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.

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.

Safety and Quality-of-Life Data from an Italian Expanded Access Program of Lenvatinib for Treatment of Thyroid Cancer.

Background: Lenvatinib, a multikinase inhibitor, is for progressive radioiodine-refractory-differentiated thyroid cancer (RR-DTC) patients. However, there are a lot of drug-related adverse events (AEs) that can affect the quality of life (QoL) of patients. The aims of this study were (a) to evaluate, and compared with other series, the safety of lenvatinib used in RR-DTC patients enrolled in an Italian expanded access program (EAP), and (b) to evaluate their QoL during treatment with lenvatinib. Methods: To evaluate the safety, we recorded and graded all AEs during the 6 months of lenvatinib treatment in 39 RR-DTC patients. We compared the safety profile of lenvatinib observed in our patients with that reported in the study of (E7080) levatinib in differentiated cancer of the thyroid (SELECT) and tumeurs thyroidiennes refractaires (TUTHYREF) network studies. Moreover, we evaluated the QoL in our series by using the European Organization for Research and Treatment (EORTC) Quality of Life Questionnaire-Core 30 and the pain visual analogue scale (VAS). Results: The most frequent AEs among our 39 RR-DTC patients were hypertension (80.5%), fatigue (58.3%), diarrhea (36.1%), stomatitis (33.3%), hand/foot syndrome (33.3%), and weight loss (30.5%). The most prevalent grade 3/4 AE was hypertension (25%). When compared with previous studies (i.e., SELECT and TUTHYREF), a significantly lower percentage of our patients experienced diarrhea, nausea, proteinuria, and weight loss. No statistically significant differences in the QoL of our patients evaluated before, during, and at the end of follow-up (6 months after starting the therapy) were found. However, a slight improvement of the general health and emotional and cognitive status associated with a slightly worsening of physical role and social functioning was observed during these 6 months. Pain, dyspnea, insomnia, and constipation moved toward better values, while fatigue, nausea and vomiting, appetite loss, and diarrhea worsened. By comparing the pain VAS, an overall reduction of the level of pain was found. Conclusions: The safety profile of the drug was similar to that already reported with some differences in the prevalence and severity of the AEs. Regarding the QoL, the EAP showed a trend of improvement of the global health status and a reduction of symptoms correlated to the disease. The clinical impact of fatigue, anorexia/weight loss and stomatitis, mainly due to the drug itself, continues to represent the major issue in the management of these patients.

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.

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.

New Insights in Thyroid Cancer and p53 Family Proteins.

Thyroid cancers are common endocrine malignancies that comprise tumors with different clinical and histological features. Indeed, papillary and follicular thyroid cancers are slow-growing, well-differentiated tumors, whereas anaplastic thyroid cancers are undifferentiated neoplasias that behave much more aggressively. Well-differentiated thyroid carcinomas are efficiently cured by surgery and radioiodine, unlike undifferentiated tumors that fail to uptake radioactive iodine and are usually resistant to chemotherapy. Therefore, novel and more effective therapies for these aggressive neoplasias are urgently needed. Whereas most genetic events underlying the pathogenesis of well-differentiated thyroid cancers have been identified, the molecular mechanisms that generate undifferentiated thyroid carcinomas are still unclear. To date, one of the best-characterized genetic alterations leading to the development of poorly differentiated thyroid tumors is the loss of the p53 tumor suppressor gene. In addition, the existence of a complex network among p53 family members (p63 and p73) and their interactions with other factors that promote thyroid cancer progression has been well documented. In this review, we provide an update on the current knowledge of the role of p53 family proteins in thyroid cancer and their possible use as a therapeutic target for the treatment of the most aggressive variants of this disease.

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.

Heterogeneous Prognoses for pT3 Papillary Thyroid Carcinomas and Impact of Delayed Risk Stratification.

BACKGROUND: Papillary thyroid carcinomas (PTC) in the pT3 category constitute a heterogeneous group of tumors with a variable risk of recurrence. The objectives of this study were (i) to estimate disease-free survival (DFS) and identify prognostic factors associated with recurrence in a cohort of pT3 PTC, and (ii) to evaluate the concept of delayed risk stratification in a cohort of pT3 tumors. METHODS: A total of 560 patients with pT3 PTC, treated and followed at the authors' institution, were studied. They were divided into three groups: group 1, pT3 ≤10 mm; group 2, pT3 >10 mm with extrathyroidal invasion (ETI); and group 3, pT3 due to a tumor size >4 cm. DFS was estimated using the Kaplan-Meier method, and associated prognostic features were studied in univariate and multivariate Cox model-based analyses in each group. Then, DFS was studied for each group according to the six- to eight-month status (remission or not). RESULTS: DFS at 10 years was 75% for the entire cohort and was 89%, 67%, and 82% in groups 1, 2, and 3, respectively (p < 0.0001). Multivariate analysis identified three factors significantly associated with reduced DFS: lymph node (LN) involvement, male sex, and group 2 (>1 cm with ETI). A trend toward a worse prognosis in patients with pT3 N0/Nx PTC >10 mm with ETI was found in comparison with the other pT3 N0/Nx patients. When the six- to eight-month checkup was normal, the DFS at 10 years increased to 98%, 96%, and 91% in groups 1-3, respectively. Furthermore, in this case, initial LN involvement no longer seemed to affect the prognosis in those groups. CONCLUSION: PTC ≤10 mm with ETI and large tumors >4 cm without ETI both have a low-recurrence risk when there are no adverse associated prognostic features such as LN involvement. LN involvement, especially in the lateral compartment (N1b), is a strong prognostic factor of recurrence in pT3 PTC. Delayed risk stratification can be applied in pT3 PTC patients. Those cured at the first checkup, including those with limited LN involvement, have excellent outcomes, which should prompt clinicians to adapt subsequent management accordingly.

Metastatic malignant struma ovarii with coexistence of Hashimoto's thyroiditis.

UNLABELLED: Struma ovarii is a rare ovarian teratoma characterized by the presence of thyroid tissue as the major component. Malignant transformation of the thyroidal component (malignant struma ovarii) has been reported in approximately 5% of struma ovarii. The management and follow-up of this unusual disease remain controversial. We report the case of a woman with a history of autoimmune thyroiditis and a previous resection of a benign struma ovarii that underwent hystero-annexiectomy for malignant struma ovarii with multiple papillary thyroid cancer foci and peritoneal involvement. Total thyroidectomy and subsequent radioiodine treatment lead to complete disease remission after 104 months of follow-up. The diagnosis and natural progression of malignant struma ovarii are difficult to discern, and relapses can occur several years after diagnosis. A multidisciplinary approach is mandatory; after surgical excision of malignant struma, thyroidectomy in combination with (131)I therapy should be considered after risk stratification in accordance with a standard approach in differentiated thyroid cancer patients. LEARNING POINTS: Malignant struma ovarii is a rare disease; diagnosis is difficult and management is not well defined.Predominant sites of metastasis are adjacent pelvic structures.Thyroidectomy and (131)I therapy should be considered after risk stratification in accordance with standard approaches in DTC patients.

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.

Hypertrophic Osteoarthropathy and Follicular Thyroid Cancer: A Rare Paraneoplastic Syndrome.

BACKGROUND: Hypertrophic osteoarthropathy (HOA) is a rare condition characterized by bone and joint pain and digital clubbing usually associated with bronchopulmonary diseases. Primary HOA is rare and the pathogenesis remains unclear. OBJECTIVES: Cases of HOA as a paraneoplastic syndrome associated with thyroid carcinoma are very rare - only 2 cases have been described in the literature. RESULTS: We present the first case of a 40-year-old patient affected by HOA associated with invasive differentiated follicular thyroid carcinoma operated in 2 stages. Both operations were followed by radioiodine ablation, and then a rapid unresectable local recurrence developed requiring cervical radiotherapy (70 Gy). A second treatment with 100 mCi of (131)I confirmed it was a refractory thyroid cancer. Further surgery confirmed a poorly differentiated follicular cancer and 12 cycles of chemotherapy by gemcitabine and oxaliplatin followed. During the 8 years of follow-up, cervical recurrence was stable, but severe episodes of hemoptysis occurred requiring iterative embolization of the bronchial and tracheal arteries. Other lung diseases were excluded. Digital clubbing appeared, which was associated with arthritis, bone pain and inflammatory syndrome. X-rays and magnetic resonance imaging found periosteal apposition in the long bones; bone scintigraphy confirmed the HOA diagnosis. Other causes of arthritis were eliminated. She was treated with colchicine, corticosteroids and nonsteroidal anti-inflammatory drugs, but only the combination of methotrexate and hydroxychloroquine reduced the morphine requirements. CONCLUSION: HOA is exceptionally associated with thyroid cancer and we raised the hypothesis of the secretion of a circulating factor in a patient with invasive and recurrent follicular thyroid cancer, refractory to radioiodine.

Descriptive epidemiology of human thyroid cancer: experience from a regional registry and the "volcanic factor".

Thyroid cancer (TC), the most common endocrine tumor, has steadily increased worldwide due to the increase of the papillary histotype. The reasons for this spread have not been established. In addition to more sensitive thyroid nodule screening, the effect of environmental factors cannot be excluded. Because high incidences of TC were found in volcanic areas (Hawaii and Iceland), a volcanic environment may play a role in the pathogenesis of TC. In January 2002, the Regional Register for TC was instituted in Sicily. With a population of approximately five million inhabitants with similar genetic and lifestyle features, the coexistence in Sicily of rural, urban, industrial, moderate-to-low iodine intake, and volcanic areas provides a conducive setting for assessing the environmental influences on the etiology of TC. In Sicily, between 2002 and 2004, 1,950 new cases of TC were identified, with an age-standardized rate (world) ASR(w) = 17.8/10(5) in females and 3.7/10(5) in males and a high female/male ratio (4.3:1.0). The incidence of TC was heterogeneous within Sicily. There were 2.3 times more cases in the Catania province (where most of the inhabitants live in the volcanic area of Mt. Etna): ASR(w) = 31.7/10(5) in females and 6.4/10(5) in males vs. 14.1 in females and 3.0 in males in the rest of Sicily. Multivariate analysis documented that residents in the volcanic area of Mt. Etna had a higher risk of TC, compared to the residents in urban, industrial, and iodine deficient areas of Sicily. An abnormally high concentration of several chemicals was found in the drinking water of the Mt. Etna aquifer, which provides water to most of the residents in the Catania province. Our data suggest that environmental carcinogen(s) of volcanic origin may promote papillary TC. Additional analyses, including cancer biological and molecular features, will allow a better understanding of risk factors and etiopathogenetic mechanisms.