The Synergistic Impact of Combining Mutational Markers and Sonographic Features in Triaging Patients with Single Indeterminate Thyroid Nodules to Appropriate Surgery. A Prospective Study

Background. Despite the many advances in the field of nodular thyroid disease and cytopathology reporting, fine needle aspiration cytology fails to establish a reliable diagnosis in 20-30% of cases. These nodules are labeled as cytologically indeterminate for malignancy. The term indeterminate collectively applies to nodules reported as Bethesda categories III, IV, and V. Such labeling is an eyesore to health care providers as it places their patients at risk of sub-optimal therapeutic decisions. This particularly applies to Bethesda category IV whose implied risk of malignancy falls in the gray zone between those of Bethesda categories III and V. Therefore, it can neither be considered low enough for a thyroid lobectomy to become custom, nor high enough to warrant a total thyroidectomy. An additional concern is related to benignity being the most common outcome in this subset of patients. This implies that these patients are at risk of being subjected to an unnecessary and potentially morbid thyroid lobectomy. This last concern is particularly prominent in centers around the world that customarily select patients with Bethesda IV nodules for a thyroid lobectomy. At a national level, in centers around Italy, things are quite different. Most patients with Bethesda IV nodules (equivalent to TIR 3b according to the Società Italiana di Anatomia Patologica e Citopatologia Diagnostica/ International Academy of Pathology, Italian Division/ SIAPEC-IAP) are selected for a total thyroidectomy. A procedure that could be correctly labeled as “overly radical” for this subset of patients. This study aims to tackle this nation-wide issue: the near routine selection of patients with TIR 3b/ Bethesda IV nodules for a total thyroidectomy. This is best done by developing, validating and popularizing a tool that could accurately prevent unbeneficial total thyroidectomies and at the same time be readily available, easy to assemble, and cost-effective. This rule-out tool was first developed and published by the author and his colleagues in a previous retrospective study. The tool was assembled by combining negativity for suspicious gray-scale US features, and negativity for the genetic mutations commonly encountered in differentiated thyroid cancer (namely BRAF and NRAS). The gray-scale US features selected included: irregular margins, a taller-than-wide orientation, and the presence of microcalcifications, and was based on a recently published meta-analysis in the literature. The rule-out tool, abbreviated by the authors as: (US-/ Mutation-), demonstrated high predictivity for lesions that do not require a total thyroidectomy. Its predictivity of lesions for which a thyroid lobectomy is considered sufficient therapy was 94%. The current study intends on prospectively validating the efficacy of the rule-out tool in the preoperative setting in triaging patients with Bethesda IV nodules to a lobectomy instead of a total thyroidectomy. Furthermore, demonstrate the synergism between the two components used to assemble it. Methods. Between Jan. 2016 and Jan. 2018, 200 consecutive patients presented to an academic tertiary referral center with solitary thyroid nodules lacking all suspicious sonographic features set by the authors, and labeled as suspicious for a follicular neoplasm (Bethesda category IV) following FNAC. According to the authors’ published experience three grey-scale ultrasound (US) features in single or in combination are of sufficient clinical significance to label a thyroid nodule as suspicious for malignancy. These include: irregular margins, the presence of microcalcification, and a taller-than-wide configuration. The clinical significance of these US features has also been confirmed in a recent meta-analysis in the literature. Total thyroidectomy was justifiable in 33 out of the 200 patients for one the following reasons: hypothyroidism/ a background of Hashimoto’s thyroiditis (n=30), a positive family history for thyroid cancer (n=2), or a history of radiation exposure (n=1). These cases were excluded from the study, and the remaining 167 cytology smears were analyzed for NRAS and BRAF. Only 10 were positive for a mutational marker: BRAF V600E (n=1), BRAF K601E (n=1), and NRAS (n=8). Out of these mutation-positive lesions 8 were malignant, and according to the American Thyroid Association (ATA) risk stratification, six of these were high-risk and required a total thyroidectomy as a minimum surgical treatment. Ultimately 157 patients defined the authors’ study cohort and were all subjected to a thyroid lobectomy. The rule-out tool put to test in this study consisted of two components: 1. Negativity for suspicious US features and 2. Negativity for mutational markers. It was abbreviated by the authors as: (US-/ Mutation-). Its diagnostic accuracy was assessed by calculating its negative predictive value (NPV) for both malignancy and malignancy requiring a total thyroidectomy. In other words, it was evaluated for its ability to preclude total thyroidectomy as the therapeutic modality required. Whether or not mutational marker negativity imparted an additional clinical benefit (i.e. a synergistic impact) as part of this “rule-out tool” was also evaluated. This was done by calculating the NPV of US negativity but mutational positivity (US-/mutation+) for both malignancy and malignancy requiring a total thyroidectomy and comparing it to those of (US-/mutation-). Results. The 157-patient study cohort included 27 males and 130 females, with a male to female ratio of 1:5. The average age was 44 years (range: 14-75 years), and the mean nodule size was 34 mm (20-66 mm). Following lobectomy, permanent pathology revealed 140 benign lesions and 17 malignant ones. Malignancies included: the FVPTC (n=12), classical PTC (n=2), FTC (n= 2), and tall-cell PTC (n=1). Out of the 17 malignant lesions, 8 (47%) demonstrated one or more ATA high-risk features that warranted a completion thyroidectomy. From the results obtained, the NPV of (US-/mutation-) for malignancy was 89% (140/157). This increased to 95% (149/157) for malignancy requiring a total thyroidectomy. This implies a 95% diagnostic accuracy in refuting a total thyroidectomy in this subset of patients. The synergistic impact that mutational marker negativity imparted as an essential component of the tool was assessed by calculating the NPV of US negativity but mutational positivity (US-/mutation+) for both malignancy and malignancy requiring a total thyroidectomy and comparing it to those of (US-/mutation-). The NPV of (US-/mutation+) for malignancy was 20% (2/10), and 40% (4/10) for malignancy requiring total thyroidectomy. The differences were statistically significant: [NPV for malignancy: 89% vs. 20%; p < 0.0001, and NPV for malignancy requiring total thyroidectomy: 95% s. 40%; p < 0.0001]. Conclusion. The combination of (US-/mutation-) is a valid and reliable rule-out tool with sufficient pre-operative diagnostic accuracy to spare patients with Bethesda IV nodules an overly radical total thyroidectomy

Posterior retroperitonoscopic adrenalectomy; a back door access with an unusually rapid learning curve

Posterior retroperitonoscopic adrenalectomy (PRA) has become a standard approach to the adrenal gland. The aim of this study was to report an initial experience with the procedure following a proper preparatory phase highlighting the rapidity, safety and effectiveness by which it could be introduced into a surgeon's practice. Between May 2015 and July 2016, 14 PRAs were performed in 14 patients (9 females and 5 males). The average age was 46 years, BMI: 25.5 kg/m(2), and ASA score: 2. Indications included: incidenatloma (n = 5), Conn's adenoma (n = 5), and Cushing's adenoma (n = 4). Lesions were on average 3.3 cm in size. Outcomes of interest included: operative time (OT), conversion rate, postoperative morbidity and mortality rates, and the length of hospital stay. Mean OT was 87.5 min (range 35-150 min). A significant reduction in OT occurred after the sixth procedure and was progressive thereafter. After the tenth case, the OT became less than 1 h. No conversion was required. No intra- or post-operative complications occurred, and mortality was zero. All patients commenced oral intake and ambulated following full recovery from anesthesia. The mean length of hospital stay was 3 days (range 2-6 days). PRA offers a direct access to the adrenal gland allowing for target-oriented dissection. Cognitive reorientation to the anatomy of this back door access and an adequate learning curve could be rapidly achieved by experienced and properly prepared laparoscopic surgeons. Keyword

The extent of surgery in thyroglossal cyst carcinoma

Purpose: The optimal management of thyroglossal cyst carcinoma, particularly the extent of surgery required is controversial. The aim of this study was to evaluate the need for routinely adding total thyroidectomy to Sistrunk’s operation in the management of this condition. Methods: The clinical records of 19 patients with a diagnosis of thyroglossal cyst carcinoma encountered in an 11-year period (2004–2015) were reviewed. All patients underwent total thyroidectomy in addition to Sistrunk’s procedure. The rate of concomitant thyroglossal cyst and thyroid carcinomas was calculated and cancers were staged according to the AJCC-TNM staging system. Patients were divided into two groups: those with thyroglossal cyst carcinoma only (group A) and those with a synchronous or metachronous thyroid carcinoma as well (group B). The need for radioactive iodine ablation in group A was assessed. The ability to omit total thyroidectomy based on thyroglossal cancer size and a negative thyroid ultrasound was also evaluated. Results: The rate of concomitant thyroid cancer was 63.2 % (12/19). Based on stage, three out of the seven patients in group A required radioactive iodine ablation. Total thyroidectomy was ultimately justifiable in 78.9 % (15/19) of cases. Omitting total thyroidectomy in T1 thyroglossal cyst cancers or based on a sonographically normal thyroid was associated with a 43 % risk of missing thyroid malignancy. Conclusion: The routine addition of total thyroidectomy to Sistrunk’s procedure seems to be appropriate for comprehensive loco-regional control especially that selecting a subset of patients in which it could be omitted is a difficult task

Track Recurrence after Robotic Transaxillary Thyroidectomy: A Case Report Highlighting the Importance of Controlled Surgical Indications and Addressing Unprecedented Complications

Background: Robot-assisted transaxillary thyroid surgery (RATS), widely accepted and used in Asian countries, can be an appealing treatment option both for patients with major concerns regarding a cervical scar and for their surgeons. Patients benefit from scarless neck surgery, while their surgeons benefit from improved dexterity and ergonomics compared with remote-access endoscopic thyroid surgery. However, validating any novel surgical procedure for thyroid pathology should be based on evidence regarding its feasibility, radicality, and safety compared to the time-honored, safe and effective, conventional open thyroidectomy. It should also be evaluated for potential risks that are not present with conventional approaches. Patient findings: This study reports a patient with surgical track and cervical nodal recurrence, and distant metastasis following a two-stage robot-assisted surgery, and radioactive iodine ablation therapy for a papillary thyroid carcinoma that was initially regarded a single indeterminate nodule. Summary: This case emphasizes the importance of thoroughly evaluating the oncological safety of RATS, and points out the possibility of "malignant seeding along the surgical access" being an untraditional potential complication associated with the procedure. Conclusions: While tailoring the surgical strategy to the patients' concerns and desires is important, adhering to fundamental onco-surgical principles is a priority. Furthermore, unconventional complications associated with novel surgical procedures should be properly evaluated and addressed

BRAF(K601E) Mutation in a Follicular Thyroid Adenoma

BRAF mutations represent the most common genetic alteration in papillary thyroid carcinoma (PTC). The p.V600E mutation is specific for the classic and tall-cell variants of PTC and has been associated with a more aggressive biologic behavior. On the other hand, the p.K601E mutation is peculiar to the follicular variant of PTC, and seems to be a favorable prognostic indicator. A 12-year-old boy presented with a 10-mm left-sided thyroid nodule. Fine-needle aspiration cytology reported the lesion as suspicious for a follicular neoplasm (Bethesda category IV). The patient underwent lobectomy, and histopathology revealed a follicular adenoma with normal surrounding tissue. The cytological smear was found to be positive for BRAF p.K601E mutation, and this was later confirmed on the corresponding paraffin block. This case was independently revised by 4 expert pathologists, all of whom confirmed the benign nature of the thyroid lesion. This article describes the presence of a BRAF mutation in a benign thyroid lesion. To the authors' knowledge, this is the fourth case of follicular adenoma carrying BRAF(K601E) reported in literature to date. BRAF(K601E) mutation can occur in benign thyroid lesions. This finding, in the context of the current literature and the recently proposed reclassification of the noninvasive encapsulated follicular variant of papillary thyroid carcinoma into a benign lesion, confirms the importance of preoperative BRAF p.K601E testing in offering patients a tailored treatment plan and avoiding overtreatment

Minimally invasive video-assisted thyroidectomy (MIVAT) from A to Z

A minimal access procedure does not necessarily mean that it is minimally invasive. However, as its name implies, MIVAT is a truly minimally invasive treatment modality. The advantages it offers over its conventional counterpart are indeed related to its minimally invasive nature. Furthermore, this nature has not compromised its ability to accomplish its purpose both safely and effectively. Ever since its introduction in the late 1990s, MIVAT has been progressively evolving. The indications for this procedure, which was initially surrounded by skepticism, have been expanding. Benign thyroid pathology is now considered only one of its indications among others. This article provides a detailed description of this minimally invasive, maximally effective and patient satisfying procedure so that it may be adopted by more surgeons around the globe for better patient care and to also encourage the development of further future advancements

Indeterminate Single Thyroid Nodule: Synergistic Impact of Mutational Markers and Sonographic Features in Triaging Patients to Appropriate Surgery.

background : Patients labeled as having indeterminate thyroid nodular disease following fine-needle aspiration cytology are at risk of non-optimal initial surgery: an overly radical total thyroidectomy, or an unnecessary two-stage operation. The objective of this study was to assess the impact of combining mutational markers and ultrasonographic (US) features preoperatively on predicting the risk of malignancy in patients with indeterminate nodules, thereby offering them a tailored initial surgical intervention. METHODS: The records of 258 patients who underwent conventional total thyroidectomy for single nodules reported as suspicious for a follicular neoplasm (Bethesda category IV) in a four-year period were reviewed. Main issues addressed included: certain US findings (individually and in combination), mutational markers (BRAF and NRAS), and combinations of both. Correlation of these with malignancy was assessed, as was their ability to predict malignancy. The usefulness of combining the absence of suspicious sonographic features and the absence of mutational markers was also evaluated. RESULTS: Among the 258 patients with an indeterminate diagnosis, only 90 lesions were found to be malignant. The sonographic features that correlated significantly with malignancy were irregular margins, microcalcifications, and a "taller than wide" shape. The presence of irregular margins was the feature with the highest positive predictive value. Combinations of two or more features were always associated with predictivity in excess of 90%, and at times at 100%. NRAS mutation was the most common gene alteration. Both BRAF and NRAS mutations were mutually exclusive and correlated significantly with malignancy. Their predictivity of malignancy was high, particularly when combined with suspicious sonographic features (100%). The major limitation of both suspicious sonographic features and/or mutational markers was their low occurrence in malignancy. The absence of both mutational markers and suspicious sonographic features proved extremely useful in tailoring surgical strategy, as it could have ultimately spared 143/258 patients (55%) an overly radical thyroidectomy. CONCLUSION: The preoperative utility of mutational markers and sonographic features in combination has a synergistic impact. It can predict the risk of malignancy with high accuracy, properly triaging patients to appropriate surger