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.

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.

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.

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.

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.

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.

Contemporary management of lymph node metastases from an unknown primary to the neck: I. A review of diagnostic approaches.

In an era of advanced diagnostics, metastasis to cervical lymph nodes from an occult primary tumor is a rare clinical entity and accounts for approximately 3% of head and neck malignancies. Histologically, two thirds of cases are squamous cell carcinomas (SCCs), with other tissue types less common in the neck. With modern imaging and tissue examinations, a primary tumor initially undetected on physical examination is revealed in >50% of patients and the site of the index primary can be predicted with a high level of probability. In the present review, the range and limitations of diagnostic procedures are summarized and the optimal diagnostic workup is proposed. Initial preferred diagnostic procedures are a fine-needle aspiration biopsy (FNAB) and imaging. This allows directed surgical biopsy (such as tonsillectomy), based on the preliminary findings, and prevents misinterpretation of postsurgical images. When no primary lesion is suggested after imaging and panendoscopy, and for patients without a history of smoking and alcohol abuse, molecular profiling of an FNAB sample for human papillomavirus (HPV) and/or Epstein-Barr virus (EBV) is important.

Contemporary management of lymph node metastases from an unknown primary to the neck: II. a review of therapeutic options.

Although uncommon, cancer of an unknown primary (CUP) metastatic to cervical lymph nodes poses a range of dilemmas relating to optimal treatment. The ideal resolution would be a properly designed prospective randomized trial, but it is unlikely that this will ever be conducted in this group of patients. Accordingly, knowledge gained from retrospective studies and experience from treating patients with known head and neck primary tumors form the basis of therapeutic strategies in CUP. This review provides a critical appraisal of various treatment approaches described in the literature. Emerging treatment options for CUP with metastases to cervical lymph nodes are discussed in view of recent innovations in the field of head and neck oncology and suitable therapeutic strategies for particular clinical scenarios are presented. For pN1 or cN1 disease without extracapsular extension (ECE), selective neck dissection or radiotherapy offer high rates of regional control. For more advanced neck disease, intensive combined treatment is required, either a combination of neck dissection and radiotherapy, or initial (chemo)radiotherapy followed by neck dissection if a complete response is not recorded on imaging. Each of these approaches seems to be equally effective. Use of extensive bilateral neck/mucosal irradiation must be weighed against toxicity, availability of close follow-up with elective neck imaging and guided fine-needle aspiration biopsy (FNAB) when appropriate, the human papillomavirus (HPV) status of the tumor, and particularly against the distribution pattern (oropharynx in the majority of cases) and the emergence rate of hidden primary lesions (<10% after comprehensive workup). The addition of systemic agents is expected to yield similar improvement in outcome as has been observed for known head and neck primary tumors.

Jugular and vagal paragangliomas: Systematic study of management with surgery and radiotherapy.

BACKGROUND: The definitive treatment for head and neck paraganglioma (PG) is surgical excision. Unfortunately, surgery, particularly of vagal paraganglioma (VPG; "glomus vagale") and foramen jugulare ("glomus jugulare") tumors, may be complicated by injuries to the lower cranial nerves, a high price to pay for treatment for a benign tumor. Alternatively these tumors may be followed without treatment, or irradiated. The purpose of this review was to compare the existing evidence concerning the efficacy and safety of surgery, external beam radiotherapy (EBRT), and stereotactic radiosurgery (SRS), for jugular paragangliomas (JPGs) and VPGs. METHODS: Relevant articles were reviewed using strict criteria for systematic searches. Forty-one surgical studies met the criteria which included 1310 patients. Twenty articles including 461 patients treated with EBRT, and 14 radiosurgery studies comprising 261 patients were also evaluated. Results were compared between treatment modalities using analysis of variance (ANOVA) tests. RESULTS: A total of 1084 patients with JPGs and 226 VPGs were treated with different surgical procedures. Long-term control of the disease was achieved in 78.2% and 93.3% of patients, respectively. A total of 715 patients with JPG were treated with radiotherapy: 461 with EBRT and 254 with SRS. Control of the disease with both methods was obtained in 89.1% and 93.7% of the patients, respectively. The treatment outcomes of a JPG treated with surgery or radiotherapy were compared. Tumor control failure, major complication rates, and the number of cranial nerve palsies after treatment were significantly higher in surgical than in radiotherapy series. The results of SRS and EBRT in JPGs were compared and no significant differences were observed in tumor control. Because only 1 article reported on the treatment of 10 VPGs with radiotherapy, no comparisons with surgery could be made. Nevertheless, the vagus nerve was functionally preserved in only 11 of 254 surgically treated patients (4.3%). CONCLUSION: There is evidence that EBRT and SRS offer a similar chance of tumor control with lower risks of morbidity compared with surgery in patients with JPGs. Although the evidence is based on retrospective studies, these results suggest that surgery should be considered only for selected cases, but the decision should be individual for every patient.

Merkel cell carcinoma of the head and neck.

Merkel cell carcinomas are uncommon, but aggressive, cutaneous malignancies of neuroendocrine differentiation. To the pathologist, these lesions appear as sheets of undifferentiated tumor cells with little cytoplasm and dense nuclear chromatin. They are members of the group of "small round blue cell tumors," which includes small cell carcinomas of the lung, lymphomas, and neuroblastomas. Analogous to other skin malignancies, Merkel cell carcinomas frequently arise in the head and neck region and are commonly found in the elderly population. Merkel cell carcinomas have a high propensity for regional and distant metastases, and recurrences are frequently seen. Surgical excision is the recommended first-line treatment followed by adjuvant radiation therapy. Because of the high incidence of occult regional metastasis, patients with clinical and radioghaphically negative necks should undergo elective dissection, irradiation, or preferably sentinel lymph node biopsy.

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.

Evaluation of hypercalcemia in relation to hyperparathyroidism.

Hypercalcemia, which results from the rate of calcium influx into the extracellular fluid exceeding the rate of calcium efflux from the extracellular fluid, has been reported as occurring in approximately 1% to 4% of the adult population in general, and anywhere from 0.5% to 3% of hospitalized adult populations. Hypercalcemia associated with primary hyperparathyroidism has frequently resulted in the development of pancreatitis and peptic ulcer disease; however, the pathophysiologic mechanism of this association remains uncertain. This article examines the etiology and differential diagnosis of hypercalcemia, in particular regarding its association with primary hyperparathyroidism.

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.

Assessing the impact of low baseline parathyroid hormone levels on surgical treatment of primary hyperparathyroidism.

OBJECTIVES/HYPOTHESIS: To compare patients with a parathyroid hormone index (iPTH) level less than 100 pg/mL (low baseline) with patients with an index level greater than 100 pg/mL (high baseline) relative to intraoperative iPTH levels (IOPTH), surgical findings, imaging, and outcome. STUDY DESIGN: Retrospective chart review. METHODS: : The medical records of 284 patients with primary hyperparathyroidism undergoing parathyroid exploration utilizing IOPTH were reviewed. One hundred fifty-eight patients with a low baseline iPTH level were compared with 144 patients with a high baseline iPTH level. Patients were correlated in regard to IOPTH results, surgical findings, preoperative localization imaging, and surgical outcome. RESULTS: There was no significant difference between the two groups in regard to recalcitrant disease. Twenty percent of the low baseline group of patients had multigland disease, versus 8% of the high baseline patients. The kinetic profile of iPTH degradation differed between the two groups, with the low baseline group demonstrating a significantly lower percentage drop compared to the high baseline group. CONCLUSIONS: Patients with preoperative low baseline iPTH levels are over two times more likely to have multigland disease than patients with high baseline levels. Preoperative imaging in this group appears to be less likely to yield a solitary adenoma, even in the absence of multigland disease. IOPTH degradation kinetics is variable between groups, resulting in the possibility of inconsistent correlation with complete resection. These findings suggest that the current IOPTH guidelines, with reference to adequacy of resection, may need to be amended, especially for patients with low baseline iPTH levels. Laryngoscope, 2009.

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.

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.