Keith S. Heller

The prognostic significance of nodal metastases from papillary thyroid carcinoma can be stratified based on the size and number of metastatic lymph nodes, as well as the presence of extranodal extension

BACKGROUND Ultrasound and prophylactic dissections have facilitated identification of small-volume cervical lymph node (LN) metastases in patients with papillary thyroid carcinoma (PTC). Since most staging systems do not stratify risk based on size or number of LN metastases, even a single-microscopic LN metastasis can upstage a patient with low-risk papillary thyroid microcarcinoma (PMC) to an intermediate risk of recurrence in the American Thyroid Association (ATA) system and to an increased risk of death in the American Joint Committee on Cancer (AJCC) staging system (stage III if the metastatic node is in the central neck or stage IVA if the microscopic LN metastasis is identified in the lateral neck). Such microscopic upstaging may lead to potentially unnecessary or additional treatments and follow-up studies. The goal of this review is to determine if the literature supports the concept that specific characteristics (clinically apparent size, number, and extranodal extension) of LN metastases can be used to stratify the risk of recurrence in PTC. SUMMARY In patients with pathological proven cervical LN metastases (pathological N1 disease; pN1), the median risk of loco-regional LN recurrence varies markedly by clinical staging, with recurrence rates for patients who are initially clinically N0 (clinical N0 disease; cN0) of 2% (range 0%-9%) versus rates of recurrence for patients who are initially clinically N-positive (clinical N1 disease; cN1) of 22% (range 10%-42%). Furthermore, the median risk of recurrence in pN1 patients varies markedly by the number of positive nodes, <5 nodes (4%, range 3%-8%) vs. >5 nodes (19%, range 7%-21%). Additionally, the presence of extranodal extension was associated with a median risk of recurrence of 24% (range 15%-32%) and possibly a worse disease-specific survival. CONCLUSION Our previous paradigm assigned the same magnitude of risk for all patients with N1 disease. However, small-volume subclinical microscopic N1 disease clearly conveys a much smaller risk of recurrence than large-volume, macroscopic clinically apparent loco-regional metastases. Armed with this information, clinicians will be better able to tailor initial treatment and follow-up recommendations. Implications of N1 stratification for PTC into small-volume microscopic disease versus clinically apparent macroscopic disease importantly relate to issues of prophylactic neck dissection utility, need for pathologic nodal size description, and suggest potential modifications to the AJCC TNM (tumor, nodal disease, and distant metastasis) and ATA risk recurrence staging systems.

Preoperative parathyroid scintigraphic lesion localization: accuracy of various types of readings.

PURPOSE To retrospectively compare the accuracy of various parathyroid scintigraphy readings for single-gland disease (SGD) and multigland disease (MGD) in patients with primary hyperparathyroidism, with histologic analysis as the reference standard. MATERIALS AND METHODS Institutional review board approval was obtained for this HIPAA-compliant study. Records of 462 patients with primary hyperparathyroidism who underwent preoperative imaging with a technetium 99m ((99m)Tc) sestamibi and (99m)TcO4- protocol that consisted of early and late pinhole (99m)Tc sestamibi, pinhole thyroid imaging, image subtraction, and single photon emission computed tomography (SPECT) were retrospectively reviewed. An experienced nuclear medicine physician without knowledge of other test results or of the final diagnoses graded images on a scale from 0 (definitely normal) to 4 (definitely abnormal). Early pinhole (99m)Tc sestamibi images, late pinhole (99m)Tc sestamibi images, subtraction images, SPECT images, early and late pinhole (99m)Tc sestamibi images, all planar images, and all images--including SPECT images--were read in seven sessions. Receiver operating characteristic curves were generated for each session and were used to calculate sensitivity, specificity, and accuracy. RESULTS A total of 534 parathyroid lesions were excised. Of the 462 patients, 409 had one lesion, whereas 53 had multiple lesions. Reading all images together was more accurate (89%, P = .001) than was reading early (79%), late (85%), subtraction (86%), and SPECT (83%) images separately; however, it was not significantly more accurate than reading planar images (88%) or early and late images together (87%). Reading all images was significantly less sensitive in the detection of lesions with a median weight of 600 mg or less than in the detection of lesions with a median weight of more than 600 mg (86% vs 94%, P = .004). Per-lesion sensitivity for reading all images was significantly higher for SGD than for MGD (90% vs 66%, P < .001). Sensitivity of reading all images together in the identification of patients with MGD was 62%. CONCLUSION Reviewing early, late, and subtraction pinhole images together with SPECT images maximizes parathyroid lesion detection accuracy. Test sensitivity is adversely affected by decreasing lesion weight and MGD.

Value of Fine Needle Aspiration Biopsy of Salivary Gland Masses in Clinical Decision-Making

The accuracy of fine needle aspiration biopsy (FNAB) in the diagnosis of salivary tumors has been well established. This study was undertaken to determine the impact of FNAB on patient management. One hundred one patients underwent FNAB of major salivary gland masses. The physicians initial clinical impression was compared with the FNAB diagnosis and the final diagnosis in each case. Forty patients had solitary masses thought to be benign tumors other than Warthins tumors. FNAB in 13 of these patients (33%) yielded a diagnosis permitting modification of the planned procedure. The diagnosis of Warthins tumor was suspected clinically in 23 patients. In nine of these patients (39%), FNAB resulted in a different diagnosis. Of the 10 patients believed to have malignant tumors, using FNAB, 1 was found to have sialadenitis and 1 a lymphoma. Overall, FNAB resulted in a change in the clinical approach to 35% of the patients. We recommend the performance of FNAB in almost all patients with salivary masses.

Follicular Variant of Papillary Thyroid Cancer Encapsulated, Nonencapsulated, and Diffuse: Distinct Biologic and Clinical Entities

OBJECTIVE To examine genotypic and clinical differences between encapsulated, nonencapsulated, and diffuse follicular variant of papillary thyroid carcinoma (EFVPTC, NFVPTC, and diffuse FVPTC, respectively), to characterize the entities and identify predictors of their behavior. DESIGN Retrospective medical chart review and molecular analysis. SETTING Referral center of a university hospital. PATIENTS The pathologic characteristics of 484 consecutive patients with differentiated thyroid cancer who underwent surgery by the 3 members of the New York University Endocrine Surgery Associates from January 1, 2007, to August 1, 2010, were reviewed. Forty-five patients with FVPTC and in whom at least 1 central compartment lymph node was removed were included. MAIN OUTCOME MEASURES Patients with FVPTC were compared in terms of age, sex, tumor size, encapsulation, extrathyroid extension, vascular invasion, central nodal metastases, and the presence or absence of mutations in BRAF, H-RAS 12/13, K-RAS 12/13, N-RAS 12/13, H-RAS 61, K-RAS 61, N-RAS 61, and RET/PTC1. RESULTS No patient with EFVPTC had central lymph node metastasis, and in this group, 1 patient (4.5%) had a BRAF V600E mutation and 2 patients (9%) had RAS mutations. Of the patients with NFVPTC, none had central lymph node metastasis (P > .99) and 2 (11%) had a BRAF V600E mutation (P = .59). Of the patients with diffuse FVPTC, all had central lymph node metastasis (P < .001), and 2 (50%) had a BRAF V600E mutation (P = .06). CONCLUSIONS FVPTC consists of several distinct subtypes. Diffuse FVPTC seems to present and behave in a more aggressive fashion. It has a higher rate of central nodal metastasis and BRAF V600E mutation in comparison with EFVPTC and NFVPTC. Both EFVPTC and NFVPTC behave in a similar fashion. The diffuse infiltrative pattern and not just presence or absence of encapsulation seems to determine the tumor phenotype. Understanding the different subtypes of FVPTC will help guide appropriate treatment strategies.

Management of recurrent/persistent nodal disease in patients with differentiated thyroid cancer: A critical review of the risks and benefits of surgical intervention versus active surveillance

BACKGROUND The primary goals of this interdisciplinary consensus statement are to define the eligibility criteria for management of recurrent and persistent cervical nodal disease in patients with differentiated thyroid cancer (DTC) and to review the risks and benefits of surgical intervention versus active surveillance. METHODS A writing group was convened by the Surgical Affairs Committee of the American Thyroid Association and was tasked with identifying the important clinical elements to consider when managing recurrent/persistent nodal disease in patients with DTC based on the available evidence in the literature and the groups collective experience. SUMMARY The decision on how best to manage individual patients with suspected recurrent/persistent nodal disease is challenging and requires the consideration of a significant number of variables outlined by the members of the interdisciplinary team. Here we report on the consensus opinions that were reached by the writing group regarding the technical and clinical issues encountered in this patient population. CONCLUSIONS Identification of recurrent/persistent disease requires a team decision-making process that includes the patient and physicians as to what, if any, intervention should be performed to best control the disease while minimizing morbidity. Several management principles and variables involved in the decision making for surgery versus active surveillance were developed that should be taken into account when deciding how best to manage a patient with DTC and suspected recurrent or persistent cervical nodal disease.

Parathyroid localization: Inability to predict multiple gland involvement

Preoperative localization using various imaging techniques can accurately predict the location of solitary parathyroid adenomas in about 75% of patients. Its value has been questioned because of the high success rate of parathyroid exploration without localization. The ability of localization studies to differentiate preoperatively between patients with solitary adenomas and those with multiple gland disease would be valuable because bilateral exploration might be avoided in many cases. Ultrasonography, thallium-201/technetium-99m subtraction scintigraphy, and magnetic resonance imaging were used to evaluate 16 patients with primary hyperparathyroidism who were ultimately found at surgery to have multiple enlarged parathyroid glands. No single imaging technique was able to identify more than 53% of enlarged glands, and only four patients were accurately predicted preoperatively to have enlargement of multiple parathyroid glands. Existing imaging techniques cannot be relied on to predict multiple gland involvement preoperatively. Bilateral surgical exploration is mandatory in all patients with primary hyperparathyroidism.

Clinical utility of immunohistochemistry for the detection of the BRAF v600e mutation in papillary thyroid carcinoma

BACKGROUND BRAF V600E mutation is the most common genetic alteration in papillary thyroid cancer (PTC). We used a mutation-specific antibody for immunohistochemical (IHC) detection of the BRAF V600E mutation and correlated expression with clinicopathologic features. The study was designed to validate the accuracy and determine the clinical importance of IHC detection of the BRAF V600E mutation in PTC. METHODS Direct sequencing and IHC for BRAF V600E mutation was performed in 37 consecutive patients with PTCs. IHC was scored on an intensity proportion scale. IHC positive tumors were stratified into intensity categories. The categories were assessed for clinicopathologic variables, including age, extrathyroidal extension, lymphovascular invasion, and lymph node metastases. RESULTS A total of 25 PTCs were BRAF V600E-positive and 12 were BRAF mutation-negative on IHC. The BRAF V600E mutation-specific antibody had a sensitivity of 89% and specificity of 100% for detecting the mutation. Tumors with high-intensity staining were more likely to have extrathyroidal extension. CONCLUSION IHC is an accurate method for the detection of the BRAF V600E mutation in PTC, and its ability to quantify the mutation expression may serve as a better predictor of tumor behavior than molecular sequencing. It provides a potentially rapid, easily applicable, and economic alternative to current techniques.

Accuracy of frozen section in the evaluation of salivary tumors

The records of 333 patients who underwent surgery were reviewed to document the accuracy of frozen section in the evaluation of salivary gland tumors. Frozen sections were obtained in 310 patients. The final pathologic diagnoses included 210 benign tumors and 45 malignancies. The sensitivity for the detection of malignancy was 69%, and the specificity was 96%. The specific accuracy to correctly identify the type of malignancy present was only 51%. In four patients, a false-positive diagnosis of malignancy was made. Frozen section was much more accurate in the evaluation of benign salivary tumors. Forty-three of 45 Warthins tumors were correctly identified by frozen section. Two tumors thought to be Warthins tumors on frozen section proved to be low-grade mucoepidermoid carcinomas. One tumor reported to be a benign mixed tumor was actually a malignant mixed tumor. In this series of patients, frozen section proved to be no more accurate in the evaluation of salivary tumors than what has been reported in the literature for fine-needle aspiration biopsy.

No Need to Abandon Unilateral Parathyroid Surgery

Author(s): Hodin, Richard; Angelos, Peter; Carty, Sally; Chen, Herb; Clark, Orlo; Doherty, Gerard; Duh, Quan-Yang; Evans, Douglas B; Heller, Keith; Inabnet, William; Kebebew, Electron; Pasieka, Janice; Perrier, Nancy; Sturgeon, Cord

Relation of Final Intraoperative Parathyroid Hormone Level and Outcome Following Parathyroidectomy

OBJECTIVE To determine if final intraoperative parathyroid hormone (IOPTH) level predicts those at risk for recurrence after parathyroidectomy. Minimally invasive parathyroid exploration guided by preoperative imaging and IOPTH level is an accepted alternative to bilateral exploration for the treatment of primary hyperparathyroidism (HPT). However, additional enlarged, hypercellular parathyroid glands are present in some patients in whom IOPTH levels fall to normal after excision of a single adenoma. At least 15% of patients are normocalcemic with elevated PTH levels (PPTH) after parathyroidectomy. In these patients, a higher risk of recurrent HPT has been found. DESIGN Retrospective review of medical records. SETTING University teaching hospital. PATIENTS The records of all 194 patients who underwent successful initial parathyroidectomy for nonfamilial HPT in 2007 and 2008 by 1 surgeon were reviewed. MAIN OUTCOME MEASURES Intraoperative PTH level was measured prior to incision (baseline); at excision of the abnormal gland; at 5, 10, 15, and 20 minutes after excision; and at various additional times as needed. Of the patients, 71% underwent minimally invasive parathyroid exploration. Calcium, PTH, and 25-hydroxyvitamin D levels were measured during the first month after surgery in all patients and after 3 months or more in 80%. Patients were divided into 5 groups depending on the following final IOPTH levels: lower than 10 pg/mL (group l) (to convert PTH to nanograms per liter, multiply by 1.0); 10 to 19 pg/mL (group 2); 20 to 29 pg/mL (group 3); 30 to 39 pg/mL (group 4); and 40 pg/mL or higher (group 5). RESULTS Of the patients, 82% had a single adenoma, 9% had double adenomas, and 9% had 3 or more abnormal glands. The final IOPTH/baseline IOPTH value in groups 1 to 5 was 7%, 11%, 16%, 23%, and 26%, respectively. There was no significant difference in the preoperative calcium among the groups. All 3 patients with persistent HPT and 5 patients with PPTH were in group 5. One of the 96 patients in groups 1 and 2 and 5 of the 72 patients in groups 3 and 4 had PPTH at the last evaluation. CONCLUSION Patients with a final IOPTH level of 40 pg/mL or higher are at higher risk of having persistent HPT and should be followed up closely and indefinitely following parathyroidectomy.