Long-term follow-up of differentiated thyroid carcinoma in children and adolescents.

Objectives The aims were to analyze the clinical features, response to treatment, prognostic factors and long-term follow-up of children and adolescents with differentiated thyroid carcinoma (DTC). Methods Eighty patients with DTC were studied retrospectively. All underwent total or near-total thyroidectomy, and in 75 cases, ablative iodine therapy was recommended. Patients were assessed periodically by tests for serum thyroglobulin levels and whole-body iodine scans. Age, gender, initial clinical presentation, histology, tumor stage, postoperative complications, radioiodine treatment protocol, treatment response, thyroglobulin (Tg), recurrence and long-term disease progression were evaluated. Results Seventy patients completed >2 years of follow-up (23 males, 47 females; median age: 14 years; range: 3-18 years). Sixty-two patients showed papillary DTC and eight, follicular DTC. Sixty-five percent presented nodal metastasis and 16%, pulmonary metastasis at diagnosis. Six months after first radioiodine treatment, 36.2% of patients were free of disease. Seven recurrences were documented. At the end of follow-up, overall survival was 100%, and 87.2% of patients were in complete remission. Nine patients had persistent disease. We found a significant association between stage 4 and persistent disease. Hundred percent of patients with negative Tg values at 6 months posttreatment were documented free of disease at the end of the follow-up. The analysis of disease-free survival based on radioiodine treatment protocols used showed no statistically significant differences. Conclusions DTC in children and adolescents is frequently associated with presence of advanced disease at diagnosis. Despite this, complete remission was documented after treatment in most cases, with a good prognosis in the long-term follow-up. Negative posttreatment thyroglobulin and stage 4 at diagnosis were significant prognostic variables.

THERAPY OF ENDOCRINE DISEASE Immunotherapy of advanced thyroid cancer: from bench to bedside.

Immunotherapy has arisen in use in the field of oncology with seven immune checkpoint inhibitors approved for the treatment of a variety of cancer histologies. Depending on the cancer type, the success rate might be different, but in average it is about 20%, with some cases showing a durable response, lasting also after the interruption of the treatment, with a clear benefit on OS. The development of an efficacious cure for advanced thyroid carcinomas is still an unmet need and immunotherapy represents an interesting alternative option also for this cancer. However, very few clinical trials have been accomplished and very few studies exploring a way to overcome resistance have been performed. In this review, we will summarize the mechanisms of immune escape, with a special reference to follicular-derived thyroid carcinoma. Furthermore, we will try to speculate on the use of immune checkpoint inhibitors for the treatment of follicular-derived advanced thyroid carcinoma. Finally, we will summarize the ongoing clinical trials and the future directions of the field.

Eosinophil Cationic Protein in Patients with Differentiated Thyroid Cancer Treated with Radioactive Iodine 131.

Published data indicate the involvement of eosinophil granulocytes and eosinophil cationic protein (ECP) in tumor defense. The aim of this study was to analyze serum ECP concentrations in patients with differentiated thyroid cancer (DTC) before, 3 days and 7 days after radioactive iodine (131-I) therapy. Association of ECP concentrations with histological type of tumor, stage of disease and/or levels of selected T-helper 2 (Th2) cytokines was examined. The study population included 17 DTC patients and 10 control subjects. ECP was measured by fluoroimmunoassay (FIA). Th2 (cytokines interleukin 4 (IL-4), interleukin 5 (IL-5), and interleukin 13 (IL-13)) were determined by enzyme-linked immunosorbent assays (ELISA). We found that ECP values in DTC patients before radioactive iodine therapy were approximately two-fold higher than in the controls, but the difference was statistically significant only if the patients with DTC and associated Hashimoto thyroiditis (HT) were included. There was no correlation between the serum concentrations of IL-5 and ECP. Radioactive iodine therapy led to a decrease in serum ECP level which did not follow the decline in serum protein levels. Additional studies are needed to determine the significance of these findings.

Pediatric differentiated thyroid carcinoma: trends in practice and outcomes over 40 years at a single tertiary care institution.

BACKGROUND: This study aims to analyze changes in characteristics, practice and outcomes of pediatric differentiated thyroid cancer (DTC) at our tertiary care institution. METHODS: Patients <21 years of age diagnosed between 1973 and 2013 were identified. Clinicopathological data, treatment and outcomes were obtained by a retrospective review. RESULTS: Thirteen males and 68 females were divided into Group A (n=35, diagnosed before July 1993) and Group B (n=46, diagnosed after July 1993). Group B was more likely to undergo neck ultrasound (US) (70% vs. 23%, p<0.0001) and fine-needle aspiration (FNA) biopsy (80% vs. 26%, p<0.0001). Patients in Group B more often underwent total thyroidectomy as a definitive surgical treatment (87% vs. 69%, p=0.04). There was no difference in radioactive iodine use. Recurrence-free survival was similar. CONCLUSIONS: Increased use of US and FNA has affected initial surgical management in the latter part of the study, possibly due to extension of adult DTC guidelines. The effects of the new pediatric DTC guidelines need further study.

Multifocal choroidal metastases from thyroid carcinoma: a case report.

We present the case of a 62-year-old female patient, with follicular variant of papillary thyroid carcinoma, which presented to our department for a severe decrease in vision at right eye level. Despite a complex therapy, that included a near-total thyroidectomy, thyroid I-131 ablation, suppressive therapy with LT4, and external beam radiotherapy with cobalt- 60, the patient developed multiple lung, mediastinal, liver, and bone metastases, followed after 1 year, by multifocal choroidal metastases. The complex ocular investigations performed for the diagnosis and follow-up of the choroidal metastases are presented. A review of the literature was also performed. The rarity of choroidal metastases in patients with thyroid carcinoma imposes, for their detection, periodic ocular examinations.

Deaths due to differentiated thyroid cancer: a South Island, New Zealand experience: 1984-2009.

AIM: To assess differentiated thyroid cancer (DTC) deaths from the northern half of New Zealand's South Island. METHODS: Retrospective review of Christchurch Hospital Thyroid Clinic and Oncology Department clinical records of resident patients who died of differentiated thyroid cancer of follicular cell origin over the 25-year period 1984-2009. RESULTS: During the 25-year study period 25 patients died from differentiated thyroid cancer. All patients (17 female, 8 male) were Caucasian, with median age 65 years (47-86 years) at presentation. Most (24/25) patients presented with advanced (15 Stage IV, 9 Stage III) disease. Three patients initially presented with cervical lymphadenopathy and four patients with distant metastases--three patients with bone metastases, and one with a pleural effusion. The pathological classification of the tumours included 14 papillary cancers (four were follicular variants), six follicular cancers and five Hurthle cell cancers. The majority of primary tumours were large (>4 cm) and 11 were locally invasive. However one patient had a small (1.3 cm) papillary cancer and presented with a pleural effusion. Surgical removal of the primary tumour was attempted in 24 of the 25 patients, 18 received postoperative radioiodine 131I therapy, and three had external beam radiation therapy. The median survival from diagnosis was 5.5 years (0.2-22 years) with two Stage IV patients (both with Hurthle cell cancers) dying within 4 months. The majority of patients died of metastatic disease but seven died of local disease. CONCLUSIONS: During the 25-year study period, 25 patients died of differentiated thyroid cancer which approximates to one DTC death per year in our region. The median age at diagnosis was 65 years with no patients <45 years of age, and the female to male ration was 2.1:1. Most patients presented with advanced disease--7 patients (28%) had distant metastases. Hurthle cell cancers were over-represented (20%) in our series.

New insight in the follow-up strategies of differentiated thyroid cancer.

Differentiated thyroid carcinoma (DTC), either papillary or follicular, has usually a very good prognosis with an overall mortality of less than 10%. In recent decades, the clinical presentation of DTC has been changing from advanced cases requiring intense treatment and surveillance to cancer detected by fortuitous neck ultrasonography requiring less aggressive treatment and follow-up. Given the changing presentation of DTC in the last years, the aim of DTC follow-up is to ensure the most effective and less invasive follow-up for a disease that nowadays is mostly cured just with surgery and is rarely fatal. The concept of "Ongoing Risk Stratification" or "Delayed Risk Stratification" which better define the patient risk based on the results of the initial treatment, can maximize the beneficial effects of aggressive therapy in patients with DTC who are likely to benefit from it, while minimizing potential complications and side effects in low-risk patients who will achieve complete remission.

Long-term follow-up of patients with papillary and follicular thyroid cancer: a prospective study on 715 patients.

PURPOSE: This prospective study evaluated the recurrence rate in 715 patients with differentiated thyroid cancer who had no evidence of persistent disease after total thyroidectomy and lymph node dissection in 94% of them followed up by radioiodine ablation (30-100 mCi) and assessed the predictive value of the initial thyroglobulin (Tg) levels for detecting recurrence, both during levothyroxine (LT4) treatment and after TSH stimulation. PATIENTS AND METHODS: Patients had Tg determinations performed at 3 months on LT4 treatment (Tg1) and at 9-12 months after stimulation by either thyroid hormone withdrawal or recombinant human TSH (Tg2); the Access kit was used (functional sensitivity of 0.11 ng/ml); they had undetectable anti-Tg antibodies. Patients were followed up annually. Predictive values were calculated by comparing Tg levels (Tg1 and Tg2) and the outcome in terms of recurrence. RESULTS: During the median follow-up of 6.2 yr, 32 patients had a recurrence. Assuming a cutoff level for Tg1 at 0.27 ng/ml, Tg1 sensitivity and specificity reached 72 and 86%, respectively, whereas predictive positive and negative values were 20 and 99%, respectively. With a cutoff level for Tg2 at 1.4 ng/ml, sensitivity and specificity reached 78 and 90%, respectively, whereas positive and negative predictive values were 26 and 99%, respectively. CONCLUSION: This large prospective cohort of patients presented a low rate of recurrence. Initial Tg measurements allow to predict long-term recurrence with an excellent specificity. Stimulated Tg determination presented a slightly higher sensitivity than Tg determination on LT4. TSH stimulation may be avoided when Tg measured 3 months after ablation is less than 0.27 ng/ml during LT4 treatment.

Follicular variant of papillary thyroid carcinoma presenting as a toxic nodule by I-123 scintigraphy.

The risk of malignancy in a "hot" thyroid nodule detected by radioiodine scintigraphy is rare. We report a case of a 63-year-old man with a hyperfunctioning nodule demonstrated by radioiodine scintigraphy and cytology suspicious for follicular variant of papillary thyroid carcinoma (FVPTC). There were no locoregional or distant metastases at initial diagnosis. Histopathologic examination following thyroidectomy confirmed the presence of an encapsulated FVPTC. A year into follow-up, his I-131 whole body scan performed following the withdrawal from exogenous thyroid hormone was negative, whereas his serum thyroglobulin (Tg) levels were intermediate. A subsequent PET/CT scan revealed a small, but stable, metabolically active pretracheal lymph node, which on biopsy was confirmed to be stage III FVPTC. In conclusion, the presence of hyperfunctioning thyroid nodule(s) does not preclude malignancy and, therefore, proper cytohistologic evaluation in such patients may help to exclude a coexistent thyroid carcinoma. Patients treated for localized PTC may benefit from serial PET/CT follow-up in the early detection and management of recurrence or distant metastases.

Management of well-differentiated thyroid cancer in 2010: perspectives of a head and neck surgical oncologist.

OBJECTIVE: To review the terminology and controversy regarding the performance of prophylactic lymph node dissection for patients without evidence suggestive of pathologic adenopathy. METHODS: Terminology of lymph node levels in the neck and chest, and the issues regarding lymph node dissection, are reviewed. In addition, differences between lymph nodes are reviewed and discussed. RESULTS: Management of lymph nodes in this disease process has become the most contentious aspect of surgical decision-making due to the ambiguity of their prognostic significance and the prevalence of nodal metastases in very early primary tumors. Performance of prophylactic central compartment node dissection is not technically any more difficult than therapeutic node dissection when clinically significant nodes are encountered. It is therefore reasonable to consider this technique as an important adjunct to a total thyroidectomy for the purpose of enhanced disease staging, prevention of nodal recurrence, and avoidance of having to re-enter the previously operated central compartment. A recent study is reviewed and discussed in detail. The literature regarding the prognostic significance of extracapsular spread in lymph nodes is also presented. CONCLUSIONS: Morphologic characteristics of metastatic lymph nodes in thyroid cancer vary greatly. However, the reporting of these differences is lacking. The presence of extracapsular extension in a lymph node has prognostic significance. The clinician should be aware of these variations and the impact that they may have on recurrence risk and disease-specific survival.

Conservative management of well-differentiated thyroid cancer.

BACKGROUND: Controversy exists over the optimal surgical treatment of well-differentiated thyroid cancer. Conservative surgical management reduces the risk of complications and maintains an overall survival rate equivalent to the more extensive approach. METHODS: We conducted a retrospective review of all patients with well-differentiated thyroid cancer greater than 1 cm (180 patients) who underwent surgery between 1982 and 2002 by a single general surgeon at our institution. The prevailing philosophy was to be as conservative as possible, and the predominant resection was lobectomy and isthmusectomy on the affected side. RESULTS: In total, 90% of patients were in a definable low-risk group: 75% had conservative surgery with 4 recurrences and no mortality, 25% had extensive surgery with 3 recurrences and no mortality. The other 10% were in a definable high-risk group: 90% had extensive surgery with 9 recurrences and 4 deaths. Overall, there were 22 sites of recurrence in 16 patients. There was no recurrence in the residual thyroid tissue, with a median follow-up of 10 years. Three recurrences occurred in the resected thyroid bed; each of these patients had undergone extensive surgery. Twelve recurrences were in lymph nodes; 67% of these patients had extensive surgery. All except 1 of 7 distant metastases occurred in the high-risk group, despite the patient having undergone extensive local surgery. Recurrence did not affect survival in the low-risk group. The extensive surgery group had a 3.4% incidence of recurrent laryngeal nerve injury and a 1.1% incidence of permanent hypocalcemia, with none in the conservative surgery group. CONCLUSION: Conservative surgery for low-risk patients with well-differentiated thyroid cancer appears to be sufficient and avoids complications without significantly increased risk for local, regional or distant recurrence.

Approach to the thyroid cancer patient with extracervical metastases.

Patients with distant, or extracervical, metastases from differentiated thyroid cancer require multimodality diagnostic, therapeutic, and monitoring approaches. Whereas cure is the initial goal, especially in those with small, radioiodine-avid pulmonary metastases, improved survival and management of symptoms become the primary objective in many patients with persistent disease, especially those with bone metastases. Levothyroxine therapy with suppression of serum TSH is a primary therapy in all patients with advanced differentiated thyroid cancer, and this therapy has been shown to improve overall survival and slow disease progression. Radioiodine is also an important systemic therapy for those patients with radioiodine-avid disease who respond to this targeted therapy. In this review, we compare standard fixed-dose radioiodine therapy vs. the dosimetric approach. Directed therapy such as external beam radiotherapy, surgery, and embolization is generally considered for large or painful lesions. Careful collaborations with multiple specialties through tumor boards or other mechanisms help to optimize complex management decisions in these patients with advanced thyroid cancer. Multimodality monitoring focused on the organ of interest such as pulmonary [computed tomography (CT)], bone (magnetic resonance imaging, CT, bone scan), and brain (CT, magnetic resonance imaging) metastases as well as general metastatic surveillance (bone scan, (18)F-fluorodeoxyglucose-positron emission tomography) aid decision making about careful monitoring vs. directed or systemic therapy. (18)F-fluorodeoxyglucose-positron emission tomography imaging has an additional role in patient prognosis and guiding directed therapy for fluorodeoxyglucose-avid lesions. Patients with asymptomatic, stable, radioiodine-resistant metastases may be carefully monitored for disease progression. Patients with symptomatic disease should receive directed therapy with the goal of symptom relief. Patients with progressive metastatic disease should be considered for clinical trials or targeted systemic therapy (sorafenib or sunitinib), although these agents are not Food and Drug Administration (FDA) approved for patients with thyroid cancer. The goals of therapy for patients with extracervical metastases should be to improve survival, relieve symptoms, and decrease the morbidity of disease progression and limit the morbidity associated with therapy.

Prevalence, clinical significance and prognostic value of anti-thyroglobulin antibodies in the follow-up of patients with differentiated thyroid carcinoma: a retrospective study.

AIM: Elevated persistent value of antithyroglobulin antibodies (Ab-Tg) in differentiated thyroid carcinoma (DTC) patients may interfere with Tg determination. The aim of the study was to evaluate the use of Ab-Tg as tumor marker as a replacement for thyroglobulin (Tg). METHODS: From 1990 al 2004 767 patients have been treated and followed, mean follow-up years 6.9+/-2.4. Thirty-two patients Ab-Tg positive after radioiodine ablation, who had showed during the follow-up stable indosable value di Tg, have undergone analysis. RESULTS: The recurrences were statistically more significant when Ab-Tg were increased, than when Ab-Tg were stable or diminished during the time (P<0.0001). Lymphocytic thyroditis was found in thirteen patients (40.6%) at histological specimen after thyroidectomy. The persistence of lymphocytic thyroditis has not modified the value of Ab-Tg as tumor marker (P<0.001). The 10/32 (31.2%) patients Tg negative have been compared to the 61/712 patients Ab-Tg positive (8.6%) who relapse. The recurrence rate was significantly higher for the first group of patients than that for the second (P<0.0001). Multivariate analisys showed N1 (P<0.001; OR 2.51) and Ab-Tg positive (P<0.001; OR: 6.15) associated with recurrences. CONCLUSIONS: Ab-Tg must be determined, in concomitance with Tg, during the follow-up of DTC, to establish the accuracy of Tg, in order to use it as tumour marker. It must be kept in mind that the strongest indication for relapse due to Ab-Tg is an increasing of level in the same patient measured in the long time. Persistent elevated Ab-Tg levels are prognostic of future recurrences.

Thyroid nodules and cancers in children.

The incidence of thyroid nodules in children is estimated to be 1 to 1.5% based on clinical examination. Children with thyroid nodules, compared to adults with thyroid nodules, have a fourfold greater risk of developing malignant thyroid disease. Differentiated thyroid carcinoma is the most common pediatric endocrine tumor, constituting 0.5-3% of all childhood malignancies. The thyroid is one of the most frequent sites of secondary neoplasm in children who receive radiation therapy for other malignancies. Thyroid carcinoma has been studied extensively in adults. However, the pediatric literature on this subject is much less complete, owing to the rarity of its diagnosis. This article reviews the predisposing factors, genetics, pathology, pathogenesis , clinical presentation, detailed treatment and follow-up management of children with thyroid carcinoma. Additionally, a discussion regarding the controversial aspects of radioiodine therapy in children is included.

Thyroid papillary microcarcinoma: a descriptive and meta-analysis study.

The authors review anatomical, clinical characteristics and prevalence of thyroid microcarcinoma. Diagnostic procedures and risk factors of aggressiveness at diagnosis and during follow-up are also covered. The possible clinical, pathologic and therapeutic risk factors are analyzed by meta-analysis study. Treatment procedures by different authors and guidelines suggested by societies are reported.

Follicular variant of papillary thyroid carcinoma: a diagnostic challenge for clinicians and pathologists.

The follicular variant of papillary thyroid carcinoma (FVPTC) presents a type of papillary thyroid cancer that has created continuous diagnosis and treatment controversies among clinicians and pathologists. In this review, we describe the nomenclature, the clinical features, diagnostic problems and the molecular biology of FVPTC. It is important for clinicians to understand this entity as the diagnosis and management of this group of patient may be different from other patients with conventional PTC. The literature suggests that FVPTC behaves in a way similar, clinically, to conventional papillary thyroid carcinoma. However, there are some genotypic differences which may characterise this neoplasm. These parameters may account for the phenotypic variation described by some scientists in this type of cancer. Further understanding can only be achieved by defining strict pathological criteria, in-depth study of the molecular biology and long term follow-up of the optional patients with FVPTC.