Thyroid Diseases: Zeiger MA

Gharib H, Papini E, Valcavi R, Baskin HJ, Crescenzi A, Dottorini ME, Duick DS, Guglielmi R, Hamilton CR, Zeiger MA, Zini M, Anonymous00012. · No affiliation provided · Endocr Pract. · Pubmed #16596732 No free full text.

Abstract: Thyroid nodules are common and are frequently benign. Current data suggest that the prevalence of palpable thyroid nodules is 3% to 7% in North America; the prevalence is as high as 50% based on ultrasonography (US) or autopsy data. The introduction of sensitive thyrotropin (thyroid-stimulating hormone or TSH) assays, the widespread application of fine-needle aspiration (FNA) biopsy, and the availability of high-resolution US have substantially improved the management of thyroid nodules. This document was prepared as a collaborative effort between the American Association of Clinical Endocrinologists (AACE) and the Associazione Medici Endocrinologi (AME). Most Task Force members are members of AACE. We have used the AACE protocol for clinical practice guidelines, with rating of available evidence, linking the guidelines to the strength of recommendations. Key observations include the following. Although most patients with thyroid nodules are asymptomatic, occasionally patients complain of dysphagia, dysphonia, pressure, pain, or symptoms of hyperthyroidism or hypothyroidism. Absence of symptoms does not rule out a malignant lesion; thus, it is important to review risk factors for malignant disease. Thyroid US should not be performed as a screening test. All patients with a palpable thyroid nodule, however, should undergo US examination. US-guided FNA (US-FNA) is recommended for nodules > or = 10 mm; US-FNA is suggested for nodules < 10 mm only if clinical information or US features are suspicious. Thyroid FNA is reliable and safe, and smears should be interpreted by an experienced pathologist. Patients with benign thyroid nodules should undergo follow-up, and malignant or suspicious nodules should be treated surgically. A radioisotope scan of the thyroid is useful if the TSH level is low or suppressed. Measurement of serum TSH is the best initial laboratory test of thyroid function and should be followed by measurement of free thyroxine if the TSH value is low and of thyroid peroxidase antibody if the TSH value is high. Percutaneous ethanol injection is useful in the treatment of cystic thyroid lesions; large,symptomatic goiters may be treated surgically or with radioiodine. Routine measurement of serum calcitonin is not recommended. Suggestions for thyroid nodule management during pregnancy are presented. We believe that these guidelines will be useful to clinical endocrinologists, endocrine surgeons, pediatricians, and internists whose practices include management of patients with thyroid disorders. These guidelines are thorough and practical, and they offer reasoned and balanced recommendations based on the best available evidence.

Cobin RH, Gharib H, Bergman DA, Clark OH, Cooper DS, Daniels GH, Dickey RA, Duick DS, Garber JR, Hay ID, Kukora JS, Lando HM, Schorr AB, Zeiger MA, Anonymous00002. · No affiliation provided · Endocr Pract. · Pubmed #11430305 No free full text.

This publication has no abstract.

Manahan MA, Dackiw AP, Ball DW, Zeiger MA. · Department of Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA. · Endocr Pract. · Pubmed #17360306 No free full text.

Abstract: OBJECTIVE: To report a rare case of metastatic growth hormone (GH)-secreting pituitary carcinoma causing acromegaly. METHODS: We present a case report and review the available literature on this topic. RESULTS: A 68-year-old woman presented with persistent acromegaly after treatment for a GH-secreting pituitary adenoma. Evaluation of long-standing cervical adenopathy revealed findings consistent with a metastatic neuroendocrine tumor. Further work-up revealed additional thyroid, parathyroid, and cervical masses. After operative treatment including total thyroidectomy, subtotal parathyroidectomy, partial thymectomy, and right modified radical neck dissection, the patient's symptoms diminished, and her GH levels approached the normal range. Surgical pathology findings were consistent with a GH-secreting pituitary carcinoma metastatic to the cervical lymph nodes, multinodular thyroid hyperplasia with a focus of papillary microcarcinoma, and parathyroid hyperplasia. CONCLUSION: Overall, pituitary carcinomas are extremely rare. To date, about 100 cases have been reported in the world's literature, and of these, only 19 cases originated from GH-secreting cells. Our examination of the symptoms, signs, diagnosis, and treatment of our patient, in comparison with the previously reported cases, should enhance awareness of this unusual disease process.

Diehl S, Umbricht CB, Dackiw AP, Zeiger MA. · Department of Surgery, Division of Endocrine and Oncologic Surgery, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA. · Thyroid. · Pubmed #16029124 No free full text.

Abstract: There is a compelling need for improvement in the diagnosis of thyroid nodules, in predicting thyroid cancer prognosis and, in the treatment of recurrent well-differentiated and anaplastic thyroid cancer. In this review we discuss the impact of genomic technologies such as microarrays, SAGE, and proteomics on the diagnosis, prognosis and treatment of thyroid cancer. Gene expression profiling using these technologies has shown promising results in the molecular classification of different types of cancer, including thyroid. Furthermore, microarrays have been successfully used to identify prognostic markers in other cancer-types, offering the possibility to better tailor thyroid cancer treatment schemes. Lastly, novel therapeutic targeting against tyrosine kinases have shown promising results in the treatment of several cancers and might prove to be beneficial for patients with recurrent or undifferentiated thyroid cancer.

Zeiger MA, Dackiw AP. · Department of Surgery, Division of Endocrine and Oncologic Surgery, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA. · J Surg Oncol. · Pubmed #15719377 No free full text.

Abstract: The precise diagnosis of follicular thyroid lesions is frequently debated because of the subjective nature of capsular invasion as well as both the histological and cytological characteristics. Furthermore, several different prognostic indices have been devised to examine prognosis associated with thyroid cancer. Herein, we describe how these confounding elements can affect the ability to accurately predict prognosis for patients with follicular thyroid lesions.

Zeiger MA, Meeker AK. · The Department of Surgery, Division of Endocrine and Oncologic Surgery, The Johns Hopkins Medical Institutions, Baltimore, MD, USA. · Curr Drug Targets Immune Endocr Metabol Disord. · Pubmed #15379727 No free full text.

Abstract: Telomerase is known to be activated in almost all cancer cells and is quiescent in almost all normal cells. Therefore, it follows that therapeutic strategies directed against cancer would include the targeting of telomerase, as well as the use of telomerase. Several approaches have been used both in vitro and in vivo and include the following: 1) antisense; 2) immunotherapy directed against hTERT; and 3) the use of telomerase promoter to direct cytotoxic therapy. Herein we review these approaches and discuss their potential applicability against thyroid cancer.

Segev DL, Clark DP, Zeiger MA, Umbricht C. · Departments of Surgery, Pathology and Oncology, Johns Hopkins Medical Institutions, 720 Rutland Avenue, Ross 756, Baltimore, Maryland 21205, USA. · Acta Cytol. · Pubmed #14526667 No free full text.

Abstract: Fine needle aspiration (FNA) is currently the best diagnostic tool for thyroid nodules. However, the cytologic category of indeterminate or suspicious lesion, which is found in 10-15% of cases, remains a challenge. Since neither clinical presentation nor intraoperative frozen section is often helpful in differentiating these lesions and since surgical procedures for benign and malignant lesions differ, there is a clear need to develop ancillary tests. In this review we identify 12 potential markers of thyroid malignancy that have been examined in thyroid cytologic samples. Although many of these markers hold promise as adjuncts to FNA cytology, multicenter studies have often shown limitations in the predictive value of these assays due to lack of specificity, sensitivity or both. The recent development, however, of tissue microarray techniques to validate promising new markers suggests that improvements in the approach to indeterminate thyroid FNA samples may soon be at hand. This review presents a summary of the issues facing the development of a clinically useful diagnostic test in the differential diagnosis of thyroid nodules.

Segev DL, Umbricht C, Zeiger MA. · Department of Surgery, Johns Hopkins Medical Institutions, 600 N. Wolfe Street, Baltimore, MD 21287, USA. · Surg Oncol. · Pubmed #12946479 No free full text.

Abstract: A number of molecular abnormalities have been described in association with the progression from normal thyroid tissue to benign adenomas to well-differentiated and finally anaplastic epithelial thyroid cancer. These include upregulation of proliferative factors, such as growth hormones and oncogenes, downregulation of apoptotic and cell-cycle inhibitory factors, such as tumor suppressors, disruption of normal cell-to-cell interactions, and cellular immortalization. The progression model for thyroid carcinoma has not been proven, but evidence suggests that an evolutionary molecular process is involved, especially in the development of follicular thyroid cancers for which there are distinct intermediate phenotypes. We present a comprehensive evaluation of factors involved in thyroid tumorigenesis and attempt to describe preliminary attributes of a progression model. The organization of this model should also provide a template for the incorporation of new information as it is derived from large-scale genomic studies.

Morita SY, Somervell H, Umbricht CB, Dackiw AP, Zeiger MA. · Endocrine Surgery Section, Department of Surgery, The Johns Hopkins Medical Institutions, Baltimore, MD, USA. · Surgery. · Pubmed #19040989 No free full text.

Abstract: BACKGROUND: Previous investigators have reported the incidence of thyroid nodules in patients with primary hyperparathyroidism; others have noted the incidence of primary hyperparathyroidism in patients who underwent thyroidectomy. It is well known that both of these entities coexist. In this article, we present a single-center experience with the incidence of concomitant thyroid nodular disease and primary hyperparathyroidism in patients who underwent parathyroidectomy or thyroidectomy. METHODS: From May 2006 to December 2007, 526 patients underwent thyroidectomy, parathyroidectomy, or both. Operations were performed by surgeons in the Johns Hopkins Endocrine Surgery Section after screening preoperatively for concomitant thyroid nodular disease or primary hyperparathyroidism. RESULTS: Among the 200 patients who underwent a parathyroidectomy, 102 (51.0%) were found to have thyroid nodular disease. Six percent of these 200 patients also had a thyroid malignancy. Of the 326 patients who were primarily seen for thyroid disease, the incidence of primary hyperparathyroidism was 3.1%. CONCLUSION: By implementing a comprehensive approach to patients who present with thyroid disease or primary hyperparathyroidism, concomitant pathology may be elucidated preoperatively. This approach will facilitate the detection of otherwise unsuspected thyroid cancer and hyperparathyroidism as well as prevent unnecessary reoperative surgery.

Wang Y, Kowalski J, Tsai HL, Marik R, Prasad N, Somervell H, Lo PK, Sangenario LE, Dyrskjot L, Orntoft TF, Westra WH, Meeker AK, Eshleman JR, Umbricht CB, Zeiger MA. · Department of Surgery, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21287, USA. · Thyroid. · Pubmed #18816183 No free full text.

Abstract: BACKGROUND: Although fine-needle aspiration (FNA) biopsy of thyroid nodules is very sensitive in detecting thyroid malignancy, it remains ambiguous in 20-30% of cases. Current biomarkers for thyroid cancer lack either the sensitivity or specificity to substantially address this clinical problem. The aim of this study was to investigate the gene expression patterns of human telomerase reverse transcriptase (hTERT) alternative splice variants in benign and malignant thyroid tumors in an attempt to find a more reliable biomarker in the differential diagnosis of thyroid nodules. METHODS: One hundred and thirty-three thyroid tumors from eight histopathological tumor types were collected from patients undergoing thyroid surgery at Johns Hopkins Hospital. Gene expression patterns of hTERT alternative splice variants were investigated in the tumors by nested reverse transcriptase-PCR. Telomerase enzyme activity was evaluated in a subset of 16 samples associated with the different hTERT patterns. Association of c-myc expression and hTERT patterns was also examined. RESULTS: Malignant thyroid tumors exhibited a greater proportion of the active full-length hTERT transcript (0.57 +/- 0.15) than inactive splice variants, alpha(-) (0.13 +/- 0.02), or beta(-)/alpha(-)beta(-) deletion transcripts (0.30 +/- 0.11; p < 0.001). The opposite was observed in benign tumors, which exhibited greater proportions of beta(-)/alpha(-)beta(-) deletion transcripts (0.64 +/- 0.08) than either the full-length (0.19 +/- 0.06) or alpha(-) deletion transcripts (0.17 +/- 0.02; p < 0.001). Similar results were observed among a diagnostically challenging subset of 50 thyroid tumors that were suspicious for malignancy on FNA. Further, increased telomerase enzymatic activity was only associated with expression of the full-length hTERT isoform. In contrast, c-myc expression, which has been implicated in hTERT regulation, correlated with overall hTERT transcription without specificity for expression of the full-length isoform. CONCLUSIONS: These differences in gene expression patterns of hTERT alternative splice variants may provide a useful adjunct to FNA diagnosis of suspicious thyroid tumors.

Banks ND, Kowalski J, Tsai HL, Somervell H, Tufano R, Dackiw AP, Marohn MR, Clark DP, Umbricht CB, Zeiger MA. · Division of Plastic and Reconstructive Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. · Thyroid. · Pubmed #18788917 No free full text.

Abstract: BACKGROUND: The management of patients with thyroid fine-needle aspiration (FNA) specimens that are neither benign nor malignant still remains problematic. Efforts to improve their management have focused on identifying risk factors that predict malignancy. This study seeks to identify clinical and tumor characteristics that predict thyroid malignancy among patients with indeterminate or suspicious FNA and to develop a diagnostic predictor model. METHODS: The records of 639 patients with an indeterminate or suspicious thyroid FNA between January 1995 and April 2005 were reviewed. Patient and tumor characteristics were evaluated for their potential to predict malignancy in the final surgical histopathology. A diagnostic predictor model was designed based on statistically significant predictors. Patients seen between April 2005 and April 2007 were used to validate the model. RESULTS: Patient age, nodule size, and FNA cytopathology were identified as risk factors. Patients at extremes of age were at increased risk. Patients 50 years of age had the lowest risk of malignancy. For patients less than age 50, the risk increased 3% for each year decrease in age (p = 0.001). After 50, the risk increased 3.4% for each year increase in age (p = 0.016). Nodules 2.5 cm had the lowest likelihood of malignancy. For smaller nodules, the risk increased 53% per cm decrease in size (p < 0.001). For larger nodules, the risk increased 39% per cm increase (p < 0.001). Patients with FNA cytology suspicious for papillary thyroid carcinoma had the greatest risk of malignancy (p < 0.001). CONCLUSIONS: A predictor model was created using the variables age, nodule size, and FNA cytology to predict thyroid malignancy.

Prasad NB, Somervell H, Tufano RP, Dackiw AP, Marohn MR, Califano JA, Wang Y, Westra WH, Clark DP, Umbricht CB, Libutti SK, Zeiger MA. · Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. · Clin Cancer Res. · Pubmed #18519760 links to  free full text

Abstract: PURPOSE: Although fine-needle aspiration biopsy is the most useful diagnostic tool in evaluating a thyroid nodule, preoperative diagnosis of thyroid nodules is frequently imprecise, with up to 30% of fine-needle aspiration biopsy cytology samples reported as "suspicious" or "indeterminate." Therefore, other adjuncts, such as molecular-based diagnostic approaches are needed in the preoperative distinction of these lesions. EXPERIMENTAL DESIGN: In an attempt to identify diagnostic markers for the preoperative distinction of these lesions, we chose to study by microarray analysis the eight different thyroid tumor subtypes that can present a diagnostic challenge to the clinician. RESULTS: Our microarray-based analysis of 94 thyroid tumors identified 75 genes that are differentially expressed between benign and malignant tumor subtypes. Of these, 33 were overexpressed and 42 were underexpressed in malignant compared with benign thyroid tumors. Statistical analysis of these genes, using nearest-neighbor classification, showed a 73% sensitivity and 82% specificity in predicting malignancy. Real-time reverse transcription-PCR validation for 12 of these genes was confirmatory. Western blot and immunohistochemical analyses of one of the genes, high mobility group AT-hook 2, further validated the microarray and real-time reverse transcription-PCR data. CONCLUSIONS: Our results suggest that these 12 genes could be useful in the development of a panel of markers to differentiate benign from malignant tumors and thus serve as an important first step in solving the clinical problem associated with suspicious thyroid lesions.

Zeiger MA. · Endocrine Surgery Section, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287, USA. · Cancer J. · Pubmed #16925968 No free full text.

This publication has no abstract.

Hu S, Liu D, Tufano RP, Carson KA, Rosenbaum E, Cohen Y, Holt EH, Kiseljak-Vassiliades K, Rhoden KJ, Tolaney S, Condouris S, Tallini G, Westra WH, Umbricht CB, Zeiger MA, Califano JA, Vasko V, Xing M. · Department of Medicine, Division of Endocrinology and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. · Int J Cancer. · Pubmed #16858683 No free full text.

Abstract: The role of aberrant tumor suppressor gene methylation in the aggressiveness of papillary thyroid cancer (PTC) has not been documented. By showing promoter methylation-induced gene silencing in PTC-derived cell lines, we first demonstrated the functional consequence of methylation of several recently identified tumor suppressor genes, including those for tissue inhibitor of metalloproteinase-3 (TIMP3), SLC5A8, death-associated protein kinase (DAPK) and retinoic acid receptor beta2 (RARbeta2). We then investigated the role of methylation of these genes in the aggressiveness of PTC by examining the relationship of their aberrant methylation to clinicopathological characteristics and BRAF mutation in 231 primary PTC tumors. Methylation of TIMP3, SLC5A8 and DAPK was significantly associated with several aggressive features of PTC, including extrathyroidal invasion, lymph node metastasis, multifocality and advanced tumor stages. Methylation of these genes was also significantly associated with BRAF mutation in PTC, either individually or collectively in various combinations. Methylation of these genes, either individually or collectively, occurred more frequently in more aggressive classical and tall-cell PTC subtypes than in less aggressive follicular-variant PTC, with the latter known to infrequently harbor BRAF mutation. Several other tumor suppressor genes investigated were not methylated. These results suggest that aberrant methylation and hence silencing of TIMP3, SLC5A8, DAPK and RARbeta2, in association with BRAF mutation, may be an important step in PTC tumorigenesis and progression.

Rosen J, He M, Umbricht C, Alexander HR, Dackiw AP, Zeiger MA, Libutti SK. · Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institute of Health, Bethesda, MD 20892, USA. · Surgery. · Pubmed #16360390 No free full text.

Abstract: BACKGROUND: Thyroid nodules are common; fine-needle aspirations commonly are read as indeterminate, necessitating surgery to exclude carcinoma. We developed a 6-gene array-based predictor model to diagnose benign versus malignant thyroid lesions. In this study, we verified whether quantitative reverse transcription-polymerase chain reaction (qRT-PCR) using this model reliably can differentiate benign from malignant thyroid nodules. METHODS: Molecular profiles of benign (follicular adenomas, hyperplastic nodules) and malignant tumors (papillary thyroid carcinomas, follicular variants of papillary thyroid carcinomas) were analyzed using qRT-PCR from our 6-gene model (kit, Hs.296031, Hs.24183, LSM7, SYNGR2, C21orf4). The gold standard was standard pathologic criteria. A diagnosis-predictor model was built by using the training samples and was then used to predict the class of 10 additional samples analyzed as unknowns. RESULTS: Our predictor model using 47 training samples correctly predicted 9/10 unknowns. One sample diagnosed as benign by standard histologic criteria was diagnosed as malignant by our model (sensitivity 75%; specificity, 100%; positive predictive value, 100%; negative predictive value, 85.7%). CONCLUSIONS: Molecular diagnosis with our 6-gene model can differentiate between benign and malignant thyroid tumors with high sensitivity and specificity. In combination, these genetic markers may be a reliable test to preoperatively diagnose the malignant potential of thyroid nodules.

Xing M, Westra WH, Tufano RP, Cohen Y, Rosenbaum E, Rhoden KJ, Carson KA, Vasko V, Larin A, Tallini G, Tolaney S, Holt EH, Hui P, Umbricht CB, Basaria S, Ewertz M, Tufaro AP, Califano JA, Ringel MD, Zeiger MA, Sidransky D, Ladenson PW. · Division of Endocrinology and Metabolism, Johns Hopkins University School of Medicine, 1830 East Monument Street, Suite 333, Baltimore, Maryland 21287, USA. · J Clin Endocrinol Metab. · Pubmed #16174717 links to  free full text

Abstract: CONTEXT: Use of BRAF mutation in papillary thyroid cancer (PTC) has the potential to improve risk stratification of this cancer. OBJECTIVE: The objective of the study was to investigate the prognostic value of BRAF mutation in patients with PTC. DESIGN, SETTING, AND SUBJECTS: In a multicenter study of 219 PTC patients, data on their clinicopathological characteristics and clinical courses between 1990 and 2004 were retrospectively collected, and their tumor BRAF mutation status was determined. Associations of BRAF mutation with initial tumor characteristics and subsequent recurrence were analyzed. MAIN OUTCOME MEASURE: Relationships between the BRAF mutation status and clinicopathological outcomes, including recurrence, were measured. RESULTS: We found a significant association between BRAF mutation and extrathyroidal invasion (P < 0.001), lymph node metastasis (P < 0.001), and advanced tumor stage III/IV (P = 0.007) at initial surgery. This association remained significant on multivariate analysis, adjusting for conventional clinicopathological predictors of recurrence excluding the histological PTC subtype, but was lost when the tumor subtype was included in the model. BRAF mutation was also significantly associated with tumor recurrence, 25 vs. 9% with and without mutation, respectively (P = 0.004), during a median of 15 (interquartile range, 3-29) months of follow-up. This association remained significant on multivariate analysis adjusting for conventional clinicopathological predictors of recurrence, even including the PTC subtype (odds ratio, 4.0; 95% confidence interval, 1.1-14.1; P = 0.03). BRAF mutation was even an independent predictor of recurrence in patients with stage I/II disease, 22 vs. 5% with and without BRAF mutation, respectively (P = 0.002). BRAF mutation was also more frequently associated with absence of tumor I-131 avidity and treatment failure of recurrent disease. CONCLUSIONS: In patients with PTC, BRAF mutation is associated with poorer clinicopathological outcomes and independently predicts recurrence. Therefore, BRAF mutation may be a useful molecular marker to assist in risk stratification for patients with PTC.

Hoque MO, Rosenbaum E, Westra WH, Xing M, Ladenson P, Zeiger MA, Sidransky D, Umbricht CB. · Department of Otolaryngology, Head and Neck Surgery, The Johns Hopkins Medical Institutions, 720 Rutland Avenue, Ross 743, Baltimore, Maryland 21205, USA. · J Clin Endocrinol Metab. · Pubmed #15840741 links to  free full text

Abstract: CONTEXT: Cancer-specific molecular markers are needed to supplement the cytopathological assessment of thyroid tumors, because a majority of patients with cytologically indeterminate nodules currently undergo thyroidectomy without a definitive diagnosis. OBJECTIVE: The aim of this study was the quantitative assessment of promoter hypermethylation and its relation to the BRAF mutation in thyroid tumors. DESIGN: Quantitative hypermethylation of Rassf1A, TSHR, RAR-beta2, DAPK, S100, p16, CDH1, CALCA, TIMP3, TGF-beta, and GSTpi was tested on a cohort of 82 benign and malignant thyroid tumors and five thyroid cancer cell lines. SETTING: The study was conducted at a tertiary research hospital. PATIENTS: Patients underwent surgical resection for a thyroid tumor from 2000 to 2003 at our institution. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURE: Final surgical pathology diagnosis was the main outcome measure. RESULTS: Thyroid tumors showed hypermethylation for the following markers: Rassf1A, TSHR, RAR-beta2, DAPK, CDH1, TIMP3, and TGF-beta. A trend toward multiple hypermethylation was evident in cancer tissues, with hypermethylation of two or more markers detectable in 25% of hyperplasias, 38% of adenomas, 48% of thyroid cancers, and 100% of cell lines. A rank correlation analysis of marker hypermethylation suggests that a subset of these markers is epigenetically modified in concert, which may reflect an organ-specific regulation process. Furthermore, a positive correlation was found between the BRAF mutation and RAR-beta2, and a negative correlation was found between the BRAF mutation and Rassf1A. CONCLUSIONS: Methylation-induced gene silencing appears to affect multiple genes in thyroid tissue and increases with cancer progression. Additional markers with better discriminatory power between benign and malignant samples are needed for the diagnostic assessment of cytologically indeterminate thyroid nodules.

Umbricht CB, Conrad GT, Clark DP, Westra WH, Smith DC, Zahurak M, Saji M, Smallridge RC, Goodman S, Zeiger MA. · Department of Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA. · Clin Cancer Res. · Pubmed #15355904 links to  free full text

Abstract: PURPOSE: Patients with a preoperative cytologic diagnosis of a suspicious thyroid nodule present a therapeutic dilemma because surgery differs for benign and malignant lesions. To address this issue, several molecular markers, including human telomerase reverse transcriptase (TERT), have been tested as markers of thyroid cancer. Because most studies select cases falling into well-defined categories to test new markers, they may overestimate their discriminatory power when applied to samples that are difficult to classify. Fine-needle aspirates (FNAs) of the thyroid with indeterminate cytology are an example of such cases. EXPERIMENTAL DESIGN: We examined whether assessing TERT mRNA by reverse transcription-PCR could have improved the surgical management in a cohort of 100 patients undergoing thyroidectomy for indeterminate FNA results. RESULTS: Ninety percent of 48 cancers were TERT positive, as were 35% of 52 benign lesions. When 10 cases with concomitant lymphocytic thyroiditis were excluded, the overall sensitivity of TERT was 91% (95% confidence interval, 80-98%) and specificity was 79% (64-90%). No clinical or tumor variable contributed to the predictive ability of TERT except for tumor size, which added only marginally. Basing the surgical approach on the TERT assay alone would have reduced lobectomies performed for malignant disease from 11 to 4 cases and reduced total thyroidectomies for benign lesions from to 15 to 9, an overall 50% reduction in suboptimal treatment. CONCLUSIONS: The overall performance of preoperative differential diagnosis for thyroid tumors with indeterminate FNA results can be substantially improved by the inclusion of molecular markers such as TERT.

Cohen Y, Rosenbaum E, Clark DP, Zeiger MA, Umbricht CB, Tufano RP, Sidransky D, Westra WH. · Department of Otolaryngology, and Head and Neck Surgery, Division of Head and Neck Cancer Research, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA. · Clin Cancer Res. · Pubmed #15102681 links to  free full text

Abstract: BACKGROUND: Fine needle aspiration (FNA) is routinely used in the preoperative evaluation of thyroid nodules, but subsequent patient management is often complicated by the inability to decisively recognize malignancy on cytologic grounds alone. Activating mutations of the BRAF oncogene commonly occur in papillary thyroid carcinomas (PTCs) but not in other types of benign and malignant thyroid lesions. Mutational analysis of FNAs could enhance selection of thyroid nodules for surgical removal. METHODS: Ninety-five excised PTCs along with 49 corresponding FNAs were evaluated for BRAF mutations by a newly developed assay that uses a novel primer extension method (MutectorR assay) and by direct sequencing. An additional 42 FNAs from thyroid nodules that were excised based on a suspicion of malignancy were also evaluated. RESULTS: BRAF mutations were identified in 36 of the 95 (38%) excised PTCs. By histological subtype, BRAF mutations were more common in conventional PTCs than in the follicular variant (67% versus 12%; P < 0.0001; chi(2)). Analysis of the preoperative FNAs accurately reflected BRAF status of the resected PTC in 46 of the 49 paired samples (94% concordance). In FNA samples grouped according to the preoperative cytologic findings (malignant, n = 25; benign, n = 11; and indeterminate, n = 55), a BRAF mutation confirmed the diagnosis of PTC in 72% of carcinomas within the malignant group, and it established the diagnosis of PTC in 16% of carcinomas within the indeterminate group. BRAF mutations were not detected in FNAs from 32 benign thyroid lesions. Direct sequencing and the MutectorR assay yielded completely concordant results. CONCLUSIONS: BRAF mutations are common in conventional PTCs, and they are specific for PTC. A BRAF mutation can be reliably detected in cells aspirated from a thyroid nodule suggesting a role for this marker in the preoperative evaluation of thyroid nodules.

Mazzanti C, Zeiger MA, Costouros NG, Umbricht C, Westra WH, Smith D, Somervell H, Bevilacqua G, Alexander HR, Libutti SK, Costourous N. · Surgery Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA. · Cancer Res. · Pubmed #15087409 links to  free full text

Abstract: DNA microarrays allow quick and complete evaluation of a cell's transcriptional activity. Expression genomics is very powerful in that it can generate expression data for a large number of genes simultaneously across multiple samples. In cancer research, an intriguing application of expression arrays includes assessing the molecular components of the neoplastic process and utilizing the data for cancer classification (Miller LD, et al. Cancer Cell 2002;2:353-61). Classification of human cancers into distinct groups based on their molecular profile rather than their histological appearance may prove to be more relevant to specific cancer diagnoses and cancer treatment regimes. Several attempts to formulate a consensus about classification and treatment of thyroid carcinoma based on standard histopathological analysis have resulted in published guidelines for diagnosis and initial disease management (Sherman SI. Lancet 2003;361:501-11). In the past few decades, no improvement has been made in the differential diagnosis of thyroid tumors by fine needle aspiration biopsy, specifically suspicious or indeterminate thyroid lesions, suggesting that a new approach to this should be explored. Therefore, in this study, we developed a gene expression approach to diagnose benign versus malignant thyroid lesions in 73 patients with thyroid tumors. We successfully built a 10 and 6 gene model able to differentiate benign versus malignant thyroid tumors. Our results support the premise that a molecular classification system for thyroid tumors is possible, and this in turn may provide a more accurate diagnostic tool for the clinician managing patients with suspicious thyroid lesions.

Barden CB, Shister KW, Zhu B, Guiter G, Greenblatt DY, Zeiger MA, Fahey TJ. · Department of Surgery, New York Presbyterian Hospital and Weill Medical College of Cornell University, New York 10021, USA. · Clin Cancer Res. · Pubmed #12738736 links to  free full text

Abstract: PURPOSE: Thyroid nodules are common, with a lifetime risk of developing a clinically significant thyroid nodule of 10% or higher. Preoperative diagnosis was greatly enhanced by the introduction of fine needle aspiration in the 1970s, but there has been little advancement since that time. Discrimination between benign and malignant follicular neoplasms is currently not possible by fine needle aspiration and can even be difficult after full pathologic review. The purpose of these studies is to identify genes expressed in follicular adenomas and carcinomas of the thyroid that will permit molecular differentiation of these neoplasms. Experimental Design: Gene expression patterns of 17 thyroid follicular tumors were analyzed by oligonucleotide array analysis. Gene profiles for follicular adenomas and carcinomas were identified, and the two groups were compared for differences in expression levels. The differentially expressed genes were used to perform a hierarchical clustering analysis training set. Five follicular tumors with diagnosis undisclosed to the investigators and 2 minimally invasive carcinomas were entered into the cluster analysis as a test set to determine whether diagnosis by gene profile correlated with that obtained by pathologic evaluation. RESULTS: Thyroid follicular adenomas and carcinomas showed strikingly distinct gene expression patterns. The expression patterns of 105 genes were found to be significantly different between follicular adenoma and carcinoma. Many uncharacterized genes contributed to the distinction between tumor types. For five follicular tumors for which the final diagnosis was undisclosed, the clustering algorithm gave the correct diagnosis in all 5 cases. CONCLUSIONS: Gene profiling is a useful tool to predict the molecular diagnosis of follicular thyroid tumors. Genes were identified that reliably differentiate follicular thyroid carcinoma from adenoma. This study provides insight into genes that may be important in the molecular pathogenesis of follicular thyroid tumors, as well candidates for preoperative diagnosis of follicular thyroid carcinoma.

Parwani AV, Galindo R, Steinberg DM, Zeiger MA, Westra WH, Ali SZ. · Department of Pathology, The Johns Hopkins Hospital, Baltimore, Maryland 21287-6940, USA. · Diagn Cytopathol. · Pubmed #12672098 No free full text.

Abstract: Solitary fibrous tumor (SFT) is an uncommon mesenchymal neoplasm that arises primarily from the pleura. Extrapleural occurrences are rare. To our knowledge, there is no published account of this entity in the thyroid in the cytopathology literature. We report the case of a 61-yr-old man who was evaluated at The Johns Hopkins Hospital for a slow-growing thyroid mass that was present for 2 yr despite thyroid hormone suppression. Thyroid-stimulating hormone (TSH) was within normal limits. The patient underwent ultrasound-guided fine-needle aspiration (FNA), which showed predominantly discohesive slender spindle-shaped cells and fragments of collagenized stromal tissue. After the FNA diagnosis of "thyroid neoplasm" was made, the patient underwent a near-total thyroidectomy, which revealed a SFT. Differential diagnosis of spindle cell lesions in thyroid is also presented.

Siddiqui MT, Greene KL, Clark DP, Xydas S, Udelsman R, Smallridge RC, Zeiger MA, Saji M. · Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Diagn Mol Pathol. · Pubmed #11385322 No free full text.

Abstract: Fine-needle aspiration (FNA) is a highly sensitive method in the differential diagnosis of thyroid nodules. However, 10% of thyroid FNAs are indeterminate for cancer, and thus additional markers may be useful diagnostically. The authors have demonstrated previously that human telomerase reverse transcriptase (hTERT) gene expression is useful in the distinction of benign lesions from malignant lesions. They therefore wondered whether the detection of hTERT gene expression was feasible using archival slides. To establish an experimental system, ribonucleic acid was extracted from human anaplastic thyroid carcinoma cell line (ARO) in cytologic specimens, and reverse transcription-polymerase chain reaction (RT-PCR) for hTERT expression was performed. RT-PCR analysis for hTERT gene detection was then performed using 58 Diff-Quik-stained archival FNA samples collected retrospectively. RT-PCR for human thyroglobulin (hTg) or beta-actin gene expression served as a positive control. Successful PCR results were obtained from 48 of the 58 cases. All 10 slides in which no RT-PCR products were noted were older than 3 years. hTERT gene expression was demonstrated in FNAs from two of seven cases (29%) of hyperplastic nodule, one of one case (100%) of Hashimoto's thyroiditis, three of eight cases (38%) of follicular adenoma, three of eight cases (38%) of Hürthle cell adenoma, three of four cases (75%) of follicular carcinoma, two of two cases (100%) of Hürthle cell carcinoma, and 11 of 18 cases (61%) of papillary carcinoma. All but one of the available 33 corresponding frozen samples exhibited the same RT-PCR results. This study demonstrates that Diff-Quik-stained thyroid FNA specimens less than 3 years old can be used for the detection of hTERT gene expression by RT-PCR. This test, along with careful cytopathologic examination, may improve our ability to differentiate benign lesions from malignant lesions in indeterminate FNA samples from thyroid nodules.

Zeiger MA, Smallridge RC, Clark DP, Liang CK, Carty SE, Watson CG, Udelsman R, Saji M. · Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287-8611, USA. · Surgery. · Pubmed #10598207 No free full text.

Abstract: BACKGROUND: Although fine-needle aspiration (FNA) is the most sensitive method for the detection of thyroid carcinoma, it cannot provide a definitive diagnosis of malignancy in 60% of the patients operated on for suspicious lesions. Recently, human telomerase reverse transcriptase (hTERT) has been found to be a diagnostic marker of malignancy. We therefore sought to determine whether hTERT gene expression could serve as an adjunct to FNA in the differential diagnosis of thyroid nodules. METHODS: Twenty-four FNA samples from thyroid nodules that were suspected of malignancy were collected. RNA was extracted, and hTERT gene expression was examined by RT-PCR. Cytologic and histologic examinations were also performed. RESULTS: Two of three follicular, three of three Hürthle cell, and eight of eight papillary thyroid carcinomas had corresponding FNA samples that were positive for hTERT. One of two Hürthle cell adenomas was hTERT positive. FNA samples from three follicular adenomas and five hyperplastic nodules were negative for hTERT. Positive and negative predictive values were 93% and 90%, respectively. CONCLUSIONS: The detection of hTERT gene expression in thyroid FNA samples holds promise as a diagnostic marker in the distinction of benign from malignant thyroid lesions. Its application could alter the surgical management of these patients.

Saji M, Xydas S, Westra WH, Liang CK, Clark DP, Udelsman R, Umbricht CB, Sukumar S, Zeiger MA. · Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. · Clin Cancer Res. · Pubmed #10389936 links to  free full text

Abstract: Ten percent of fine-needle aspirations (FNAs) of the thyroid are deemed "indeterminate" or "suspicious" for malignancy by the cytopathologist, but most of these lesions are benign. Therefore, additional markers of malignancy may prove to be a useful adjunct. The catalytic component of telomerase, human telomerase reverse transcriptase (hTERT), has been found to be reactivated in immortalized cell lines. Reverse transcription-PCR of the hTERT gene revealed expression in 15 (79%) of 19 malignant thyroid neoplasms, including 6 of 6 follicular carcinomas and 9 of 13 papillary carcinomas. In contrast, hTERT gene expression was detected in only 5 (28%) of 18 benign thyroid nodules, including 2 of 7 follicular adenomas and 3 of 11 hyperplastic nodules. All five benign thyroids exhibiting hTERT gene expression had lymphocytic thyroiditis. No normal thyroids exhibited hTERT gene expression. Telomerase enzyme activity was examined in all 37 nodules and was found to correlate with hTERT gene expression in 35 (95%) nodules. The two cases in which telomerase activity and hTERT expression results were discrepant were in two papillary carcinomas that were telomerase activity negative and hTERT positive. Finally, we have demonstrated that hTERT gene expression can be measured in in vivo FNA samples. These results suggest that hTERT expression may be more accurate than telomerase activity in distinguishing benign from malignant and may be measured in FNA samples from suspicious thyroid lesions.