Parathyroid Retrospective Analysis of Neoplasms Incidence (pTRANI Study): An Italian Multicenter Study on Parathyroid Carcinoma and Atypical Parathyroid Tumour.

BACKGROUND: Parathyroid cancer (PC) is a rare sporadic or hereditary malignancy whose histologic features were redefined with the 2022 WHO classification. A total of 24 Italian institutions designed this multicenter study to specify PC incidence, describe its clinical, functional, and imaging characteristics and improve its differentiation from the atypical parathyroid tumour (APT). METHODS: All relevant information was collected about PC and APT patients treated between 2009 and 2021. RESULTS: Among 8361 parathyroidectomies, 351 patients (mean age 59.0 ± 14.5; F = 210, 59.8%) were divided into the APT (n = 226, 2.8%) and PC group (n = 125, 1.5%). PC showed significantly higher rates (p < 0.05) of bone involvement, abdominal, and neurological symptoms than APT (48.8% vs. 35.0%, 17.6% vs. 7.1%, 13.6% vs. 5.3%, respectively). Ultrasound (US) diameter >3 cm (30.9% vs. 19.3%, p = 0.049) was significantly more common in the PC. A significantly higher frequency of local recurrences was observed in the PC (8.0% vs. 2.7%, p = 0.022). Mortality due to consequences of cancer or uncontrolled hyperparathyroidism was 3.3%. CONCLUSIONS: Symptomatic hyperparathyroidism, high PTH and albumin-corrected serum calcium values, and a US diameter >3 cm may be considered features differentiating PC from APT. 2022 WHO criteria did not impact the diagnosis.

Clinical features of thyroid cancer in paediatric age. Experience of a tertiary centre in the 2000-2020 period.

PURPOSE: To describe the clinical features of a paediatric cohort affected by differentiated thyroid cancer (DTC) followed in a tertiary Department of Paediatric Endocrinology. METHODS: Clinical data of 41 patients affected by DTC in the 2000-2020 period were reviewed. RESULTS: The main risk factor was autoimmune thyroiditis (39%). Cytological categories were TIR3b in 39%, TIR4 in 9.8%, TIR5 in 51.2%. After total thyroidectomy, radioiodine treatment was performed in 38 subjects (92.7%). ATA low-risk category was assigned in 11 (30.5%), intermediate-risk category in 15 (41.7%), and high-risk category in 10 patients (27.8%). Age at diagnosis was 15.1 ± 0.92 years in low-risk category, 14.7 ± 0.59 in intermediate-risk category, 11.7 ± 0.89 years in high-risk category (p = 0.01). TIR3b was manly observed in low-risk class (63.6%), while TIR5 was mainly reported in intermediate and high-risk class (60 and 80% respectively) (p = 0.04). Post-surgery stimulated thyroglobulin was increased in high-risk class (407.8 ± 307.1 ng/ml) [p = 0.04]. Tumour size was larger in high-risk category (42.6 ± 2.6 mm), than in low and intermediate-risk categories (19.4 ± 3.5 mm and 28.5 ± 3.9 mm, respectively) (p = 0.008). Patients in intermediate and high-risk categories displayed more tumour multifocality (60 and 90% respectively) (p < 0.005). Disease relapse was mainly observed in high risk category (40%, p = 0.04). CONCLUSION: DTC in childhood is more aggressive than in adults, but the overall survival rate is excellent. The therapeutic approach is still heterogeneous, especially in low-risk category. Further studies are needed to standardise management and reduce disease persistence in childhood.

18F-FDG PET/CT concurrent with first radioiodine post-therapeutic scan in high risk differentiated thyroid cancer: a useful tool or just an expensive diversion?

BACKGROUND: Aim of the present study was to evaluate the clinical impact of fluorine-18F-fluorodeoxyglucose PET/CT (18F-FDG-PET/CT) concurrent with post-therapeutic whole-body radioiodine scan (TxWBS) after first radioiodine (RAI) treatment in patients with high-risk differentiated thyroid carcinoma (DTC). METHODS: This was a retrospective, single-center study including 39 patients with DTC (22 females, 17 males, median age 54; IQR: 35-60 years, 87% papillary thyroid cancer, 13% follicular thyroid cancer). All patients underwent 18F-FDG-PET/CT and RAI treatment, both performed off L-T4 about 3 months after total thyroidectomy. TxWBS was obtained 3 days afterwards using planar technique and SPECT/CT of neck and thorax regions. Semiquantitative analysis was performed on positive 18F-FDG-PET/CT scans to assess SUVmax, SUVratio, MTV and TLG values in target lesions (hottest 18F-FDG-positive lesion present in each patient). Receiver operating characteristics (ROC) curve analysis was obtained to establish a cut-off point for SUVmax able to predict the presence of RAI nonavid lesions. Univariate and multivariate analyses were executed to find out predictive factors for abnormal 18F-FDG-PET/CT imaging. RESULTS: In 11 (28%) patients 18F-FDG-PET/CT and TxWBS were both negative and in 9 (23%) both positive, showing loco-regional or distant metastases. In 14 patients (36%) 18F-FDG-PET/CT showed more lesions than TxWBS, while in 5 (13%) patients more lesions were present at TxWBS than 18F-FDG-PET/CT. Overall, 23 patients (59%) showed 18F-FDG avid lesions and 18F-FDG-PET/TC changed the management in 14 (36%), including the choice to perform RAI therapy with higher activities than expected, lymph-node dissection for loco-regional metastases, direct therapy for solitary bone metastases. Through ROC curve analysis, a value superior to 7.25 of SUVmax was able to predict the presence of RAI non-avid lesion at TxWBS. Serum stimulated thyroglobulin and extranodal invasion resulted to be risk factors for abnormal 18F-FDG-PET/CT imaging. However, only extranodal invasion turned out to be an independent risk factor for abnormal 18F-FDG-PET/CT. CONCLUSIONS: The present study demonstrated the clinical value of RAI-concurrent 18F-FDG-PET/CT in patients with high-risk DTC. However, some questions remain open, including the pretherapeutic thyroglobulin level to use as indication to 18F-FDG-PET/CT and the predictive value of 18F-FDG-PET/CT semiquantitative parameters.

18F-fluorocholine PET/CT semi-quantitative analysis in patients affected by primary hyperparathyroidism: a comparison between laboratory and functional data.

INTRODUCTION: This retrospective study aims to establish 18F-fluorocholine (FCH) positron emission tomography/computed tomography (PET/CT) performance in finding hyperfunctioning parathyroid glands, analyze a potential role for semi-quantitative PET parameters and assess factors that may influence PET/CT outcome. METHODS: Forty patients with suspect primary hyperparathyroidism (pHPT) and negative/equivocal conventional imaging underwent FCH-PET/CT in our Institution. For every lesion, visual and semi-quantitative analyses were performed on PET/CT images. In qualitative analysis, a lesion was considered positive if a clear focus of uptake, significantly higher than normal thyroid tissue, was identifiable. Ectopic focal uptake was also regarded as positive PET result. Lesion SUVMax was measured by assigning a spheric VOI to the suspect area of uptake. Thyroid SUVMean was assessed by placing a spheric VOI inside the contralateral thyroid lobe, and SUVratio was calculated using this background region. All patients were subsequently submitted to surgery and histopathologic workup. Sensitivity, positive predictive value (PPV) and accuracy were calculated based on histopathologic reports for every lesion. Pearson's test was used to assess a correlation between laboratory and histopathologic features with SUVr. RESULTS: Four out of the 40 patients who underwent surgery for pHPT had more than one histologic proven unhealthy parathyroid and three had papillary thyroid cancer (PTC). A total of 48 lesions were analyzed. We found 42/48 lesions (87.5%) to have true-positive uptake, whereas three lesions (6.7%) had false-positive uptake (PTC). Three histologic proven parathyroid adenomas showed no uptake (6.7%); the sensitivity/PPV were 93.3% and accuracy was 87,8%. Pearson's test showed a significant correlation between PTH values and parathyroid size with SUVr values (r = 0.56 and 0.55, respectively, p < 0.01 for both features). DISCUSSION: As stated in recent literature, we observed excellent diagnostic sensitivity of FCH-PET/CT in patients with pHPT, providing surgeons a fine tool to optimize treatment. More studies are needed to improve the evaluability of semi-quantitative parameters towards a further improvement of diagnostic accuracy.

The THYCOVIT (Thyroid Surgery during COVID-19 pandemic in Italy) study: results from a nationwide, multicentric, case-controlled study.

The outbreak of the COVID-19 pandemic has led to a disruption of surgical care. The aim of this multi-centric, retrospective study was to evaluate the impact of the pandemic on surgical activity for thyroid disease among the Italian Units of Endocrine Surgery. Three phases of the pandemic were identified based on the epidemiological situation and the public measures adopted from the Italian Government (1st phase: from 9th March to 3rd May 2020; 2nd phase: from 4th May to 14th June; 3rd phase: from 15th June to 31st). The patients operated upon during these phases were compared to those who underwent surgery during the same period of the previous year. Overall, 3892 patients from 28 Italian endocrine surgical units were included in the study, 1478 (38%) operated upon during COVID-19 pandemic, and 2414 (62%) during the corresponding period of 2019. The decrease in the number of operations was by 64.8%, 44.7% and 5.1% during the three phases of COVID-19 pandemic, compared to 2019, respectively. During the first and the second phases, the surgical activity was dedicated mainly to oncological patients. No differences in post-operative complications were noted between the two periods. Oncological activity for thyroid cancer was adequately maintained during the COVID-19 pandemic.

Parathyroid Carcinoma: An Up-to-Date Retrospective Multicentric Analysis.

Parathyroid carcinoma (PC) is a rare disease responsible for about 1% of primary hyperparathyroidism (PHPT) cases. PC usually has an indolent course, tough to differentiate from the benign causes of PHPT, and the only certain diagnosis is histologic. The gold standard surgical treatment is the en bloc resection associated with the homolateral thyroid loboistmectomy. The aim of this study was to underline the main differences between PC and benign PHPT, along with gathering epidemiological knowledge relative to PC in our region. Data from the regional cancer network (Rete Oncologica del Piemonte e della Valle d'Aosta) since 2007 have been reported, including 21 patients from three hospitals (AO S. Croce e Carle of Cuneo, AOU Città della Salute of Turin, and ASL Città di Torino). The incidence of the disease, gender, age at time of diagnosis, presence of renal and bone symptoms, serum calcium and PTH levels, surgical technique performed, and percentage of recurrence were analysed. PC data were than compared with a series of patients affected by benign PHPT, referred to ASL Città di Torino, Maria Vittoria Hospital, from 2007 to 2019. A PC incidence of 0.05 cases per 100,000 inhabitants was found in our region. Benign forms occurred more frequently in females (p=0.0002), while PC equally occurred in males and females and affected younger patients (p=0.026). Serum calcium and PTH levels were significantly higher in PC patients; accordingly, typical PHPT symptoms were more frequently reported in PC than in benign PHPT. In the PC group, the en bloc resection shows a 13 times lower risk for relapse compared with all the other surgical techniques. PC is equally gender distributed, and the average patients' age is in the fifth decade of life. It is usually functioning, with greater biochemical activity and multiple symptoms. A not-radical surgical resection is associated with a higher recurrence rate. A meticulous presurgical evaluation of PHPT patients showing PC's evocative features is mandatory to obtain a complete disease extirpation.

Tracheobronchopathia osteochondroplastica in recurrent retrosternal goiter. Surgical management.

Tracheobronchopathia osteochondroplastica (TPO) is a rare pathology characterized by a progressive segmentary stenosis of the respiratory tract due to proliferation of osteocartilagineous nodules in the lumen of the distal part of the trachea and large bronchial trunks. Prognosis is usually benign, but some cases with an acute progression and a lethal outcome have been described. Clinical presentation is non specific, the chest x-ray is generally normal and there are not typical radiological signs of suspicion: diagnosis of TPO is usually incidental. We report a case of TPO associated with a retrosternal recurrent goiter. The CT scan conducted to evaluate the extension and the vascular relationships showed the characteristic lesions of the TPO with a segmental stenosis of the trachea greater than 70%. A bronchofiberoscopy confirmed the suspect of TPO. To date, the clinical studies carried out do not show a certain etiology, but all agree that chronic damage or chronic inflammations could be the cause of the onset of structural anomalies of the respiratory tract In literature, there is only a report which describes an association between TPO and thyroid pathology. It is obscure whatever these disease could be etiologically or fortuitously associated but a relationship cannot be completely excluded. Surgeons, anesthetists and radiologists which deal with thyroid pathology must recognize the disease, especially in the presence of bulky retrosternal goiters, to make a correct diagnosis and provide adequate perioperative management. KEY WORDS: Mediastinal goiter, Osteocartilagineous Nodules, Tracheal Stenosis, Total Thyroidectomy, Tracheobronchopathia Osteochondroplastica.

Clinical challenges with calcitonin-negative medullary thyroid carcinoma.

PURPOSE: Medullary thyroid carcinoma (MTC) is a relatively uncommon malignant tumor of the parafollicular C cells of the thyroid, which distinguishing feature is the production of calcitonin (CT). CT is a well-recognized tool in the diagnosis and the postsurgical follow-up of patients with MTC with a high sensitivity and specificity, and represents a powerful prognostic indicator. Usually, there is a direct correlation between tumor size and basal CT levels. However, few cases of CT-negative MTCs have been reported in literature and criteria for diagnosis and follow-up are still controversial. METHODS: We performed a brief review on CT-negative MTC and reported our experience on this rare condition, focusing on the clinical characteristics at presentation, the histological and immunostaining features, and the management. RESULTS: Fifteen cases of large, palpable, CT-negative MTCs have been reported in the literature so far; moreover, we reported four cases followed at our center. CONCLUSIONS: Although CT-negative MTC is rare, normal/low serum levels of CT and CEA cannot completely exclude the possibility of the diagnosis, when suspected. It is well accepted that early diagnosis is crucial, but there is still no consensus on the optimal postoperative surveillance strategy. The ultrasound evaluation of the cervical region, together with abdominal computerized tomography scan, chest X-ray, and fluorine18-fluorodeoxyglucose ((18)F-FDG) PET/computed tomography (FDG-PET/CT), would be recommended in the follow-up of such cases.

Ultrasound surveillance for radiation-induced thyroid carcinoma in adult survivors of childhood cancer.

INTRODUCTION: The optimal surveillance strategy to screen for thyroid carcinoma childhood cancer survivors (CCS) at increased risk is still debated. In our clinical practice, beside neck palpation we routinely perform thyroid ultrasound (US). Here we describe the results obtained using this approach. METHODS: We considered all CCS referred to our long term clinic from November 2001 to September 2014. One hundred and ninety-seven patients who had received radiation therapy involving the thyroid gland underwent US surveillance. Thyroid US started 5 years after radiotherapy and repeated every 3 years, if negative. RESULTS: Among 197 CCS previously irradiated to the thyroid gland, 74 patients (37.5%) developed thyroid nodules, and fine-needle aspiration was performed in 35. In 11 patients the cytological examination was suspicious or diagnostic for malignancy (TIR 4/5), whereas a follicular lesion was diagnosed in nine. Patients with TIR 4/5 cytology were operated and in all cases thyroid cancer diagnosis was confirmed. The nine patients with TIR 3 cytology also underwent surgery and a carcinoma was diagnosed in three of them. Prevalence of thyroid cancer was 7.1%. Tumour size ranged between 4 and 25 mm, but six (43%) were classified T3 because of extra-thyroidal extension. Six patients had nodal metastases; in eight patients the tumour was multifocal. At the time of the study all patients are disease free, without evidence of surgery complications. CONCLUSION: Applying our US surveillance protocol, the prevalence of radiation-induced thyroid cancer is high. Histological features of the thyroid cancers diagnosed in our cohort suggest that most of them were clinically relevant tumours.

Predictors of Malignancy in Children with Thyroid Nodules.

OBJECTIVE: To evaluate the diagnostic accuracy of clinical, laboratory, and ultrasound (US) imaging characteristics of thyroid nodules in assessing the likelihood of malignancy. STUDY DESIGN: Data from 184 children and adolescents with thyroid nodules were evaluated and compared with respective cytologic/histologic outcomes. A regression model was designed to assess the predictors associated with malignancy and to calculate ORs. RESULTS: Twenty-nine malignant neoplasms (25 papillary, 1 medullary, 3 Hurtle-cell carcinomas), 8 follicular adenomas, and 147 goitrous nodules (92 based on cytology, 55 on follow-up) were diagnosed. Fine-needle aspiration biopsy diagnostic accuracy, sensitivity, and specificity were 91%, 100%, and 88%, respectively. Male sex, compression symptoms, palpable lymphopathy, thyroid stimulating hormone concentration, microcalcifications, indistinct margins, hypoechoic US pattern, pathologic lymph node alterations, and increased intranodular vascularization were associated with malignancy. Regular margins, mixed echoic pattern, and peripheral-only vascularization were associated with benignity. During follow-up, nodule growth was associated with malignant disease, especially with levothyroxine therapy. A multivariate analysis confirmed that microcalcifications, hypoechoic pattern, intranodular vascularization, lymph node alterations, and thyroid stimulating hormone concentration were independent predictors of malignant outcome. For each predictor, we provide sensitivity, specificity, and positive/negative predictive values. CONCLUSIONS: Clinical, laboratory, and US features of nodules can be used as predictors of malignancy in children. Although none has diagnostic accuracy as high as that of fine-needle aspiration biopsy, these predictors should be considered in deciding the diagnostic approach of children with thyroid nodules.

Thyroidectomy for Painful Thyroiditis Resistant to Steroid Treatment: Three New Cases with Review of the Literature.

Thyroidal pain is usually due to subacute thyroiditis (SAT). In more severe forms prednisone doses up to 40 mg daily for 2-3 weeks are recommended. Recurrences occur rarely and restoration of steroid treatment cures the disease. Rarely, patients with Hashimoto's thyroiditis (HT) have thyroidal pain (painful HT, PHT). Differently from SAT, occasional PHT patients showed no benefit from medical treatment so that thyroidectomy was necessary. We report three patients who did not show clinical response to prolonged high dose prednisone treatment: a 50-year-old man, a 35-year-old woman, and a 33-year-old woman. Thyroidectomy was necessary, respectively, after nine-month treatment with 50 mg daily, two-month treatment with 75 mg daily, and one-month treatment with 50 mg daily. The two women were typical cases of PHT. Conversely, in the first patient, thyroid histology showed features of granulomatous thyroiditis, typical of SAT, without fibrosis or lymphocytic infiltration, typical of HT/PHT, coupled to undetectable serum anti-thyroid antibodies. Our data (1) suggest that not only PHT but also SAT may show resistance to steroid treatment and (2) confirm a previous observation in a single PHT patient that increasing prednisone doses above conventional maximal dosages may not be useful in these patients.

Utilility of flow cytometry as ancillary study to improve the cytologic diagnosis of thyroid lymphomas.

BACKGROUND: To evaluate the efficacy of the use of flow cytometry (FC) immunophenotyping together with fine-needle aspiration cytology (FNAC) in the diagnosis of thyroid lymphoma. METHODS: FC was performed in parallel with FNAC in 35 samples of suspected thyroid lymphoma over a 12 years period. Results were correlated with histological or molecular findings and follow-up, when available. RESULTS: A final diagnosis of lymphoma was given in 13 of 35 (37.1%) specimens. Among the 22 cases considered negative for lymphoma by FC, 11 were diagnosed as thyroiditis by cytology, 7 as reactive, 2 were anaplastic carcinoma, and 2 cases were considered cytologically suspicious for lymphoma but were not confirmed by further investigations. Histology on core biopsy or molecular analysis was available in 12 of 13 lymphoma cases (92.3%). Data obtained by the combination cytology/FC were confirmed in all cases on histology biopsies. Correlation with histology showed a sensitivity and a specificity of 100% for the combination cytology/FC. CONCLUSIONS: FC is an important additional test that can contribute with cytology to the identification of lymphomas of the thyroid. FC can detect the presence of small neoplastic lymphocyte populations and may contribute to the diagnosis of cases in which the lymphoid infiltrate is difficult to interpret on cytology alone.

Diagnostic performance of elastography in cytologically indeterminate thyroid nodules.

Cytological examination of material from fine-needle aspiration biopsy is the mainstay of diagnosis of thyroid nodules, thanks to its remarkable accuracy and scarcity of complications. However, follicular lesions (also called indeterminate lesions or Thy3 in the current classification), a heterogeneous group of lesions in which cytology is unable to give a definitive diagnosis to, represent its main limit. Elastography has been proposed as a potential diagnostic tool to define the risk of malignancy in the aforementioned nodules, but at present there is no conclusive data due to the small number of specifically addressed studies and the lack of concordance among them. The objective of our study was to evaluate the role of real-time elastography (RTE) for refining diagnosis of Thy3 nodules, by integrating diagnostic information provided by traditional ultrasound (US). The study included 108 patients with Thy3 nodules awaiting for surgery, which were evaluated by US (considering hypoecogenicity, irregular margins, microcalcifications, halo sign, and intranodular vascularization) and RTE. Nodules were classified at RTE using a four-class color scale. At histologic examination, 75 nodules were benign and 33 malignant. As expected, none of the ultrasound parameters alone was adequate in predicting malignancy or benignity of the nodules; in the presence of at least two US risk factors, we obtained 61 % sensitivity, 83 % specificity, and 77 % accuracy with 6.8 OR (95 % CI 2.4-20.4). RTE scores 3 and 4 showed 76 % sensitivity, 88 % specificity, 74 % PPV, and 89 % NPV with diagnostic accuracy of 84 %; the data are statistically significant (p < 0.0001) with a OR of 21.9 (95 % CI 7.1-76). By combining RTE with US parameters, the presence of at least 2 characters of suspicion had 88 % sensitivity and 94 % NPV with 23.8 OR (95 % CI 7-106.3). The use of combined RTE and US leads to the identification of two patients subpopulations which have a significantly different malignancy risk (6 vs. 63 %); further studies are needed to verify if it is possible to send only the first group to thyroidectomy and the other to follow-up.

Early surgery and survival of patients with anaplastic thyroid carcinoma: analysis of a case series referred to a single institution between 1999 and 2012.

BACKGROUND: Extensive resection of the tumor has been associated with better survival of anaplastic thyroid carcinoma (ATC) patients. However, surgery is not the rule for ATC patients with distant metastases at the time of diagnosis (stage IV-C), regardless of tumor resectability. The aim of this work was to explore the potential role of surgery in ATC patients, including those in stage IV-C. METHODS: We considered all the consecutive ATC patients referred to our institution from June 1999 to July 2012. Patients with stage IV-A incidentally discovered ATC were excluded because of their better prognosis. All patients eligible for surgery at the time of diagnosis were first operated with the intent to obtain a macroscopically complete resection (R0, R1), or a R2 resection with minimal macroscopical residual tumor. These operations were defined as "maximal debulking," whereas operations that did not achieve this goal were defined as "partial debulking." After surgery, almost all patients received adjuvant chemotherapy, associated to radiotherapy in more than 50% of patients. RESULTS: There were 55 eligible patients (34 women; median age 73.15 years). Thirty-one patients had distant metastases (stage IV-C). The median overall survival was 5.55 months [CI 4.94-6.60], with no difference according to stage. "Maximal debulking" was obtained in 70.73% of operated patients as a first modality and resulted associated with better survival than "partial debulking" (6.57 months [CI 5.52-12.09] vs. 3.25 months [CI 0.66-4.80]), without any difference between stage IV-B and IV-C patients. Furthermore, 21% of patients submitted to "maximal debulking" died secondary to local progression of the tumor, whereas this was the case for 69% of patients treated with "partial debulking" or not operated at all. CONCLUSIONS: Early "maximal debulking," followed by adjuvant therapy, can improve the survival and ameliorate the quality of residual life preventing the risk of suffocation. This effect is also observed in patients with distant metastasis at diagnosis and treated with this approach: they have an outcome similar to that observed in stage IV-B patients. We thus suggest that surgery may be considered in the management of all ATC patients, and should not be restricted a priori to stages IV-A and IV-B.

Cytomorphologic and molecular features of hobnail variant of papillary thyroid carcinoma: case series and literature review.

Recent reports indicate that hobnail papillary thyroid carcinoma (HPTC) is a rare, but very aggressive variant of papillary thyroid carcinoma. The authors describe the cytological features of five HPTC on fine-needle aspiration biopsies (FNAB). Moreover, their immunophenotype and the presence of B-RAF mutation by pyrosequencing were investigated. The patients' (three females and two males) age ranged from 27 to 86 (mean 65) years. Tumor size ranged from 2 to 9 cm (mean 4.2 cm). FNAB were highly cellular with a bloody background and scant colloid. The cells were arranged in papillary-like clusters or in micropapillary groups. The cell population consisted of medium-sized cells with "tear-drop" cytoplasm, apically placed nuclei that produced a surface bulge leading to a hobnail appearance. At higher magnification, nuclei showed variable degrees of atypia, occasional pink intranuclear pseudoinclusions, and grooves. Nuclear stratification and atypical mitotic figures were usually present. Immunocytochemistry revealed positive staining for thyroglobulin, thyroid transcriptor factor-1, Hector Battifora Mesothelial Antigen-1, partial loss of E-cadherin expression, and nuclear expression of p53 protein. B-RAF mutation was present in three out of five cytological cases. Immunohistochemical and molecular results were confirmed on histological sections. Recognizing the unique cytological features of HPTC should help to avoid misdiagnosis of this rare variant.

Segmental tracheal resection for invasive differentiated thyroid carcinoma. Our experience in eight cases.

PURPOSE: In differentiated thyroid carcinoma (DTC), complete resection of local disease provides the longest survival and the best palliation. In pursuit of this goal, segmental tracheal or laryngotracheal resection can be performed on patients with DTC invading the airway. The study summarizes the technical aspects of the intervention and analyzes its results in eight patients. METHODS: The results of eight tracheal or laryngotracheal resections for DTC invading the airway were analyzed. Three patients presented with local recurrent disease, whereas five underwent airway resection at the time of thyroidectomy or shortly after. All received a circumferential sleeve resection of the trachea (2­4 tracheal rings) that in three cases extended to the cricoid, followed by end-to-end anastomosis. RESULTS: Pathologic evaluation identified seven papillary and one poorly differentiated carcinomas. No postoperative deaths occurred; one patient required surgical reexploration because of postoperative bleeding, and two air leaks resolved with conservative treatment. Functional results were excellent. During follow-up, one patient died of lung and bone metastases, while in two cases locally persistent/recurrent disease has been detected; two patients are currently free of disease, and in the last three cases only persistent thyroglobulin levels are indicative of residual disease. CONCLUSIONS: In our experience, segmental airway resection is safe, provides excellent functional results, and can warrant adequate control of local disease.

Histone deacetylase inhibition affects sodium iodide symporter expression and induces 131I cytotoxicity in anaplastic thyroid cancer cells.

BACKGROUND: Anaplastic thyroid cancers (ATCs) represent only 1%-2% of all thyroid tumors, but they account for up to 50% of the mortality. Treatment of differentiated thyroid carcinomas is well standardized and the use of radioiodine represents an essential step; in contrast, there is no standardized therapeutic approach for anaplastic tumors and their prognosis is poor. The resistance of ATC to radioiodine treatment is principally due to the absence of expression of the sodium iodide symporter (NIS), mainly due to epigenetic silencing. The acetylation status of histones is involved in the epigenetic control of gene expression and is usually disrupted in advanced thyroid cancer. Histone deacetylase inhibitors have been demonstrated as potent anticancer drugs with several different effects on cell viability and differentiation. METHODS: Stabilized ATC cell lines (BHT-101 and CAL-62) and primary cultures from patients who underwent thyroidectomy for ATC were treated with the histone deacetylase inhibitor LBH589. After treatment, we evaluated the expression and function of NIS. Gene expression was evaluated by real-time polymerase chain reaction (RT-PCR), NIS promoter activity was determined with a luciferase reporter assay, and protein expression was assessed through immunofluorescence. We tested the protein function by (125)I uptake and efflux experiments; finally the cytotoxic effect of (131)I was determined with a clonogenic assay. RESULTS: Our results demonstrate that treatment with LBH589 leads to NIS RNA expression as shown by RT-PCR and luciferase assay, and to protein expression as determined by immunofluorescence in vitro and by immunohistochemistry in xenograft tumors. Moreover, (125)I uptake and efflux experiments show the correct protein function and iodine retention, which translate into cytotoxicity effects, as demonstrated by a clonogenic assay with (131)I. CONCLUSIONS: This study supplies a new potential strategy for the treatment of ATC by modifying gene expression with the aim of inducing responsiveness towards radioiodine therapy.

Histone deacetylase inhibition modulates E-cadherin expression and suppresses migration and invasion of anaplastic thyroid cancer cells.

CONTEXT: Anaplastic thyroid cancer cells are characterized by a mesenchymal phenotype, as revealed by spindle-shaped cells and absent or reduced levels of E-cadherin. Epigenetic silencing is considered one of the leading mechanisms of E-cadherin impairment, which causes the acquisition of the invasive and metastatic phenotype of anaplastic thyroid cancer. OBJECTIVES: In this study we investigated the effects of histone deacetylase inhibition on E-cadherin expression, cell motility, and invasion in anaplastic thyroid cancer cell cultures. DESIGN: Three stabilized cell lines and primary cultures of anaplastic thyroid cancer were treated with various histone deacetylase inhibitors. After treatment, we evaluated histone acetylation by Western blotting and E-cadherin expression by RT-real time PCR. The proper localization of E-cadherin/ß-catenin complex was assessed by immunofluorescence and Western blot. Transcription activity of ß-catenin was measured by luciferase reporter gene and cyclin D1 expression. The effect on cell motility and invasion was studied both in vitro using scratch-wound and transwell invasion assays and in anaplastic thyroid carcinomas tumor xenografts in mice in vivo. RESULTS: Histone deacetylase inhibition induced the E-cadherin expression and the proper membrane localization of the E-cadherin/ß-catenin complex, leading to reduced cancer cell migration and invasion. CONCLUSIONS: We here demonstrate an additional molecular mechanism for the anticancer effect of histone deacetylase inhibition. The antiinvasive effect in addition to the cytotoxic activity of histone deacetylase inhibitors opens up therapeutic perspectives for the anaplastic thyroid tumor that does not respond to conventional therapy.