplastic carcinomas, they grow very rapidly but, unlike the former, are radio-responsive. The additional use of chemotherapy is necessary when they are of advanced stage or demonstrate poor prognostic factors.

Factors affecting acute skin toxicity in patients having breast irradiation after conservative surgery: a prospective study of treatment practice at the Royal Marsden Hospital.

The results are presented of a prospective study of acute skin toxicity in 197 patients with early stage breast cancer, who were treated by conservative surgery and postoperative radiotherapy. We have examined the factors determining the severity of the acute skin reaction with particular reference to the degree of dry or moist desquamation at the completion of treatment. One hundred and ten patients had treatment with radiotherapy alone. The remaining 87 received synchronous chemotherapy with breast irradiation, using either the 3M or the 2M regimen, consisting of mitoxantrone and methotrexate, with (3M) or without Mitomycin-C (2M). Patients were analysed according to both the severity and the site of the skin reaction, age, dose, dose variation across the central outline, treatment technique, beam energy, field separation and breast size. A univariate analysis of these results, which has been presented as an odds ratio of the likelihood of developing a moderate or severe reaction in comparison with those scored as mild, has shown that several factors are associated with an increase in the acute skin reaction. These include the use of the semi-supine technique (odds ratio (OR) = 7.3 (95% CI 3.7-14.6)), beam energy (60Co: 6-10 MV photons OR = 5.9 (95% CI 2.6-13.4)), field separation (> or = 20 cm: < 20 cm OR = 4.1 (95% CI 2.2-7.8)), dose variation across the central outline (> or = 10%: < 10% OR = 9.7 (95% CI 2.6-36.4)), inclusion of the axilla (OR = 4.6 (95% CI 2.4-8.9)), and bust size (bra cup size C and D: A and B OR = 4.6 (95% CI 2.7-11.9)). Using multivariate logistic regression, the technique of radiation delivery and bust size were shown to be independently significant variables affecting acute skin reaction. In view of the high correlation between variables (e.g. radiotherapy technique and beam energy) it is still not possible to specify with definite certainty which is the primary variable causing the skin reaction. However 20/57 (35%) of patients treated by the semisupine technique sustained a severe skin reaction, with > 10% dry or moist desquamation in the treatment field. This compares with only 6/140 (4%) patients treated by the supine method. A possible mechanism by which treatment using the semisupine technique may enhance acute toxicity is discussed. We conclude that there are both treatment and patient related factors that will increase the acute skin reaction after breast irradiation.

An acute toxicity study on the effects of synchronous chemotherapy and radiotherapy in early stage breast cancer after conservative surgery.

One hundred and ninety-seven patients with early stage breast cancer, who were treated initially with conservative surgery, were evaluated prospectively for acute toxicity after completing post-operative irradiation. Eighty-seven of these patients had synchronous chemotherapy with the 3M regimen (mitoxantrone, methotrexate and Mitomycin-C) during radiotherapy. The results indicate that patients receiving chemotherapy and radiotherapy (CRT) showed no significant difference in acute skin toxicity (AST) when compared with those treated with radiotherapy alone (RTO), with an odds ratio (OR = 0.6) and 95% confidence intervals (0.3-1.1) of developing either a moderate or severe, compared with a mild, skin reaction. Even after controlling for other confounding factors, such as treatment technique and beam energy, patients treated with the supine technique using 6-10 MV photons still displayed no significant difference in AST, with 12/74 (16%) patients in the CRT group and 14/66 (21%) in the RTO group developing a moderate or severe skin reaction (OR = 0.7 (95% CI 0.3-1.7)). Four of the 87 patients treated with CRT developed symptomatic acute radiation pneumonitis, three of whom were found to have > 3 cm of lung length on their simulator or check films. The volume of lung included within the treatment field was found to be statistically significant (P = 0.005) in predicting the onset of radiation pneumonitis in the CRT group. None of these patients has suffered any symptomatic late lung toxicity. We conclude that synchronous chemotherapy and radiotherapy, when using the 3M regimen, is feasible for patients having adjuvant treatment for early stage breast carcinoma and there is no significant increase in AST. However, it is associated with an increase in acute radiation pneumonitis when a significant volume of lung is included within the radiation treatment field.

Medullary carcinoma of the thyroid misdiagnosed as differentiated thyroid carcinoma.

Four patients are presented, who were initially diagnosed and treated for differentiated thyroid carcinoma, but subsequently discovered to have medullary carcinoma. We suggest that tumour histopathology needs to be carefully reviewed in all cases of thyroid cancer, especially those having atypical clinical or pathological features. This should be completed prior to further therapeutic intervention, such as the administration of ablative radioactive iodine.

Brain metastases in patients with differentiated thyroid carcinoma.

We present a retrospective review of six patients who developed brain metastases in our series of 649 with differentiated thyroid carcinoma seen at the Royal Marsden Hospital between 1936 and 1991. Prognosis was poor, with survival 1-19 months from the diagnosis of brain metastases in five patients. One patient remains alive at 18 months. A dosimetric approach may help to individualize and optimize treatment.

Primary non-Hodgkin's lymphoma of the thyroid with bone marrow infiltration at presentation.

Primary non-Hodgkin's lymphoma of the thyroid is predominantly a disorder of elderly females. Most patients present with limited disease and receive local irradiation. Presentation with advanced disease is uncommon and, consequently, bone marrow examination is not always done. We report a patient with primary thyroid lymphoma who had bone marrow infiltration at presentation and discuss the importance of this investigation in management.

Dose-response study on thyrotoxic patients undergoing positron emission tomography and radioiodine therapy.

With the acknowledged problems associated with assessment of functioning thyroid mass and hence radiation dose, our policy had been to give 75 MBq iodine-131 at 6-monthly intervals to patients with Graves' disease until they became euthyroid. Since positron emission tomography (PET) has been available at this hospital, the radiation dose to the thyroid has been calculated with an accuracy of approximately 20%, the thyroid mass being determined from an iodine-124 PET scan. A dose-response study has been carried out on 65 patients who have received single or cumulative radiation doses of < 80 Gy. The results show that patients who receive a low radiation dose (< 20 Gy) at their first treatment have a high probability of remaining toxic at 12 months. In contrast, patients who receive higher radiation doses (> 40 Gy) at their first treatment have a high probability of control. The probability of becoming euthyroid increases more rapidly with increasing radiation dose than the probability of becoming hypothyroid. Following this dose-response study, a new treatment protocol has been introduced. A 124I PET tracer study prior to 131I therapy will be performed to enable a prescribed thyroid dose of 50 Gy to be delivered to patients with Graves' disease. Further 131I therapy will only be considered if patients are still toxic at 12 months.

Eosinophilic folliculitis occurring after bone marrow autograft in a patient with non-Hodgkin's lymphoma.

Eosinophilic pustular folliculitis is a rare disorder previously reported predominantly in Japanese people who are otherwise healthy. Recently, the disorder has been noted in patients with acquired immune deficiency syndrome, as has eosinophilic folliculitis, a similar but distinct entity. The authors report a patient with eosinophilic folliculitis who was immunocompromised after high dose chemotherapy and bone marrow autograft for treatment of non-Hodgkin's lymphoma.