Management of Medullary Thyroid Cancer: Patterns of Recurrence and Outcomes of Reoperative Surgery.

BACKGROUND: There remains uncertainty regarding the optimal extent of initial surgery and management of recurrent disease in medullary thyroid cancer (MTC). We aim to describe the patterns of disease recurrence and outcomes of the reoperative surgery in a cohort of consecutively treated patients at a specialized tertiary referral center. PATIENTS AND METHODS: A retrospective cohort study of 235 surgically treated patients with MTC at a tertiary referral center was performed using prospectively collected data. RESULTS: In the study period 1986-2022, 235 patients underwent surgery for MTC. Of these, 45 (19%) patients had reoperative surgery for cervical nodal recurrence at a median (range) 2.1 (0.3-16) years following the index procedure. After a median follow-up of 4 years, 38 (84%) patients remain free of structural cervical recurrence, although 15 (33%) underwent 2 or more reoperative procedures. No long-term complications occurred after reoperative surgery. Local cervical recurrence was independently predicted by pathologically involved nodal status (OR 5.10, P = .01) and failure to achieve biochemical cure (OR 5.0, P = .009). Local recurrence did not adversely affect overall survival and was not associated with distant recurrence (HR 0.93, P = .83). Overall survival was independently predicted by high pathological grade (HR 10.0, P = .002) and the presence of metastatic disease at presentation (HR 8.27, P = 0018). CONCLUSION: Loco-regional recurrence in MTC does not impact overall survival, or the development of metastatic disease, demonstrating the safety of the staged approach to the clinically node-negative lateral neck. When recurrent disease is technically resectable, reoperative surgery can be undertaken with minimal morbidity in a specialized center and facilitates structural disease control.

Lobectomy and completion thyroidectomy rates increase after the 2015 American Thyroid Association Differentiated Thyroid Cancer Guidelines update.

Background: The 2015 American Thyroid Association (ATA) Guidelines permit thyroid lobectomy (TL) or total thyroidectomy in the management of low-risk papillary thyroid cancer (PTC). As definitive risk-stratification is only possible post-operatively, some patients may require completion thyroidectomy (CT) after final histopathological analysis. Methods: A retrospective cohort study of patients undergoing surgery for low-risk PTC in a tertiary referral centre was undertaken. Consecutive adult patients treated from January 2013 to March 2021 were divided into two groups (pre- and post-publication of ATA Guidelines on 01/01/2016). Only those eligible for lobectomy under rule 35(B) of the ATA Guidelines were included: Bethesda V/VI cytology, 1-4 cm post-operative size and without pre-operative evidence of extrathyroidal extension or nodal metastases. We examined rates of TL, CT, local recurrence and surgical complications. Results: There were 1488 primary surgical procedures performed for PTC on consecutive adult patients during the study period, of which 461 were eligible for TL. Mean tumour size (P = 0.20) and mean age (P = 0.78) were similar between time periods. The TL rate increased significantly from 4.5 to 18% in the post-publication period (P < 0.001). The proportion of TL patients requiring CT (43 vs 38%) was similar between groups (P = 1.0). There was no significant change in complications (P = 0.55) or local recurrence rates (P = 0.24). Conclusion: The introduction of the 2015 ATA Guidelines resulted in a modest but significant increase in the rate of lobectomy for eligible PTC patients. In the post-publication period, 38% of patients who underwent TL ultimately required CT after complete pathological analysis.

A Retrospective Cohort Study with Validation of Predictors of Differentiated Thyroid Cancer Outcomes.

Background: The goal of radioactive iodine (RAI) in differentiated thyroid cancer (DTC) is to treat metastasis and reduce recurrence risk. International guidelines provide broad risk stratification to aid treatment decisions, but a more nuanced approach to individualize care is warranted. We developed a predictive risk model for DTC. Methods: We performed a retrospective multivariable analysis of 899 patients who received RAI after thyroidectomy at a quaternary center in Australia between 2008 and 2016. Collected data included age, gender, histology, stimulated thyroglobulin (sTg), and 8th American Joint Committee Cancer (AJCC) staging. The ATA Modified Initial Risk (ATA) was calculated retrospectively. Recurrence was defined as clinically significant progression requiring either surgical intervention or administration of a second activity of RAI. Synchronous metastasis was defined as distant metastasis (i.e., outside of the neck) that was present at the time of diagnosis on structural imaging or initial post-iodine treatment scan. The features significantly associated with synchronous metastasis or recurrence were employed in the generation of a predictive risk model. A separate cohort of 393 patients who received RAI in 2017-2021 was used for validation. Results: On multivariate analysis, sTg ≥10 µg/L, extrathyroidal extension (ETE) and lymph node involvement predicted recurrence. Independent of ATA, patients with sTg ≥10 µg/L had a shorter disease-free survival (DFS) than those with sTg <10 µg/L (p < 0.001). The ETE stratified by four histological categories was significantly associated with worse DFS (p < 0.001). In a subset of patients, the presence of thyroglobulin antibody (TgAb) did not influence recurrence in patients with sTg <10 µg/L. On multivariate analysis, widespread ETE, sTg ≥10 µg/L, multifocal papillary thyroid cancer and follicular thyroid cancer were positively associated with synchronous metastasis. A predictive risk model was developed to estimate synchronous metastasis/recurrence risk and validated successfully in the second cohort. Conclusions: Our novel predictive risk model modifies and extends ATA stratification by including sTg and ETE, which we found to be independent predictors of both recurrence and synchronous metastasis in DTC.

Life-threatening diarrhea in neuroendocrine tumors: two case reports.

BACKGROUND: Neuroendocrine tumors are rare, heterogeneous neoplasms that produce a wide variety of clinical symptoms. Diarrhea in neuroendocrine tumors is incredibly common and is usually benign in nature. We report two extreme cases of diarrhea in metastatic neuroendocrine tumors that threatened fatality and provide evidence for steroids as a novel agent in the management of vasoactive intestinal peptide tumors. CASE PRESENTATION: A 63-year-old Caucasian male with a grade 2 (Ki-67 17%) metastatic small bowel neuroendocrine tumor, and a 43-year-old female with a grade 2 (Ki-67 5%) metastatic pancreatic vasoactive intestinal peptide tumor. Both patients suffered life-threatening diarrhea despite extensive treatment modalities, including new systemic agents. This case explains how a lack of compliance and patient under-reporting of symptoms contributed to their challenging clinical course. Only steroids had a significant sustained effect on the diarrhea of the patient with vasoactive intestinal peptide tumor. CONCLUSIONS: This report discusses two rare cases of life-threatening diarrhea in neuroendocrine tumors and stresses the importance of accurate clinical history taking, patient education, and compliance for symptom control. The report suggests steroids as a potential novel pharmaceutical option in the management of vasoactive intestinal peptide tumors; this is of great significance as it may provide a new approach to their management and potentially act as a life-saving agent in other oncology patients.

Change in Practice of Radioactive Iodine Administration in Differentiated Thyroid Cancer: A Single-Centre Experience.

OBJECTIVE: Our study aimed to analyse temporal trends in radioactive iodine (RAI) treatment for thyroid cancer over the past decade; to analyse key factors associated with clinical decisions in RAI dosing; and to confirm lower activities of RAI for low-risk patients were not associated with an increased risk of recurrence. METHODS: Retrospective analysis of 1,323 patients who received RAI at a quaternary centre in Australia between 2008 and 2018 was performed. Prospectively collected data included age, gender, histology, and American Joint Committee on Cancer stage (7th ed). American Thyroid Association risk was calculated retrospectively. RESULTS: The median activities of RAI administered to low-risk patients decreased from 3.85 GBq (104 mCi) in 2008-2016 to 2.0 GBq (54 mCi) in 2017-2018. The principal driver of this change was an increased use of 1 GBq (27 mCi) from 1.3% of prescriptions in 2008-2011 to 18.5% in 2017-2018. In patients assigned as low risk per ATA stratification, lower activities of 1 GBq or 2 GBq (27 mCi or 54 mCi) were not associated with an increased risk of recurrence. In patients assigned to intermediate- or high-risk categories who received RAI as adjuvant therapy, there was no difference in risk of recurrence between 4 GBq (108 mCi) and 6 GBq (162 mCi). CONCLUSIONS: Our data demonstrate an evolution of RAI activities consistent with translation of ATA guidelines into clinical practice. Use of lower RAI activities was not associated with an increase in recurrence in low-risk thyroid cancer patients. Our data also suggest lower RAI activities may be as efficacious for adjuvant therapy in intermediate- and high-risk patients.

Multimodality Treatment Improves Locoregional Control, Progression-Free and Overall Survival in Patients with Anaplastic Thyroid Cancer: A Retrospective Cohort Study Comparing Oncological Outcomes and Morbidity between Multimodality Treatment and Limited Treatment.

BACKGROUND: Patients with anaplastic thyroid cancer (ATC) have poor overall survival, and the optimal management approach remains unclear. The aim of this study is to evaluate our experience with multimodality (MMT) versus limited treatment (LT) for ATC. PATIENTS AND METHODS: A cohort study of patients with ATC managed in a tertiary referral center was undertaken. The outcomes of MMT were compared with those of LT. The primary outcome measures were locoregional control and progression-free and overall survival. Secondary outcome measures were treatment-related complications and factors associated with improved survival. RESULTS: In total, 59 patients (35 females) with a median age of 73 years (range 39-99 years) and ATC stage IVA (n = 2), IVB (n = 28), or IVC (n = 29) were included. LT was utilized in 25 patients (42%), and 34 cases had MMT. MMT patients had a longer time of locoregional control (18.5 versus 1.9 months; p < 0.001), progression-free survival (3.5 versus 1.2 months; p < 0.001), and overall survival (6.9 versus 2.0 months; p < 0.001) when compared with LT. For patients with stage IVC ATC, locoregional control (p = 0.03), progression-free survival (p < 0.001), and overall survival (p < 0.001) were superior in the MMT cohort compared with LT. MMT had more treatment-related complications than LT (p < 0.001). An Eastern Cooperative Oncology Group performance status < 2 (HR 0.30; p = 0.001) and MMT (HR 0.35; p = 0.008) were associated with improved overall survival. CONCLUSION: MMT is likely to improve locoregional control, progression-free survival, and overall survival in selected ATC patients including stage IVC tumors but comes with a greater complication risk.

Complexities surrounding the diagnosis and management of hypercalcaemia in pregnancy.

SUMMARY: Hypercalcaemia in pregnancy is uncommon, with associated adverse obstetric and perinatal outcomes for both the mother and the fetus. Determination of causality is central to its management. Diagnostic imaging techniques are limited during pregnancy and the diagnosis is made more complex by physiological changes in calcium and vitamin D homeostasis in pregnancy. Further, therapeutic options are limited due to safety considerations for the pregnant woman and the developing foetus. Three cases of hypercalcaemia in pregnancy will be presented, highlighting the distinct aetiologies and management strategies for hypercalcaemia in pregnancy and the importance of early measurement of serum calcium in pregnancy screening. LEARNING POINTS: There are complex physiological changes in calcium balance in pregnancy, including increased calcium intestinal absorption and renal excretion. Hypercalcaemia in pregnancy is uncommon but has important potential maternal and foetal complications, making a compelling argument for routine antenatal, calcium screening. Identifying the cause of hypercalcaemia in pregnancy can be challenging due to the complex placental interplay in biochemical test interpretation and due to safety constraints restricting imaging and surgery. Acute medical management of hypercalcaemia must be considered in the context of both maternal and foetal well-being, along with gestational age and specific consideration for the safety of the developing fetus in late gestation.

Predicting distant metastatic disease in differentiated thyroid cancer: a matched case-control study.

BACKGROUND: The occurrence of distant metastasis (DM) is the most important prognostic factor influencing survival outcomes in differentiated thyroid cancer (DTC). Identifying patients who are likely to develop DM and offering these cases more aggressive surgical approaches and I-131 therapy, is paramount to achieving the best possible outcomes. DM on presentation in DTC are uncommon, with an incidence of 1-9%. However, the incidence of DTC is rising and the disease affects a relatively young cohort of patients. The aims of this study were to investigate predictive factors in the development of DM by comparing a homogenous group of DTC patients with and without DM, and to illustrate the overall and disease-specific survival (DSS) rates of DTC patients presenting with DM. METHODS: A matched case-control study of patients with DTC and DM was undertaken. The study group comprised a consecutive series of cases with DM treated in the period 1968-2014. Patients with DM at initial presentation were identified (DTC-DM group). A control group of patients without DM were matched based on age, gender, tumour size and histological subtype. The primary outcome measures were overall and disease-free survival. Secondary outcome measures were lymph node involvement (LNI), extra-thyroidal extension (ETE) of tumour and presence of BRAFV600E mutation identified on immunohistochemistry. RESULTS: A total of 2547 patients with DTC were reviewed and of these 83 (3.26%) had DM at initial presentation. At 5 and 10 years, the overall survival rates for DTC-DM patients were 89.6% and 64%, respectively. The 5 and 10 year DSS rates for DTC-DM cases were 90.2% and 67.3%, respectively. When compared to the DTC group, the DTC-DM group had significantly higher rates of ETE (63% vs. 29.5%, P < 0.0001) and LNI (32.5% vs. 18.8%, P = 0.044). Among patients with papillary thyroid cancer (PTC), the presence of BRAFV600E mutation was significantly associated with DM (62.2% vs. 36.8%, P = 0.028). CONCLUSION: ETE, LNI and BRAFV600E mutation in PTC are significant predictors for the development of distant metastatic disease.

Suppurative thyroiditis: Systematic review and clinical guidance.

OBJECTIVE: Acute suppurative thyroiditis (AST) is a rare but potentially fatal condition which can initially be difficult to distinguish from the more common subacute thyroiditis (SAT). We aim to update understanding of this medical emergency. DESIGN: A systematic review over the past 20 years was performed on the epidemiology, clinical features, investigations, management and outcomes of AST. All full-text cases of microscopy or culture- proven AST in the English literature were included. RESULTS: 200 cases of AST have been described in 148 articles from January 2000 - January 2020. Bacterial AST is most common, often presenting with neck pain (89%) and fever (82%). Immunosuppression and pyriform sinus fistula are the most common causes, most often due to gram-positive aerobes. Transient hyperthyroidism is common (42%). Aspiration and antibiotics are becoming a more common treatment. Overall mortality was 7.8%. Tuberculous and fungal AST are less likely to present with fever and neck pain. Fungal AST is more common in immunosuppressed individuals (31%) and has a high overall mortality (33%). Tuberculous AST is more common in TB endemic areas. CONCLUSION: The symptoms and signs of AST commonly overlap with SAT and initially can be hard to diagnose. AST can be rapidly morbid or even fatal. Clinicians need to consider AST when they assess patients with thyroiditis who are systemically unwell, have high fever, high white cell count and c-reactive protein, tender neck and abnormal neck imaging. An investigative and treatment strategy is described based on a systematic review of the literature.

Prophylactic central lymph node dissection informs the decision of radioactive iodine ablation in papillary thyroid cancer.

BACKGROUND: Prophylactic central lymph node dissection (CLND) in papillary thyroid cancer (PTC) is controversial. We aimed to investigate if prophylactic CLND aids risk stratification and contributes to the decision for postoperative RAI ablation. METHODS: Patients undergoing thyroidectomy for PTC and prophylactic CLND were identified from an endocrine surgical unit database. Pathology reports where reviewed for number and size of lymph nodes and patients stratified by risk according to the ATA guidelines. RESULTS: 426 patients were identified with PTC ≤4 cm and prophylactic CLND. 96 patients (23%) had central lymph node metastasis (CLNM) that qualified them for the intermediate risk group. In 17 patients (4%), the CLNM data led to upgrading independently of other histopathological characteristics. Correcting for multiple variables, CLNM was an independent factor contributing to RAI treatment. CONCLUSION: Prophylactic CLND provides information to aid the selection of RAI ablation independent of primary cancer histology for risk stratification in 4% of patients. This benefit should be carefully balanced with the risk of CLND and patient treatment choice when deciding on management of PTC ≤4 cm.

Early postoperative stimulated serum thyroglobulin quantifies risk of recurrence in papillary thyroid cancer.

BACKGROUND: Postoperative follow-up of papillary thyroid cancer includes serial serum thyroglobulin levels. This study aimed to determine whether stimulated thyroglobulin levels measured in the early postoperative period can accurately quantify the risk of recurrence in papillary thyroid cancer. METHODS: We undertook a cohort study of patients who underwent total thyroidectomy for papillary thyroid cancer ≥10 mm in the period 2000 to 2016 with complete biochemical data. All patients had a postoperative stimulated thyroglobulin measured within 3 months after total thyroidectomy. Structural recurrence was defined as disease detected on imaging and confirmed on histology. Biochemical disease was defined as patients with stimulated serum thyroglobulin ≥1 ng/mL with no evidence of structural disease. RESULTS: This study included 502 patients with a mean age of 50 years and median tumor diameter of 20 mm. Median follow-up was 18 months. Stimulated postoperative thyroglobulin was measured before radioiodine-ablation and was categorized into 3 groups: (1) 219 (44%) patients had thyroglobulin <1 ng/mL; (2) 55 (11%) had 1ng/mL ≤ thyroglobulin <2 ng/mL; and (3) 228 (45%) had thyroglobulin ≥2 ng/mL. The structural recurrence rate for each group was 5%, 2%, and 30%, respectively (P < .0001). CONCLUSION: In patients undergoing total thyroidectomy for papillary thyroid cancer, early postoperative stimulated thyroglobulin accurately quantifies the risk of structural disease recurrence.

Surgery alone for papillary thyroid microcarcinoma is less costly and more effective than long term active surveillance.

BACKGROUND: Papillary thyroid microcarcinoma is a subtype of thyroid cancer that may be managed with active surveillance rather than immediate surgery. Active surveillance decreases complication rates and may decrease health care costs. This study aims to analyze complication rates of thyroid surgery, papillary thyroid microcarcinoma recurrence, and survival rates. Additionally, the costs of surgery versus hypothetic active surveillance for papillary thyroid microcarcinoma are compared in an Australian cohort. METHODS: Papillary thyroid microcarcinoma patients were included from a prospectively collected surgical cohort of patients treated for papillary thyroid cancer between 1985 and 2017. The primary outcomes were the complications of thyroid surgery, recurrence-free survival, overall survival, and cost of surgical treatment and active surveillance. RESULTS: In a total of 349 patients with papillary microcarcinoma with a median age of 48 years (range, 18-90 years), the permanent operative complications rate was 3.7%. Postoperative radioactive iodine did not decrease recurrence-free survival (P = .3). The total cost of surgical treatment was $10,226 Australian dollars, whereas hypothetic active surveillance was at a yearly cost of $756 Australian dollars. Estimated cost of surgical papillary thyroid microcarcinoma treatment was equivalent to the cost of 16.2 years of active surveillance. CONCLUSION: Surgery may have a long-term economic advantage for younger Australian patients with papillary thyroid microcarcinoma who are likely to require more than 16.2 years of follow-up in an active surveillance scheme.

Straddling medical specialties: should we have more comprehensive advanced training?

Over careers spanning 35 years each, we have witnessed great advances in medicine especially in genetics, imaging, immunotherapies and targeted cancer therapies. Our respective specialties of endocrinology and medical oncology have come to overlap significantly necessitating better communication and skills across both specialties. We will highlight common scenarios that straddle endocrinology and medical oncology. The same broad issues apply to other closely related specialties, albeit with different clinical challenges. At present, we see expensive and inefficient cross-referrals to other subspecialists or sometimes no referral at all, leading to significant clinical omissions. Opportunities for dual advanced training, or for more comprehensive single advanced training could more efficiently lead to enhanced patient care and communication.

Clinical challenges of a co-secreting TSH/GH pituitary adenoma.

SUMMARY: Co-secreting thyrotropin/growth hormone (GH) pituitary adenomas are rare; their clinical presentation and long-term management are challenging. There is also a paucity of long-term data. Due to the cell of origin, these can behave as aggressive tumours. We report a case of a pituitary plurihormonal pit-1-derived macroadenoma, with overt clinical hyperthyroidism and minimal GH excess symptoms. The diagnosis was confirmed by pathology showing elevated thyroid and GH axes with failure of physiological GH suppression, elevated pituitary glycoprotein hormone alpha subunit (αGSU) and macroadenoma on imaging. Pre-operatively the patient was rendered euthyroid with carbimazole and underwent successful transphenoidal adenomectomy (TSA) with surgical cure. Histopathology displayed an elevated Ki-67 of 5.2%, necessitating long-term follow-up. LEARNING POINTS: Thyrotropinomas are rare and likely under-diagnosed due to under-recognition of secondary hyperthyroidism. Thyrotropinomas and other plurihormonal pit-1-derived adenomas are more aggressive adenomas according to WHO guidelines. Co-secretion occurs in 30% of thyrotropinomas, requiring diligent investigation and long-term follow-up of complications.

Clinical guidance for radioiodine refractory differentiated thyroid cancer.

Prognosis from differentiated thyroid cancer is worse when the disease becomes refractory to radioiodine. Until recently, treatment options have been limited to local therapies such as surgery and radiotherapy, but the recent availability of systemic therapies now provides some potential for disease control. Multitargeted kinase inhibitors (TKIs) including lenvatinib and sorafenib have been shown to improve progression-free survival in phase III clinical trials, but are also associated with a spectrum of adverse effects. Other TKIs have been utilized as "redifferentiation" agents, increasing sodium iodide symporter expression in metastases and thus restoring radioiodine avidity. Some patients whose disease progresses on initial TKI therapy will still respond to a different TKI and clinical trials currently in progress will clarify the best options for such patients. As these drugs are not inexpensive, care needs to be taken to minimize not only biological but also financial toxicity. In this review, we examine the basic biology of radioiodine refractory disease and discuss optimal treatment approaches, with specific focus on choice and timing of TKI treatment. This clinical field remains fluid, and directions for future research include exploring biomarkers and considering adjuvant TKI use in certain patient groups.

ACTH-secreting medullary thyroid cancer: a case series.

Medullary thyroid cancer (MTC) is a rare neuroendocrine tumour that originates from the parafollicular cells of the thyroid gland. The most common presentation of MTC is with a single nodule; however, by the time of diagnosis, most have spread to the surrounding cervical lymph nodes. Cushing's syndrome is a rare complication of MTC and is due to ectopic adrenocorticotrophic hormone (ACTH) secretion by tumour cells. Cushing's syndrome presents a challenging diagnostic and management issue in patients with MTC. Tyrosine kinase inhibitors (TKI) previously used for the management of metastatic MTC have become an important therapeutic option for the management of ectopic ACTH in metastatic MTC. The article describes three cases of ectopic ACTH secretion in MTC and addresses the significant diagnostic and management challenges related to Cushing's syndrome in metastatic MTC. LEARNING POINTS: Medullary thyroid cancer (MTC) is a rare neuroendocrine tumour.Cushing's syndrome is a rare complication of MTC that has a significant impact on patients' morbidity and mortality.Tyrosine kinase inhibitors (TKI) provide an important therapeutic option for the management of ectopic ACTH in metastatic MTC.

Disease Progression in Papillary Thyroid Cancer with Biochemical Incomplete Response to Initial Therapy.

BACKGROUND: Dynamic risk stratification is utilized in the follow-up of patients with papillary thyroid carcinoma (PTC). Analysis of outcomes after biochemical incomplete response (BIR) to initial therapy will allow better individualization of care. METHODS: A total of 494 patients with PTC were followed prospectively. Immunohistochemistry (IHC) for BRAFV600E mutation was completed on all surgical specimens. After exclusion of patients with inadequate data, 353 patients were stratified into four categories of response to initial therapy: excellent, biochemical incomplete, structural incomplete, or indeterminate. Patients with BIR, defined as elevated stimulated thyroglobulin >2 µg/L with negative imaging, were analysed for progression of disease. The primary outcome measure was development of structural recurrence. RESULTS: Forty-nine of 353 (13.9%) patients had BIR. BRAFV600E mutation was present in 32 of 49 (65.3%) with BIR. Progression to structural recurrence occurred in 8 of 49 (16.3%) with BIR, all of whom were positive for the BRAFV600E mutation (p = 0.02). Nine patients (18%) with BIR remitted during follow-up to no evidence of disease (6 had additional RAI therapy). After mean follow-up of 35 months, 12 patients with BIR (24%) remained biochemically abnormal with no structural evidence of disease. CONCLUSIONS: Patients with BIR following initial treatment for PTC have generally favorable outcomes. Positive IHC for BRAFV600E identifies patients at risk of structural disease recurrence.