Impact of prophylactic central neck dissection on oncologic outcomes of papillary thyroid carcinoma: a review.

Prophylactic neck dissection (PND) for papillary thyroid carcinoma (PTC) is controversial. Our aim was to assess current levels of evidence (LE) according to the Oxford Centre for Evidence-based Medicine ( http://www.cebm.net/?O=1025 ) regarding the oncologic benefits of PND. Data were analyzed via MEDLINE keywords: PTC, differentiated thyroid carcinoma, PND, central lymph node metastases, central compartment, recurrence-free survival. There was conflicting evidence regarding the rate of reoperation for recurrence, with some studies showing a lower rate after PND with increased recurrence-free survival and a higher rate of undetectable pre- and post-ablation thyroglobulin levels (LE 4), whereas other studies did not show a difference (LE 4). Only one study (LE 4) showed improved disease-specific survival with PND. PND may improve recurrence-free survival, although this is supported by only a low LE. Current recommendations can only be based on low-level evidence.

Metastatic renal cell carcinoma to the thyroid with cervicothoracic venous tumor thrombosis.

INTRODUCTION: Metastatic renal cell carcinoma (RCC) represents 25%-42% of metastatic thyroid malignancies. Propensity for RCC to demonstrate intravascular extension to the inferior vena cava is well documented. We present an analogous phenomenon of intravascular extension to the internal jugular vein (IJV) from thyroid gland metastasis. METHODS: A 69-year-old male presented with metastatic RCC of the right thyroid lobe. Imaging demonstrated tumor thrombosis of the ipsilateral IJV, extending inferiorly to the junction of the brachiocephalic, subclavian, and internal jugular veins within the mediastinum. RESULTS: Surgical excision required control of both the IJV in the neck and mediastinal venous great vessels via sternotomy, prior to subtotal thyroidectomy and venotomy for en bloc resection. CONCLUSION: This case report describes metastatic RCC to the thyroid gland with cervicothoracic venous tumor thrombosis successfully treated with subtotal thyroidectomy, sternotomy for venotomy and tumor thrombectomy, and preservation of IJV conduit.

Thyroidectomy Outcomes in Patients Identified With RET Pathogenic Variants Through a Population Genomic Screening Program.

Importance: Population-based genomic screening can facilitate early detection of medullary thyroid carcinoma (MTC) in patients with pathogenic/likely pathogenic (P/LP) RET variants. Objective: To evaluate the clinical treatment and patient outcomes after identification of P/LP RET proto-oncogene variants associated with the risk of MTC via a population genomic screening program. Design, Setting, Participants: This retrospective cross-sectional study was completed between June 1, 2016, and May 31, 2022, for a mean follow-up period of 22.4 months (range, 2-76 months). The study included patients who were identified as having P/LP RET variants through a population genomic screening program at a rural tertiary care center and who underwent thyroidectomy after results disclosure. Main Outcomes and Measures: The outcomes of interest were preoperative evaluation and treatment-related outcomes. Measures included imaging and laboratory findings, extent of surgery, pathologic diagnosis, and staging. Results: Seventy-five patients were identified as having P/LP RET variants exclusively through genomic screening. Twenty of these patients (27%; 11 women [55%] and 9 men [45%]; median age, 48 years [range, 22-73 years]) underwent total thyroidectomy; 13 of these patients (65%) also had a central neck dissection. No patients had clinically apparent disease at the time of surgery. Pathologic findings indicated MTC for 12 patients and papillary thyroid carcinoma in 2. Of patients with MTC, 10 had stage I disease, 1 had stage II disease, 1 had stage III disease, and none had stage IV disease. Based on postoperative surveillance imaging and laboratory results, no patient had evidence of recalcitrant disease. Conclusions and Relevance: In this cross-sectional study, all malignant neoplasms identified on surgical pathology were clinically occult, with surgical intervention based solely on the identification of the P/LP RET variant via population genomic screening. This finding suggests that genomic screening may provide opportunities for early detection and treatment of MTC, with the potential for improved patient outcomes.

The surgical management of renal hyperparathyroidism.

Secondary and tertiary hyperparathyroidism (HPT) develop in patients with renal failure due to a variety of mechanisms including increased phosphorus and fibroblast growth factor 23 (FGF23), and decreased calcium and 1,25-dihydroxy vitamin D levels. Patients present with various bone disorders, cardiovascular disease, and typical laboratory abnormalities. Medical treatment consists of controlling hyperphosphatemia, vitamin D/analog and calcium administration, and calcimimetic agents. Improved medical therapies have led to a decrease in the use of parathyroidectomy (PTX). The surgical indications include parathyroid hormone (PTH) levels >800 pg/ml associated with hypercalcemia and/or hyperphosphatemia despite medical therapy. Other indications include calciphylaxis, fractures, bone pain or pruritis. Transplant recipients often show decreased PTH, calcium and phosphorus levels, but some will have persistent HPT. Evidence suggests that PTX may cause deterioration in renal graft function in the short-term calling into the question the indications for PTX in these patients. Pre-operative imaging is only occasionally helpful except in re-operative PTX. Operative approaches include subtotal PTX, total PTX with or without autotransplantation, and possible thymectomy. Each approach has its proponents, advantages and disadvantages which are discussed. Intraoperative PTH monitoring has a high positive predictive value of cure but a poor negative predictive value and therefore is of limited utility. Hypocalcemia is the most common complication requiring aggressive calcium administration. Benefits of surgery may include improved survival, bone mineral density and alleviation of symptoms.

Thyroid incidentalomas: to treat or not to treat.

Incidental lesions of the thyroid gland are an increasing problem facing clinicians. While asymptomatic palpable lesions are detected in only 4-7% of the population, currently available imaging modalities are sensitive enough to detect lesions in 20-30% of the population. Guidelines for managing these incidentalomas are limited, largely due to lack of well-powered prospective studies. This review will address the currently available data on thyroid incidentalomas, detected through clinical examination, cross-sectional imaging, ultrasound, and PET scans. We will focus on the modalities of detection and risk of malignancy, further investigation and management options and the deficiencies therein. We propose a pragmatic algorithm when faced with this clinical dilemma under differing circumstances.

The role of intraoperative measurement of parathyroid hormone in parathyroid surgery.

Technological developments have significantly contributed to the rapid evolution of the surgical management of parathyroid disorders. The ability to physiologically determine the intraoperative status of the patient is now possible through the assessment of changing levels of intact parathyroid hormone (PTH) during surgery. In most patients with primary hyperparathyroidism, this method provides biochemical confirmation of hyperfunctional gland removal, and is predictive of a eucalcemic state and surgical cure. Patients with renal-induced disease (excluding tertiary hyperparathyroidism) do not follow the same kinetic decline in PTH and are therefore less likely to benefit from this modality. An emerging population of patients with primary disease and lower baseline levels of intact PTH appear to demonstrate a greater likelihood of manifesting multiple gland disease and do not follow a consistently predictable kinetic degradation profile. Although this category of patients will require further investigation, potentially resulting in modification of the utility of intraoperative determination of PTH levels, it is clear that this modality represents a very powerful technique which has significantly enhanced the surgical treatment of parathyroid disease.

Mesenchymal chondrosarcoma of the head and neck.

Mesenchymal chondrosarcoma of the head and neck is an uncommon tumor with a potential for exhibiting highly aggressive behavior. When these tumors arise in the head and neck region, they appear to have a predilection for the maxillofacial skeleton; less often, they may involve other soft tissue sites in the head and neck. The diagnosis is challenging and may be assisted by molecular pathologic techniques when only limited tissue is available for analysis. Management is primarily surgical. Although adjuvant radiation appears to convey some benefit by reducing tumor bulk when these lesions have extended beyond bony confines, there is no evidence to suggest that this is associated with improved outcome. Chemotherapy does not appear to be effective in the limited experience documented thus far. Patients with complete local control following resection should be followed closely for development of distant metastasis, which signifies a worse clinical outcome. Future effective therapy may be found in the identification of molecular targets responsive to adjuvant chemotherapy or biologic modifiers.

Elective and therapeutic selective neck dissection.

Selective neck dissection is a modification of the more comprehensive modified radical or radical neck dissection that is designed to remove only those nodal levels considered to be at risk for harboring nodal metastases. The role of selective neck dissection continues to evolve: while initially designed as a staging and diagnostic procedure for patients without clinical evidence of nodal disease, a growing body of literature suggests that selective neck dissection has a therapeutic role in patients with clinical and histologic evidence of nodal metastases. The rationale behind selective neck dissection, its application in the clinically negative but histologically node-positive neck and the extended application of selective neck dissection in patients with clinical evidence of nodal disease are discussed.

Morphoproteomic and pharmacoproteomic rationale for mTOR effectors as therapeutic targets in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) has a relatively high mortality rate and poor prognosis. Recently, we showed that overexpression of phosphorylated (p) nuclear factor-kappaB (NF-kappaB) in squamous cell carcinoma of the tonsil (SCCT) and high grade dysplasia is associated with a poor prognosis. Because the mammalian target of the rapamycin (mTOR) pathway contributes to the activation of NF-kappaB through immunophilin/mTOR signaling, we investigated: (a) the immunohistochemical expression and state of activation and potential clinical significance of components of the mTOR signal transduction pathway in SCCT patients (morphoproteomics); and (b) the inhibitory effects of rapamycin on the growth and state of activation of mTOR in 2 HNSCC cell lines (pharmacoproteomics). Archival biopsy materials from 39 patients with SCCT were studied by immunohistochemistry for the expression of p-mTOR (Ser 2448), and p-p70S6K (Thr 389), and/or cyclin D1. Results for SCCT were compared with adjacent non-neoplastic epithelium, when present, and with normal tonsillar epithelium from approximately age-matched controls; clinical outcomes were also assessed. SCCT showed mTOR (Ser 2448) expression in 93% (30/32 cases) with 2+ or 3+ plasmalemmal and/or cytoplasmic intensity in 84% vs 42% in surface epithelium from normal tonsils (p <0.001). The mean combined expression score (signal intensity x percentage of positive cells) for p-p70S6K was significantly greater in the SCCT group vs adjacent non-neoplastic squamous epithelium and normal tonsillar epithelium of the control group (p <0.05). A relationship existed between higher p-p70S6K expression levels in the non-neoplastic squamous epithelium adjacent to the SCCT and increased risk of death from disease (hazard ratio = 7.9; 95% confidence interval (CI) = 2.1 to 29.9; p = 0.002). There was also a relationship between nuclear expression of cyclin D1 in SCCT and shortened recurrence-free survival (p = 0.015). Two human HNSCC cell lines, SCC-15 and FaDu, were incubated with and without rapamycin to assess its impact on growth and on the expression of p-mTOR. Rapamycin in a dose-dependent fashion inhibited growth more in SCC-15, which correlated with a greater reduction in constitutively activated p-mTOR (Ser 2448) as shown by Western blotting. In conclusion, these morphoproteomic and pharmacoproteomic data collectively provide a rationale for selecting mTOR effectors as therapeutic targets in HNSCC.

Update on primary head and neck mucosal melanoma.

Primary mucosal melanomas (PMMs) of the head and neck are uncommon malignancies that arise mainly in the nasal cavity and paranasal sinuses, followed by the oral cavity. The mainstay of treatment is radical surgical resection followed by adjuvant radiotherapy in selected patients with high-risk features. Multimodality therapy has not been well studied and is not standardized. Adjuvant radiotherapy seems to improve locoregional control but does not improve overall survival (OS). Elective neck dissection is advocated in patients with oral PMM. Systemic therapy should be considered only for patients with metastatic or unresectable locoregional disease. Despite improvements in the field of surgery, radiotherapy, and systemic therapy, patients with PMM still face a very unfavorable prognosis (5-year disease-free survival [DFS] <20%) with high rates of locoregional recurrence and distant metastasis. The present review aims to summarize the current state of knowledge on the molecular biology, pathological diagnosis, and management of this disease.

Nuclear factor-kappaB pathway as a therapeutic target in head and neck squamous cell carcinoma: pharmaceutical and molecular validation in human cell lines using Velcade and siRNA/NF-kappaB.

BACKGROUND: Nuclear factor-kappaB (NF-kappaB) is synthesized in the cytoplasm, complexed with its inhibitor, I-kappaB, and NF-kappaB is released in an activated (phosphorylated) form following phosphorylation of I-kappaB and proteasomal degradation of the NF-kappaB.p-kappaB complex. The free p-NF-kappaB can then be translocated to the nucleus where it effects transcriptional activation of genes leading to the synthesis of proteins that are generally pro-growth and anti-apoptosis. OBJECTIVE: To gain insight into the role of the NF-kappaB pathway in head and neck squamous cell carcinoma (HNSCC), we selected two HNSCC cell lines, SCC-15 of lingual origin and FaDu of pharyngeal origin, with constitutively activated (phosphorylated) NF-kappaB. We assessed the impact of interrupting the NF-kappaB pathway at the level of proteasomal degradation using Velcade (bortezomib), a proteasome inhibitor, and at the pretranslational level in the synthesis of NF-kappaB using a small interfering RNA (siRNA). RESULTS: Velcade produced a dose-dependent inhibition of cell growth in both cell lines. At 30 nM, Velcade inhibited cell growth in the SCC-15 cell line by 40%. In both cell lines, Velcade induced nuclear overexpression of p21(WAF1), an inhibitor of G1 cell cycle progression, which appeared to be independent of p53 expression. Addition of siRNA augmented the inhibitory effects of Velcade in FaDu cells; siRNA/NF-kappaB alone led to a 48% decline in basal expression of NF-kappaB protein levels and effected a 25% inhibition of cell growth. In the presence of Velcade (30 nM), siRNA/NF-kappaB increased growth inhibition from 43 to 65%. CONCLUSIONS: The mechanisms involved in growth inhibitory effects of Velcade on HNSCC cell lines include the NF-kappaB pathway, suggesting the possible therapeutic use of Velcade or other NF-kappaB pathway inhibitors (eg, curcumin). The data also suggest that combining siRNA/NF-kappaB with Velcade might achieve greater reduction in the growth of HNSCC in patients with constitutively activated NF-kappaB.

Current philosophy in the surgical management of neck metastases for head and neck squamous cell carcinoma.

Neck dissection is an important treatment for metastases from upper aerodigestive carcinoma; an event that markedly reduces survival. Since its inception, the philosophy of the procedure has undergone significant change from one of radicalism to the current conservative approach. Furthermore, nonsurgical modalities have been introduced, and, in many situations, have supplanted neck surgery. The refinements of imaging the neck based on the concept of neck level involvement has encouraged new philosophies to evolve that seem to benefit patient outcomes particularly as this relates to diminished morbidity. The purpose of this review was to highlight the new paradigms for surgical removal of neck metastases using an evidence-based approach.

Management of sarcomas of the head and neck in adults.

Sarcomas account for less than 1% of all malignant neoplasms occurring in the head and neck in adults. These tumors exhibit variable growth and degrees of aggressiveness which are primarily dependent on histologic grade. The pattern of growth demonstrated by sarcomas is generally by local advancement with high-grade tumor exhibiting extensive involvement of adjacent visceral and neurovascular structures. Regional metastasis is uncommon. Etiologic considerations include the tumorigenic effects of prior external beam radiotherapy and the development of second malignancies in the form of sarcomas. The clinical presentation of these neoplasms is variable and dependent on subsite of involvement as well as the aggressiveness of tumor growth. Histologic diagnosis is frequently challenging, often requiring the aid of immunohistochemical staining techniques. Treatment is predominantly surgical, utilizing wide local excision where en-bloc resection is feasible. Radiotherapy, by means of external beam or implant, plays an important adjunctive role in management, especially for tumors where en-bloc resection with margin control is not possible. Chemotherapy regimens are available for soft tissue neoplasms and osteosarcoma and are primarily designed to improve local control. Survival is predicted on the incidence of local recurrence and risk of distant metastasis, both of which are influenced by tumor grade. Low-grade tumors exhibit improved survival over that of less differentiated tumors.

Management of malignant sublingual salivary gland tumors.

The majority of tumors of the sublingual gland are malignant, with adenoid cystic carcinoma and mucoepidermoid carcinoma being the most frequent. Many other malignant tumor types have also been reported. The sublingual gland anatomically is not a unit organ and while it is described anatomically as being confined to the anterior floor of the mouth, salivary tissue may be located laterally along the submandibular duct and posterior floor of the mouth. Diagnosis should be suspected when any thickening or raised lesion presents in this area and a biopsy performed to confirm malignancy before planning further treatment. Surgery is the treatment of choice, and should include an en-block resection of the anterior floor of mouth as a minimum, and may include a portion of mandible, as well as a supraomohyoid neck dissection. Adjuvant radiotherapy should be considered in most of the patients after surgical excision.

Paragangliomas of the head and neck.

Paragangliomas are neuroendocrine tumors derived from the extra-adrenal paraganglia of the autonomic nervous system. Within the head and neck, they are generally defined and named according to their site of origin, and may be found frequently neighboring vascular structures. Physiologic activity is rare in these neoplasms and they may exhibit patterns of inheritance which predispose their occurrence in families, often with multicentricity. These tumors generally exhibit a slow rate of growth, most often presenting asymptomatically as a space occupying mass lesion noted clinically or radiographically. The most common paraganglioma of the head and neck is the carotid body tumor followed by the jugulo-tympanic and vagal varieties. Other rare sites where this tumor may occur include; the larynx, sinonasal chambers and orbit. Diagnosis is generally made through a combination of clinical findings and radiographic studies. Magnetic resonance represents the most important imaging modality for the evaluation and characterization of suspected head and neck paraganglioma. Definitive management for these lesions should be carefully considered in relation to both tumor and patient-oriented factors, especially in regard to the potential morbidity of treatment. Surgery and radiation therapy represent the main treatment modalities for paraganglioma. The selection of treatment depends on the size, location, and biologic activity of the tumor as well as the overall fitness of the patient. Although radiotherapy may be effective in arresting growth of these tumors, rarely is the neoplasm eliminated without surgical resection. Surgery may be associated with significant morbidity, primarily as a consequence of incurring major cranial nerve injury. Patient selection (relative to age and medical condition) should be carefully considered prior to recommending aggressive surgery for paragangliomas of head and neck, especially in those patients at risk for disabling surgical morbidity.

Directed parathyroid exploration: evolution and evaluation of this approach in a single-institution review of 346 patients.

OBJECTIVES/HYPOTHESIS: Critical evaluation of a directed exploration protocol used by a single surgeon in the management of surgical parathyroid disease. STUDY DESIGN: Retrospective chart review was made of patients surgically managed for hyperparathyroidism at an academic tertiary care center. METHODS: Three hundred forty-six patients were evaluated for biochemically proven hyperparathyroidism between March 1995 and February 2002. A directed exploration protocol was implemented in appropriately selected patients with primary hyperparathyroidism and in patients with secondary or tertiary hyperparathyroidism requiring repeat operation. The protocol included preoperative technetium-99m sestamibi imaging for hyperfunctional parathyroid localization, targeted neck exploration, rapid intraoperative parathyroid hormone determination, and limited-stay discharge from the ambulatory surgical recovery unit. Data collection was accomplished by entering patient evaluation, management, and outcome information prospectively into collective case report forms. A retrospective analysis of the data was conducted for the purpose of evaluating the effectiveness of the protocol. RESULTS: Sustained normocalcemia beyond 6 months postoperatively was achieved in 323 of 327 (99%) patients with primary hyperparathyroidism. Eighty-four percent (84%) of patients with secondary or tertiary hyperparathyroidism achieved normocalcemia or had resolution of symptoms as a measure of therapeutic success. The complication rate for the entire series of patients was 2.8%. Ninety-two percent of positive findings on sestamibi scan correctly predicted the location of an adenoma, whereas a negative finding accurately predicted the absence of an enlarged gland in a "usual" location in 81% of patients. Twenty-six patients (9%) had a false-positive finding on the scan, whereby a solitary adenoma was found contralateral to the side indicated by the scan. Overall, the positive predictive value for sestamibi imaging in the series was 91%. Intraoperative parathyroid hormone determination yielded an overall rate of reduction of 80% from preoperative levels during directed exploration. Sustained normocalcemia was achieved in all patients in whom intraoperative parathyroid hormone determination demonstrated a minimum decline of 50% from preoperative levels following resection of hyperfunctional parathyroid tissue (adenoma[s]). The majority (72%) of patients were managed in an outpatient (ambulatory surgery) setting and were discharged to home within 8 to 12 hours after surgery. CONCLUSION: The directed exploration protocol for surgical management of hyperparathyroidism generated surgical rates of success that were as good as and, in most cases, improved over that of traditional bilateral exploration. This achievement was associated with low morbidity and reduced time and facility utilization, conveying improved cost-effectiveness. This surgical strategy should serve to enhance the capability of the surgeon to safely and efficiently manage the majority of patients with surgical parathyroid disease.

Strobovideolaryngoscopy in the management of acute laryngeal trauma.

Surgical intervention in the management of acute laryngeal trauma can sometimes pose a difficult decision. The objective of this study is to evaluate the effectiveness of strobovideolaryngoscopy (SVL) in determining the course of management for patients sustaining acute laryngeal trauma. A 20-year retrospective study of patients presenting with acute laryngeal trauma was performed in order to determine if the addition of SVL during the study period changed the management of certain acute laryngeal injuries. Patients sustaining blunt laryngeal trauma evaluated at our institution from 1981 to the present were reviewed. There were 40 patients identified that were grouped by severity according to the Schaefer classification. Analysis included mechanism of injury, clinical presentation, assessment, treatment, and outcome. Group 1 injuries were the most common, with motor vehicle accident (MVA) the most frequent mechanism of injury. Initial assessment included fiberoptic laryngoscopy and computed tomography (CT) imaging in all patients not requiring immediate exploration. SVL was used in 20 patients, with 7 undergoing stroboscopy within 24 hours of presentation. All 7 patients were managed conservatively without surgical intervention or the need to establish an alternative airway. SVL improves the clinical assessment of patients with acute laryngeal injury. This study supports its use and found it to be an important factor in determining the need for surgical intervention. SVL may also shorten the hospital stay in these patients.

Genetics of hereditary head and neck paragangliomas.

BACKGROUND: The purpose of this study was to give an overview on hereditary syndromes associated with head and neck paragangliomas (HNPGs). METHODS: Our methods were the review and discussion of the pertinent literature. RESULTS: About one third of all patients with HNPGs are carriers of germline mutations. Hereditary HNPGs have been described in association with mutations of 10 different genes. Mutations of the genes succinate dehydrogenase subunit D (SDHD), succinate dehydrogenase complex assembly factor 2 gene (SDHAF2), succinate dehydrogenase subunit C (SDHC), and succinate dehydrogenase subunit B (SDHB) are the cause of paraganglioma syndromes (PGLs) 1, 2, 3, and 4. Succinate dehydrogenase subunit A (SDHA), von Hippel-Lindau (VHL), and transmembrane protein 127 (TMEM127) gene mutations also harbor the risk for HNPG development. HNPGs in patients with rearranged during transfection (RET), neurofibromatosis type 1 (NF1), and MYC-associated factor X (MAX) gene mutations have been described very infrequently. CONCLUSION: All patients with HNPGs should be offered a molecular genetic screening. This screening may usually be restricted to mutations of the genes SDHD, SDHB, and SDHC. Certain clinical parameters can help to set up the order in which those genes should be tested.

Vascularized tissue to reduce fistula following salvage total laryngectomy: a systematic review.

OBJECTIVES/HYPOTHESIS: Pharyngocutaneous fistulae (PCF) are known to occur in nearly one-third of patients after salvage total laryngectomy (STL). PCF has severe impact on duration of admission and costs and quality of life and can even cause severe complications such as bleeding, infection and death. Many patients need further surgical procedures. The implications for functional outcome and survival are less clear. Several studies have shown that using vascularized tissue from outside the radiation field reduces the risk of PCFs following STL. This review and meta-analysis aims to identify the evidence base to support this hypothesis. DATA SOURCES: English language literature from 2004 to 2013 REVIEW METHODS: We searched the English language literature for articles published on the subject from 2004 to 2013. RESULTS: Adequate data was available to identify pooled incidence rates from seven articles. The pooled relative risk derived from 591 patients was 0.63 (95% CI: 0.47 to 0.85), indicating that patients who have flap reconstruction/reinforcement reduced their risk of PCF by one-third. CONCLUSION: This pooled analysis suggests that there is a clear advantage in using vascularized tissue from outside the radiation field in the laryngectomy defect. While some studies show a clear reduction in PCF rates, others suggest that the fistulae that occur are smaller and rarely need repair.