Prospective study and proposal of an outcome predictive nomogram in a consecutive prospective series of differentiated thyroid cancer based on the new ATA risk categories and TNM.

Introduction: The personalized management of differentiated thyroid cancer (DTC) is currently based on the postoperative TNM staging system and the ATA risk stratification system (RSS), both updated in 2018 and 2015, respectively. Purpose: We aimed to evaluate the impact of the last two editions of TNM and ATA RSS in the prediction of persistent/recurrent disease in a large series of DTC patients. Patients and methods: Our prospective study included 451 patients undergone thyroidectomy for DTC. We classified the patients according to TNM (both VIII and VII ed.) and stratified them according to the ATA RSS (both 2015 and 2009). We then evaluated the response to the initial therapy after 12-18 months according to the ATA "ongoing" risk stratification, and analyzed the variables associated with persistent/recurrent disease by multivariate analysis. Results: The performance of the last two ATA RSSs was not significantly different. By staging patients according to the VIII or VII TNM editions, we found significant differences only in the distribution of patients with structural disease classified in stages III and IV. At multivariate analysis, only T-status and N-status were independently associated with persistent/recurrent disease. Overall, ATA RSSs and TNMs showed low predictive power in terms of persistent/recurrent disease (by Harrell's test). Conclusions: In our series of DTC patients, the new ATA RSS as well as the VIII TNM staging provided no additional benefit compared to the previous editions. Moreover, the VIII TNM staging system may underestimate disease severity in patients with large and numerous lymph node metastases at diagnosis.

Recurrent parathyromatosis in a patient with concomitant MEN1 and CASR gene alterations: Clinical management of a case report and literature review.

Introduction: Parathyromatosis is a rare cause of primitive hyperparathyroidism characterized by the presence of numerous parathyroid tissue foci in the neck/mediastinum, due to hyperplasia of parathyroid embryologic residues (primary-form) or to local parathyroid tissue implantation (secondary-form). 63 cases have been described in the literature. In our patient parathyromatosis was due to a combination of two mutations. Case report: A 36-years-old woman was diagnosed with osteoporosis secondary to primary hyperparathyroidism. Subsequent right parathyroidectomy showed a parathyroid adenoma. The follow-up was negative but after 10 years she had a relapse. The genetic screening showed a rare intronic mutation of the MEN1 gene and a heterozygous mutation never described in exon 8 of the CASR gene, coding for the calcium receptor. Calcemia and PTH increased over the years with the onset of nephrocalcinosis and the worsening of osteoporosis despite the therapy with Cinacalcet, bisphosphonates and Vitamin D. She had therefore two additional surgical procedures (parathyroid tissue without malignancy). At follow-up she showed elevated levels of PTH (>1000 pg/ml) and calcium (11.2 mg/dl) and CT scans multiple subcentimetric nodules in the neck/upper mediastinum. Since the 68Ga-DOTATATE showed an increased uptake in the neck/mediastinum, lanreotide was added. After two months there was a significant biochemical response but, unfortunately, after six months, the patient showed a new worsening. Conclusions: a rare case of parathyromatosis due to a combination of two genetic alterations never described. The main issues concern the diagnosis and the radical treatment. Somatostatin analogues may have a useful role in both diagnosis and therapy.

Is multifocality a risk factor in low-risk papillary thyroid cancer?

INTRODUCTION: Multifocality in papillary thyroid cancer (PTC) is a common event, ranging from 18% to 87%. Additional multiple foci are frequently very small and generally detected in pathology specimens. The mechanisms of intrathyroidal spread, and its correlation with age, gender, tumour size, and lymph node metastases remain unclear. Moreover, studies assessing the prognostic impact of PTC multifocality have yielded non-univocal results. We aimed to evaluate the following: a) the histopathological and clinical characteristics associated with multifocal PTC; and b) the impact of multifocality on the long-term outcome. MATERIAL AND METHODS: We analysed a consecutive series of 2814 PTC patients without evidence of microscopic extrathyroidal extension (T1a, T1b, and T2), all of whom had undergone total thyroidectomy and were followed-up (median 4.7 years) in our thyroid clinic. Females comprised 81.3% and males 18.7% (F/M = 4.4/1), with a median age at diagnosis of 45.0 years. Patients were subdivided into 2 groups: 72.7% unifocal tumour and 27.3% multifocal tumour. Post-surgical radioiodine ablation (RAI) (30-100 mCi of 131-I) was performed in 1425 (50.6%) patients. All patients were periodically followed with thyroglobulin and anti-thyroglobulin antibodies measurements and with neck ultrasonography under L-thyroxine therapy and subjected to additional radioiodine administration or another therapeutic measure if not cured. RESULTS: Patients in the multifocal group were older (median age 46.4 vs. 44.5 years, respectively, p < 0.05) and presented a lower F/M ratio (F/M = 3.7/1 and 4.7/1; p = 0.01). T1a and T1b tumours showed no significant difference in multifocality rate whereas T2 tumours were less frequently multifocal (14.2% vs. 10.9%, p < 0.05). Multifocal tumours were more frequent in N1b (11.3% vs. 7.8%, p < 0.01) and less frequent in Nx (50.5% vs. 56.8%, p < 0.01), with no difference between the N0 and N1a groups. The clinical outcome was similar in the 2 group of patients (88.2 % in the unifocal group vs. 90.2% in the multifocal group). CONCLUSIONS: Multifocality is more frequent in older and male patients, in smaller tumours, and in N1b. However, multifocality "per se" was not associated, in our study, with worse clinical outcome in PTC patients.

Orbital metastasis from thyroid cancer: a case report and review of the literature.

BACKGROUND: Differentiated thyroid cancer (DTC) is generally associated with an excellent prognosis. However up to 20% of DTC patients have disease events during subsequent follow-up; rarely patients present an aggressive disease with distant metastases (DM), mainly in the lung and bone. Metastases at unusual sites may also occur, generally in patients with disseminated disease. Orbital localization is rare and only few cases have been described so far. CASE DESCRIPTION: A 36 years-old man, treated with chemo and radiotherapy during childhood for non-Hodgkin lymphoma, was referred for suspicious lymph node (LN) and multiple lung metastases. Total thyroidectomy and latero-cervical (LC) lymphadenectomy were performed: papillary thyroid cancer (PTC), 25 mm, 11/17 LN metastases; pT2N1bM1. Post-treatment total body scan with I-131 showed LN and lung uptake. Eighteen months from diagnosis he presented progressive diplopia, proptosis and right exophthalmos due to an 18 mm orbital metastasis. Hence, due to I-131 refractoriness for structural disease progression despite I-131 therapy, he started therapy with Lenvatinib for 6 months, with initial partial response followed by disease progression, and then with Cabozantinib, which he stopped after 6 months for adverse events and disease progression after therapy reduction. Currently, the patient is receiving Lenvatinib, rechallenge therapy, with disease stabilization and biochemical response. Molecular analysis, performed on both primary and relapsed tumor didn't show any significant pathogenic alteration. CONCLUSIONS: This case of DTC with an unusual metastasis in the orbit, may suggest that patient's exposure to chemo- and radiotherapy during pediatric age might have played a role in the subsequent development of this unusually aggressive tumor, reinforcing the recommendation of long-term and intensive follow-up of these patients.

Risk of Benign and Malignant Thyroid Disorders in Subjects Treated for Paediatric/Adolescent Neoplasia: Role of Morphological and Functional Screening.

BACKGROUND: Patients treated for paediatric/adolescent (P/A) neoplasia have a high incidence of both benign and malignant thyroid diseases. Given the high incidence of sequelae, literature data show a clinical benefit of morpho-functional thyroid screening in paediatric/adolescent cancer survivors and a careful lifetime follow-up. PATIENTS AND METHODS: The incidence of thyroid alterations was evaluated in a consecutive series of 343 patients treated with chemotherapy (CHE) and radiotherapy (RTE) or only with CHE for P/A tumours between 1976 and 2018 (mean age at time of primary paediatric malignancy 7.8 ± 4.7 years). All patients underwent thyroidal morpho-functional evaluation between 2000 and 2019. RESULTS: 178 patients (51.9%) were treated only with CHE and 165 (48.1%) with CHE+RTE. A functional and/or structural thyroid disease was diagnosed in 147 (42.5%; 24.2% in CHE and 62.4% in CHE+RTE group; p = 0.0001). Of note, 71 (20.7%) patients with no evidence of disease at first evaluation developed a thyroid alteration during the follow-up. Primitive hypothyroidism was diagnosed in 54 patients (15.7%; 11.2% in CHE vs. 20.6% in CHE+RTE group; p = 0.01) and hyperthyroidism in 4. Sixty-three patients developed thyroid nodules (18.4%; 4.0% in CHE and 14.1% in CHE+RTE group; p < 0.001); thyroid cancer was diagnosed in 30 patients (8.7%; 4.5% in CHE and 12.4% in CHE + RTE group; p = 0.007). CONCLUSIONS: In patients treated with CHE+RTE, the prevalence of hypothyroidism and nodular pathology, both malignant and benign, were significantly greater than in patients treated with CHE. However, also in the CHE group, the frequency of thyroid disease is not negligible and the pathogenetic mechanisms remain to be clarified. Our data suggest the clinical benefit of morpho-functional thyroid screening in P/A cancer survivors.

Differentiated Thyroid Cancer in Children and Adolescents: Long Term Outcome and Risk Factors for Persistent Disease.

Background: Pediatric differentiated thyroid cancer (P-DTC) frequently presents with advanced disease. The study aim was to evaluate the outcome of P-DTC and a modified 2015 American Thyroid Association risk classification (ATA-R). Methods: A retrospective study of consecutive P-DTC patients was performed. The ATA-R for P-DTC was used with a cut-off of ≤ 5 N1a for low-risk. The outcome could be excellent response (ER) (thyroglobulin < 1 ng/mL and no evidence of disease (EoD) at imaging), biochemical incomplete response (BIR) (thyroglobulin ≥ 1 ng/mL and no EoD at imaging) or structural incomplete response (SIR) (EoD at imaging). Results: We studied 260 P-DTC (70% females; median age at diagnosis 14 years; 93% total thyroidectomy and 82% lymph node dissection). The ATA-R was low in 30% cases, intermediate in 15% and high in 55%, including 31.5% with distant metastases. Radioiodine treatment was administered in 218 (83.8%), and further radioiodine and surgery was performed in 113 (52%) and 76 (29%) patients, respectively. After a median follow-up of 8.2 years, the outcome was ER in 193 (74.3%), BIR in 17 (6.5%) and SIR in 50 (19.2%). Independent predictors of SIR or BIR at first and last visits were ATA-R intermediate or high. Conclusion: P-DTC has an excellent prognosis. Modified ATA-R is a useful prognostic tool in P-DTC to guide management.

Giant parathyroid adenoma: a rare cause of primary hyperparathyroidism mimicking a carcinoma.

Not required for Clinical Vignette.

Differentiated Thyroid Cancer, From Active Surveillance to Advanced Therapy: Toward a Personalized Medicine.

Differentiated thyroid cancer (DTC) is the most frequent endocrine malignancy and represents the most rapidly increasing cancer diagnosis worldwide. In the last 20 years, this increase has been mostly due to a higher detection of small papillary thyroid cancers, with doubtful effects on patients' outcome. In fact, despite this growth, cancer-related death remained stable over the years. The growing detection of microcarcinomas associated to the indolent behavior of these cancers led to the development of strategies of active surveillance in selected centers of different countries. Moreover, toward a more personalized approach in the management of DTC patients, surgical treatments became more conservative, favoring less extensive options in patients at low risk of recurrence. The rise in lobectomy in low-risk cases and the need to avoid further therapies, with controversial impact on recurrences and cancer-related death in selected intermediate risk cases, led to reconsider the use of radioiodine treatment, too. Since clinicians aim to treat different patients with different modalities, the cornerstone of DTC follow-up (i.e., thyroglobulin, thyroglobulin autoantibodies, and neck ultrasound) should be interpreted consistently with this change of paradigm. The introduction of novel molecular target therapies (i.e., tyrosine kinase inhibitors), as well as a better understanding of the mechanisms of immune checkpoint inhibitor therapies, is radically changing the management of patients with advanced DTC, in whom no treatment option was available. The aim of this review is to analyze the most recent developments of the management of DTC, focusing on several key issues: active surveillance strategies, initial treatment, dynamic risk re-stratification, and therapeutic options in advanced DTC.

Time to Separate Persistent From Recurrent Differentiated Thyroid Cancer: Different Conditions With Different Outcomes.

Context: Differentiated thyroid cancer (DTC) has an excellent prognosis, but up to 20% of patients with DTC have disease events after initial treatment, indistinctly defined as persistent/recurrent disease. Objective: To evaluate the prevalence and outcome of "recurrent" disease (relapse after being 12 months disease-free) compared with "persistent" disease (present ab initio since diagnosis). Design: Retrospective analysis of persistent/recurrent disease in patients with DTC (1990 to 2016) with 6.5 years of mean follow-up. Setting: Tertiary referral center for thyroid cancer. Patients: In total, 4292 patients all underwent surgery ± 131I treatment of DTC. Main Outcome Measures: DTC cure of disease persistence or recurrence. Results: A total of 639 of 4292 (14.9%) patients had disease events after initial treatment, most (498/639, 78%) with persistent disease and 141 (22%) with recurrent disease. Relative to patients with recurrent disease, patients with persistent disease were significantly older (mean age 46.9 vs 45.7 years) and with a lower female to male ratio (1.9/1 vs 4.8/1). Moreover, in this group, structured disease was more frequent (65.7% vs 41.1%), and more important, distant metastases were significantly more frequent (38.4% vs 17.0%). At multivariate analysis, male sex (OR = 1.7), age (OR = 1.02), follicular histotype (OR = 1.5), T status (T3; OR = 3), and N status (N1b; OR = 7.7) were independently associated with persistent disease. Only the N status was associated with recurrent disease (N1b; OR = 2.5). Conclusions: In patients with DTC not cured after initial treatment, persistent disease is more common and has a worse outcome than recurrent disease. Postoperative status evaluated during first-year follow-up may have important clinical implications for planning tailored treatment strategies and long-term follow-up procedures.

Differentiated thyroid cancer in children: Heterogeneity of predictive risk factors.

OBJECTIVE: To correlate clinical and pathological characteristics at diagnosis with patient long-term outcomes and to evaluate ongoing risk stratifications in a large series of paediatric differentiated thyroid cancers (DTC). STUDY DESIGN: Retrospective analysis of clinical and pathological prognostic factors of 124 paediatric patients with DTC (age at diagnosis <19 years) followed up for 10.4 ± 8.4 years. Patients with a follow-up >3 years (n = 104) were re-classified 18 months after surgery on the basis of their response to therapy (ongoing risk stratification). RESULTS: Most patients had a papillary histotype (96.0%), were older than 15 years (75.0%) and were diagnosed because of clinical local symptoms (63.7%). Persistent/recurrent disease was present in 31.5% of cases during follow-up, but at the last evaluation, only 12.9% had biochemical or structural disease. The presence of metastases in the lymph nodes of the lateral compartment (OR 3.2, 95% CI, 1.28-7.16, P = 0.01) was the only independent factor associated with recurrent/persistent disease during follow-up. At the last evaluation, biochemical/structural disease was associated with node metastases (N1a, N1b) by univariate but not multivariate analysis. Ongoing risk stratification compared to the initial risk classification method better identified patients with a lower probability of persistent/recurrent disease (NPV = 100%). CONCLUSIONS: In spite of the aggressive presentations at diagnosis, paediatric patients with DTC show an excellent response to treatment and often a favourable outcome. N1b status should be considered a strong predictor of persistent/recurrent disease which, as in adults, is better predicted by ongoing risk stratification.

Anaplastic Thyroid Cancer in Sicily: The Role of Environmental Characteristics.

BACKGROUND: Anaplastic thyroid cancer (ATC) is a rare but extremely aggressive cancer of the thyroid, contributing up to 30-40% of thyroid cancer-specific mortality. We analyzed ATC characteristics and survival rates in Sicily to evaluate the possible influence of environmental factors. With this aim, data regarding ATC incidences in urban/rural and industrial, iodine-deficient, and volcanic vs control areas were compared in Sicily as well as ATC data from Sicily and USA. METHODS: Using the Sicilian Register of Thyroid Cancer (SRTC) database incidence, age, gender, tumor size and histotype, extrathyroidal extension, stage, and coexistence with pre-existing differentiated thyroid cancer (DTC) were evaluated in different areas of Sicily and also compared with Surveillance Epidemiology and End Results data in USA. RESULTS: Forty-three ATCs were identified in Sicily in the period 2002-2009. In our series only age <70 years at diagnosis (p = 0.01), coexistence with DTC (p = 0.027) and tumor size ≤6 cm (p = 0.012) were significant factors for increased survival at univariate analysis (only age at multivariate analysis). No difference in ATC incidence was found in urban vs rural areas and in iodine-deficient and industrial vs control areas. By contrast, in the volcanic area of Sicily, where DTC incidence is doubled relative to the rest of the island, also ATC incidence was increased. ATC data in Sicily were similar to those reported in the same period in the USA where overall survival rate at 6 and 12 months, however, was smaller. CONCLUSION: The similar ATC data observed in Sicily and USA (having different genetic background and lifestyle) and the increased ATC incidence in the volcanic area of Sicily paralleling the increased incidence of papillary thyroid cancer are compatible with the possibility that casual additional mutations, more frequent in a background of increased cell replication like DCT, are the major causes of ATC rather than genetic background and/or direct environmental influences.

Thyroid Cancer in the Pediatric Age in Sicily: Influence of the Volcanic Environment.

BACKGROUND/AIM: Pediatric thyroid cancer (TC) is rare but its incidence is increasing. We analyzed incidence and characteristics of pediatric TC in Sicily and comparatively evaluated data from the volcanic and non-volcanic areas. MATERIALS AND METHODS: All incident pediatric (0-19 years) TCs in Sicily between 2002-2009 were analyzed for the area of residence and compared to data for adults. RESULTS: A total of 54 differentiated TCs (DTC) and nine medullary TCs were diagnosed in Sicily in children between 2002-2009. DTC age standardized rate for the world population (ASRw) was 0.8/105 in females and 0.2/105 in males, with a higher incidence in the volcanic area (ASRw=1.4/105 in females, 0.5/105 in males) vs. the rest of Sicily (ASRw=0.6/105 in females, 0.1/105 in males). Pediatric TCs were larger in size and more frequently with extrathyroid extension and lymph-node involvement in comparison to TCs in adults. CONCLUSION: In the volcanic environment of Sicily, TC incidence is markedly increased in children, suggesting a short-term effect of unidentified carcinogens of volcanic origin.

Prognostic Factors for Adrenocortical Carcinoma Outcomes.

PURPOSE: Adrenocortical carcinoma (ACC) is an aggressive tumor characterized by a high recurrence rate and poor response to treatment. This study analyzes a consecutive series of ACC patients to evaluate the prognostic value of various clinical and pathological characteristics. METHODS: We retrospectively evaluated 32 ACC patients followed at our Medical Center from 1997 to 2015 and evaluated the prognostic value of age at diagnosis, gender, tumor functional status, stage, and type of treatment with respect to overall survival (OS) and disease-free survival (DFS), as determined by Kaplan-Meier curves. RESULTS: ACC was associated with hormonal overproduction in 50% of cases, and patients with isolated hyperandrogenism had a better prognosis. Recurrence was observed in 12/26 (46.2%) patients with no evidence of disease after surgery. Tumor size [hazard ratio (HR) 1.32, 95% confidential intervals (CI) 1.12-1.64; p = 0.007], ki-67 (HR 1.06, 95% CI 1.02-1.11; p = 0.009) and advanced stage at diagnosis (III-IV) (HR 6.51, 95% CI 1.65-24.68; p = 0.006) were associated with recurrence in the 26 R0 patients in the univariate analysis. Advanced stage was an independent risk factor for recurrence in the multivariate analysis (HR 8.10, 95% CI 1.55-41.35; p = 0.01). Five-year survival was 40.0%. Positive resection margins (HR 10.61, 95% CI 3.02-38.31; p = < 0.001), ki-67 (HR 1.04, 95% CI 1.01-1.07; p = 0.01) and advanced stage (HR 11.31, 95% CI 1.45-87.76; p = 0.02) were associated with poor survival in all 32 patients, but only positive resection margins were an independent predictor of mortality in the multivariate analysis (HR 6.22, 95% CI 1.44-26.05; p = 0.01). CONCLUSION: ACC has a poor prognosis with a high recurrence rate. Tumor stage at diagnosis and the completeness of surgical excision are the most relevant prognostic factors.

Familial Non-Medullary Thyroid Cancer Represents an Independent Risk Factor for Increased Cancer Aggressiveness: A Retrospective Analysis of 74 Families.

OBJECTIVES: To assess whether familial non-medullary thyroid cancer (FNMTC) represents an independent risk factor for increased aggressiveness of the tumor, as concern as the clinical presentation and the long-term follow-up in respect of sporadic differentiated thyroid cancer (SDTC). DESIGN: Retrospective study; 1976-2014. PATIENTS AND METHODS: Seventy-four FNMTC families (151 affected individuals): family relationship and number of affected family members were evaluated. Clinical and histopathological features and outcome were compared to that of 643 SDTC patients followed in the same period according to the same institutional protocols. Median follow-up was 57.7 months (range 12-136) in FNMTC and 59.7 (range 15-94.6) in SDTC patients. RESULTS: Three cases occurred in 3 families and 2 cases in the other 71. F:M was 3.7:1 in FNMTC and 4.3:1 in SDTC (NS). The family relationship was siblings in 62.2%. Mean age at diagnosis was lower in FNMTC than in SDTC (p < 0.005). Papillary/follicular histotype distribution was similar (86%). Papillary tumors were more frequently multifocal in FNMTC (p = 0.004) and with lymph-node metastases (p = 0.016). Disease-free survival (DFS) was shorter in FNMTC vs. SDTC (p < 0.0001) with 74.8 vs. 90.8% patients free of disease at the last control (p < 0.005). Three patients died in FNMTC group vs. 1 in SDTC (p = 0.02). CONCLUSION: Familial non-medullary thyroid cancer displays distinct characteristics as earlier age of onset and increased aggressiveness at diagnosis and a higher rate of persistent/recurrent disease and mortality with a shorter DFS in respect with SDTC. FNMTC patients, therefore, should be followed accurately. As the specific gene (or genes) responsible for susceptibility for FNMTC has not yet been identified, a low frequency periodic screening of relatives DTC patients may be useful to identify FNMTC patients at early stage of disease.

Thyroid cancer in thyroglossal duct cysts requires a specific approach due to its unpredictable extension.

CONTEXT: Differentiated thyroid cancer (DTC) in thyroglossal duct cysts is uncommon. The requirement of total thyroidectomy and lymph node dissection is still controversial. SETTING: The study was performed in a referral thyroid cancer center at an academic hospital. PATIENTS: We conducted a single center retrospective study of a consecutive series of 26 patients with DTC in thyroglossal duct cyst, all having undergone cyst resection and total thyroidectomy. MAIN OUTCOME MEASURES: Diagnostic modalities, surgical treatment, histopathological features, and clinical outcome were included in the study. RESULTS: Thyroglossal duct cyst cancer histotype was papillary in 23 of 26 patients (88.5%) and follicular-Hurthle in 3 of 26 cases (11.5%). A concomitant papillary DTC in the thyroid gland was found in 16 of 26 cases (61.5%), and it was multifocal in 8 of 16 cases (50%). At presentation, the patients with cancer in both the thyroglossal duct cyst and the thyroid were older than the patients who only had cancer in the thyroglossal duct cyst (44.9 ± 7.6 vs 32.0 ± 12.7; P = .006). Lymph node dissection, performed in 17 of 26 patients (65.4%), indicated that the central compartment was involved in 6 patients (35.3%, all having cancer also in the thyroid), the laterocervical compartments in 10 patients (58.8%), and the submental in 4 (23.5%). Six patients (23.1%) had persistent disease at 6-year median follow-up. CONCLUSIONS: DTC in thyroglossal duct cysts occurs at a younger age and with more aggressive features at presentation. Concomitant cancer in the thyroid and lymph node metastases is present in most cases. Lymph node compartment involvement is different from that of cancers in the thyroid gland. Therefore, surgical treatment should include both thyroglossal duct cyst resection and total thyroidectomy, with individualized surgical nodal dissection. Subsequent management should follow current DTC guidelines.