Kevin T. Brumund

Metastases to the Thyroid: A Review of the Literature from the Last Decade

BACKGROUND Although clinically evident metastases of nonthyroid malignancies (NTMs) to the thyroid gland are uncommon, it is important to suspect them in patients who present with a new thyroid mass and a history, however far back, of prior malignancy. In fact, metastases from NTMs to the thyroid gland have been reported in 1.4%-3% of all patients who have surgery for suspected cancer in the thyroid gland. Here we review the literature over the last decade regarding this topic. SUMMARY Based on recent literature, the most common NTMs that metastasize to the thyroid gland are renal cell (48.1%), colorectal (10.4%), lung (8.3%), and breast carcinoma (7.8%), and sarcoma (4.0%). Metastases of NTMs to the thyroid are more common in women than men (female to male ratio=1.4 to 1) and in nodular thyroid glands (44.2%). The mean and median intervals between diagnosing NTMs and their metastases to thyroid gland are 69.9 and 53 months, respectively. In 20% of cases the diagnosis of the NTM and its metastases to the thyroid was synchronous. Recent reports indicate that there is a higher frequency of sarcoma metastasizing to the thyroid gland than reported in prior years. Fine-needle aspiration biopsy (FNAB) of thyroid masses is useful in diagnosis of thyroid metastases. However, this requires information about the NTM so that the proper antibodies can be used for immunohistochemical analysis; therefore it is of lesser utility if the NTM is occult. In patients with preexisting thyroid pathology the FNAB diagnosis can be more difficult due to more than one lesion being present. CONCLUSIONS It is important to keep in mind that the thyroid gland can be a site of metastases for a variety of tumors when evaluating a thyroid nodule, especially in a patient with a prior history of malignancy. In patients with thyroid lesions and a history of malignant disease, regardless of time elapsed since the initial diagnosis of the primary neoplasm, disease recurrence or progression of malignancy must be considered until proven otherwise.

Electronic cigarettes induce DNA strand breaks and cell death independently of nicotine in cell lines

OBJECTIVES Evaluate the cytotoxicity and genotoxicity of short- and long-term e-cigarette vapor exposure on a panel of normal epithelial and head and neck squamous cell carcinoma (HNSCC) cell lines. MATERIALS AND METHODS HaCaT, UMSCC10B, and HN30 were treated with nicotine-containing and nicotine-free vapor extract from two popular e-cigarette brands for periods ranging from 48 h to 8 weeks. Cytotoxicity was assessed using Annexin V flow cytometric analysis, trypan blue exclusion, and clonogenic assays. Genotoxicity in the form of DNA strand breaks was quantified using the neutral comet assay and γ-H2AX immunostaining. RESULTS E-cigarette-exposed cells showed significantly reduced cell viability and clonogenic survival, along with increased rates of apoptosis and necrosis, regardless of e-cigarette vapor nicotine content. They also exhibited significantly increased comet tail length and accumulation of γ-H2AX foci, demonstrating increased DNA strand breaks. CONCLUSION E-cigarette vapor, both with and without nicotine, is cytotoxic to epithelial cell lines and is a DNA strand break-inducing agent. Further assessment of the potential carcinogenic effects of e-cigarette vapor is urgently needed.

EGFR Kinase Promotes Acquisition of Stem Cell-Like Properties: A Potential Therapeutic Target in Head and Neck Squamous Cell Carcinoma Stem Cells

Members of the EGFR/ErbB family of tyrosine kinases are found to be highly expressed and deregulated in many cancers, including head and neck squamous cell carcinoma (HNSCC). The ErbB family, including EGFR, has been demonstrated to play key roles in metastasis, tumorigenesis, cell proliferation, and drug resistance. Recently, these characteristics have been linked to a small subpopulation of cells classified as cancer stem cells (CSCs) which are believed to be responsible for tumor initiation and maintenance. In this study, we investigated the possible role of EGFR as a regulator of “stemness” in HNSCC cells. Activation of EGFR by the addition of EGF ligand or ectopic expression of EGFR in two established HNSCC cell lines (UMSCC-22B and HN-1) resulted in the induction of CD44, BMI-1, Oct-4, NANOG, CXCR4, and SDF-1. Activation of EGFR also resulted in increased tumorsphere formation, a characteristic ability of cancer stem cells. Conversely, treatment with the EGFR kinase inhibitor, Gefinitib (Iressa), resulted in decreased expression of the aforementioned genes, and loss of tumorsphere-forming ability. Similar trends were observed in a 99.9% CD44 positive stem cell culture derived from a fresh HNSCC tumor, confirming our findings for the cell lines. Additionally, we found that these putative cancer stem cells, when treated with Gefitinib, possessed a lower capacity to invade and became more sensitive to cisplatin-induced death in vitro. These results suggest that EGFR plays critical roles in the survival, maintenance, and function of cancer stem cells. Drugs that target EGFR, perhaps administered in combination with conventional chemotherapy, might be an effective treatment for HNSCC.

Frontolateral vertical partial laryngectomy without tracheotomy for invasive squamous cell carcinoma of the true vocal cord: a 25-year experience

On the basis of an inception cohort of 270 patients with a previously untreated invasive squamous cell carcinoma of the true vocal cord (232 T1N0M0, 35 T2N0M0, and 3 T3N0M0) and a minimum of 3 years of follow-up, the authors analyze the oncological and functional outcomes following frontolateral vertical partial laryngectomy without tracheotomy. The 5-year Kaplan-Meier actuarial survival estimate ranged from 83.1% for T1 tumors to 67.2% for T2 tumors (p = .005). On univariate analysis, a significant statistical relationship was noted between reduced survival and the following variables: increased age, increased Charlson comorbidity index score over grade 0, increased tobacco intake, increased alcohol intake, increased T stage, local failure, nodal failure, and development of a metachronous second primary cancer. The hospital mortality rate was 0.4%. A significant postoperative surgical complication was noted in 49 patients (18.1%). The predominant significant surgical complication was wound infection (19 patients; 7%), followed by seroma and major subcutaneous emphysema. No significant statistical relationship was noted in a comparison of each significant postoperative complication (including postoperative death) with the variables under analysis. The incidence of secondary tracheotomy was 0.4%. The incidence of completion laryngectomy due to functional problems was 0%. The 5-year Kaplan-Meier actuarial local control estimate was 91% for T1 tumors and 68.7% for T2 tumors (p < .0001). Within the T1 tumors, the 5-year Kaplan-Meier actuarial local control estimate ranged from 96.2% for tumors without anterior commissure involvement to 74.7% for tumors with anterior commissure involvement (p = .0002). On univariate analysis, a significant statistical relationship was noted between an increase in local recurrence and the following variables: increased T stage, anterior commissure involvement, and pathological margin involvement. The overall disease control rate and laryngeal preservation rate were 92.9% and 93.3%, respectively.

Analysis of Age and Disease Status as Predictors of Thyroid Cancer-Specific Mortality Using the Surveillance, Epidemiology, and End Results Database

BACKGROUND Age at diagnosis is incorporated into all relevant staging systems for differentiated thyroid carcinoma (DTC). There is growing evidence that a specific age cutoff may not be ideal for accurate risk stratification. We sought to evaluate the interplay between age and oncologic variables in patients with DTC using the largest cohort to date. METHODS The Surveillance, Epidemiology, and End RESULTS (SEER) database was queried to identify patients with DTC as their only malignancy for the period 1973 to 2009. Multivariate analyses using a range of age cutoffs and age subgroupings were utilized in order to search for an optimal age that would provide the most significant risk stratification between young and old patients. The primary outcome was disease-specific survival (DSS) and covariates included: age, race, sex, tumor/nodal/metastasis (TNM) stage, decade of diagnosis, and radioactive iodine therapy. RESULTS A total of 85,740 patients were identified. Seventy-six percent of patients were American Joint Committee on Cancer (AJCC) stage I, 8% were stage II, 7% were stage III, and 8% were stage IV. Age over 45 years (hazard ratio [HR] 19.2, p<0.001) and metastatic disease (HR 13.1, p<0.001) were the strongest predictors of DSS. Other factors that significantly predicted DSS included: not receiving radioactive iodine (RAI; HR 1.3, p=0.002), T3 (HR 2.6, p<0.001), and T4 disease (HR 3.3, p<0.001), and nodal spread (HR 2.6 to 3.3, p<0.001). Female sex showed a significant protective effect (HR 0.7, p=0.001). Adjusting the age-group cutoff from 25 to 55 years showed consistently high HRs for advanced age, without a distinct change at any point. Comparing HRs for T, N, and M stage between young and old patient subgroups showed that advanced disease increased the risk for DSS regardless of age, and was oftentimes a worse prognosticator in young patient groups. CONCLUSIONS The contribution of age at diagnosis to a patients DSS is considerable, but there is no age cutoff that affords any unique risk-stratification in patients with DTC.

Predictors of Hypocalcemia after Thyroidectomy: Results from the Nationwide Inpatient Sample

Hypocalcemia is a common complication following thyroidectomy. However, the incidence of postoperative hypocalcemia varies widely in the literature, and factors associated with hypocalcemia after thyroid surgery are not well established. We aimed to identify incidence trends and independent risk factors of postoperative hypocalcemia using the nationwide inpatient sample (NIS) database from 1998 to 2008. Overall, 6,605 (5.5%) of 119,567 patients who underwent thyroidectomy developed hypocalcemia. Total thyroidectomy resulted in a significantly higher increased incidence (9.0%) of hypocalcemia when compared with unilateral thyroid lobectomy (1.9%; P < .001). Thyroidectomy with bilateral neck dissection, the strongest independent risk factor of postoperative hypocalcemia (odds ratio, 9.42; P < .001), resulted in an incidence of 23.4%. Patients aged 45 years to 84 years were less likely to have postoperative hypocalcemia compared with their younger and older counterparts (P < .001). Hispanic (P = .003) and Asian (P = .027) patients were more likely, and black patients were less likely (P = .003) than white patients to develop hypocalcemia. Additional factors independently associated with postoperative hypocalcemia included female gender, nonteaching hospitals, and malignant neoplasms of thyroid gland. Hypocalcemia following thyroidectomy resulted in 1.47 days of extended hospital stay (3.33 versus 1.85 days P < .001).

Reconstruction of the hypopharynx: current trends.

Purpose of reviewReconstruction of the hypopharynx continues to present a clinical challenge for the reconstructive surgeon. Trends continue to evolve as many viable options exist, depending on individual patient characteristics and institutional preferences. The article reviews the most current literature available on the subject. Recent findingsSurgical resections resulting in pharyngoesophageal defects require timely reconstruction to minimize patient morbidity while optimizing quality of life, specifically in regards to speech and swallowing. Contemporary reconstructive options include various gastrointestinal flaps, pedicled myocutaneous flaps, and fasciocutaneous free flaps. Institutional trends often depend on the availability, training, and expertise of the reconstructive surgeon. The current options available differ in their complication rate and overall morbidity, and must take into account each patients general medical health. Increased availability of surgeons trained in microvascular reconstruction and the continued high published success rates have made free flaps an attractive option for hypopharyngeal reconstruction. Functional outcome regarding swallowing and speech rehabilitation after free flap reconstruction is promising. SummaryWith continued publication of overall high success rates coupled with superior functional outcome and increased availability of surgeons trained in microvascular reconstruction, fasciocutaneous free flap reconstruction of the hypopharynx will probably surpass intestinal flaps in reliability and popularity.

Transcriptome sequencing uncovers novel long noncoding and small nucleolar RNAs dysregulated in head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma persists as one of the most common and deadly malignancies, with early detection and effective treatment still posing formidable challenges. To expand our currently sparse knowledge of the noncoding alterations involved in the disease and identify potential biomarkers and therapeutic targets, we globally profiled the dysregulation of small nucleolar and long noncoding RNAs in head and neck tumors. Using next-generation RNA-sequencing data from 40 pairs of tumor and matched normal tissues, we found 2808 long noncoding RNA (lncRNA) transcripts significantly differentially expressed by a fold change magnitude ≥2. Meanwhile, RNA-sequencing analysis of 31 tumor-normal pairs yielded 33 significantly dysregulated small nucleolar RNAs (snoRNA). In particular, we identified two dramatically down-regulated lncRNAs and one down-regulated snoRNA whose expression levels correlated significantly with overall patient survival, suggesting their functional significance and clinical relevance in head and neck cancer pathogenesis. We confirmed the dysregulation of these noncoding RNAs in head and neck cancer cell lines derived from different anatomic sites, and determined that ectopic expression of the two lncRNAs inhibited key EMT and stem cell genes and reduced cellular proliferation and migration. As a whole, noncoding RNAs are pervasively dysregulated in head and squamous cell carcinoma. The precise molecular roles of the three transcripts identified warrants further characterization, but our data suggest that they are likely to play substantial roles in head and neck cancer pathogenesis and are significantly associated with patient survival.

Nicotine Promotes Acquisition of Stem Cell and Epithelial-to-Mesenchymal Properties in Head and Neck Squamous Cell Carcinoma

The ability of nicotine to enhance the malignancy of cancer cells is known; however, the possibility that nicotine could regulate a cancer stem cell phenotype remains to be well-established. In this study we sought to determine whether long-term exposure to nicotine could promote cancer stem cell-like properties in two head and neck squamous cell carcinoma cell lines, UMSCC-10B and HN-1. Nicotine treatment induced epithelial-to-mesenchymal transition (EMT) in both cell lines by repressing E-cadherin expression, and led to the induction of stem cell markers Oct-4, Nanog, CD44 and BMI-1, which was reversed upon ectopic re-expression of E-cadherin. Nicotine-treated cells formed spheres at a higher efficiency than non-treated cells, formed larger tumors when injected into mice, and formed tumors with 4-fold greater efficiency compared to control cells when injected at limiting doses. Consistent with previous literature, nicotine-treated cells demonstrated a greater capacity for survival and also a higher tendency to invade. Comparison of microRNA profiles between nicotine and control cells revealed the upregulation of miR-9, a repressor of E-cadherin, and the downregulation of miR-101, a repressor of EZH2. Taken together, these results suggest that nicotine may play a critical role in the development of tobacco-induced cancers by regulating cancer stem cell characteristics, and that these effects are likely mediated through EMT-promoting, microRNA-mediated pathways. Further characterization of such pathways remains a promising avenue for the understanding and treatment of tobacco-related cancers.

Outpatient Video-Assisted Thoracoscopic Surgery (VATS) for Ectopic Mediastinal Parathyroid Adenoma: A Case Report and Review of the Literature

Up to 20% of abnormal parathyroid glands causing primary or secondary hyperparathyroidism are located ectopically. Of these, approximately 1%-2% reside in the mediastinum and may not always be resectable through a traditional cervical approach. Recently, video-assisted thoracoscopic surgery (VATS) has arisen as a minimally invasive method for resecting mediastinal parathyroid glands and avoiding the complications and higher morbidity of a sternotomy. In this paper, we present a case of a patient with asymptomatic hyperparathyroidism and an ectopic parathyroid on sestamibi imaging in the mediastinum. Initially, the patient underwent a bilateral cervical exploration, left upper parathyroidectomy, and partial thymectomy; however, postoperatively, he continued to have persistently elevated serum calcium and parathyroid hormone levels. Ultimately, management consisted of parathyroidectomy through a VATS approach, along with intraoperative parathyroid assay monitoring and frozen-section pathologic analysis. The patient was successfully discharged to home several hours after surgery. To our knowledge, this is the first reported case of mediastinal ectopic parathyroid adenoma treated with outpatient VATS.