Michael P. Hier

Serum Proteomic Approach for the Identification of Serum Biomarkers Contributed by Oral Squamous Cell Carcinoma and Host Tissue Microenvironment

The lack of serum biomarkers for head and neck carcinoma limits early diagnosis, monitoring of advanced disease, and prediction of relapses in patients. We conducted a comprehensive proteomics study on serum from mice bearing orthotopic human oral squamous cell carcinomas (OSCC) with distinct invasive phenotypes. Matched established cell lines were transplanted orthotopically into tongues of RAG-2/gamma(c) mice and mouse serum was analyzed by 2-dimensional-differential gel electrophoresis(2D-DIGE)/liquid chromatography (LC)-MS/MS and by online 2D-LC-MS/MS of iTRAQ labeled samples. We identified several serum proteins as being differentially expressed between control and cancer-bearing mice and between noninvasive and invasive cancer (p<0.05). Differentially expressed proteins of human origin included the epidermal growth factor receptor (EGFR), cytokeratins, G-protein coupled receptor 87, Rab11 GTPase, PDZ-domain containing proteins, and PEST-containing nuclear proteins. Identified proteins of mouse origin included clusterin, titin, vitronectin, vitamin D-binding protein, hemopexin, and kininogen I. The levels of serum and cell secreted EGFR were further validated to match proteomic data regarding the inverse correlation with the invasive phenotype. In summary, we report a comprehensive patient-based proteomics approach for the identification of potential serum biomarkers for OSCC using an orthotopic xenograft mouse model.

Thyroid gland management in total laryngectomy: Meta-analysis and surgical recommendations

Objectives: 1) Review the incidence of thyroid gland invasion by squamous cell laryngeal carcinoma reported in the literature. 2) Assess the association between thyroid gland invasion and anatomical characteristics of the laryngeal tumor. Data Sources: MEDLINE (1967-2007) and EMBASE (1980-2007). These databases were supplemented with 61 patients from McGill University who underwent total laryngectomy with hemi- or total thyroidectomy from 2001-2006. Review Methods: Systematic review for series of laryngeal carcinoma that commented on thyroid gland invasion according to tumor subsite and pathological characteristics. Total laryngectomy specimens for primary laryngeal squamous cell carcinoma with concomitant thyroid resection were included in the analysis. Results: In total, eight series (n = 399) were included in the meta-analysis. Thyroid gland invasion was present in 33 laryngectomy specimens (8%); the principal method of invasion of the gland was by direct extralaryngeal extension. Subglottic extension > 10 mm (OR 7.22 [2.05 to 25.46]; P = 0.002), transglottic tumors (OR 3.23 [1.16 to 9.00]; P = 0.025), and subglottic subsite (OR 5.66 [1.34 to 23.87]; P = 0.018) were all significantly associated with thyroid gland invasion. Cartilaginous invasion by tumor was not a significant predictor of thyroid gland invasion (P > 0.05). Conclusions: Thyroid gland invasion is not a general feature of squamous cell laryngeal carcinoma. When present, it is strongly associated with anteroinferior spread of advanced laryngeal tumors. Thyroidectomy may only be required during total laryngectomy for transglottic tumors, subglottic tumors, and tumors with subglottic extension >10 mm.

Body Mass Index in the Evaluation of Thyroid Cancer Risk

BACKGROUND Obesity has been linked to numerous diseases including thyroid cancer, but the exact nature of the relationship, especially with respect to patients with thyroid nodules, remains unclear. The objective of this study was to evaluate the impact of body mass index (BMI) on thyroid cancer risk in a population of patients with indeterminate cytology on fine-needle aspiration biopsy (FNAB). METHODS A total of 253 consecutive patients with indeterminate thyroid nodule FNABs who underwent total thyroidectomy in a tertiary care teaching hospital between 2002 and 2007 were reviewed. Height and weight reported on the anesthesia summary were recorded for each patient. Malignancy rates were calculated for the underweight, normal, overweight, and obese groups stratified according to their BMI. Subanalyses according to age and sex were also performed. RESULTS The risk of malignancy tended to be lower in obese patients compared to patients with BMIs in the underweight, normal, and overweight ranges (52% vs. 61%, p = 0.195). In men, a BMI classified as obese was associated with a significantly lower rate of malignancy (36% vs. 72%, p = 0.003). Women older than 45 years were a subgroup in which higher malignancy rates were associated with obesity (65% vs. 54%, p = 0.293). Conversely, in men over the age of 45 years and women under 45 years, a BMI in the obesity range was linked to a lower incidence of malignancy (20% vs. 68% p = 0.009 and 36% vs. 68% p = 0.043, respectively). When older women were excluded from the population studied, the rate of malignancy in obese patients was 36% versus 70% in nonobese patients (p = 0.002) with an associated reduction of 5% in the risk of malignancy per increased unit of BMI. CONCLUSIONS For patients with FNAB results of indeterminate significance, a higher BMI correlates with lower rates of thyroid malignancy for all patients except women over the age of 45 years.

The role of sentinel lymph node biopsy in differentiated thyroid carcinoma.

OBJECTIVE To determine whether sentinel lymph node (SLN) biopsy can accurately predict central compartment metastasis in patients with differentiated thyroid carcinoma. DESIGN Prospective clinical study. SETTING Academic tertiary care center. PATIENTS Ninety-eight patients (82 women and 16 men; mean age, 48.3 years) underwent a total thyroidectomy and central compartment dissection. INTERVENTION Peritumoral injection of methylene blue dye, 1%, followed by SLN biopsy. MAIN OUTCOME MEASURES The final pathology report established the presence of metastasis among SLNs and lymph nodes that did not stain blue (non-SLNs [NSLNs]). RESULTS Differentiated thyroid carcinoma was found in 75 of 98 patients (77%). Seventy of 75 patients with differentiated thyroid carcinoma presented with SLNs and/or NSLNs within the central compartment. Fifteen of 70 patients had metastasis-positive SLNs, while 55 had metastasis-negative SLNs. Six of 15 patients with positive SLNs also had positive NSLNs. No patients with negative SLNs were found to have positive NSLNs. Sentinal lymph node status was a highly significant predictor of NSLN result (Fisher exact test, P < .001). The accuracy, sensitivity, specificity, and positive and negative predictive values of SLN biopsy were 87%, 100%, 86%, 40%, and 100%, respectively. CONCLUSIONS To our knowledge, this is the largest series of SLN biopsy in patients with differentiated thyroid carcinoma. Our experience suggests that this is an accurate and noninvasive means to identify subclinical lymph node metastasis. Because negative SLNs correlate strongly with a negative central compartment (100% in this study, P < .001), this technique can be used as an intraoperative guide when determining the extent of surgery necessary in cervical level VI.

Fine-needle aspiration biopsies in the management of indeterminate follicular and Hurthle cell thyroid lesions

Objectives: To determine the value of fine-needle aspiration biopsies (FNABs) of the thyroid and stratify the risk of malignancy within the indeterminate FNAB diagnostic category at our institution. Study design: Case series with chart review of preoperative FNABs of consecutive patients who underwent total thyroidectomy between 2005 and 2007. Subjects and Methods: A total of 115 cases were reviewed, and FNABs were categorized into four groups: benign, positive or suspicious for malignancy, indeterminate (follicular or Hurthle cell lesions), and nondiagnostic. Cytohistologic correlation was then established. Results: The accuracy of FNAB in detecting thyroid malignancy was 88 percent with false-negative and false-positive rates of 13 percent and 7 percent, respectively. Overall, 52 percent of the indeterminate cases were carcinomas (48 percent of follicular lesions and 62 percent of Hurthle cell lesions). In the presence of cytologic atypia, the rate of malignancy increased to 75 percent and 83 percent for the follicular and Hurthle cell lesions, respectively. Conclusions: FNAB is an accurate and helpful method for the evaluation of thyroid nodules with results directly correlating with management. Surgery should be considered for FNABs categorized as indeterminate, especially in the presence of cytologic atypia. Because of the high false-negative rate, benign FNABs require close follow-up with ultrasound examination and periodic biopsies.

Defining Success of Parathyroidectomy in Hyperparathyroidism

Objective To clearly define what constitutes successful parathyroidectomy in patients with primary hyperparathyroidism and to review our institutions results. Methods A retrospective chart review was conducted for consecutive patients who underwent parathyroidectomy at a university-affiliated tertiary care center between January 1998 and February 2006. Intraoperative pre- and post-excision PTH levels were recorded. PTH and calcium levels were recorded at 3 – 6 month intervals in the first 2 years and then yearly. Results 84 patients were analyzed. 50 (60%) had normal calcium and normal PTH levels following surgery, 28 (33%) had normal calcium and elevated PTH following surgery, and 6 (7%) had both elevated calcium and PTH. The mean follow-up time was 2.23 years, with a range of 0.25 to 5 years. Conclusions Surgery was successful, as indicated by normocalcemia, in 78 patients (93%). Of these 78 patients, 28 (33%) developed persistent PTH elevation without developing hypercalcemia. Other studies have studied this subgroup of patients with normalized post-operative calcium and consistently elevated PTH levels and noted that these new set points persist. Consequently, successful parathyroidectomy should be defined by serum calcium and not PTH levels.

Thyroid Gland Management in Total Laryngectomy: Meta-analysis

Objective 1. Review the incidence of thyroid gland invasion by squamous cell laryngeal carcinoma in the literature. 2. Correlate thyroid gland invasion with anatomical characteristics of the laryngeal tumor. Do laryngeal tumors which invade the thyroid gland share certain characteristics which can aid in determing the management of the thyroid gland during total laryngectomy? Methods Systematic review of MEDLINE (1967–2007) and EMBASE (1980–2007) for all total laryngectomy series which commented on thyroid gland invasion according to tumor subsite and pathological characteristics. These results were supplemented with 61 patients from our centers who underwent total laryngectomy with hemi- or total thyroidectomy. Eleven series in total (n = 535) were included in the meta-analysis (fixed effects model). Results Thyroid gland invasion was present in 47 laryngectomy specimens (9%); the main method of invasion of the gland was by direct extralaryngeal extension. Subglottic extension > 10mm (OR 6.27 [2.16 to 18.19]; p = 0.0007), subglottic subsite (OR 4.32 [1.53 to 12.19]; p = 0.006), and transglottic subsite (OR 4.10 [1.75 to 9.57]; p = 0.001) were significantly correlated with thyroid gland invasion. Cartilagenous invasion by tumor was not a significant predictor of thyroid gland invasion (p>0.05). Conclusions Thyroid gland invasion is not a general feature of squamous cell laryngeal carcinoma. When present, it is strongly associated with anteroinferior spread of laryngeal tumors. Thyroidectomy should only be performed during total laryngectomy for transglottic tumors, subglottic tumors, and tumors with subglottic extension >10mm. In these cases, total thyroidectomy is warranted to maximize locoregional control.

Incidence of Micropapillary Carcinoma in Total Thyroidectomy

Objective (1) Compare prognostic factors in thyroid micropapillary carcinoma (MPC) <5 mm versus >=5 mm. (2) To compare MPC characteristics in patients with pre-existing thyroid carcinoma to patients with no other thyroid carcinoma. Methods Pathology results were reviewed for consecutive total thyroidectomy patients between 2002 and 2007 (n=835). Hemithyroidectomies and completion thyroidectomies were excluded. Statistical significance of the difference in incidences was calculated using Fishers exact test and chi-squared analysis. Results MPC was found in 50.2% of total cases. Where the size was <5mm (64%), 9.3% extended beyond the thyroid capsule, 51.7% were multifocal, and 27.5% were bilateral. In MPCs >=5 mm (36%), the data showed 25.2%, 70.9%, 51%, respectively (p-value always < 0.05). In the 314 patients with no other thyroid malignancy, MPC was found in 47.1% of cases. 14.9% had capsular extension; 50% were multifocal, of which 56.8% were bilateral. In the 521 patients with malignant disease, the data showed 52.1%, 15.1%, 63.2%, and 63.3%, respectively, with p-values via Fishers exact test .22, .112, .003, and .07. Conclusions In this study, MPC was found in 50.2% of patients. MPCs >=5 mm carried an increased risk for extracapsular spread, multifocality, and bilaterality. While patients with malignancies of the thyroid (aside from MPC) more commonly have multifocal MPCs, there was no significant difference in bilaterality, size, or extracapsular spread in MPCs in the presence of malignant vs. benign disease.