Victor Bernet

Clinical and molecular features of Hürthle cell carcinoma of the thyroid

CONTEXT Hürthle cell cancer (HCC) of the thyroid remains the subject of controversy with respect to natural course, treatment, and follow-up. OBJECTIVE The objective of the study was to evaluate the clinical and molecular features associated with outcome in HCC. DESIGN The study was a review of 173 HCC cases treated at Mayo Clinic over 11 years with a median 5.8-year follow-up. RESULTS None of the patients with minimally invasive histology had persistent disease, clinical recurrence, or disease-related death. Male gender and TNM stage were independently associated with increased risk of clinical recurrence or death in widely invasive patients. The 5-year cumulative probability of clinical recurrence or death was higher in patients with TNM stage III-IV (females, 74%; males, 91%) compared with patients with TNM stage I-II (females, 0%; males, 17%). Pulmonary metastases were best identified by computed tomography, whereas radioactive iodine scans were positive in only two of 27 cases. Thyroglobulin was detectable in patients with clinical disease, with the notable exception of five patients with distant metastases. The common TERT C228T promoter mutation was detected in both widely invasive and minimally invasive tumors. TERT mRNA was below the limit of detection in all samples. CONCLUSION Widely invasive HCC with TNM stage III-IV is aggressive, with low probability of recurrence-free survival. Males have worse outcomes than females. Minimally invasive HCC appears to be considerably less aggressive. Radioactive iodine scan performs poorly in detecting distant disease. Although the TERT gene is mutated in HCC, the role of this mutation remains to be demonstrated.

Management of recurrent and persistent metastatic lymph nodes in well-differentiated thyroid cancer: A multifactorial decision-making guide for the thyroid cancer care collaborative

Well‐differentiated thyroid cancer (WDTC) recurs in up to 30% of patients. Guidelines from the American Thyroid Association (ATA) and the National Comprehensive Cancer Network (NCCN) provide valuable parameters for the management of recurrent disease, but fail to guide the clinician as to the multitude of factors that should be taken into account. The Thyroid Cancer Care Collaborative (TCCC) is a web‐based repository of a patients clinical information. Ten clinical decision‐making modules (CDMMs) process this information and display individualized treatment recommendations.

American Thyroid Association Statement on Remote-Access Thyroid Surgery

BACKGROUND Remote-access techniques have been described over the recent years as a method of removing the thyroid gland without an incision in the neck. However, there is confusion related to the number of techniques available and the ideal patient selection criteria for a given technique. The aims of this review were to develop a simple classification of these approaches, describe the optimal patient selection criteria, evaluate the outcomes objectively, and define the barriers to adoption. METHODS A review of the literature was performed to identify the described techniques. A simple classification was developed. Technical details, outcomes, and the learning curve were described. Expert opinion consensus was formulated regarding recommendations for patient selection and performance of remote-access thyroid surgery. RESULTS Remote-access thyroid procedures can be categorized into endoscopic or robotic breast, bilateral axillo-breast, axillary, and facelift approaches. The experience in the United States involves the latter two techniques. The limited data in the literature suggest long operative times, a steep learning curve, and higher costs with remote-access thyroid surgery compared with conventional thyroidectomy. Nevertheless, a consensus was reached that, in appropriate hands, it can be a viable option for patients with unilateral small nodules who wish to avoid a neck incision. CONCLUSIONS Remote-access thyroidectomy has a role in a small group of patients who fit strict selection criteria. These approaches require an additional level of expertise, and therefore should be done by surgeons performing a high volume of thyroid and robotic surgery.

ACTIVE SURVEILLANCE FOR PAPILLARY THYROID MICROCARCINOMA: NEW CHALLENGES AND OPPORTUNITIES FOR THE HEALTH CARE SYSTEM.

OBJECTIVE The dramatic increase in papillary thyroid carcinoma (PTC) is primarily a result of early diagnosis of small cancers. Active surveillance is a promising management strategy for papillary thyroid microcarcinomas (PTMCs). However, as this management strategy gains traction in the U.S., it is imperative that patients and clinicians be properly educated, patients be followed for life, and appropriate tools be identified to implement the strategy. METHODS We review previous active surveillance studies and the parameters used to identify patients who are good candidates for active surveillance. We also review some of the challenges to implementing active surveillance protocols in the U.S. and discuss how these might be addressed. RESULTS Trials of active surveillance support nonsurgical management as a viable and safe management strategy. However, numerous challenges exist, including the need for adherence to protocols, education of patients and physicians, and awareness of the impact of this strategy on patient psychology and quality of life. The Thyroid Cancer Care Collaborative (TCCC) is a portable record keeping system that can manage a mobile patient population undergoing active surveillance. CONCLUSION With proper patient selection, organization, and patient support, active surveillance has the potential to be a long-term management strategy for select patients with PTMC. In order to address the challenges and opportunities for this approach to be successfully implemented in the U.S., it will be necessary to consider psychological and quality of life, cultural differences, and the patients clinical status.

New therapeutic options for advanced forms of thyroid cancer

Introduction: While the vast majority of patients with thyroid cancer have an excellent prognosis, those with more aggressive courses experience significant morbidity and mortality. Advanced forms of thyroid cancer are typically refractory to standard therapy. Numerous agents with potential usefulness in the treatment of advanced thyroid cancer have recently come under study. Areas covered: This article reviews agents identified through a systematic review of the scientific literature as being under investigation for treatment of advanced thyroid cancer. A search of both PubMed and the NCI Clinical Trials website was performed to identify such agents having reached Phase II or III testing. Improved understanding of cancer cell signaling pathways has led to the identification of > 500 kinases as potential therapeutic targets. Additional agents of interest include those that inhibit neoangiogenesis, alter epigenetic factors or stimulate antitumor immune reactions. While presently available agents have shown promise in improving progression-free survival (PFS), complete responses are not seen and significant adverse side effects are encountered. Expert opinion: The development of numerous new anticancer agents holds the promise of treatment regimens that will extend PFS and ultimately overall survival in patients with advanced thyroid cancer. Anticipated future developments include individualized, multimodal treatment regimens based on specific tumor cell biology and driver mutations.

Database and registry research in thyroid cancer: Striving for a new and improved national thyroid cancer database

BACKGROUND Health registries have become extremely powerful tools for cancer research. Unfortunately, certain details and the ability to adapt to new information are necessarily limited in current registries, and they cannot address many controversial issues in cancer management. This is of particular concern in differentiated thyroid cancer, which is rapidly increasing in incidence and has many unknowns related to optimal treatment and surveillance recommendations. SUMMARY In this study, we review different types of health registries used in cancer research in the United States, with a focus on their advantages and disadvantages as related to the study of thyroid cancer. This analysis includes population-based cancer registries, health systems-based cancer registries, and patient-based disease registries. It is important that clinicians understand the way data are collected in, as well as the composition of, these different registries in order to more critically interpret the clinical research that is conducted using that data. In an attempt to address shortcoming of current databases for thyroid cancer, we present the potential of an innovative web-based disease management tool for thyroid cancer called the Thyroid Cancer Care Collaborative (TCCC) to become a patient-based registry that can be used to evaluate and improve the quality of care delivered to patients with thyroid cancer as well as to answer questions that we have not been able to address with current databases and registries. CONCLUSION A cancer registry that follows a specific patient, is integrated into physician workflow, and collects data across different treatment sites and different payers does not exist in the current fragmented system of healthcare in the United States. The TCCC offers physicians who treat thyroid cancer numerous time-saving and quality improvement services, and could significantly improve patient care. With rapid adoption across the nation, the TCCC could become a new paradigm for database research in thyroid cancer to improve our understanding of thyroid cancer management.

Reversible renal insufficiency attributable to thyroid hormone withdrawal in a patient with type 2 diabetes mellitus.

OBJECTIVE To present a case of papillary thyroid carcinoma and the need for follow-up surveillance in a patient with type 2 diabetes mellitus who was being treated with metformin. METHODS The clinical and laboratory findings are summarized, and results of whole-body scanning are described. A discussion addresses the importance of monitoring renal function during thyroid hormone withdrawal for scintigraphic imaging with use of radioactive iodine. RESULTS A 60-year-old man with type 2 diabetes was diagnosed with metastatic papillary thyroid carcinoma, and renal insufficiency developed during withdrawal from thyroid hormone for surveillance 131 I whole-body scanning. An increase in thyroglobulin attributable to recombinant human thyrotropin stimulation led to detection of persistent cancer, and thyroid hormone withdrawal was begun in preparation for further 131 I treatment. Pretherapy laboratory results revealed a thyrotropin level of 46.1 mIU/mL, a thyroglobulin level of 13.7 ng/mL, and an increased serum creatinine (Cr) concentration from a baseline of 0.9 mg/dL to 1.9 mg/dL while the creatinine clearance (CrCl) was 67 mL/min. Therapy with metformin was immediately discontinued. On the basis of results from 131 I whole-body dosimetry, the patient was treated with 250 mCi of 131 I. Levothyroxine therapy was resumed approximately 72 hours after 131 I therapy, and blood tests 2 weeks thereafter revealed a Cr of 1.1 mg/dL and a CrCl of 105 mL/min. The metformin treatment was then reinitiated without any complications. CONCLUSION Patients with hypothyroidism can have up to a 20 to 30% decrease in glomerular filtration rate, which tends to resolve when euthyroidism is achieved. In patients with diabetes taking metformin who have hypothyroidism for any reason including thyroid hormone withdrawal, serum Cr levels should be monitored until thyroid hormone levels normalize. Metformin therapy should be discontinued in patients with significant renal impairment, defined as either a serum Cr level of 1.5 mg/dL or more in men and 1.4 mg/dL or more in women or a CrCl of less than 60 mL/min.

Thyroid Function and Exercise

Thyroid hormone receptors are present in virtually every tissue in the body, thereby permitting an important physiologic role for the two thyroid hormones, thyroxine (T4) and triiodothyronine (T3). Skeletal and cardiac muscle function, pulmonary performance, metabolism, and the neurophysiologic axis are only a few of the important areas that are affected by thyroid hormone levels (1). Any abnormality in thyroid function causing either an excess or deficiency in circulating thyroid hormone levels can lead to changes in body function at rest and during exercise. The presence of thyroid disease can have a major impact on exercise tolerance resulting in reduced performance of strenuous activities. On the other hand, exercise itself may have direct or indirect effects on thyroid function, either secondary to acute alterations in the integrity of the pituitary—thyroid axis or to the more long-lasting changes noted in well-trained athletes to be discussed below. Alterations in thyroid function in well-trained athletes might be viewed as an adaptive mechanism associated with enhanced performance possibly serving to provide a better balance between energy consumption and expenditure. Underlying energy balance does appear to play an important role in the effects exercise may have on the pituitary and thyroid axis. Reports in the literature indicate that athletes with excessive weight loss may exhibit a “low T3 syndrome” accompanied by amenorrhea (in women) as well as other alterations in pituitary function (2). Fortunately, thyroid diseases usually can be treated effectively, and most individuals with thyroid disorders should expect to obtain resolution of their thyroid-related symptoms, including those associated with a negative impact on their exercise tolerance. Gail Devers, who has been very public about her experience with Graves’ disease, is a well-known sprinter who went on to win Olympic fame following treatment for her Graves’ disease and may act as a case in point.

Practice Trends in Patients with Persistent Detectable Thyroglobulin and Negative Diagnostic Radioiodine Whole Body Scans: A Survey of American Thyroid Association Members

BACKGROUND Management of patients with thyroglobulin (Tg)-positive/scan-negative thyroid cancer remains challenging. American Thyroid Association (ATA) guidelines recommend potential use of empiric (131)I therapy and various scanning modalities, but no standard for managing such cases exists. METHODS We surveyed ATA members to assess current practice in management of patients with Tg-positive/scan-negative disease. Members participated in a web-based survey of six case scenarios of Tg elevations but iodine scan negativity. RESULTS A total of 288 ATA members (80% male) participated. Patient age, sex, and basal and stimulated Tg varied between the cases. Respondents were asked their opinion regarding empiric (131)I therapy use, including (131)I dose, use and duration of low-iodine diet, thyroxine withdrawal or recombinant human thyrotropin (rhTSH), and utilization of additional imaging (neck ultrasound (US) or positron emission tomography/computed tomography (PET/CT)) and reconsideration of (131)I therapy. Between 16% and 51% recommended initial use of empiric (131)I for the various scenarios. The majority chose a (131)I dose between 75 and 150 mCi, and 73% employed a low-iodine diet for two or more weeks. Preference between thyroxine withdrawal versus rhTSH was evenly split. More than 98% obtained a neck US if empiric (131)I was not given; 52-89% would proceed to PET/CT if US was negative. Only 44% used rhTSH stimulation in PET scan preparation. (131)I use was more common with stimulated Tg significantly >10 ng/mL. (131)I therapy was slightly more likely with PET-positive (56%) than PET-negative status (45%). Respondents were split regarding empiric (131)I if basal and stimulated Tg increased ≥150% over two years. Providers in North America less commonly utilized (131)I treatment than those from other areas. In the face of possible heterophilic antibody interference in the Tg assay, the majority did not recommend (131)I therapy. CONCLUSIONS Empiric (131)I therapy is still utilized for patients with Tg-positive/scan-negative disease. Neck US is frequently used to further evaluate such cases as (18)FDG-PET/CT, albeit the latter is used somewhat less often. Use of (131)I therapy correlated with the degree of Tg elevation or development of Tg antibodies, and was recommended more commonly with PET-positive than PET-negative status in patients with lower Tg levels. (131)I was less commonly used by providers within North America.

Improving the adoption of thyroid cancer clinical practice guidelines

To present an overview of the barriers to the implementation of clinical practice guidelines (CPGs) in thyroid cancer management and to introduce a computer‐based clinical support system.