Carrie C. Lubitz

Annual Financial Impact of Well-Differentiated Thyroid Cancer Care in the United States

Well‐differentiated thyroid cancer (WDTC) is a prevalent disease, which is increasing in incidence faster than any other cancer. Substantial direct medical care costs are related to the diagnosis and treatment of newly diagnosed patients as well as the ongoing surveillance of patients who have a long life expectancy. Prior analyses of the aggregate health care costs attributable to WDTC in the United States have not been reported.

Accuracy of 4-dimensional computed tomography in poorly localized patients with primary hyperparathyroidism

BACKGROUND Four-dimensional computed tomography (4D-CT) utilizes multiplanar images and perfusion characteristics to identify abnormal parathyroid glands. We assessed the role of 4D-CT in patients with inconclusive preoperative ultrasound and sestamibi localization studies. METHODS Adult patients with primary hyperparathyroidism with negative or discordant standard imaging who underwent both localization with 4D-CT and operative intervention for curative intent were included. Patient characteristics, 4D-CT scan results compared with operative findings, and curative proportion were assessed. RESULTS Of the 60 patients, 4D-CT accurately lateralized 73% and localized 60% of abnormal glands found at operation. Single candidate lesions (46/60) were confirmed at operation in 70%. When multiple lesions were identified on 4D-CT (14/60), accuracy dropped to 29% (P = .03). The accuracy of 4D-CT was not different between primary and reoperative cases (P = .79). Of the 8 patients with multigland disease diagnosed perioperatively, 5 had multiple candidate lesions noted on 4D-CT. In 94% (48/51) of patients, a >50% drop in intraoperative parathormone (IOPTH) level was achieved after resection and 87% (48/55) had long-term cure with a median follow-up of 221 days. CONCLUSION 4D-CT identifies the more than half of abnormal parathyroids missed by traditional imaging and should be considered in cases with negative or discordant sestamibi and ultrasound. Bilateral exploration is warranted when multiple candidate lesions are reported on 4D-CT. Multigland disease remains a challenging entity.

Clinical and Cytological Features Predictive of Malignancy in Thyroid Follicular Neoplasms

BACKGROUND The preoperative diagnosis of malignancy in nodules suspicious for a follicular neoplasm remains challenging. A number of clinical and cytological parameters have been previously studied; however, none have significantly impacted clinical practice. The aim of this study was to determine predictive characteristics of follicular neoplasms useful for clinical application. METHODS Four clinical (age, sex, nodule size, solitary nodule) and 17 cytological variables were retrospectively reviewed for 144 patients with a nodule suspicious for follicular neoplasm, diagnosed preoperatively by fine-needle aspiration (FNA), from a single institution over a 2-year period (January 2006 to December 2007). The FNAs were examined by a single, blinded pathologist and compared with final surgical pathology. Significance of clinical and cytological variables was determined by univariate analysis and backward stepwise logistic regression. Odds ratios (ORs) for malignancy, a receiver operating characteristic curve, and predicted probabilities of combined features were determined. RESULTS There was an 11% incidence of malignancy (16/144). On univariate analysis, nodule size >OR=4.0 cm nears significance (p = 0.054) and 9 of 17 cytological features examined were significantly associated with malignancy. Three variables stay in the final model after performing backward stepwise selection in logistic regression: nodule size (OR = 0.25, p = 0.05), presence of a transgressing vessel (OR = 23, p < 0.0001), and nuclear grooves (OR = 4.3, p = 0.03). The predicted probability of malignancy was 88.4% with the presence of all three variables on preoperative FNA. When the two papillary carcinomas were excluded from the analysis, the presence of nuclear grooves was no longer significant, and anisokaryosis (OR = 12.74, p = 0.005) and presence of nucleolus (OR = 0.11, p = 0.04) were significantly associated with malignancy. Excluding the two papillary thyroid carcinomas, a nodule size >or=4 cm, with a transgressing vessel and anisokaryosis and lacking a nucleolus, has a predicted probability of malignancy of 96.5%. CONCLUSIONS A combination of larger nodule size, transgressing vessels, and specific nuclear features are predictive of malignancy in patients with follicular neoplasms. These findings enhance our current limited predictive armamentarium and can be used to guide surgical decision making. Further study may result in the inclusion of these variables to the systematic evaluation of follicular neoplasms.

Identification of borderline thyroid tumors by gene expression array analysis.

A subset of follicular lesions of the thyroid is encapsulated similar to follicular adenomas but with partial nuclear features suggestive of papillary thyroid carcinoma (PTC), raising the possibility of biologically borderline tumors.

Hobnail Variant of Papillary Thyroid Carcinoma: An Institutional Case Series and Molecular Profile

BACKGROUND Papillary thyroid carcinoma (PTC) is increasing in incidence while mortality is unchanged. Identifying patients with higher risk of recurrence and death is essential. Case series identify the hobnail variant of PTC (HVPTC), which is characterized by micropapillary architecture, apocrine features, and loss of cellular polarity. Herein, we describe the clinical course, pathologic features, and mutational profile of patients at our institution with HVPTC. METHODS A query into the surgical pathologic database (2009-2012) was performed, and clinicopathologic data were collected on all patients carrying the diagnosis of HVPTC. BRAF(V600E) testing was performed on paraffin-embedded blocks using SNaPshot mutational analysis. RESULTS Twelve patients with HVPTC were identified, with an average age of 54.1±18.8 years. Seven patients (63.6%) were AJCC Stage III or IV at presentation. Tumors were large (3.7±2.0 cm), some were multifocal (33.3%), and frequently with extrathyroidal extension (58.3%), lymphovascular invasion (41.7%), and lymph node metastasis (75%). Forty percent of the patients had concomitant tall cell features (TCF), and two had small foci of undifferentiated (anaplastic) thyroid carcinoma (ATC). Eighty percent of tumors undergoing mutational analysis had the BRAF(V600E) mutation, and the remaining 20% harbored a RET/PTC1 gene rearrangement. No other known thyroid cancer mutations were identified on SNaPshot analysis. At median follow-up of 26 months, four patients had recurrent or persistent disease, one of whom died from the disease one year after surgery. CONCLUSIONS The hobnail variant of PTC has an aggressive behavior, with a high incidence of infiltrative tumors and metastatic disease. Strikingly, all tumors in our series harbored a PTC-associated genetic abnormality, either a BRAF(V600E) mutation (80%) or a RET/PTC1 rearrangement (20%). This histologic variant warrants further study, and patients with this diagnosis should be observed closely for recurrence.

Identification of Oncogenic Mutations and Gene Fusions in the Follicular Variant of Papillary Thyroid Carcinoma

BACKGROUND The diagnosis of the follicular variant of papillary thyroid carcinoma (FVPTC) is increasingly common. Recent studies have suggested that FVPTC is heterogeneous and comprises multiple tumor types with distinct biological behaviors and underlying genetics. OBJECTIVES The purpose of this work was to identify the prevalence of mutations and gene fusions in known oncogenes in a panel representative of the common spectrum of FVPTC diagnosed at an academic medical center and correlate the clinical and pathological features obtained at the initial diagnosis with the tumor genotype. MATERIALS AND METHODS We performed SNaPshot genotyping on a panel of 129 FVPTCs of ≥1 cm for 90 point mutations or small deletions in known oncogenes and tumor suppressors and identified gene fusions using an anchored multiplex PCR assay targeting a panel of rearranged oncogenes. RESULTS We identified a mutation or gene fusion in 70% (89 of 127) of cases. Mutations targeting the RAS family of oncogenes were the most frequently observed class of alterations, present in 36% (46 of 127) of cases, followed by BRAF mutation, present in 30% (38 of 127). We also detected oncogenic rearrangements not previously associated with FVPTC, including TFG-ALK and CREB3L2-PPARγ. BRAF mutation was significantly associated with unencapsulated tumor status. CONCLUSIONS These data support the hypothesis that FVPTC is composed of distinct biological entities, with one class being identified by BRAF mutation and support the use of clinical genotyping assays that detect a diverse array of rearrangements involving ALK and PPARγ. Additional studies are necessary to identify genetic drivers in the 30% of FVPTCs with no known oncogenic alteration and to better predict behavior in tumors with known genotypes.

Diagnostic Yield of Nondiagnostic Thyroid Nodules Is Not Altered by Timing of Repeat Biopsy

BACKGROUND Guidelines from the National Cancer Institute Thyroid Fine Needle Aspiration State of the Science Conference recommend a repeat fine-needle aspiration biopsy (FNAB) after 3 months for thyroid nodules with a nondiagnostic (ND) result. Our aims were to assess which factors influenced their clinical management and to determine if the timing of the repeat FNAB affects the diagnostic yield. METHODS A retrospective institutional review of 298 patients from 1/2006 to 12/2007 with an ND FNAB was performed. The factors influencing the next step in management, including age, gender, history of radiation, presence of Hashimotos thyroiditis, thyroid-stimulating hormone levels, and ultrasound characteristics, were evaluated. The effect of the time of the repeat FNABs on their diagnostic yield was assessed. RESULTS Of the 298 patients in our cohort, 9% were referred directly for surgery, 76% had a repeat FNAB, and 15% were observed. Tumor size was the only independent variable correlated with treatment strategy after a ND FNAB. There was not a significant difference in diagnostic yields between repeat FNABs performed earlier than 3 months compared to those preformed later (p=0.58). CONCLUSION The timing of repeat FNAB for an initial ND FNAB does not affect diagnostic yield of the repeat FNAB.

Diagnosis and management of pheochromocytoma

Tumors that that secrete excessive levels of catecholamines, commonly termed “pheochromocytomas,” can arise from the adrenal gland (pheochromocytomas [PCCs]) or from the sympathetic ganglia (paragangliomas [PGLs] or extra-adrenal PCCs). The adrenal glands, also known as the suprarenal glands, are located in the retroperitoneum, superomedial to the kidneys and high up under the costal margin adjacent to the diaphragm. Histologically, the adrenal glands consist of an outer cortex and inner medulla and secrete hormones essential for normal human physiologic function. Each of the adrenal glands, in their normal size and configuration, measure approximately 3-5 cm in length, 4-6 mm in thickness, and weigh approximately 4-5 g. They are closely approximated to the superomedial aspect of the kidneys and are surrounded by a fibrous capsule of connective tissue (Gerota fascia of the kidney) outside of which is loose connective tissue and abundant perinephric and retroperitoneal fat. The adrenal glands are clearly distinguished from the surrounding fat by their bright yellow color and more nodular and fibrous consistency. The bright yellow color is the adrenal cortical tissue. The inner medulla, only apparent with adrenal sectioning after removal, is gray-brown in color. Despite the distinct color and appearance of the adrenal cortex, the retroperitoneal location and covering of fat and connective tissue can obscure the gland. A significant amount of dissection in the retroperitoneal and perirenal fat is often required to locate the adrenal glands during surgery. The adrenal glands are composed of 2 discrete and separate anatomical, embryologic, and functional regions: the adrenal cortex and the adrenal medulla. The outer layer, or the adrenal cortex, arises from the mesoderm during embryologic development and accounts for the majority of the gland substance. The cortex has 3 separate layers or zones, and each secretes a different set of hormones. The outermost layer is the zona glomerulosa and secretes the mineralocorticoid known as aldosterone. The primary function of aldosterone is to increase renal sodium reabsorption and potassium excretion. Tumors from this adrenal cortical layer that overproduce aldosterone cause a clinical syndrome termed “Conn syndrome,” and patients frequently present with hypertension and hypokalemia. The middle layer and inner regions of the cortex, the zona fasciculata and the zona reticularis, secrete glucocorticoids (cortisol) and androgens, respectively. Hormonally active tumors from these regions can cause Cushing syndrome (excess cortisol) or a virilizing syndrome (excess androgens). The innermost region of the adrenal gland is the medulla, which is derived from the same neural crest cells that comprise the sympathetic ganglia. The adrenal medulla is innervated by preganglionic fibers of the

Selenium Decreases Thyroid Cancer Cell Growth by Increasing Expression of GADD153 and GADD34

Selenium (Se) supplementation is reported to decrease the incidence and total mortality of cancer. Whereas in vitro and in vivo studies have shown a decrease in prostate, lung, and liver cancers, this has not been shown in thyroid cancer. ARO (anaplastic), NPA (BRAF positive papillary), WRO (BRAF negative papillary), and FRO (follicular) cells treated with 150 μM seleno-l-methionine (SM) were assessed for viability at 24, 48, and 72 h. Treated FRO cells were examined for cell cycle using flow cytometry, for apoptosis using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, and for gene expression using microarray. Genes identified as upregulated were confirmed by real-time PCR (RT-PCR) and proteins by Western blot analysis. SM treatment significantly decreased the proliferation of all cell lines. TUNEL assay showed no evidence of apoptosis, and flow cytometry showed a significant cell-cycle arrest in S (271% increase, P= 0.006) and G2/M (61% increase, P= 0.002) compared to control. Microarray revealed 21 differentially expressed genes with greater than twofold change. A relative overexpression of growth arrest and DNA damage inducible (GADD)34 and GADD153 in treated cells was confirmed with RT-PCR and Western blot. SM inhibits thyroid cancer cell proliferation through a time dependent upregulation of the GADD family of genes and arrest in S and G2/M phases of the cell cycle. This is the first report of selenium induced inhibition of thyroid cancer cell growth.

Preoperative basal calcitonin and tumor stage correlate with postoperative calcitonin normalization in patients undergoing initial surgical management of medullary thyroid carcinoma

BACKGROUND The optimal initial operative management of medullary thyroid cancer (MTC) and the use of biomarkers to guide the extent of operation remain controversial. We hypothesized that preoperative serum levels of calcitonin and carcinoembryonic antigen (CEA) correlate with extent of disease and postoperative levels reflect the extent of operation performed. METHODS We assessed retrospectively clinical and pathologic factors among patients with MTC undergoing at least total thyroidectomy; these factors were correlated with biomarkers using regression analyses. RESULTS Data were obtained from 104 patients, 28% with hereditary MTC. Preoperative calcitonin correlated with tumor size (P < .001) and postoperative serum calcitonin levels (P = .01) after multivariable adjustment for lymph node positivity, extent of operation, and hereditary MTC. No patient with a preoperative calcitonin level of <53 pg/mL (n = 20) had lymph node metastases. TNM stage (P = .001) and preoperative calcitonin levels (P = .04), but not extent of operation, independently correlated with the failure to normalize postoperative calcitonin. Postoperative CEA correlated with positive margins (adjusted P = 04). Neither preoperative nor postoperative CEA was correlated with lymph node positivity or extent of surgery. CONCLUSION Preoperative serum calcitonin and TMN stage, but not extent of operation, were independent predictors of postoperative normalization of serum calcitonin levels. Future studies should evaluate preoperative serum calcitonin levels as a determinate of the extent of initial operation.