Surgery for lymph node metastases of medullary thyroid carcinoma: A review.

Medullary thyroid carcinoma (MTC) is a neuroendocrine malignancy of the thyroid C cells that occurs in hereditary and sporadic clinical settings. Metastatic spread commonly occurs to cervical and mediastinal lymph nodes. MTC cells do not concentrate radioactive iodine and are not sensitive to hormonal manipulation, and therefore surgery is the most effective option for curative therapy, reduction in tumor burden, or effective palliation. In patients undergoing preventative surgery for hereditary MTC, central lymph node dissection should be considered if the calcitonin level is elevated. Preservation of parathyroid function in these young patients is of paramount importance. In patients with established primary tumors, systematic surgical removal of lymph node basins (compartmental dissection) should be guided by ultrasound mapping of lymph node metastases and level of serum calcitonin. A "berry-picking" approach is discouraged. Newly approved targeted molecular therapies offer wider treatment options for patients with progressive or metastatic disease.

Management of the Parathyroid Glands During Preventive Thyroidectomy in Patients With Multiple Endocrine Neoplasia Type 2.

OBJECTIVES: Patients with multiple endocrine neoplasia type 2 (MEN2) have mutations in the RET protooncogene and virtually all of them will develop medullary thyroid carcinoma. Family members identified by genetic testing are candidates for preventive thyroidectomy. Management of the parathyroids during thyroidectomy is controversial. Some experts advocate total parathyroidectomy with autotransplantation, whereas others recommend preserving the parathyroids in situ. METHODS: Between 1993 and 2000, we performed preventive thyroidectomies on 50 patients with MEN2A (group A). All patients had a central neck dissection (CND) combined with total parathyroidectomy and autotransplantation of parathyroid slivers to the nondominant forearm or to the neck. Between 2003 and the present, we performed 102 preventive thyroidectomies attempting to preserve the parathyroid glands in situ with an intact vascular pedicle (group B). Individual parathyroids were autotransplanted only if they appeared nonviable or could not be preserved intact. Central neck dissection was done only if the serum calcitonin was greater than 40 pg/mL. RESULTS: Permanent hypoparathyroidism occurred in 3 (6%) of 50 patients in group A, compared with 1 (1%) of 102 patients in group B (P = 0.1). After total thyroidectomy, no patient in either group developed permanent recurrent laryngeal nerve injury or hyperparathyroidism. Immediate postoperative serum calcitonin levels were in the normal range (<5 pg/mL) in 100 of 102 patients in group B. No patients in either group have died. Oncologic follow-up of patients in group B is in progress. CONCLUSIONS: In patients with MEN2A treated by preventive total thyroidectomy routine total parathyroidectomy with autotransplantation and CND gives excellent long-term results. However, preservation of the parathyroids in situ during preventive thyroidectomy combined with selective CND based on preoperative basal serum calcitonin levels is an effective and safe alternative that results in a very low incidence of hypoparathyroidism.

Biochemical cure after reoperations for medullary thyroid carcinoma: a meta-analysis.

BACKGROUND: Despite meticulous surgical techniques, calcitonin levels remain detectable in 40 % to 66 % of patients after initial surgery for medullary thyroid carcinoma (MTC), and the optimal surgical management for persistent or recurrent disease remains controversial. Previous studies suggest that biochemical cure, defined by normalization of postoperative calcitonin measurements, predicts disease-free survival. Reoperative approaches range from targeted removal of detectable disease to comprehensive compartment-oriented lymph node clearance. METHODS: A proportional meta-analysis of clinical case series of postoperative calcitonin clearance after reoperation for MTC was performed. Studies were obtained from PubMed, Embase, Scopus, and the Cochrane Library. RESULTS: Twenty-seven articles capturing data of 984 patients met the inclusion criteria for the meta-analysis. Overall, normalization of calcitonin after reoperation for MTC occurred in 16.2 % of patients [95 % confidence interval (CI) 14.0-18.5]. Stratified by operative procedure, targeted selective lymph node removal procedures had a normalization of calcitonin in 10.5 % of patients (95 % CI 6.4-14.7), while compartment-oriented procedures had a higher rate of normalization at 18.6 % (95 % CI 15.9-21.3). CONCLUSIONS: The rate of calcitonin normalization after reoperation for MTC is enhanced through use of a meticulous compartment-oriented lymph node dissection. Compartment-oriented lymph node dissection results in calcitonin normalization in 18.6 % of reoperative MTC patients and is the procedure of choice in patients in whom the goal is biochemical cure.

Anaplastic Thyroid Carcinoma, Version 2.2015.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Thyroid Carcinoma focuses on anaplastic carcinoma because substantial changes were made to the systemic therapy recommendations for the 2015 update. Dosages and frequency of administration are now provided, docetaxel/doxorubicin regimens were added, and single-agent cisplatin was deleted because it is not recommended for patients with advanced or metastatic anaplastic thyroid cancer.

Neuroendocrine tumors, version 1.2015.

Neuroendocrine tumors (NETs) comprise a broad family of tumors that may or may not be associated with symptoms attributable to hormonal hypersecretion. The NCCN Clinical Practice Guidelines in Oncology for Neuroendocrine Tumors discuss the diagnosis and management of both sporadic and hereditary NETs. This selection from the guidelines focuses on sporadic NETs of the pancreas, gastrointestinal tract, lung, and thymus.

Hereditary thyroid cancer syndromes and genetic testing.

This review focuses on both hereditary medullary thyroid cancer (MTC) and hereditary nonmedullary thyroid cancer (NMTC) and discusses the genetics, clinical diagnosis and evaluation, and surgical approach to treatment of these malignancies. Areas of innovation as well as areas of debate are highlighted and management recommendations are made.

Thyroid carcinoma, version 2.2014.

These NCCN Guidelines Insights focus on some of the major updates to the 2014 NCCN Guidelines for Thyroid Carcinoma. Kinase inhibitor therapy may be used to treat thyroid carcinoma that is symptomatic and/or progressive and not amenable to treatment with radioactive iodine. Sorafenib may be considered for select patients with metastatic differentiated thyroid carcinoma, whereas vandetanib or cabozantinib may be recommended for select patients with metastatic medullary thyroid carcinoma. Other kinase inhibitors may be considered for select patients with either type of thyroid carcinoma. A new section on "Principles of Kinase Inhibitor Therapy in Advanced Thyroid Cancer" was added to the NCCN Guidelines to assist with using these novel targeted agents.

Pheochromocytoma in an 8-year-old patient with multiple endocrine neoplasia type 2A: implications for screening.

Childhood pheochromocytoma in the setting of multiple endocrine neoplasia type 2 (MEN2) remains rare and has not been reported under the age of 12. We present an 8-year-old female with known MEN 2A, C634Y RET mutation, diagnosed with a 6 cm pheochromocytoma requiring laparoscopic adrenalectomy. Given this patient's age at diagnosis, screening guidelines should recommend annual screening beginning at age 8 for patients with MEN 2B or MEN 2A codons 630 or 634 RET mutations.

Risk factors affecting operative approach, conversion, and morbidity for adrenalectomy: a single-institution series of 402 patients.

BACKGROUND: Risk factors for selecting patients for open adrenalectomy (OA) and for conversion are limited in most series. This study aimed to investigate variables that are important in selecting patients for OA, predict risk of conversion from laparoscopic adrenalectomy (LA), and impact 30-day outcomes of OA and LA. METHODS: A retrospective cohort study of prospectively collected data was conducted. Patients (≥ 16 years old) who underwent adrenalectomy in the Division of General Surgery at Barnes-Jewish Hospital (1993-2010) were grouped by operative approach (LA vs. OA) and compared using nonparametric tests and regression analyses (α < 0.05). RESULTS: In total, 402 patients underwent 422 adrenalectomies. Compared to LA patients, those in the OA group were older (p = 0.02), had higher ASA scores (p = 0.04), larger tumor size (p < 0.01), and fewer functioning lesions (p < 0.01). OA patients more often required concurrent procedures (p < 0.01), had a longer operative time (p = 0.04), more intraoperative complications (p = 0.02), higher estimated blood loss (EBL), and larger transfusion requirement. Preoperative factors that predicted selection for OA were higher patient age (p = 0.01), higher ASA score (p = 0.03), larger tumor size (p < 0.01), nonfunctioning lesion (p < 0.01), diagnosis of adrenocortical carcinoma (p < 0.01), and the need for concomitant procedures (p < 0.01). Conversion to open or hand-assisted approach occurred in 6.2 % of LA patients. Preoperative risks for conversion included large tumor size (>8 cm) and need for concomitant procedures (p < 0.01). Multivariate analysis revealed that large indeterminate adrenal mass, adrenocortical carcinoma, tumor size (>6 cm), an open operation, conversion, concomitant procedures, operative time >180 min, and EBL >200 mL were predictors of 30-day morbidity. CONCLUSIONS: Adrenal tumor size and need for concurrent procedures significantly impact the selection of patients for OA, the likelihood of conversion, and perioperative morbidity. These metrics should be considered when assessing operative approach and risks for adrenalectomy.

Outcomes of resection of extra-adrenal pheochromocytomas/paragangliomas in the laparoscopic era: a comparison with adrenal pheochromocytoma.

INTRODUCTION: Laparoscopic adrenalectomy (LA) is the standard for removal of adrenal pheochromocytomas (pheos), but laparoscopic (LAP) resection of paragangliomas (PGs) is controversial. This study analyzes our results of resection of PGs in the LAP era. METHODS: A retrospective record review of all patients who underwent resection of intra-abdominal PGs from 1998 to 2011 was performed. Pre- and postoperative clinical, radiologic, biochemical, and pathologic data for LAP resection of PGs were compared with patients who underwent LA for adrenal pheo (LA pheo; n = 62). Statistical analysis was performed and data are reported as mean ± SD. RESULTS: Fifteen patients had resection of PGs (6 OPEN, 9 LAP) and 62 had LA pheo. Most common PG locations were perirenal or renal hilum (n = 6) and para-aortic (n = 4). One LAP PG was converted to OPEN due to inflammation from a prior biopsy. Mean age of LAP PGs was 45.3 ± 13.2 years, and mean tumor size was 3.3 ± 2.1 cm. OPEN PGs were larger (5.1 vs. 3.3 cm), had shorter operative times (173 vs. 254 min), and longer hospitalization (5.7 vs. 2.6 days) and ICU stays (1.33 vs. 0.22 days) compared with LAP PGs (p ≤ 0.05). Compared with LA pheo, operative times for LAP PG were significantly longer (254 vs. 175 min, p = 0.001) but other outcomes were similar. Complications occurred in 5.9 % of LA pheos, 22 % of LAP PGs and 67 % of OPEN PGs. CONCLUSIONS: Patients with paragangliomas can safely benefit from LAP resection with outcomes similar to adrenal pheos. In the absence of a need for contiguous organ resection, LAP resection of paragangliomas seems to be the preferred surgical approach.

Neuroendocrine tumors.

Neuroendocrine tumors comprise a broad family of tumors, the most common of which are carcinoid and pancreatic neuroendocrine tumors. The NCCN Neuroendocrine Tumors Guidelines discuss the diagnosis and management of both sporadic and hereditary neuroendocrine tumors. Most of the recommendations pertain to well-differentiated, low- to intermediate-grade tumors. This updated version of the NCCN Guidelines includes a new section on pathology for diagnosis and reporting and revised recommendations for the surgical management of neuroendocrine tumors of the pancreas.

Exclusion of malignancy in thyroid nodules with indeterminate fine-needle aspiration cytology after negative 18F-fluorodeoxyglucose positron emission tomography: interim analysis.

BACKGROUND: In all, 20% of fine-needle aspiration (FNA) biopsies of thyroid nodules have an indeterminate diagnosis; of these, 80% are found to be benign after thyroidectomy. Some previous reports indicate that positron emission tomography (PET) with (18)F-fluorodeoxyglucose (FDG) imaging may predict malignancy status. We now report results on the first 51 patients in the largest prospective study of FDG-PET in patients with an indeterminate thyroid nodule FNA. METHODS: Eligible patients had a dominant thyroid nodule that was palpable or >or=1 cm in greatest dimension as seen by ultrasonography, and indeterminate histology of the FNA biopsy specimen. Participants underwent preoperative neck FDG-PET alone or FDG-PET with computed tomography (FDG-PET/CT). Images were evaluated qualitatively and semiquantitatively using the maximum standardized uptake value (SUV(max)). Final diagnosis was determined by histopathologic analysis after thyroidectomy. Descriptive statistical analysis was performed. RESULTS: A total of 51 patients underwent preoperative FDG-PET or FDG-PET/CT. Studies without focally increased uptake localized to the lesion were considered negative. For all lesions (10 malignant, 41 benign), the sensitivity, specificity, positive-predictive value (PPV), and negative-predictive value (NPV) were 80%, 61%, 33%, and 93%, respectively. Postoperatively, two malignant and six benign lesions were found to be <1 cm by pathology examination; one lesion was not measured. When these lesions were excluded, the sensitivity, specificity, PPV, and NPV were 100%, 59%, 36%, and 100%, respectively. CONCLUSIONS: Based on these preliminary data, FDG-PET may have a role in excluding malignancy in thyroid nodules with an indeterminate FNA biopsy. This finding justifies ongoing accrual to our target population of 125 participants.

Combined [18F]Fluorodeoxyglucose positron emission tomography and computed tomography (FDG-PET/CT) for detection of recurrent, 131I-negative thyroid cancer.

BACKGROUND: Whole-body (131)I scintigraphy (WBS) and serial thyroglobulin measurement (Tg) are standard methods for detecting thyroid cancer recurrence after total/near total thyroidectomy and (131)I ablation. Some patients develop elevated Tg (Tg-positive) or there is clinical suspicion of recurrence, but WBS are negative (WBS-negative). This may reflect non-iodine-avid recurrence or metastasis. In 2002, the Centers for Medicare and Medicaid Services (CMS) approved positron emission tomography with [(18)F]fluorodeoxyglucose (FDG-PET) for Tg-positive/WBS-negative patients with follicular-cell-origin thyroid cancer. Limited data are available regarding the performance of combined FDG-PET/computed tomography (FDG-PET/CT) for detecting recurrent thyroid cancer in WBS-neg patients. METHODS: This retrospective review of prospectively collected data analyzed 65 patients who had FDG-PET/CT for suspected thyroid cancer recurrence (April 1998-August 2006). Patients were WBS-negative but were suspected to have recurrence based on Tg levels or clinical grounds. Suspected FDG-PET/CT abnormalities were reported as benign or malignant. Lesions were ultimately declared benign or malignant by surgical pathology or clinical outcome (disease progression). RESULTS: Of 65 patients who underwent FDG-PET/CT, 47 had positive FDG-PET/CT. Of the positive FDG-PET/CT, 43 studies were true positives, with 21 (49%) confirmed pathologically by surgical resection. The four false positives (3/4 confirmed pathologically) included an infundibular cyst, an inflamed supraclavicular cyst, pneumonitis, and degenerative disc disease. Of the 18 FDG-PET/CT studies that were negative, 17 were true negatives and one was a false negative (metastatic papillary carcinoma). Thus, FDG-PET/CT demonstrated a patient-based sensitivity of 98%, specificity of 81%, positive predictive value of 91%, and negative predictive value of 94%. CONCLUSIONS: FDG-PET/CT is useful for detecting thyroid cancer recurrence in WBS-negative patients, and can assist decision making.

Needle biopsy of incidentally discovered adrenal masses is rarely informative and potentially hazardous.

INTRODUCTION: The role of fine needle aspiration (FNA) biopsy in patients with incidentally discovered adrenal masses is limited. However, image-guided biopsy continues to be performed in this setting, in some cases before biochemical workup. The purpose of this study was to review the value of FNA biopsy of adrenal masses in patients referred to a large university endocrine surgical practice. METHODS: Patients referred to the endocrine surgery service at our institutions from 1997 through 2006 for evaluation of an adrenal mass were identified and those who underwent needle biopsy were selected for analysis. RESULTS: Of the 347 patients evaluated for adrenal masses, 22 (6.3%) had undergone needle biopsy before referral. Clinical presentations were incidentaloma (n = 15), suspected metastasis (n = 4), and symptomatic large mass (n = 3). In 10 cases, a radiology report had either suggested a biopsy or stated that the mass was "amenable" to biopsy. In the 15 patients with incidentaloma, 12 (80%) had nondiagnostic biopsy results and 2 showed pheochromocytoma. Biopsies were diagnostic in 2 of 4 patients with suspected metastasis and in 1 of 3 patients with a large symptomatic mass. There were 3 biopsy-related complications: 1 liver hematoma, 1 hemothorax, and 1 duodenal hematoma. No biochemical testing for pheochromocytoma was performed before biopsy in 10 patients, 5 of whom were ultimately diagnosed with pheochromocytoma. Biopsy results did not alter clinical management in any of the 22 patients in this study. CONCLUSIONS: FNA biopsy is not useful in the diagnostic workup of patients with incidentally discovered adrenal masses and rarely alters management in patients with resectable adrenal metastases and primary adrenal malignancies. Furthermore, biopsy in this setting can also be potentially hazardous. Language that suggests biopsy of adrenal masses should be avoided in radiology reports.

Metastatic disease to the breast: the Washington University experience.

BACKGROUND: Metastases to the breast occur rarely, but may be increasing in incidence as patients live longer with malignant diseases. The aim of this study is to characterize metastatic disease to the breast and to describe the management and prognosis of patients who present with this diagnosis. METHODS: A retrospective review of our institution's pathology and breast cancer databases was performed in order to identify patients with breast malignancies that were not of primary breast origin. Chart review provided additional information about the patients' primary malignancies and course of illness. RESULTS: Between 1991 and 2006, eighteen patients with metastatic disease to the breast of non-hematologic origin were identified and all had charts available for review. Among the 18 patients with disease metastatic to the breast, tissues of origin included 3 ovarian, 6 melanoma, 3 medullary thyroid, 3 pulmonary neuroendocrine, 1 pulmonary small cell, 1 oral squamous cell, and 1 renal cell. Overall mean survival after diagnosis of metastatic disease to the breast was 22.4 months. Treatment of metastases varied and included combinations of observation, surgery, radiation, and chemotherapy. Five patients (27.8%) required a change in management of their breast disease for local control. CONCLUSION: Due to the variable course of patients with metastatic disease, a multi-disciplinary approach is necessary for each patient with disease metastatic to the breast to determine optimal treatment. Based on our review, many patients survive for long periods of time and local treatment of metastases to the breast may be beneficial in these patients to prevent local complications.

Contralateral papillary thyroid cancer at completion thyroidectomy has no impact on recurrence or survival after radioiodine treatment.

BACKGROUND: This study investigated the rate of contralateral papillary thyroid cancer (PTC) in low-risk PTC patients who had completion thyroidectomy, and were referred for radioactive iodine (RAI) therapy. The study sought predictors of contralateral disease and examined the impact of contralateral disease in RAI-treated patients. METHODS: We reviewed 20 years of data from a prospective registry for 150 patients with PTC. These patients had undergone thyroid lobectomy, followed by completion thyroidectomy, and had been referred for RAI. RESULTS: Of the 150 patients, 41% had PTC in the contralateral lobe. There was no difference in the rate of contralateral disease in low-risk patients (age <45 years, T1 tumors, lymph node-negative) compared with the remainder. There were no significant differences between patients with or without contralateral disease with respect to primary tumor size, mean age, time to completion thyroidectomy, or metastatic lymph node disease. Logistic regression analyses showed no histologic parameters that correlated with contralateral disease. There were no recurrence or survival differences in patients with or without contralateral disease after resection and RAI. CONCLUSIONS: The prevalence of tumor in the contralateral lobe of low-risk patients with PTC is significant and warrants consideration for completion thyroidectomy and radioiodine treatment. Our results, however, suggest that contralateral disease does not have an impact on recurrence or survival after treatment.

Lymph node metastases in differentiated thyroid cancer under 2 cm.

BACKGROUND: The goal of this study was to evaluate the presence of lymph node metastasis in patients with T1 differentiated thyroid cancer (DTC) and determine prognostic significance for tumor recurrence and cancer-related death. METHODS: From a prospective tumor registry, we reviewed data from 551 patients with DTC who underwent total or subtotal thyroidectomy and who had primary tumor size

Medullary thyroid cancer.

The goal in managing patients who have MTC is to detect and surgically remove disease at an early stage. Tumor marker-based biochemical screening and DNA-based genetic screening have created the opportunity for effective prophylactic surgery in patients at risk for hereditary MTC. Complete surgical resection is critical for cure because cervical reoperation for persistent or recurrent disease benefits only select patients. With the advent of therapies that target the RET-activated pathways, new hope may be emerging for patients who have locally advanced or metastatic disease.

Expression profiles provide insights into early malignant potential and skeletal abnormalities in multiple endocrine neoplasia type 2B syndrome tumors.

Identifying the molecular basis for genotype-phenotype correlations in human diseases has direct implications for understanding the disease process and hence for the identification of potential therapeutic targets. To this end, we performed microarray expression analysis on benign (pheochromocytomas) and malignant (medullary thyroid carcinomas, MTCs) tumors from patients with multiple endocrine neoplasia (MEN) type 2A or 2B, related syndromes that result from distinctive mutations in the RET receptor tyrosine kinase. Comparisons of MEN 2B and MEN 2A MTCs revealed that genes involved in the process of epithelial to mesenchymal transition, many associated with the tumor growth factor beta pathway, were up-regulated in MEN 2B MTCs. This MEN 2B MTC profile may explain the early onset of malignancy in MEN 2B compared with MEN 2A patients. Furthermore, chondromodulin-1, a known regulator of cartilage and bone growth, was expressed at high levels specifically in MEN 2B MTCs. Chondromodulin-1 mRNA and protein expression was localized to the malignant C cells, and its high expression was directly associated with the presence of skeletal abnormalities in MEN 2B patients. These findings provide molecular evidence that associate the previously unexplained skeletal abnormalities and early malignancy in MEN 2B compared with MEN 2A syndrome.

Adrenal ganglioneuromas in children with multiple endocrine neoplasia type 2: a report of two cases.

CONTEXT: Pheochromocytomas of the adrenal gland are a common component of the multiple endocrine neoplasia type 2 (MEN2) syndromes. However, pure adrenal ganglioneuromas, an extremely rare pediatric tumor of neural crest origin composed of mature ganglion cells, have never been reported in association with MEN2 in humans. MEN2A is comprised of medullary thyroid carcinoma (MTC), pheochromocytoma, and parathyroid hyperplasia. MEN2B is characterized by MTC, pheochromocytoma, neural abnormalities of the gastrointestinal tract, and mucosal neuromas. EVIDENCE ACQUISITION: We report two pediatric patients, one with MEN2A and one with MEN2B, who developed isolated adrenal ganglioneuromas without evidence of pheochromocytomas. EVIDENCE SYNTHESIS: MEN2A and MEN2B are caused by activating mutations in the RET proto-oncogene, which encodes a tyrosine kinase receptor essential for signal transduction in neural crest-derived tissues, including the peripheral and enteric nervous systems, C cells of the thyroid gland, and chromaffin cells of the adrenal gland. Both pheochromocytomas and ganglioneuromas originate from neural crest cells. Interestingly, two mouse models of MEN2B exhibit adrenal ganglioneuroma formation. One mouse model develops only ganglioneuromas (but not pheochromocytomas) and expresses only one of the oncogenic RET isoforms. The other mouse model, created by site-directed mutagenesis to simulate the most common human mutation, develops both ganglioneuromas and pheochromocytomas. CONCLUSIONS: Given our two cases, our current understanding of the mouse models, and the common origins of all these tumor cell types, we recommend including ganglioneuromas as a rare, but not unexpected, component of the MEN2 syndromes.