American Association of Clinical Endocrinology And Associazione Medici Endocrinologi Thyroid Nodule Algorithmic Tool.

OBJECTIVE: The first edition of the American Association of Clinical Endocrinology/American College of Endocrinology/Associazione Medici Endocrinologi Guidelines for the Diagnosis and Management of Thyroid Nodules was published in 2006 and updated in 2010 and 2016. The American Association of Clinical Endocrinology/American College of Endocrinology/Associazione Medici Endocrinologi multidisciplinary thyroid nodules task force was charged with developing a novel interactive electronic algorithmic tool to evaluate thyroid nodules. METHODS: The Thyroid Nodule App (termed TNAPP) was based on the updated 2016 clinical practice guideline recommendations while incorporating recent scientific evidence and avoiding unnecessary diagnostic procedures and surgical overtreatment. This manuscript describes the algorithmic tool development, its data requirements, and its basis for decision making. It provides links to the web-based algorithmic tool and a tutorial. RESULTS: TNAPP and TI-RADS were cross-checked on 95 thyroid nodules with histology-proven diagnoses. CONCLUSION: TNAPP is a novel interactive web-based tool that uses clinical, imaging, cytologic, and molecular marker data to guide clinical decision making to evaluate and manage thyroid nodules. It may be used as a heuristic tool for evaluating and managing patients with thyroid nodules. It can be adapted to create registries for solo practices, large multispecialty delivery systems, regional and national databases, and research consortiums. Prospective studies are underway to validate TNAPP to determine how it compares with other ultrasound-based classification systems and whether it can improve the care of patients with clinically significant thyroid nodules while reducing the substantial burden incurred by those who do not benefit from further evaluation and treatment.

Relevance of rosette patterns in variants of papillary thyroid carcinoma.

INTRODUCTION: The detection of rosette-like clusters (RLC) of follicular cells in thyroid carcinoma has been reported mostly in the columnar cell variant of papillary thyroid carcinoma (PTC). Despite the fact that diagnosing variants of PTC is no longer encouraged by The Bethesda System for Reporting Thyroid Cytopathology, the identification of cytomorphological features such as RLC linked with these tumours might help reduce possible misinterpretation in thyroid fine needle aspiration (FNA) cytology. We accordingly investigated the potential correlation of architectural patterns including RLC with PTC variants. METHODS: We analysed 225 thyroid FNA cytology cases diagnosed as suspicious for malignancy (SFM) and positive for malignancy (M) over a 1-year time where all samples had corresponding histology. We also included 150 benign lesions from the same period. The presence of RLC vs similar appearing solid clusters, papillary structures and microfollicles were evaluated. We also performed immunocytochemistry and molecular testing for BRAFV600E. RESULTS: We included 100 (44.4%) SFM favouring PTC and 125 (55.6%) M cases with cyto-histological correlation. On histology, all SFM and M cases showed malignancy including 140 (62.2%) classic PTC and 85 (37.8%) PTC variants. The cytomorphological patterns in all FNA samples included solid (74%), papillary (89%), microfollicular (70%), and pseudo-RLC morphology (25.7%). We identified only pseudo-RLC in 33 FNA specimens from PTC variant cases that included tall cell variant (42.4%), hobnail variant (21.2%) and miscellaneous variants (36.3%) of PTC. No definitive RLC were detected in our series. Immunocytochemistry and BRAFV600E were not specifically linked with an RLC pattern. CONCLUSIONS: These findings demonstrate that in our dataset the architectural pattern of RLC was not recognised within PTC variants. However, we did identify a pseudo-RLC pattern that was observed in association with tall cell variant and hobnail variant cases of PTC.

The immunocytochemical expression of VE-1 (BRAF V600E-related) antibody identifies the aggressive variants of papillary thyroid carcinoma on liquid-based cytology.

BACKGROUND: The recently introduced monoclonal V600E antibody (clone VE1) is likely to be an alternative strategy for detecting this mutation in thyroid lesions. Although VE1 immunostaining and molecular methods used to assess papillary thyroid carcinoma in surgical specimens are in good agreement, evaluation of VE1 in cytology and cell block samples is rarely performed, and its diagnostic value in cytology has not been well established. In this study, we sought to determine if VE1 is suitable for fine needle aspiration (FNA) and cell block methods. METHODS: A total of 86 patients who had BRAF V600E mutations were investigated with molecular and immunocytochemical (ICC) analysis in 45 FNA and 41 cell blocks. In total, 83 (96.5%) patients underwent surgical treatment. Assessment of BRAF V600E mutation status was performed in 72 (83.7%) cases. RESULTS: Among the 72 cases analysed, 54 cases agreed (ICC+/BRAF+ or ICC-/BRAF-), seven cases were false positive (ICC+/BRAF-) and 11 cases were false negative (ICC-/BRAF+). False negative cases were not detected in the cell block method. The statistical analysis showed that sensitivity and specificity of ICC for detecting the BRAF V600E mutation were 61% and 77% in FNA samples and 100% and 73% in cell block. CONCLUSION: The use of antibody VE-1 is a reliable method and a negative result of VE1 immunostaining might help to save time and money, restricting the molecular test to antibody-positive cases only. The identification of the aggressive variants of papillary carcinoma might be enabled by the expression of the antibody in neoplastic cells with tall cell features.

Video-Assisted Thyroidectomy for Papillary Thyroid Carcinoma: Oncologic Outcome in Patients with Follow-Up ≥ 10 Years.

BACKGROUND: Video-assisted thyroidectomy (VAT) arisen as a valid treatment for selected patients with papillary thyroid carcinoma (PTC), but no data concerning long-term oncologic outcome are available. The primary aim of the study was to evaluate the oncologic outcome of patients who underwent VAT for PTC with a follow-up ≥ 10 years. METHODS: The medical charts of all the patients who successfully underwent VAT for PTC were reviewed. The patients with a minimum follow-up period of 120-months were included. Patients with unifocal PTC ≤ 1 cm, in the absence of lymph node metastases, without gross extracapsular invasion and age < 45 years were considered "low-risk" patients and followed with ultrasound and serum thyroglobulin (sTg) on levothyroxine (LT4); the remaining patients underwent nuclear medicine evaluation. RESULTS: Two hundred and fifty-seven patients, operated on between May 2000 and October 2006, were included. Postoperative complications included four transient recurrent palsies, 76 transient and 1 permanent hypocalcemia. One hundred and four low-risk patients were followed with ultrasound and sTg on LT4. At a mean follow-up of 136.6 months, mean sTg on LT4 was 0.1 ± 0.1 ng/ml. None of them showed recurrence. The remaining 153 patients underwent nuclear medicine evaluation. Among these 153, 62 did not undergo radioiodine ablation (RAI). At a mean follow-up of 150.8 months, mean sTg on LT4 was 0.1 ± 0.1 ng/ml. None of them showed recurrence. The remaining 91 patients underwent RAI. Mean pre-RAI sTg off-LT4 was 8.3 ± 5.8 ng/ml, mean radioiodine uptake was 2.8 ± 4.4%. Among these 91, three pN1a patients developed a lateral neck node recurrence. No other recurrence was registered. At the latest follow-up mean sTg on LT4 in this subgroup of patients was 0.1 ± 0.2 ng/ml. CONCLUSIONS: The long-term (≥ 10 years) oncologic outcome further demonstrates that VAT is a valid option for selected PTC patients.

Risk Factors for Central Neck Lymph Node Metastases in Micro- Versus Macro- Clinically Node Negative Papillary Thyroid Carcinoma.

BACKGROUND: Tumor size has been advocated as possible risk factors for occult central lymph node metastases (CNM) in papillary thyroid carcinoma (PTC) patients. This prospective study evaluated factors that could identify patients at higher risk of occult CNM, especially comparing micro-PTC and macro-PTC. METHODS: One hundred and eighty-six patients were recruited. All the patients had cN0 clinically unifocal PTC and underwent total thyroidectomy and bilateral prophylactic central neck dissection. Risk factors for occult CNM in micro- and macro-PTC patients were evaluated. RESULTS: Eighty-two patients showed CNM. The rate of CNM did not differ among different sizes cut off (≤20 mm, ≤10 mm, ≤5 mm P = NS). Significantly more pN1a than pN0 patients had pT3 tumors (35/82 vs. 26/104) (P < 0.05), extracapsular invasion (35/82 vs. 22/104) (P < 0.01) and microscopic multifocal disease (50/82 vs. 47/104) (P < 0.05). Independent risk factors for CNM were extracapsular invasion and multifocality at multivariate analysis. Risk factors for CNM in 77 micro-PTC were extracapsular invasion (16/31 pN1 vs. 10/46 pN0, P < 0.05) and multifocality (21/31 pN1 vs. 16/46 pN0, P < 0.01). Among 109 macro-PTC, risk factors for CNM were angioinvasion (15/51 pN1 vs. 7/58 pN0, P < 0.05) and classic PTC at the final histology (PTC vs. tall cell variant vs. follicular variant PTC) (P < 0.05). CONCLUSIONS: Risk factors for CNM can differ between micro- and macro-PTC, but no preoperatively known clinical parameter is predictor of CNM in cN0 clinically unifocal PTC.

Is parathyroidectomy safe and effective in patients with normocalcemic primary hyperparathyroidism?

PURPOSE: Indications and advantages of parathyroidectomy in patients with normocalcemic primary hyperparathyroidism (NHPT) are still matter of debate. We aimed to compare clinical presentation and surgical outcome between normocalcemic and hypercalcemic forms in a consecutive series of patients who underwent parathyroidectomy for primary hyperparathyroidism. METHODS: Data of 731 consecutive patients were reviewed and retrospectively compared according to normocalcemic (group A) and hypercalcemic (group B) phenotypes. RESULTS: No significant differences were found between the two groups concerning demographics and symptomatic onset. Mean preoperative PTH levels were significantly higher in group B (252.0 ± 320.7 pg/ml vs 151.7 ± 112.0; p < 0.001). Mean PTH levels in first postoperative day were significantly lower in group B (30.9 ± 26.2 vs 22.7 ± 20.7; p < 0.001). No significant difference in overall accuracy of preoperative imaging studies was found. Significantly more patients in group A underwent bilateral explorations (83 vs 255; p < 0.05). The rate of multigland disease was significantly higher in group A (13.0 vs 6.8%; p < 0.05). At a mean follow-up period of 72.9 ± 46.8 months, all but three patients, among the 96 of group A who completed follow-up evaluation, were biochemically cured. The remaining patients had persistent high PTH values. Among NHPT patients who had target organ disease before parathyroidectomy, improvement in bone density and in kidney stones was observed in 41.7 and 40.0%, and stability in 50.0 and 60.0% respectively. CONCLUSION: In normocalcemic patients, parathyroidectomy is as safe and effective as in hypercalcemic patients. In the presence of symptoms and/or target organ disease, parathyroidectomy may have a positive effect on the outcome of NHPT patients.

Predictive factors for postoperative morbidity after laparoscopic adrenalectomy for pheochromocytoma: a multicenter retrospective analysis in 225 patients.

BACKGROUND: Since the 1950s, preoperative medical preparation has been widely applied in patients with pheochromocytoma to improve intraoperative hemodynamic instability and postoperative complications. However, advancements in preoperative imaging, laparoscopic surgical techniques, and anesthesia have considerably improved management in patients with pheochromocytoma. In consequence, there is no validated consensus on current predictive factors for postoperative morbidity. The aim of this study was to determine perioperative factors which are predictive for postoperative morbidity in patients undergoing laparoscopic adrenalectomy for pheochromocytoma. STUDY DESIGN: It is a retrospective analysis of prospectively maintained databases in five medical centers from 2002 to 2013. Inclusion criteria were consecutive patients who underwent non-converted laparoscopic unilateral total adrenalectomy for pheochromocytoma. RESULTS: Two-hundred and twenty-five patients were included. All-cause and cardiovascular postoperative morbidity rates were 16% (n = 36) and 4.8% (n = 11), respectively. Preinduction blood pressure normalization after preoperative medical preparation had no impact on postoperative morbidity. However, past medical history of coronary artery disease (OR [CI95%] = 3.39; [1.317-8.727]) and incidence of intraoperative hemodynamic instability episodes (both SBP ≥ 160 mmHg and MAP < 60 mmHg) (OR [CI95%] = 3.092; [1.451-6.587]) remained independent predictors for postoperative all-cause morbidity. Similarly, past medical history of coronary artery disease (OR [CI95%] = 14.41; [3.119-66.57]), female sex (OR [CI95%] = 12.05; [1.807-80.31]), and incidence of intraoperative hemodynamic instability episodes (both SBP ≥ 200 mmHg and MAP < 60 mmHg) (OR [CI95%] = 4.13; [1.009-16.90]) remained independent predictors for postoperative cardiovascular morbidity. CONCLUSIONS: This study identifies risk factors for cardiovascular and all-cause postoperative morbidity after laparoscopic adrenalectomy in current clinical setting. These data can help physicians to guide intra-operative blood pressure management and have to be taken into account in further studies.

What is the appropriate role of minimally invasive vs. open surgery for small adrenocortical cancers?

PURPOSE OF REVIEW: The role of endoscopic adrenalectomy for adrenocortical carcinoma is the most controversial and debated points in adrenal surgery. We reviewed the most recent literature on this topic. RECENT FINDINGS: From the amount of available data (even if not conclusive), the following could be extrapolated: first, for patients with apparently localized disease the adrenal gland should be removed en bloc with the entire retroperitoneal fat pad, which also includes some periadrenal lymph nodes, but no extended resection is necessary in absence of involvement of adjacent structures; second, in experienced centers, oncologic outcome for endoscopic adrenalectomy is not inferior to open adrenalectomy when strict selection criteria and the principles of oncologic surgery are respected. When performed by nonexperienced surgeons, endoscopic adrenalectomy may be associated with a higher rate of positive margin and local recurrence; third, patients observed at specialized referral centers receive a more accurate preoperative workup that allows a better operative planning and a more comprehensive postoperative treatment. SUMMARY: Although waiting for further more exhaustive studies, we think that for suspected adrenocortical carcinoma, smaller than 8-10 cm and without pre or intraoperative evidence of local invasion, endoscopic adrenalectomy in a referral center seems to be an acceptable option.

Ipsilateral Central Neck Dissection Plus Frozen Section Examination Versus Prophylactic Bilateral Central Neck Dissection in cN0 Papillary Thyroid Carcinoma.

BACKGROUND: Ipsilateral central compartment node dissection (IpsiCCD) can reduce the morbidity of prophylactic bilateral central compartment node dissection (BilCCD) in papillary thyroid carcinoma (PTC) but it carries the risk of contralateral metastases being overlooked. Frozen section examination (FSE) of removed ipsilateral nodes has been proposed to intraoperatively assess nodal status. We compared IpsiCCD plus FSE and BilCCD in clinically unifocal and node negative PTC. METHODS: One hundred patients were prospectively assigned to undergo total thyroidectomy (TT) plus BilCCD or TT plus IpsiCCD. In the IpsiCCD group, removed lymph nodes were sent for FSE. If FSE was positive for metastases, a BilCCD was accomplished. RESULTS: The two groups included 50 patients each. Overall, occult lymph node metastases were found in 41 patients-20 in the IpsiCCD group and 21 in the BilCCD group. FSE correctly identified occult node metastases in 13 of 20 pN1a patients in the IpsiCCD group (overall accuracy 86 %). Seven node metastases were not detected at FSE-five were micrometastases (≤2 mm). Six of 13 patients in the IpsiCCD group who underwent BilCCD and 6 of 21 BilCCD pN1a patients had bilateral metastases. More patients in the BilCCD group showed transient hypocalcemia (27/50 vs. 18/50, respectively) [p = NS]. No patient experienced recurrent disease. CONCLUSIONS: FSE of ipsilateral nodes is accurate in determining nodal status, allowing the extension of the central neck clearance to be reliably modulated. Routine IpsiCCD plus FSE of the ipsilateral nodes could be a valid alternative to prophylactic BilCCD since it allows accurate staging and may reduce morbidity.

Is intraoperative calcitonin monitoring useful to modulate the extension of neck dissection in patients with medullary thyroid carcinoma?

BACKGROUND: The extension of the compartment-oriented neck dissection at primary surgery in medullary thyroid carcinoma (MTC) is controversial. Because a <50 % decrease in intraoperative calcitonin levels (IO-CT) after total thyroidectomy plus central neck dissection (TT-CND) has been associated with residual disease, IO-CT monitoring has been proposed to predict the completeness of surgery. The goal of the present prospective study was to verify the accuracy of IO-CT monitoring. METHODS: All patients scheduled for primary surgery for suspected or proven MTC between November 2010 and January 2013 were included. Calcitonin was measured pre-incision (basal level), after tumor manipulation, at the time TT-CND was accomplished (ablation level), 10 and 30 min after ablation. A decrease >50 % with respect to the highest IO-CT level 30 min after ablation was considered predictive of cure. RESULTS: Twenty-six patients were included, and IO-CT monitoring identified 18 of 23 cured patients (true negative results) and 2 of 3 patients with persistent disease (true positive result). In 5 patients with normal basal and stimulated postoperative calcitonin levels, a decrease <50 % was observed (false positive results). In one of three patients with persistent disease a >50 % decrease in IO-CT was observed (false negative results). Specificity, sensitivity, and accuracy of IO-CT were 78.2, 66.6, and 76.9 %, respectively. CONCLUSIONS: Intraoperative calcitonin monitoring is not highly accurate in predicting the completeness of surgical resection. In the present series, relying on IO-CT would result in limited resection in about one third of the patients with residual neck disease and in unnecessary lateral neck dissection in about 20 % of the cured patients.

Synchronous bilateral adrenalectomy for Cushing's syndrome: laparoscopic versus posterior retroperitoneoscopic versus robotic approach.

BACKGROUND: Synchronous endoscopic bilateral adrenalectomy (BilA) can effectively provide definitive cure of hypercortisolism in ACTH-dependent Cushing's syndrome and in primary adrenal bilateral disease. We compared three different approaches for BilA: transabdominal laparoscopic BilA (TL-BilA), simultaneous posterior retroperitoneoscopic BilA (PR-BilA), and robot-assisted BilA (RA-BilA). METHODS: All patients who underwent BilA between January 1999 and December 2012 at two referral centers (one performing TL-BilA and PR-BilA and one performing RA-BilA) were included. A comparative analysis was performed. RESULTS: Twenty-nine patients were included: 5 underwent TL-BilA, 11 underwent PR-BilA, and 13 underwent RA-BilA. No significant difference was found concerning age, gender, diagnosis, and previous abdominal surgery. No conversion to open approach was registered. Operative time was significantly shorter for the PR-BilA group than for the TL-BilA and RA-BilA groups (157.4 ± 54.6 vs 256.0 ± 43.4 vs 221.5 ± 42.2 min, respectively) (P < 0.001). No significant difference was found concerning intraoperative and postoperative complications rate and time to first flatus. Drains were used routinely after PR-BilA and TL-BilA and electively in four RA-BilA patients (P < 0.001). Hospital stay was longer in the TL-BilA and PR-BilA groups than in the RA-BilA group (12.0 ± 5.7 vs 10.8 ± 3.7 vs 4.4 ± 1.7 days, respectively) (P < 0.001). No recurrence or disease-related death was registered. CONCLUSIONS: Operative time was significantly shorter in the PR-BilA group, because it eliminates the need to reposition the patient. The number of drains and the length of hospital stay were reduced after RA-BilA, but this was likely related to different management protocols in different settings. Because no significant difference was found in terms of postoperative outcome, none of the three operative approaches can be considered the preferable one.

Morbidity of central neck dissection: primary surgery vs reoperation. Results of a case-control study.

PURPOSE: Complication rate in reoperative central neck node surgery is one of the main arguments to favor prophylactic central neck dissection at first operation in patients with papillary thyroid carcinoma. We evaluated if reoperative central neck dissection implies an increased postoperative morbidity. Secondarily, we aimed also to verify the effectiveness of the surgical resection of reoperative central neck dissection. METHODS: Forty-one patients who underwent reoperative central neck dissection after initial thyroidectomy for papillary thyroid carcinoma between January 2008 and May 2012 were compared to 41 controls who underwent central neck dissection at initial operation. RESULTS: The two groups were well matched for age, sex, and pN stage (P = 0.296, 0.199, and 1.000, respectively). Three patients had distant metastases at presentation. No significant difference was found concerning mean number of removed nodes (P = 0.064). No significant difference was found between the reoperative and the control groups concerning transient hypocalcemia (17 vs 19, respectively) (P = 0.901) and transient recurrent nerve palsy (2 vs 2) (P = 0.608). Follow-up was completed in 69 out of all the included patients (85.2 %). At a mean follow-up of 33 months, two patients (2.9 %) experienced nodal recurrence. CONCLUSIONS: Morbidity of central neck dissection is similar for primary surgery and reoperation. In high-volume centers, reoperative central neck dissection can be safely accomplished when needed, allowing to achieve locoregional control in most of patients.

Actual incidence and clinical behaviour of follicular thyroid carcinoma: an institutional experience.

Follicular thyroid carcinoma classically accounts for 10-32% of thyroid malignancies. We determined the incidence and the behaviour of follicular thyroid carcinoma in an endemic goitre area. A comparative analysis between minimally invasive and widely invasive follicular thyroid carcinoma was performed. The medical records of all patients who underwent thyroidectomy from October 1998 to April 2012 for thyroid malignancies were reviewed. Those who had a histological diagnosis of follicular carcinoma were included. Among 5203 patients, 130 (2.5%) were included. Distant metastases at presentation were observed in four patients. Sixty-six patients had a minimally invasive follicular carcinoma and 64 a widely invasive follicular carcinoma. In 63 patients an oxyphilic variant was registered. Minimally/widely invasive ratio was 41/26 for usual follicular carcinoma and 25/38 for oxyphilic variant (P < 0.05). Patients with widely invasive tumors had larger tumors (P < 0.001) and more frequently oxyphilic variant (P < 0.05) than those with minimally invasive tumours. No significant difference was found between widely invasive and minimally invasive tumors and between usual follicular carcinoma and oxyphilic variant regarding the recurrence rate (P = NS). The incidence of follicular thyroid carcinoma is much lower than classically retained. Aggressive treatment, including total thyroidectomy and radioiodine ablation, should be proposed to all patients.

Italian Guidelines for the Management of Sporadic Primary Hyperparathyroidism.

AIM: This guideline (GL) is aimed at providing a clinical practice reference for the management of sporadic primary hyperparathyroidism (PHPT) in adults. PHPT management in pregnancy was not considered. METHODS: This GL has been developed following the methods described in the Manual of the Italian National Guideline System. For each question, the panel appointed by Associazione Medici Endocrinology (AME) and Società Italiana dell'Osteoporosi, del Metabolismo Minerale e delle Malattie dello Scheletro (SIOMMMS) identified potentially relevant outcomes, which were then rated for their impact on therapeutic choices. Only outcomes classified as "critical" and "important" were considered in the systematic review of evidence. Those classified as "critical" were considered for the clinical practice recommendations. RESULTS: The present GL provides recommendations about the roles of pharmacological and surgical treatment for the clinical management of sporadic PHPT. Parathyroidectomy is recommended in comparison to surveillance or pharmacologic treatment in any adult (outside of pregnancy) or elderly subject diagnosed with sporadic PHPT who is symptomatic or meets any of the following criteria: • Serum calcium levels >1 mg/dL above the upper limit of normal range. • Urinary calcium levels >4 mg/kg/day. • Osteoporosis disclosed by DXA examination and/or any fragility fracture. • Renal function impairment (eGFR <60 mL/min). • Clinic or silent nephrolithiasis. • Age ≤50 years. Monitoring and treatment of any comorbidity or complication of PHPT at bone, kidney, or cardiovascular level are suggested for patients who do not meet the criteria for surgery or are not operated on for any reason. Sixteen indications for good clinical practice are provided in addition to the recommendations. CONCLUSION: The present GL is directed to endocrinologists and surgeons - working in hospitals, territorial services or private practice - and to general practitioners and patients. The recommendations should also consider the patient's preferences and the available resources and expertise.

Can intraoperative frozen section influence the extension of central neck dissection in cN0 papillary thyroid carcinoma?

PURPOSE: Ipsilateral central compartment node dissection has been proposed to reduce the morbidity of prophylactic bilateral central compartment node dissection in papillary thyroid carcinoma (PTC), but it carries the risk of contralateral metastases being overlooked in approximately 25 % of patients. We aimed to verify if frozen section examination (FSE) can identify patients who could benefit from bilateral central compartment node dissection. METHODS: All the consenting patients with clinically unifocal PTC, without any preoperative evidence of lymph node involvement, observed between September 2010 and September 2011 underwent total thyroidectomy plus bilateral central compartment node dissection. Ipsilateral central compartment nodes were sent for FSE. RESULTS: Forty-eight patients were included. Mean number of removed nodes was 13.2 ± 6.8. Final histology showed lymph node metastases in 21 patients: ipsilateral in 15, bilateral in 6. FSE accurately predicted lymph node status in 43 patients (27 node negative, 16 node positive). Five node metastases were not detected at FSE: three were micrometastases (≤ 2 mm). Sensitivity, specificity and overall accuracy of FSE in definition of N status status were 80.7, 100, and 90 %, respectively. CONCLUSIONS: FSE is accurate in predicting node metastases in clinically unifocal node negative PTC and can be useful in determining the extension of central compartment node dissection. False-negative results are reported mainly in case of micrometastases, which usually have limited clinical implications.

Update regarding the role of PD-L1 in oncocytic thyroid lesions on cytological samples.

AIMS: Several papers have shown that programmed death-ligand 1 (PD-L1) expression is a relevant predictive biomarker in anti-PD-L1 cancer immunotherapy. While its role in several human cancers is correlated with poor prognosis and resistance to anticancer therapies, in thyroid cancers the role of PD-L1 remains questionable. Few articles have studied PD-L1 in thyroid fine-needle aspiration cytology (FNAC), demonstrating a possible correlation with papillary thyroid carcinoma. However, its role in oncocytic thyroid lesions remains controversial. We accordingly examine the performance of PD-L1 immunostaining in liquid based cytology (LBC) from oncocytic lesions. METHODS: From January 2019 to March 2021, 114 thyroid lesions diagnosed by FNAC from lesions with a predominant oncocytic component, were enrolled for evaluation by PD-L1 immunostaining on both LBC and corresponding histology samples. RESULTS: The FNAC cohort included 51 benign (B, negative controls), 4 atypia of undetermined significance/follicular lesions of undetermined significance (AUS/FLUS), 57 follicular lesions (follicular neoplasm/suspicious for FN, FN/SFN) and 2 suspicious for malignancy (SFM) cases. Fifty-four cases (11B, 2 AUS/FLUS, 39 FN/SFN and 2 SFM) had histological follow-up including: 1B case resulted as a hyperplastic oxyphilic nodule in Hashimoto thyroiditis (HT), 10B as goitre, 2 AUS/FLUS cases as oncocytic adenomas (OAs); 39 FN/SFN included 27 OAs, 4 FA and 8 oncocytic follicular carcinoma (OFC). The two SFM cases were diagnosed on histopathology as OAs. Increased plasma membrane and cytoplasmic PD-L1 expression were found in 47 cases of the LBC cases (41.2%). Among the histological series, 67.3% of OAs and 75% of OFC had PD-L1 expression, while negative PD-L1 was found in hyperplastic oncocytic cells in HT. A positivity in more than 30% of the neoplastic cells was found in 72.9% of the cases including six OFC. CONCLUSIONS: These data suggest that PD-L1 expression is expressed in oncocytic thyroid lesions. While weak PD-L1 expression failed to discriminate benign from malignant lesions, OFC demonstrated more intense cytoplasmic and membranous expression.

Updates from Our Institutional Experience with Thyroid Nodules Diagnosed as Metastases.

BACKGROUND: Thyroid metastases (TMs) are a rare entity, ranging between 0 and 24% in the autopsy series. In the assessment of the best management, the discrimination between a primary and a metastatic thyroid lesion is crucial. In this regard, fine needle aspiration cytology (FNAC) is likely to play a crucial role especially when ancillary techniques (i.e., immunocytochemistry (ICC) and molecular testing) are carried out. METHODS: We searched for all the TMs diagnosed using FNAC and analyzed between 2014 and 2023. The cases were processed with liquid-based (LBC) and ICC and molecular testing performed on LBC-stored material. RESULTS: We reported 2.2% (19 cases) of TMs out of 1022 malignancies. TMs included: 1 larynx carcinoma (LX-Ca), 1 melanoma, 2 breast carcinomas (B-Ca), 3 lung carcinomas (LG-Ca), 4 gastro-intestinal carcinomas (GI-Ca), and 8 clear cell renal carcinomas (CCRC). All patients had a previous cancer history, between 300 and 2 months from the primary cancers. The morphological features were supported by ICC, which were contributive in 100% of cases. All TMs cases were characterized by multiple thyroid nodules except the melanoma case. Four cases underwent total thyroidectomy (1 B, 1 LX, 1 melanoma, and 1 CCRC) whilst 15 TMs were treated with radio-chemotherapy. CONCLUSIONS: FNAC empowered the diagnostic workup of patients with TMs avoiding useless surgery. The low sensitivity of cytology might be reinforced by the application of ancillary techniques. We found a predominant rate of kidney metastatic carcinomas, followed by lung and breast. TMs are frequently multifocal and in a context of a systemic disease so a tailored therapy seems to be the best treatment.

Diagnostic role of FNA cytology in the evaluation of cervical lymph nodes in thyroid cancers: Combined evaluation of thyroglobulin in eluate from FNA cytology.

BACKGROUND: The presurgical evaluation of cervical lymph nodes (CLNs) in the management of thyroid malignant lesions is crucial for the extent of surgery or detection of metastases. In these last decades, fine-needle aspiration cytology (FNAC) has been shown to have a central role in the detection of nodal thyroid metastases. It is adopted for the possibility of confirming suspected metastases either in the presurgical phase or in the follow-up of patients after thyroidectomy. However, FNAC from CLNs can be challenging, especially in cystic lesions. In this regard, the combination of FNAC with thyroglobulin measurement in the eluate from FNAC (Tg-FNAC) seems to increase the sensitivity of FNAC in the detection of CLN metastases. The role of FNAC and Tg-FNAC was investigated in this series. METHODS: One hundred fifty-three prospective cytological samples of CLNs were studied along with surgical follow-up in the period between 2020 and 2022. Immunocytochemistry (ICC) was performed on liquid-based cytology-stored material. RESULTS: One hundred fifty-nine enlarged CLNs included 19 central lymph nodes and 140 CLNs. Forty-two thyroidal CLN metastases and 117 reactive lymph nodes were found. Thirty-one CLN dissections were performed in patients with a previous diagnosis of thyroid carcinoma (mostly papillary thyroid carcinoma [PTC]), whereas 128 CLNs with a concomitant suspicious and/or malignant thyroid nodule were found. There was one false-positive case among all the malignant histologically confirmed cases, and two of 117 reactive CLNs (1.7%) had a diagnosis of metastatic PTC. Markedly high Tg-FNAC was found in all metastatic CLNs, including 11 cystic metastatic CLNs detected by Tg-FNAC with a negative FNAC. ICC (including Tg, CK-19, and LCA) recognized nine cases with low Tg-FNAC and scant suspicious thyrocytes. Tg-FNAC plus FNAC diagnosed 94.2% of malignancies. CONCLUSIONS: FNAC represents a valid method for the evaluation of CLNs, especially combined with ICC. Tg-FNAC is an additional method with a useful role in FNAC.

p53 expression in cytology samples may represent a marker of early-stage cancer.

BACKGROUND: TP53 gene plays a major role in the negative control of cell proliferation and in the regulation of signaling cascades. TP53 mutation may have a relevant role in the malignant transformation of thyroid cells as well as thyroid tumor progression. TP53 mutation has been detected only in few well differentiated thyroid carcinomas and is absent in benign conditions. METHODS: A total of 162 prospective thyroid cytology and corresponding histological samples diagnosed from atypia of indeterminate significance (AUS) to malignant, were studied via immunocytochemistry for p53. Hence, 50 benign lesions (B) were used as negative control. Molecular analysis for p53 only was performed. RESULTS: The cytology resulted in 50 B, 48 AUS, 40 follicular neoplasms (FNs), 23 suspicious for malignancy (SFM), and 1 malignant (M) case. The authors reported 102 negative and 60 positive p53 cases. The 60 positive cases included 27 cases with weak and/or focal cytoplasmic positivity (+1) and 33 with cases moderate (2+) to strong (3+) cytoplasmic and/or nuclear expression. Overall, 71 cases had histology (2 B, 11 AUS, 37 FN, 20 SFM, and 1 M) including 61.7% benign and 38.2% malignant diagnoses. Only 16 of 71 (5 FN, 10 SFM, and 1 M) were p53-positive. Furthermore, 100% AUS and 86.5% FN cases were p53-negative, none of which had malignant histology. All p53-positive cases were associated with a larger nodule size, tall-cell variant subtype, multifocality, extra thyroidal infiltration, and nodal metastases. Noninvasive follicular thyroid neoplasm with papillary like nuclear features were negative for p53. Few discrepancies in p53 intensity were observed on histology; there were no differences with the molecular testing. CONCLUSIONS: p53 might be useful in discriminating thyroid follicular lesions. p53 is likely to be a useful diagnostic marker in recognizing indeterminate lesions that are well-differentiated thyroid cancers.

Italian Guidelines for the Management of Non-Functioning Benign and Locally Symptomatic Thyroid Nodules.

AIM: This guideline (GL) is aimed at providing a reference for the management of non-functioning, benign thyroid nodules causing local symptoms in adults outside of pregnancy. METHODS: This GL has been developed following the methods described in the Manual of the National Guideline System. For each question, the panel appointed by Associazione Medici Endocrinology (AME) identified potentially relevant outcomes, which were then rated for their impact on therapeutic choices. Only outcomes classified as "critical" and "important" were considered in the systematic review of evidence and only those classified as "critical" were considered in the formulation of recommendations. RESULTS: The present GL contains recommendations about the respective roles of surgery and minimally invasive treatments for the management of benign symptomatic thyroid nodules. We suggest hemithyroidectomy plus isthmectomy as the first-choice surgical treatment, provided that clinically significant disease is not present in the contralateral thyroid lobe. Total thyroidectomy should be considered for patients with clinically significant disease in the contralateral thyroid lobe. We suggest considering thermo-ablation as an alternative option to surgery for patients with a symptomatic, solid, benign, single, or dominant thyroid nodule. These recommendations apply to outpatients, either in primary care or when referred to specialists. CONCLUSION: The present GL is directed to endocrinologists, surgeons, and interventional radiologists working in hospitals, in territorial services, or private practice, general practitioners, and patients. The available data suggest that the implementation of this GL recommendations will result in the progressive reduction of surgical procedures for benign thyroid nodular disease, with a decreased number of admissions to surgical departments for non-malignant conditions and more rapid access to patients with thyroid cancer. Importantly, a reduction of indirect costs due to long-term replacement therapy and the management of surgical complications may also be speculated.