Thyroid Diseases: Shah JP

Sherman SI, Angelos P, Ball DW, Byrd D, Clark OH, Daniels GH, Dilawari RA, Ehya H, Farrar WB, Gagel RF, Kandeel F, Kloos RT, Kopp P, Lamonica DM, Loree TR, Lydiatt WM, McCaffrey J, Olson JA, Ridge JA, Shah JP, Sisson JC, Tuttle RM, Urist MM, Anonymous00403. · The University of Texas M.D. Anderson Cancer Center, USA. · J Natl Compr Canc Netw. · Pubmed #17623612 No free full text.

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Sherman SI, Angelos P, Ball DW, Beenken SW, Byrd D, Clark OH, Daniels GH, Dilawari RA, Ehya H, Farrar WB, Gagel RF, Kandeel F, Kloos RT, Kopp P, Lamonica DM, Loree TR, Lydiatt WM, McCaffrey J, Olson JA, Ridge JA, Robbins R, Shah JP, Sisson JC, Thompson NW, Anonymous00251. · University of Texas M.D. Anderson Cancer Center, USA. · J Natl Compr Canc Netw. · Pubmed #16002006 No free full text.

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Shaha AR, Tuttle RM, Shah JP. · No affiliation provided · J Surg Oncol. · Pubmed #17192917 No free full text.

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Shah JP. · Memorial Sloan-Kettering Cancer Center, New York, NY, USA. · Eur Arch Otorhinolaryngol. · Pubmed #18546003 No free full text.

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Patel SG, Escrig M, Shaha AR, Singh B, Shah JP. · Head and Neck Service, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. · J Surg Oncol. · Pubmed #11870661 No free full text.

Abstract: BACKGROUND AND OBJECTIVE: Well-differentiated thyroid carcinoma (WDTC) is diagnosed in approximately 1.5% of thyroglossal duct cysts (TGDC). No clear consensus exists regarding further management after adequate excision of the cyst, especially the role of total thyroidectomy and postoperative radioactive iodine therapy. The current review was undertaken in an attempt to clarify these issues. METHODS: Demographic, clinical, tumor, treatment, pathology, and outcome data on 57 eligible patients reported in recent literature were pooled together with 5 patients treated at our institution for this analysis. RESULTS: A Sistrunk operation was performed for resection of the thyroglossal duct cyst in the majority (90%) of patients. Histologic examination of the tumor in the cyst revealed that papillary carcinoma was the most frequent (92%) histologic type. A total thyroidectomy was performed consequent to the diagnosis of thyroglossal duct cyst carcinoma in approximately half of the 62 patients. A malignant tumor was reported in 27% of the thyroidectomy specimens. Postoperative radioactive iodine therapy was administered in 16 (26%) patients. With a median follow-up of 71 months (range 1-456 months), the 5- and 10-year Kaplan-Meier overall survival was 100 and 95.6%, respectively. There were no disease-related deaths reported in any of the patients. Univariate analysis revealed that the only significant predictor of overall survival was the extent of primary surgery for the thyroglossal cyst. The addition of total thyroidectomy to Sistrunk operation did not have a significant impact on outcome (P = 0.1). Patients treated with postoperative radioactive iodine (RAI) fared significantly worse than those that did not need RAI, which may be explained by the fact that this modality would generally be used in patients with higher risk tumors. CONCLUSIONS: The Sistrunk operation is adequate for most patients with incidentally diagnosed TGDC carcinoma in the presence of a clinically and radiologically normal thyroid gland. Results of adequate excision using the Sistrunk operation are excellent and the concept of risk-groups should be used to identify patients, who would benefit from more aggressive treatment.

Rivera M, Tuttle RM, Patel S, Shaha A, Shah JP, Ghossein RA. · Department of Pathology, Memorial Sloan-Kettering Cancer Center , New York, New York, USA. · Thyroid. · Pubmed #19191744 No free full text.

Abstract: BACKGROUND: Encapsulated papillary thyroid carcinoma (EPTC) can have a histologic growth pattern similar to the one seen in classical papillary thyroid carcinoma (PTC) or akin to the follicular variant of PTC (FVPTC). This study aims to assess the behavior of EPTC according to its growth pattern. METHODS: All cases of thyroid carcinomas treated at our institution between 1980 and 2000 were reviewed and reclassified according to current histopathologic criteria. RESULTS: After review by two pathologists, 106 cases were included. Forty-three (41%) of the cases were identified as encapsulated classical PTC (E-CPTC) and 63 (59%) as encapsulated FVPTC (E-FVPTC). E-FVPTC had a higher rate of vascular invasion (16/63; 25%) than E-CPTC (2/43; 5%) (p = 0.007). In contrast, E-CPTC had a higher frequency of capsular invasion (28/43; 65%) than E-FVPTC (24/63, 38%) (p = 0.01). The lymph node metastatic rate was significantly higher in E-CPTC (11/43, 26%) compared to E-FVPTC (2/63, 3%) (p = 0.0014). All 34 noninvasive E-FVPTC lacked evidence of nodal metastases while 4 of 15 (27%) noninvasive E-CPTC presented with nodal disease (p = 0.006). Distant metastasis occurred only in four cases of E-FVPTC at presentation. These four FVPTC had extensive capsular and/or vascular invasion and no nodal disease. None of noninvasive EPTC recurred, including 30 patients treated by lobectomy without radioactive iodine (RAI) therapy (median follow-up: 8.9 years). CONCLUSION: E-CPTC resembles classical PTC in its propensity to metastasize to lymph nodes and its vascular/capsular invasive pattern while E-FVPTC behaves more like follicular carcinoma/adenoma group of tumors. Meticulous search for capsular and vascular invasion can reliably predict the metastatic potential of E-FVPTC but not of E-CPTC. The latter can therefore be treated like unencapsulated classical PTC. Noninvasive E-FVPTC could be managed like minimally invasive follicular carcinoma by lobectomy without RAI therapy. Invasive E-FVPTC seem quite indolent if no distant metastases are found at presentation.

Lin SF, Yu Z, Riedl C, Woo Y, Zhang Q, Yu YA, Timiryasova T, Chen N, Shah JP, Szalay AA, Fong Y, Wong RJ. · Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. · Surgery. · Pubmed #18063085 No free full text.

Abstract: BACKGROUND: Anaplastic thyroid carcinoma (ATC) is a fatal disease resistant to all conventional treatments. Novel therapies are needed to improve dismal outcomes. METHODS: A replication-competent vaccinia virus (GLV-1h68) was engineered by inserting expression cassettes encoding Renilla luciferase-green fluorescent protein (GFP), beta-galactosidase, and beta-glucuronidase into the genome of LIVP strain. Infection of 6 ATC cell lines by GLV-1h68 was detected in vitro at 12, 24, and 36 hours. Viral proliferation was measured through viral plaque assays. Cytotoxicity was measured daily at a multiplicity of infection (MOI) of 0.01, 0.1 and 1. RESULTS: Viral infection was detected in all cell lines by 24 hours and increased in intensity at 36 hours. Logarithmic viral replication was detected in all cell lines. At MOI 1, <13% cell survival was measured in 5 cell lines by day 7. At MOI 0.01, 3 cell lines showed <21% cell survival by day 7. Luciferase and beta-galactosidase activity at 24 hours correlated with cytotoxicity at MOI 0.01 on day 5. CONCLUSION: A replication-competent vaccinia virus has significant infectious and oncolytic activity against a panel of human ATC. These results encourage future in vivo and clinical studies for this novel agent to treat this fatal cancer.

Are C, Hsu JF, Ghossein RA, Schoder H, Shah JP, Shaha AR. · Division of Surgical Oncology, Department of Surgery, Eppley Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA. · Ann Surg Oncol. · Pubmed #17713821 No free full text.

Abstract: BACKGROUND: We previously reported a high incidence of primary thyroid cancer in fluorodeoxyglucose positron-emission tomogram (FDG-PET)-detected incidental thyroid abnormalities. The aim of our study was to determine if these FDG-PET-detected thyroid malignancies represent a more-aggressive variant of primary thyroid carcinoma. MATERIALS AND METHODS: All patients that underwent operative intervention for FDG-PET-detected incidental thyroid abnormalities were identified (June 2003 to April 2006). Patients with a diagnosis of primary thyroid carcinoma on final histopathology were included in the study. The patient demographics and histopathological findings were analyzed to identify adverse prognostic features. RESULTS: In 11,500 patients, 17,250 FDG-PET scans were performed; 377 of these patients (3.2% of patients and 2.1% of FDG-PET scans) had findings positive for thyroid abnormality. Of the 32 patients that underwent operative intervention, 22 patients with a final diagnosis of primary thyroid malignancy were included in the study. A greater number of patients [12 patients, (54%)] were noted to harbor poor prognostic variants of primary thyroid carcinoma on final histopathology [tall-cell variant: 11 patients (50%) and poorly differentiated thyroid carcinoma: 1 patient (4%)]. Extra-thyroidal extension (ETE) was noted in the majority of patients [14 patients (63%)]. In patients with tall cell variant on final histopathology, the rate of ETE was even higher [10 patients (90%)]. CONCLUSION: Thyroid malignancies incidentally detected on FDG-PET scan harbor a high rate of unfavorable prognostic features and may represent a more-aggressive variant of primary thyroid carcinoma. These patients need to be subjected to further investigation with a view to possible operative intervention.

Ong SC, Schöder H, Patel SG, Tabangay-Lim IM, Doddamane I, Gönen M, Shaha AR, Tuttle RM, Shah JP, Larson SM. · Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. · J Nucl Med. · Pubmed #17401085 links to  free full text

Abstract: Medullary thyroid carcinoma (MTC) is a rare endocrine tumor arising from the C-cells of the thyroid gland. Calcitonin is the principal serum tumor marker. A rising calcitonin level after total thyroidectomy for localized disease generally indicates residual, recurrent, or metastatic disease. The role of (18)F-FDG PET in MTC remains somewhat unclear. We reviewed our own experience with (18)F-FDG PET in postthyroidectomy MTC patients with elevated calcitonin. METHODS: From our database, we identified patients with suspected residual, recurrent, or metastatic MTC and elevated calcitonin who had been referred for (18)F-FDG PET between January 2000 and October 2005. (18)F-FDG PET findings were classified as positive or negative on the basis of visual interpretation of the scan. Standardized uptake values (SUVs) were also calculated. The (18)F-FDG PET findings were verified by histopathologic examination, when available, or other imaging studies and clinical follow-up. Any negative (18)F-FDG PET result was considered false-negative. RESULTS: Twenty-eight patients underwent a total of 38 (18)F-FDG PET studies. Calcitonin levels ranged from 106 to 541,000 pg/mL (median, 7,260 pg/mL). There were 23 true-positive, 1 false-positive, and 14 false-negative (18)F-FDG PET scans, yielding an overall sensitivity of 62%. There was no true-positive finding when calcitonin levels were below 509 pg/mL (n = 5). Using an arbitrary cutoff of 1,000 pg/mL, we found that the sensitivity in scans with calcitonin levels greater than 1,000 pg/mL increased to 78% (21/27; 95% confidence interval, 58%-91%). The mean SUV of all lesions with (18)F-FDG uptake was 5.3 +/- 3.2 (range, 2.0-15.9). Among the 14 patients with false-negative (18)F-FDG PET findings, 8 had concurrent anatomic imaging studies and only 2 of these had positive findings. CONCLUSION: (18)F-FDG PET can detect residual, recurrent, or metastatic MTC with a reasonable sensitivity of 78% when the calcitonin level is above 1,000 pg/mL but appears of limited use if the calcitonin level is below 500 pg/mL.

Are C, Hsu JF, Schoder H, Shah JP, Larson SM, Shaha AR. · Department of Surgical Oncology, Memorial Sloan-Kettering Cancer Center, 1233 York Avenue, 16 I, New York, New York, 10021, USA. · Ann Surg Oncol. · Pubmed #17024553 No free full text.

Abstract: BACKGROUND: Incidental thyroid abnormalities are increasingly detected in patients undergoing PET scans. The aim of this study was to review our experience with the management of PET detected thyroid incidentalomas in a large single institution series. METHODS: All PET scans performed from May 2003 to July 2005 were reviewed and patients with incidental thyroid abnormalities were identified. From this group, patients that underwent further investigation were analyzed. Data relating to PET scan findings, FNA diagnoses, operative details, and histopathology was reviewed. RESULTS: In 8,800 patients, 16,300 PET scans were performed of whom 263 patients (2.9% of patients and 1.6% of PET scans) had findings positive for thyroid abnormality. Thyroid malignancy was noted in 42% (24 patients) of the 57 patients that underwent FNA. In the group of 27 patients that were subjected to operative intervention, 74% (20 patients) were noted to have a malignant diagnosis. The final histopathology revealed primary thyroid carcinoma in all these 20 patients (19 patients with papillary carcinoma and one patient with primary thyroid lymphoma). The factors that correlated with an increased risk of malignancy were the presence of physical finding (p = 0.01) and focal (p < 0.01) or unilateral uptake (p < 0.01) on PET scan. The average SUV was not useful in differentiating benign (9.2) from malignant lesions (8.2, p = 0.7). CONCLUSIONS: PET detected incidental thyroid abnormalities are rare. In patients with positive PET scan findings and suspicious features, the incidence of primary thyroid malignancy is very high. These patients warrant further investigation followed by possible operative intervention.

Ghossein RA, Hiltzik DH, Carlson DL, Patel S, Shaha A, Shah JP, Tuttle RM, Singh B. · Department of Pathology Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. · Cancer. · Pubmed #16534796 links to  free full text

Abstract: BACKGROUND: Follicular carcinomas of the thyroid gland, including its oncocytic variant (so-called Hurthle cell carcinoma), are subdivided into the indolent encapsulated ("minimally invasive") and the clinically aggressive widely invasive tumors. There are, however, cases of encapsulated follicular carcinoma that recur and metastasize. Identifying these cases at the time of diagnosis is crucial for prognostic and therapeutic considerations. Because to the authors' knowledge most studies do not focus exclusively on the encapsulated Hurthle cell carcinoma (EHC), the current study attempted to identify predictors of recurrence in EHC. METHODS: A tumor was defined as EHC if it was encapsulated, macroscopically well defined with microscopic but no macroscopic evidence of vascular or capsular invasion, and composed of > 75% follicular oncocytic cells. Retrospective chart review and microscopic examination identified 50 primary tumors meeting the above criteria at the Memorial Sloan-Kettering Cancer Center between 1967 and 2005. The cases were analyzed for various histologic and clinical parameters. Each parameter was correlated with recurrence-free survival (RFS). RESULTS: Seven of 50 (14%) patients developed disease recurrence. All patients who developed recurrence were found to have a high number of foci of vascular invasion (> or = 4). In univariate analysis, > or = 4 foci of vascular invasion (P <.0001), tumor size > 4 cm (P = .049), the presence of mitosis (P = .018), and a solid/trabecular growth pattern (P = .009) were found to be correlated with a decreased RFS. Extensive capsular invasion, gender, and age did not confer a statistically higher recurrence rate. The finding of a solid/trabecular growth and mitosis correlated with the presence of numerous foci (> or = 4) of vascular invasion (P = .01 and P = .005, respectively). CONCLUSIONS: A diligent search for vascular invasion is recommended in EHC that display mitosis or a solid/trabecular growth pattern. The presence of > or = 4 foci of vascular invasion should alert the pathologist and the clinician to a significantly higher risk of recurrence in EHC.

Hiltzik D, Carlson DL, Tuttle RM, Chuai S, Ishill N, Shaha A, Shah JP, Singh B, Ghossein RA. · Department of Otolaryngology-Head and Neck Surgery, Columbia University, New York, NY, USA. · Cancer. · Pubmed #16470605 links to  free full text

Abstract: BACKGROUND: Poorly differentiated thyroid carcinomas (PDTC) occupy an intermediate position at the prognostic level on the spectrum of thyroid carcinoma progression. However, their histologic definition is controversial. The objective of the current study was to assess the prognostic significance of PDTC defined on the basis of mitosis and necrosis and search for prognostic markers within this group of tumors that are predictive of overall survival (OS) and progression-free survival (PFS). METHODS: PDTC was defined as thyroid carcinoma with follicular cell differentiation at the histologic and/or immunohistochemical levels and displaying tumor necrosis and/or > or = 5 mitoses per 10 high-power fields (x400). Retrospective chart review and microscopic examination identified 58 patients with primary tumors meeting the above criteria and seen at the Memorial Sloan-Kettering Cancer Center between 1992 and 2004. These 58 patients were analyzed for various histologic, clinical, and imaging parameters. Each parameter was correlated with OS and PFS. RESULTS: Of the 58 patients studied, 22 (38%) patients died of disease with a 5-year OS rate of 60%. Forty-three of the 58 patients (74%) developed disease recurrence or disease progression, with a 5-year PFS rate of 25%. The median follow-up for the entire patient population was 42.6 months (range, 4-205 mos). A tumor size > 4 cm was found to be correlated with a decreased PFS time (P < 0.001). Those tumors with a capsule demonstrated a significantly improved OS compared with unencapsulated tumors (P = 0.001). The extent of capsular invasion was found to be a significant adverse factor for PFS (P = 0.05). The presence of extrathyroid extension into perithyroid soft tissue was found to be correlated with a decreased OS (P = 0.001) and PFS (P = 0.004). Of 27 patients with distant metastasis, 19 (70%) had concentrated radioactive iodine (RAI) at their metastatic sites. On multivariate analysis, extrathyroid extension and tumor size emerged as the only significant variables in predicting PFS (P = 0.04 and P = 0.01, respectively) whereas extrathyroid extension was found to be the sole independent prognostic factor for OS (P = 0.01). Growth pattern and cell type did not appear to influence outcome. CONCLUSIONS: PDTC defined on the basis of mitosis and necrosis constitutes a group of tumors that is more aggressive and homogeneous than PDTC defined by growth pattern. Within this group of patients, microstaging (tumor size, the extent of capsular invasion, and, especially, extrathyroid extension), and not growth pattern or cell type, is able to stratify patients into different prognostic categories. RAI uptake occurs in a significant number of patients with PDTC.

Patel KN, Maghami E, Wreesmann VB, Shaha AR, Shah JP, Ghossein R, Singh B. · Laboratory of Epithelial Cancer Biology, Head and Neck Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. · Surgery. · Pubmed #16360383 links to  free full text

Abstract: BACKGROUND: We recently identified MUC1 as a target driving selection for 1q21 amplification and validated it as an independent marker of aggressive behavior in thyroid cancer (TC). The aims of this study were to determine whether TC cell lines retain MUC1 expression patterns that are seen in primary tumors, assess the role of MUC1 in tumor maintenance, and develop a virally delivered anti-MUC1 RNA interference (RNAi) that is effective in decreasing MUC1 expression in vitro. METHODS: Fifteen TC cell lines were screened for MUC1 protein expression. Cell lines with varying MUC1 protein levels were treated with anti-MUC1 monoclonal antibody to assess cell viability. A recombinant retroviral short hairpin RNAi delivery system against MUC1 was developed. Efficacy and optimal dosing of short hairpin RNA against MUC1 was determined. RESULTS: MUC1 expression patterns in TC cell lines were found to be similar to that seen in primary tumors. Treatment with anti-MUC1 antibody resulted in a significant decrease in cell viability in MUC1 over-expressing cell lines. MUC1-779 RNAi construct showed excellent infection efficiency and reproducible silencing. CONCLUSION: These data offer functional evidence that implicates MUC1 over-expression as a key molecular event in the pathogenesis of aggressive TC. Retrovirally delivered anti-MUC1 RNAi is effective in silencing MUC1 and merits further investigation to establish therapeutic efficacy and safety in anticipation of potential clinical application.

Yu Z, Eisenberg DP, Singh B, Shah JP, Fong Y, Wong RJ. · Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. · Int J Cancer. · Pubmed #15382081 No free full text.

Abstract: Although many thyroid cancers carry a favorable prognosis, there is a subgroup of patients with more aggressive histologies. Current therapies offer no significant survival benefit to patients with anaplastic thyroid carcinomas, which are considered fatal. Oncolytic herpes simplex viruses (HSVs) have potent antitumor effects against a variety of human malignancies. We assessed the activity of a replication-competent, attenuated, oncolytic HSV (NV1023) against 7 different thyroid cancers, including one papillary (NPA-187), one follicular (WRO82-1), one medullary (DRO81-1) and 4 anaplastic (DRO90-1, ARO, KAT-4C and KAT-18) cell lines. Only the follicular WRO82-1 line was resistant to NV1023 infection and cell lysis at a concentration of 5 viral pfu per cell (MOI 5). All other cell lines at MOI 5 demonstrated >95% infection in vitro at day 2 by X-gal staining and >88% cell death at day 4 by cytotoxicity assays. Even at MOI 0.1, 4 of these lines displayed complete cell death by day 7. Viral proliferation assays revealed that all of the nonfollicular cell lines supported logarithmic viral replication. Flank tumors of NPA-187, DRO81-1, DRO90-1 and ARO in athymic nude mice were treated with NV1023 (2 x 10(7) pfu). All NPA-187 tumors completely regressed following a single dose. DRO81-1 tumors demonstrated partial response with a single dose and significant improvement with 3 serial doses. ARO and DRO90-1 tumors showed a significant response following either single injection (54 +/- 22 and 292 +/- 138 mm3, respectively) or 3 serial injections (33 +/- 14 and 241 +/- 68 mm3, respectively) compared to saline injections (472 +/- 193 and 1,257 +/- 204 mm3, respectively) at day 20. These data suggest that herpes oncolytic therapy may be effective for the treatment of aggressive thyroid carcinomas and merits further investigation.

Wreesmann VB, Ghossein RA, Hezel M, Banerjee D, Shaha AR, Tuttle RM, Shah JP, Rao PH, Singh B. · Laboratory of Epithelial Cancer Biology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. · Genes Chromosomes Cancer. · Pubmed #15188460 No free full text.

Abstract: The majority of thyroid tumors are classified as papillary (papillary thyroid carcinomas; PTCs) or follicular neoplasms (follicular thyroid adenomas and carcinomas; FTA/FTC) based on nuclear features and the cellular growth pattern. However, classification of the follicular variant of papillary thyroid carcinoma (FVPTC) remains an issue of debate. These tumors contain a predominantly follicular growth pattern but display nuclear features and overall clinical behavior consistent with PTC. In this study, we used comparative genomic hybridization (CGH) to compare the global chromosomal aberrations in FVPTC to the PTC of classical variant (classical PTC) and FTA/FTC. In addition, we assessed the presence of peroxisome proliferator-activated receptor-gamma (PPARG) alteration, a genetic event specific to FTA/FTC, using Southern blot and immunohistochemistry analyses. In sharp contrast to the findings in classical PTC (4% of cases), CGH analysis demonstrated that both FVPTC (59% of cases) and FTA/FTC (36% of cases) were commonly characterized by aneuploidy (P = 0.0002). Moreover, the pattern of chromosomal aberrations (gains at chromosome arms 2q, 4q, 5q, 6q, 8q, and 13q and deletions at 1p, 9q, 16q, 17q, 19q, and 22q) in the follicular variant of PTC closely resembled that of FTA/FTC. Aberrations in PPARG were uniquely detected in FVPTC and FTA/FTC. Our findings suggest a stronger relationship between the FVPTC and FTA/FTC than previously appreciated and support further consideration of the current classification of thyroid neoplasms.

Wreesmann VB, Sieczka EM, Socci ND, Hezel M, Belbin TJ, Childs G, Patel SG, Patel KN, Tallini G, Prystowsky M, Shaha AR, Kraus D, Shah JP, Rao PH, Ghossein R, Singh B. · Laboratory of Epithelial Cancer Biology, Head and Neck Service, Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. · Cancer Res. · Pubmed #15172984 links to  free full text

Abstract: Clinicopathological variables used at present for prognostication and treatment selection for papillary thyroid carcinomas (PTCs) do not uniformly predict tumor behavior, necessitating identification of novel prognostic markers. Complicating the assessment is the long natural history of PTC and our rudimentary knowledge of its genetic composition. In this study we took advantage of differences in clinical behavior of two distinct variants of PTC, the aggressive tall-cell variant (TCV) and indolent conventional PTC (cPTC), to identify molecular prognosticators of outcome using complementary genome wide analyses. Comparative genome hybridization (CGH) and cDNA microarray (17,840 genes) analyses were used to detect changes in DNA copy number and gene expression in pathological cPTC and TCV. The findings from CGH and cDNA microarray analyses were correlated and validated by real-time PCR and immunohistochemical analyses on a series of 100 cases of cPTC and TCV. Genes identified by this approach were evaluated as prognostic markers in cPTC by immunohistochemistry on tissue arrays. CGH identified significant differences in the presence (76 versus 27%; P = 0.001) and type of DNA copy number aberrations in TCV compared with cPTC. Recurrent gains of 1p34-36, 1q21, 6p21-22, 9q34, 11q13, 17q25, 19, and 22 and losses of 2q21-31, 4, 5p14-q21, 6q11-22, 8q11-22, 9q11-32, and 13q21-31 were unique to TCV. Hierarchical clustering of gene expression profiles revealed significant overlap between TCV and cPTC, but further analysis identified 82 dysregulated genes differentially expressed among the PTC variants. Of these, MUC1 was of particular interest because amplification of 1q by CGH correlated with MUC1 amplification by real-time PCR analysis and protein overexpression by immunohistochemistry in TCV (P = 0.005). Multivariate analysis revealed a significant association between MUC1 overexpression and treatment outcome, independent of histopathological categorization (P = 0.03). Analysis of a validation series containing a matched group of aggressive and indolent cPTCs confirmed the association between MUC1 overexpression and survival (relative risk, 2.3; 95% confidence interval, 1.1-5.5; P = 0.03). Our data suggest that MUC1 dysregulation is associated with aggressive behavior of PTC and may serve as a prognostic marker and potential therapeutic target in this disease.

Shoup M, Stojadinovic A, Nissan A, Ghossein RA, Freedman S, Brennan MF, Shah JP, Shaha AR. · Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. · J Am Coll Surg. · Pubmed #12892796 No free full text.

Abstract: BACKGROUND: Distant metastasis is uncommon in differentiated thyroid cancer and the prognosis is unclear. This study aims to evaluate outcomes and to define independent variables that are associated with tumor-related mortality in patients with distant metastasis from thyroid carcinoma. STUDY DESIGN: A retrospective review of the thyroid cancer research database identified 336 patients with distant metastasis from differentiated thyroid carcinoma treated at a single institution between 1941 and 2000. After excluding patients with local or regional recurrence, distant disease was either the first site of recurrence or was detected at the time of diagnosis of the primary tumor in 242 patients (72%). Patient, tumor, and treatment-related factors were analyzed for their relation to disease-specific survival (DSS) using multivariate Cox regression and the log-rank test. RESULTS: Median survival was 4.1 years and 10-year DSS was 26%. Distant disease was synchronous with the primary diagnosis in 97 of 242 (40%) patients. The site of metastasis was lung only in 103 (43%) patients, bone only in 80 (33%), other sites in 14 (6%), and more than one organ system in 45 (19%). Multivariate analysis identified age 45 years or more, symptoms, site other than lung only or bone only, and no radioactive iodine treatment for the metastasis as predictors of poor outcome with 13%, 11%, 16%, and 12% 10-year DSS, respectively. This compares with age less than 45 years, asymptomatic presentation, metastasis only in the lung or bone, and radioactive iodine treatment with 10-year DSS rates of 58%, 45%, 32%, and 33%, respectively (all p < 0.0001). Radioactive iodine treatment was more often given in patients who were less than 45 years of age, asymptomatic, and with metastasis only in the lung or bone only (p = 0.03, 0.11, 0.01). CONCLUSIONS: Longterm survival is possible in patients with distant metastasis from differentiated thyroid cancer. This retrospective study found that age of 45 years or more, site other than lung only or bone only, and symptoms at the time of diagnosis are associated with poorer outcomes.

Stojadinovic A, Shaha AR, Orlikoff RF, Nissan A, Kornak MF, Singh B, Boyle JO, Shah JP, Brennan MF, Kraus DH. · Department of Surgery, Walter Reed Army Medical Center, Washington, D.C., USA. · Ann Surg. · Pubmed #12454521 links to  free full text

Abstract: OBJECTIVE: To analyze voice function before and after thyroidectomy for patients with normal preoperative voice using a standardized multidimensional voice assessment protocol. SUMMARY BACKGROUND DATA: The natural history of post-thyroidectomy voice disturbances for patients with preserved laryngeal nerve function has not been systematically studied and characterized with the intent of using the data for postoperative voice rehabilitation. METHODS: During a prospective single-arm study, patients with normal voice underwent functional voice testing using a standardized voice grading scale and a battery of acoustic, aerodynamic, glottographic, and videostroboscopic tests before, 1 week after, and 3 months after thyroidectomy. Differences in observed sample means were evaluated using analysis of covariance or t test; categorical data was analyzed using the Fisher exact or chi-square test. RESULTS: Fifty-four patients were enrolled; 50 and 46 were evaluable at 1 week and 3 months, respectively. No patient developed recurrent laryngeal nerve injury; one had superior laryngeal nerve injury. Fifteen (30%) patients reported early subjective voice change and seven (14%) reported late (3-month) subjective voice change. Forty-two (84%) patients had significant objective change in at least one voice parameter. Six (12%) had significant alterations in more than three voice measures, of which four (67%) were symptomatic, whereas 25% with three or fewer objective changes had symptoms. Patients with persistent voice change at 3 months had an increased likelihood of multiple (more than three) early objective changes (43% vs. 7%). Early maximum phonational frequency range and vocal jitter changes from baseline were significantly associated with voice symptoms at 3 months. CONCLUSIONS: Early vocal symptoms are common following thyroidectomy and persist in 14% of patients. Multiple (more than three) objective voice changes correlate with early and late postoperative symptoms. Alterations in maximum phonational frequency range and vocal jitter predict late perceived vocal changes. Factors other than laryngeal nerve injury appear to alter post-thyroidectomy voice. The variability of patient symptoms underscores the importance of understanding the physiology of dysphonia.

Wreesmann VB, Ghossein RA, Patel SG, Harris CP, Schnaser EA, Shaha AR, Tuttle RM, Shah JP, Rao PH, Singh B. · Laboratory of Epithelial Cancer Biology, Head and Neck Service, New York, New York 10021, USA. · Am J Pathol. · Pubmed #12414503 links to  free full text

Abstract: Several lines of evidence suggest that follicular cell-derived thyroid cancers represent a continuum of disease that progresses from the highly curable well-differentiated thyroid cancers to the universally fatal anaplastic cancers. However, the genetic mechanisms underlying thyroid cancer progression remain ill defined. We compared the molecular-cytogenetic profiles derived from comparative genomic hybridization (CGH) analysis of major histological variants of thyroid cancer to define genetic variables associated with progression. Overall, a sequential increase in chromosomal complexity was observed from well-differentiated papillary thyroid cancer to poorly differentiated and anaplastic carcinomas, both in terms of the presence of CGH detectable abnormalities (P = 0.003) and the median number of abnormalities per case (P < 0.001). The presence of multiple abnormalities common to all thyroid cancer variants, including gains of 5p15, 5q11-13, 19p, and 19q and loss of 8p, suggests that these tumors are derived from a common genetic pathway. Gains of 1p34-36, 6p21, 9q34, 17q25, and 20q and losses of 1p11-p31, 2q32-33, 4q11-13, 6q21, and 13q21-31 may represent secondary events in progression, as they were only detected in poorly differentiated and anaplastic carcinomas. Finally, recurrent gains at 3p13-14 and 11q13, and loss of 5q11-31 were unique to anaplastic carcinomas, suggesting they may be markers for anaplastic transformation. Our data suggests that the development of chromosomal instability underlies the progression to more aggressive phenotypes of thyroid cancer and sheds light on the possible genomic aberrations that may be selected for during this process.

Stojadinovic A, Shoup M, Nissan A, Ghossein RA, Shah JP, Brennan MF, Shaha AR. · Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York , USA. · Ann Surg Oncol. · Pubmed #12374663 No free full text.

Abstract: BACKGROUND: We identified factors predictive of outcome for recurrent differentiated thyroid carcinoma (DTC). METHODS: Fifty-seven patients with local (LR), regional (RRec), and/or distant recurrence (DR) of 431 recurrent DTCs were studied. Disease-specific survival (DSS) rate was estimated with the Kaplan-Meier method. Univariate and multivariate comparisons were conducted by log-rank and Cox regression analysis. RESULTS: The median follow-up was 13 years. Distribution of the first relapse was LR only (35%), LR and RRec (23%), LR and DR (30%), and LR, RRec, and DR (12%). Factors predictive of resectability were a long (>or=5-year) disease-free interval (DFI) and subclinical and thyroid remnant recurrence. Only 26% of symptomatic and 45% of thyroid bed LR, and 43% with DFI <5 years, could be resected completely. No isolated thyroid remnant and 75% of thyroid bed LR resulted in tumor-related mortality. Age <45 years, subclinical recurrence, isolated LR, and the ability to render the patient disease free independently predicted DSS. Fifteen-year DSS for LR only; LR and RRec; LR and DR; and LR, RRec, and DR were 49%, 28%, 15%, and 0%, respectively. CONCLUSIONS: Isolated thyroid remnant recurrence defines a benign phenotype. Age, method of detection, site and extent of recurrence, and the ability to render the patient disease free predict outcome for recurrent DTC. Multimodality long-term follow-up is warranted to detect recurrence at a subclinical potentially curative stage.

Stojadinovic A, Shoup M, Ghossein RA, Nissan A, Brennan MF, Shah JP, Shaha AR. · Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. · Surgery. · Pubmed #12075176 No free full text.

Abstract: BACKGROUND: The role of operations for distantly metastatic well-differentiated thyroid carcinoma (DTC) is poorly defined. We review the indications for operation for metastatic DTC. METHODS: This study consists of 260 patients treated between 1941 and 2000 for metastatic DTC, of which 59 (23%) underwent operations. Median follow-up was 7 years (range, 1 to 49 years). Metastases were identified clinically in 157 (60%) and radiologically in 103 (40%) patients. The disease-specific survival was estimated with the Kaplan-Meier method. RESULTS: Twenty-four patients (9%) were disease-free with resection. Palliative resection was indicated for painful bone metastasis, pathologic fracture, or symptomatic spinal cord involvement (35/260, 14%). Patients who could undergo complete metastasectomy survived longer than those having incomplete/palliative resection or nonoperative treatment for metastatic DTC (5-year disease-specific survival, 78% vs 43% vs 46%, P =.03). CONCLUSIONS: Solitary distant metastasis of DTC amenable to complete resection is infrequent. Complete metastasectomy may be associated with improved survival for localized distant disease. Palliative resection is indicated to improve quality of life for symptomatic distant metastasis.

Stojadinovic A, Hoos A, Ghossein RA, Urist MJ, Leung DH, Spiro RH, Shah JP, Brennan MF, Singh B, Shaha AR. · Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. · Ann Surg Oncol. · Pubmed #11888879 No free full text.

Abstract: BACKGROUND: The aim of this study was to define the clinical behavior and prognostic indicators of outcome in Hürthle cell cancer (HCC). METHODS: Diagnosis was confirmed for 56 patients with HCC treated between 1940 and 2000, who form the basis of this study. Primary end points were relapse-free survival (RFS) and disease-specific survival (DSS). Data were analyzed with the Kaplan-Meier method and by log-rank test. RESULTS: The extent of thyroid resection did not predict outcome. Recurrence was a significant predictor of tumor-related mortality. Significant adverse predictors of RFS and DSS were degree of invasion, size >4 cm, extrathyroidal extension, and initial nodal or distant metastases. The most significant predictor of outcome was extent of invasion. Eight-year RFS values for low- and high-risk groups were 100% and 24%. Corresponding rates of 8-year DSS were 100% and 58%. CONCLUSIONS: Widely invasive HCC is an aggressive malignancy that identifies patients who are at high risk for recurrence and tumor-related death. Patients with HCC have a prognosis that is reliably predicted by degree of invasion, tumor size, extrathyroidal disease extension, and initial nodal or distant metastasis. Recurrence portends a poor outcome. High-risk patients and those with recurrence should be considered for adjuvant therapy.

Hoos A, Stojadinovic A, Singh B, Dudas ME, Leung DH, Shaha AR, Shah JP, Brennan MF, Cordon-Cardo C, Ghossein R. · Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. · Am J Pathol. · Pubmed #11786411 links to  free full text

Abstract: Hürthle cell tumors are rare thyroid neoplasms for which disease biology is poorly understood and diagnosis of carcinoma can be challenging. The aim of the study was to characterize molecular expression profiles of Hürthle cell tumors and to determine the clinical significance of identified phenotypes. Paraffin-embedded tissue cores of normal thyroid (n = 18), and histopathologically well-defined Hürthle cell adenomas (n = 27), Hürthle cell tumors of unknown malignant behavior (n = 7), and minimally (n = 14) and widely (n = 21) invasive Hürthle cell carcinomas were arrayed in triplicate on tissue microarrays. Expression profiles of p53, mdm-2, p21, Bcl-2, cyclin D1, and Ki-67 were detected by immunohistochemistry and correlated with clinicopathological data and patient outcome using standard statistical methodology. Median follow-up time was 8 years. High Ki-67 proliferative index was evident only in the clinically aggressive widely invasive Hürthle cell carcinomas and was associated with significantly reduced relapse-free (P = 0.001) and disease-specific (P < 0.001) survival. The molecular phenotype of Hürthle cell tumors, independent of histopathological subtype diagnosis, was characterized by p53(-), mdm-2(+), p21(+/-), cyclin D1(-), and Bcl-2(+/-). Normal thyroid tissue demonstrated a p53(-), mdm-2(-), p21(-), cyclin D1(-), and Bcl-2(+) phenotype. The Bcl-2(+) phenotype was associated with improved relapse-free survival (P = 0.04) and disease-specific survival (P = 0.01) in widely invasive carcinomas and the Ki-67(+)/Bcl-2(-) phenotype was associated with the diagnosis of widely invasive Hürthle cell carcinoma (P < 0.001). This study demonstrates that tissue microarray-based profiling allows identification of molecular markers that are associated with patient prognosis. High Ki-67 proliferative index was associated with adverse outcome in Hürthle cell neoplasms. Together with down-regulation of Bcl-2, high Ki-67 proliferative index may be useful for diagnosing widely invasive Hürthle cell carcinomas. Molecular alterations in the p53 pathway play a role in Hürthle cell tumorigenesis, but other unidentified molecular changes seem to be required to induce the malignant phenotype.

Stojadinovic A, Ghossein RA, Hoos A, Urist MJ, Spiro RH, Shah JP, Brennan MF, Shaha AR, Singh B. · Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. · J Clin Oncol. · Pubmed #11352953 No free full text.

Abstract: PURPOSE: Controversy exists over the ability of morphology to predict the biologic behavior of Hürthle cell carcinoma. The aim of this study was to conduct a critical histopathologic review of Hürthle cell carcinoma and to correlate morphologic parameters with clinical outcome. PATIENTS AND METHODS: Patients with histologically confirmed Hürthle cell carcinoma treated between 1940 and 2000 form the basis of this study. Adenomas were excluded. Tumors of unknown malignant behavior ([UMB] n = 17) had solid growth pattern, incomplete capsular invasion (Ci), or both but no vascular invasion (Vi). Minimally invasive carcinomas ([MIC] n = 23) had one focus of intra- or extracapsular Vi, one focus of complete Ci, or both. Widely invasive carcinomas ([WIC] n = 33) demonstrated more than one focus of Vi, more than one focus of Ci, or both. The primary end points were relapse-free survival (RFS) and disease-specific survival (DSS). Rates of recurrence/death were estimated by Kaplan-Meier method. The univariate influence of prognostic factors on end points was analyzed by log-rank test, and multivariate analysis was performed by Cox regression. RESULTS: Median follow-up was 8 years. No patients with UMB or MIC relapsed or died of disease. Of WIC, 73% relapsed and 55% died of disease. Age, size, and extent of resection did not influence outcome. Adverse predictors of RFS and DSS among WIC were extrathyroidal extension, nodal metastasis, positive margin, and solid growth pattern (P <.05). Both Ci and Vi were associated with worse DSS (P <.05). On multivariate analysis, extrathyroidal extension and nodal metastases were independent predictors of outcome (P <.05). CONCLUSION: Patients with Hürthle cell carcinoma have a prognosis that is predicted by well-defined histomorphologic characteristics. Unlike differentiated thyroid cancer, nodal metastases predict a worse outcome in widely invasive Hürthle cell carcinoma, as does extrathyroidal extension.

Singh B, Lim D, Cigudosa JC, Ghossein R, Shaha AR, Poluri A, Wreesmann VB, Tuttle M, Shah JP, Rao PH. · Head and Neck Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. · Surgery. · Pubmed #11114620 No free full text.

Abstract: BACKGROUND: Determination of the genetic composition of papillary thyroid cancers may help explain differences in observed clinical behavior. Comparative genomic hybridization (CGH) is a novel molecular cytogenetic assay that allows simultaneous detection of gains, losses, and amplification of genetic information, making it an ideal screening tool. The aim of this study was to identify genetic aberrations occurring in papillary thyroid cancers by using CGH analysis. METHODS: CGH analysis was performed on 21 individual cases of papillary thyroid cancers. Nonparametric statistical comparisons were performed with the Fisher exact test. RESULTS: Genetic abnormalities were identified by CGH in 10 of 21 cases (48%). A recurrent pattern of aberrations was seen in cases where genetic changes were detected, involving losses at chromosome arms 1p and 9q and chromosomes 17, 19, and 22, and gains at chromosome 4 and chromosome arms 5q, 6q, 9q, and 13q. The loss of chromosome 22 was unique to younger patients (P =.05) and was associated with a higher rate of regional lymphatic metastasis (19% vs 80%, P =.02). CONCLUSIONS: Two genetically unique groups of patients were identified by using CGH analysis. One group had no detectable aberrations; the other had a recurrent pattern of aberrations, localizing to the identical chromosomal loci. This pattern of aberrations suggests that the involved loci may contain genes important in thyroid carcinogenesis. The clinical significance of the presence of copy number changes detected by CGH needs to be determined. In addition, molecular cloning of involved genes in each of the aberrations is warranted.