Mark S. Sywak

Association Between BRAF V600E Mutation and Mortality in Patients With Papillary Thyroid Cancer

IMPORTANCE BRAF V600E is a prominent oncogene in papillary thyroid cancer (PTC), but its role in PTC-related patient mortality has not been established. OBJECTIVE To investigate the relationship between BRAF V600E mutation and PTC-related mortality. DESIGN, SETTING, AND PARTICIPANTS Retrospective study of 1849 patients (1411 women and 438 men) with a median age of 46 years (interquartile range, 34-58 years) and an overall median follow-up time of 33 months (interquartile range, 13-67 months) after initial treatment at 13 centers in 7 countries between 1978 and 2011. MAIN OUTCOMES AND MEASURES Patient deaths specifically caused by PTC. RESULTS Overall, mortality was 5.3% (45/845; 95% CI, 3.9%-7.1%) vs 1.1% (11/1004; 95% CI, 0.5%-2.0%) (P < .001) in BRAF V600E-positive vs mutation-negative patients. Deaths per 1000 person-years in the analysis of all PTC were 12.87 (95% CI, 9.61-17.24) vs 2.52 (95% CI, 1.40-4.55) in BRAF V600E-positive vs mutation-negative patients; the hazard ratio (HR) was 2.66 (95% CI, 1.30-5.43) after adjustment for age at diagnosis, sex, and medical center. Deaths per 1000 person-years in the analysis of the conventional variant of PTC were 11.80 (95% CI, 8.39-16.60) vs 2.25 (95% CI, 1.01-5.00) in BRAF V600E-positive vs mutation-negative patients; the adjusted HR was 3.53 (95% CI, 1.25-9.98). When lymph node metastasis, extrathyroidal invasion, and distant metastasis were also included in the model, the association of BRAF V600E with mortality for all PTC was no longer significant (HR, 1.21; 95% CI, 0.53-2.76). A higher BRAF V600E-associated patient mortality was also observed in several clinicopathological subcategories, but statistical significance was lost with adjustment for patient age, sex, and medical center. For example, in patients with lymph node metastasis, the deaths per 1000 person-years were 26.26 (95% CI, 19.18-35.94) vs 5.93 (95% CI, 2.96-11.86) in BRAF V600E-positive vs mutation-negative patients (unadjusted HR, 4.43 [95% CI, 2.06-9.51]; adjusted HR, 1.46 [95% CI, 0.62-3.47]). In patients with distant tumor metastasis, deaths per 1000 person-years were 87.72 (95% CI, 62.68-122.77) vs 32.28 (95% CI, 16.14-64.55) in BRAF V600E-positive vs mutation-negative patients (unadjusted HR, 2.63 [95% CI, 1.21-5.72]; adjusted HR, 0.84 [95% CI, 0.27-2.62]). CONCLUSIONS AND RELEVANCE In this retrospective multicenter study, the presence of the BRAF V600E mutation was significantly associated with increased cancer-related mortality among patients with PTC. Because overall mortality in PTC is low and the association was not independent of tumor features, how to use BRAF V600E to manage mortality risk in patients with PTC is unclear. These findings support further investigation of the prognostic and therapeutic implications of BRAF V600E status in PTC.

Association Between BRAF V600E Mutation and Recurrence of Papillary Thyroid Cancer

PURPOSE To investigate the prognostic value of BRAF V600E mutation for the recurrence of papillary thyroid cancer (PTC). PATIENTS AND METHODS This was a retrospective multicenter study of the relationship between BRAF V600E mutation and recurrence of PTC in 2,099 patients (1,615 women and 484 men), with a median age of 45 years (interquartile range [IQR], 34 to 58 years) and a median follow-up time of 36 months (IQR, 14 to 75 months). RESULTS The overall BRAF V600E mutation prevalence was 48.5% (1,017 of 2,099). PTC recurrence occurred in 20.9% (213 of 1,017) of BRAF V600E mutation-positive and 11.6% (125 of 1,082) of BRAF V600E mutation-negative patients. Recurrence rates were 47.71 (95% CI, 41.72 to 54.57) versus 26.03 (95% CI, 21.85 to 31.02) per 1,000 person-years in BRAF mutation-positive versus -negative patients (P < .001), with a hazard ratio (HR) of 1.82 (95% CI, 1.46 to 2.28), which remained significant in a multivariable model adjusting for patient sex and age at diagnosis, medical center, and various conventional pathologic factors. Significant association between BRAF mutation and PTC recurrence was also found in patients with conventionally low-risk disease stage I or II and micro-PTC and within various subtypes of PTC. For example, in BRAF mutation-positive versus -negative follicular-variant PTC, recurrence occurred in 21.3% (19 of 89) and 7.0% (24 of 342) of patients, respectively, with recurrence rates of 53.84 (95% CI, 34.34 to 84.40) versus 19.47 (95% CI, 13.05 to 29.04) per 1,000 person-years (P < .001) and an HR of 3.20 (95% CI, 1.46 to 7.02) after adjustment for clinicopathologic factors. BRAF mutation was associated with poorer recurrence-free probability in Kaplan-Meier survival analyses in various clinicopathologic categories. CONCLUSION This large multicenter study demonstrates an independent prognostic value of BRAF V600E mutation for PTC recurrence in various clinicopathologic categories.

miR-195 and miR-483-5p Identified as Predictors of Poor Prognosis in Adrenocortical Cancer

Purpose: Adrenocortical adenomas are common, whereas adrenocortical carcinomas are rare. Discriminating between benign and malignant adrenocortical tumors using conventional histology can be difficult. In addition, adrenocortical carcinomas generally have poor prognosis and limited treatment options. MicroRNAs are short noncoding RNAs that are involved in regulation of gene transcription. Experimental Design: To identify microRNAs involved in the pathogenesis of adrenocortical tumors, expression profiling of microRNAs was done on a cohort of 22 adrenocortical carcinomas, 27 adrenocortical adenomas, and 6 normal adrenal cortices. Results: Twenty-three microRNAs were found to be significantly differentially expressed between adrenocortical carcinomas and adrenocortical adenomas. miR-335 and miR-195 were significantly downregulated in adrenocortical carcinomas compared with adrenocortical adenomas. This result was further validated in an external cohort of six adrenocortical carcinomas and four adrenocortical adenomas. Using Kaplan-Meier analysis, downregulation of miR-195 and upregulation of miR-483-5p in adrenocortical carcinomas were significantly associated with poorer disease-specific survival. Conclusions: These findings indicate that deregulation of microRNAs is a recurring event in human adrenocortical carcinomas and that aberrant expression of miR-195 and miR-483-5p identifies a subset of poorer prognosis adrenocortical carcinomas. (Clin Cancer Res 2009;15(24):7684–92)

Immunohistochemistry for SDHB divides gastrointestinal stromal tumors (GISTs) into 2 distinct types.

The Carney triad (CT) is gastrointestinal stromal tumor (GIST), paraganglioma, and pulmonary chondroma. The GISTs of CT show different clinical, molecular, and morphologic features to usual adult GISTs but are similar to the majority of pediatric GISTs. We postulated that these GISTs would show negative staining for succinate dehydrogenase B (SDHB). We performed SDHB immunohistochemistry on GISTs arising in 5 individuals with CT, 1 child, 7 individuals with GIST in young adulthood including 2 with germline KIT mutations, 3 individuals with neurofibromatosis 1, one 63-year-old female with multifocal gastric epithelioid GIST with lymph node metastases, and 104 consecutive unselected individuals with apparently sporadic GIST. The GISTs and paragangliomas arising in CT, the pediatric GIST, and the multifocal gastric GIST from the 63-year-old showed negative SDHB staining. GISTs from the 7 young adults and 3 with neurofibromatosis were SDHB positive. Of the unselected GISTs, 101 (97%) were positive. One of the negative GISTs arose in a 48-year-old female with previous recurrent multifocal gastric GISTs and the other 2 arose in females also in their 40s with gastric GISTs with epithelioid morphology. We conclude that negative staining for SDHB is characteristic of the GISTs of CT and the subgroup of pediatric GISTs which it resembles. Furthermore, when negative staining occurs in apparently sporadic GISTs in adults, the GISTs show morphologic and clinical features similar to pediatric and CT type GISTs. GISTs may therefore be divided into type 1 (SDHB positive) and type 2 (SDHB negative) subtypes.

A multicenter cohort study of total thyroidectomy and routine central lymph node dissection for cN0 papillary thyroid cancer

BACKGROUND The role of routine central lymph node dissection (CLND) for papillary thyroid cancer (PTC) remains controversial. The aim of this study was to evaluate the impact of routine CLND after total thyroidectomy (TTx) in the management of patients with PTC who were clinically node negative at presentation with emphasis on stimulated thyroglobulin (Tg) levels and reoperation rates. METHODS This retrospective, multicenter, cohort study used pooled data from 3 international Endocrine Surgery units in Australia, the United States, and England. All study participants had PTC >1 cm without preoperative evidence of lymph node disease (cN0). Group A patients had TTx alone and group B had TTx with the addition of CLND. RESULTS There were 606 patients included in the study. Group A had 347 patients and group B 259 patients. Stimulated Tg values were lower in group B before initial radioiodine ablation (15.0 vs 6.6 ng/mL; P = .025). There was a trend toward a lower Tg at final follow-up in group B (1.9 vs 7.2 ng/mL; P = .11). The rate of reoperation in the central compartment was lower in group B (1.5 vs 6.1%; P = .004). The number of CLND procedures required to prevent 1 central compartment reoperation was calculated at 20. CONCLUSION The addition of routine CLND in cN0 papillary thyroid carcinoma is associated with lower postoperative Tg levels and reduces the need for reoperation in the central compartment.

Increasing incidence of thyroid cancer is due to increased pathologic detection

BACKGROUND There has been a marked increase in the incidence of thyroid cancer worldwide over recent decades. Patients with retrosternal goiter (RSG) are not picked up generally by common surveillance techniques such as ultrasound. The aim of this project was to study the incidence of thyroid cancer in patients with RSG. METHODS This is a retrospective cohort study. Documented were patient demographics as well as the size, type, and numbers of thyroid cancers. The number of routine histologic blocks examined for multinodular goiter in the different time periods was also examined. RESULTS Within a cohort of 13,793 thyroidectomies performed over 40 years, there were 2,260 patients (14%) who underwent surgery for RSG. The percentage of patients with RSG containing thyroid cancer increased from 3.6 to 7.5% (P < .05); however, once papillary microcarcinomas (PMC) (</=10 mm) were excluded there was no increase in cancer incidence (3.4-3.5%, P = .9). The increase in the number of PMCs diagnosed is associated with the increase in the routine number of blocks sampled over the 40-year time period (P < .01). CONCLUSION This study has confirmed an increase in the incidence of thyroid cancer over 4 decades. However, that increase appears to be due to an increase in the diagnosis of PMC associated with increased sampling of resected specimens by pathologists, raising the possibility that the current epidemic of thyroid cancer may be largely manmade.

AUSTRALIAN ENDOCRINE SURGEONS GUIDELINES AES06/01. POSTOPERATIVE PARATHYROID HORMONE MEASUREMENT AND EARLY DISCHARGE AFTER TOTAL THYROIDECTOMY: ANALYSIS OF AUSTRALIAN DATA AND MANAGEMENT RECOMMENDATIONS

Background:  The risk of hypocalcaemia after thyroidectomy has traditionally mandated inpatient monitoring for signs and symptoms as well as frequent measurement of serum calcium levels. In recent years there has been much interest in the published work about the use of intact parathyroid hormone (PTH) to better predict hypocalcaemia after thyroidectomy. Although generally accurate, the use of intact parathyroid hormone in Australia has not become widespread. On behalf of the Australian Endocrine Surgeons an analysis of Australian data on the use of PTH levels to predict hypocalcaemia after thyroidectomy was carried out. The data were analysed with a view to making recommendations about the use of this test in clinical practice and the feasibility of achieving safe early discharge for patients.

BRAFV600E mutation is associated with an increased risk of nodal recurrence requiring reoperative surgery in patients with papillary thyroid cancer

BACKGROUND The role of the B-isoform of the Raf kinase (BRAF) mutation BRAF(V600E) as an independent prognostic factor in papillary thyroid cancer (PTC) remains controversial. Some studies suggest that tumors containing BRAF(V600E) have decreased radioiodine avidity and present a greater risk of nodal recurrence and distant metastases. METHODS Paraffin-embedded specimens from consecutive patients who underwent surgery for PTC before 2003 were independently reviewed by an endocrine pathologist. DNA was extracted, amplified by polymerase chain reaction, and the presence of the BRAF(V600E) mutation was determined by restriction digest. Tumor characteristics and long-term disease outcomes were analyzed according to BRAF(V600E) status. RESULTS BRAF(V600E) was identified in 60 (59%) of 101 patients. At a median follow-up of 106 months, the overall disease-free survival was 78%. Clinically evident nodal recurrence occurred in 11% of BRAF(V600E)-positive patients, and all patients required lateral neck dissection (P = .02). In contrast, subclinical nodal recurrence occurred in 7% of BRAF(V600E)-negative patients, and all recurrences were successfully ablated with radioactive iodine. There was a trend toward poorer disease-free survival among patients with stage III/IV PTC and BRAF(V600E) mutation (P = .08). All 5 disease-related deaths occurred in patients with BRAF(V600E)-positive primary tumors (P = .06). CONCLUSION The BRAF(V600E) mutation in PTC is associated with an increased risk of palpable nodal recurrence and the need for reoperative surgery.

Central lymph node dissection as a secondary procedure for papillary thyroid cancer: Is there added morbidity?

BACKGROUND Routine central lymph node dissection (CLND) for papillary thyroid cancer (PTC) at the time of initial thyroidectomy has been advocated with a demonstrated decrease in post-ablation serum thyroglobulin compared to total thyroidectomy alone. Patients now present with central compartment metastatic disease after initial thyroid cancer surgery, or with a diagnosis of PTC after diagnostic lobectomy requiring completion thyroidectomy, and an undissected central compartment. Our aim was to compare the clinical outcomes in patients with PTC who underwent CLND as a secondary event with those having initial CLND. METHODS A retrospective cohort study of 193 patients who underwent CLND for PTC between June 2002 and November 2007 was undertaken. Data gathered included patient demographics, number of lymph nodes excised, lymph node involvement, and incidence of postoperative complications. RESULTS One-hundred and seventy (M/F: 28/142) patients (Grp A) had a CLND as part of their primary surgical procedure while 23 (M/F: 10/13) patients (Grp B) underwent CLND as a secondary procedure (12 therapeutic/11 prophylactic procedures). The mean number of lymph nodes sampled and the % involved in the 2 groups A and B were 9.2 vs 10.2 and 64% vs 61%, respectively. Similarly, the incidence of temporary hypocalcemia (12% vs 9%), permanent hypoparathyroidism (1.8% vs 0%), temporary recurrent laryngeal nerve (RLN) paresis (3% vs 4%), permanent RLN paresis (0.6% vs 0%), and wound infection (0.6% vs 4.3%) was comparable in groups A and B. CONCLUSION This study demonstrates that there is no additional morbidity when CLND is performed as a secondary procedure for patients with PTC. Secondary CLND should be performed in patients with proven central compartment metastatic disease after previous thyroidectomy and can be offered safely as a prophylactic procedure to patients at high risk for central lymph node metastasis when CLND has not been performed at initial primary operation for PTC.

ROUTINE LEVEL VI LYMPH NODE DISSECTION FOR PAPILLARY THYROID CANCER: SURGICAL TECHNIQUE

Total thyroidectomy is the treatment of choice for clinically significant papillary thyroid cancer (PTC); however, 10–15% develop palpable local recurrence in the cervical lymph nodes. Metastases in the cervical lymph nodes account for 75% of loco‐regional recurrence and up to 50% of these patients eventually die of their disease. It is generally accepted that surgical excision of grossly involved lymph node disease should be carried out. The role of routine lymph node dissection, however, is greeted with far more controversy. Regional lymph node metastases have been shown to be associated with more frequent tumour recurrence. Not only is recurrence associated with increased disease‐related mortality, but recent data have shown that the presence of involved lymph nodes is associated with adverse survival. Additionally, there have been significant changes to the way patients are managed after treatment for PTC in recent years. Surveillance previously relied on clinical assessment and radioiodine scans whereas now the use of serum thyroglobulin and high‐resolution ultrasound are the standard as evidenced by recommendations by the American Thyroid Association. These techniques have greater sensitivity and subsequently lymph node metastases are being detected earlier and more frequently. This has led to a paradigm shift in the aims of treatment of PTC, from a focus on survival data to a focus on disease‐free status. Routine central neck lymph node dissection can be carried out with no increased morbidity and can achieve lower 6‐month stimulated thyroglobulin levels when compared with total thyroidectomy alone. Routine ipsilateral level VI lymph node dissection in addition to total thyroidectomy should be carried out for the management of clinically significant PTC.