Ronald Ghossein

Memorial Sloan-Kettering Cancer Center, New York, New York, United States

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Publications (131)761.16 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Introduction In contrast to other head and neck cancers, the impact of histological thyroid specimen margin status in differentiated thyroid cancer (DTC) is not well understood. The aim of this study was to investigate the prognostic value of margin status on local recurrence in DTC. Methods The records of 3664 consecutive patients treated surgically for DTC between 1986 and 2010 were identified from an institutional database. Patients with less than total thyroidectomy, unresectable or gross residual disease, M1 disease at presentation and those with unknown pathological margin status were excluded from analysis. In total, 2616 patients were included in the study; 2348 patients (90%) had negative margins and 268 patients (10%) had positive margins. Microscopic positive margin status was defined as tumor present at the specimen's edge on pathological analysis. Patient, tumor and treatment characteristics were compared by Pearson's chi square test. Local recurrence free survival (LRFS) was calculated for each group using the Kaplan Meier method. Results The median age of the cohort was 48 years (range 7- 91yrs) and the median follow up was 50 months (range 1-330 months). Age, gender and histology types were similar between groups. As expected, patients who had positive margins were more likely to have larger tumors (p<0.001), extrathyroidal extension (ETE) (p<0.001), multicentric disease (p<0.001), nodal disease (p<0.001), and were more likely to receive adjuvant RAI therapy (p<0.001) as well as external beam radiotherapy (EBRT) (p<0.001). The LRFS at 5 years for patients with positive margins status was slightly poorer compared to patients with negative margins (98.9% vs 99.5%, p=0.018). 12 patients developed local recurrence; 8/2348 (0.34%) patients with negative, and 4/263 (1.52%) patients with positive margins. Univariate predictors of LRFS were gender (p=0.006), gross ETE (<0.001) and positive margins (p=0.018). However when controlling for presence of gross ETE on multivariate analysis, microscopic positive margin status was not an independent predictor of LRFS (p=0.193). Conclusion Patients with resectable, M0 disease that undergo total thyroidectomy have an excellent 5 year LRFS of 99.4%. Microscopic positive margin status was not a significant predictor for local failure after adjusting for ETE or pathological T stage.
    Thyroid: official journal of the American Thyroid Association 06/2015; DOI:10.1089/thy.2015.0141 · 3.84 Impact Factor
  • Bin Xu, Ronald Ghossein
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    ABSTRACT: Encapsulated carcinomas of follicular cell origin are subject to considerable controversies. This group includes an encapsulated/well-circumscribed (E/WC) follicular variant of papillary carcinoma (FVPTC) and encapsulated follicular and Hurthle cell carcinoma (EFC, EHC respectively). FVPTC usually presents as an E/WC tumor and less commonly as an infiltrative neoplasm. E/WC FVPTC rarely metastasizes to lymph nodes, whereas infiltrative tumors often present with cervical nodal metastases. Many studies revealed FVPTC in general to be genetically close to the follicular adenomas (FA)/EFC group of tumors. This is particularly true for the E/WC FVPTC which has a high rate of RAS and lack BRAFV600E mutations. Infiltrative FVPTC has an opposite molecular profile closer to classical papillary carcinoma than to FA/EFC (BRAFV600E > RAS mutations). Noninvasive E/WC FVPTCs are extremely indolent even if treated with lobectomy alone. While EFC and EHC with capsular invasion only have an excellent outcome, those with extensive (≥4 foci) lymphovascular invasion (LVI) have a significant rate of distant recurrence. The prognosis of those with focal LVI seems good, but more studies are needed to confirm their behavior. In EHC, those with extensive/significant LVI have a different RNA expression profile than those with less LVI. EHC appear to recur earlier, are less RAI avid, and have a different mutation profile than EFC. Noninvasive E/WC FVPTC should be treated conservatively. There is therefore a need to reclassify the E/WC FVPTC in order to prevent overtreatment. In view of their molecular and behavioral differences, EHC should not be considered a subset of EFC.
    Endocrine Pathology 05/2015; DOI:10.1007/s12022-015-9376-5 · 1.64 Impact Factor
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    ABSTRACT: Predictive role of undetectable thyroglobulin (Tg) in patients with poorly differentiated thyroid carcinoma (PDTC) is unclear. Our goal was to report on Tg levels following total thyroidectomy and adjuvant RAI in PDTC patients and to correlate Tg levels with recurrence. Forty patients with PDTC with no distant metastases at presentation (M0) and managed by total thyroidectomy and adjuvant RAI were identified from a database of 91 PDTC patients. Of these, 31 patients had Tg values recorded and formed the basis of our analysis. A nonstimulated Tg level <1 ng/ml was used as a cutoff point for undetectable Tg levels. Association of patient and tumor characteristics with Tg levels was examined by χ (2) test. Recurrence-free survival (RFS) stratified by postop Tg level was calculated by Kaplan-Meier method and compared by log-rank test. Twenty patients had undetectable Tg (<1 ng/ml) and 11 had detectable Tg (≥1 ng/ml; range 2-129 ng/ml) following surgery. After adjuvant RAI, 24 patients had undetectable Tg (<1 ng/ml) and 7 had detectable Tg (≥1 ng/ml; range 1-57 ng/ml). Patients with undetectable Tg were less likely to have pathologically positive margins compared to those with detectable Tg (33 vs. 72 % respectively; p = 0.03). Patients with undetectable Tg levels had better 5-year regional control and distant control than patients with detectable Tg level (5-year regional recurrence-free survival 96 vs. 69 %; p = 0.03; 5-year distant recurrence-free survival 96 vs. 46 %, p = 0.11). Postoperative thyroglobulin levels in subset of patients with PDTC appear to have predictive value for recurrence. Patients with undetectable Tg have a low rate of recurrence.
    Annals of Surgical Oncology 04/2015; DOI:10.1245/s10434-015-4567-3 · 3.94 Impact Factor
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    ABSTRACT: Phosphoinositide-3-kinase (PI3K)-α inhibitors have shown clinical activity in squamous cell carcinomas (SCCs) of head and neck (H&N) bearing PIK3CA mutations or amplification. Studying models of therapeutic resistance, we have observed that SCC cells that become refractory to PI3Kα inhibition maintain PI3K-independent activation of the mammalian target of rapamycin (mTOR). This persistent mTOR activation is mediated by the tyrosine kinase receptor AXL. AXL is overexpressed in resistant tumors from both laboratory models and patients treated with the PI3Kα inhibitor BYL719. AXL dimerizes with and phosphorylates epidermal growth factor receptor (EGFR), resulting in activation of phospholipase Cγ (PLCγ)-protein kinase C (PKC), which, in turn, activates mTOR. Combined treatment with PI3Kα and either EGFR, AXL, or PKC inhibitors reverts this resistance. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cancer cell 04/2015; 27(4):533-46. DOI:10.1016/j.ccell.2015.03.010 · 23.89 Impact Factor
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    ABSTRACT: The Afirma gene expression classifier (GEC) is used to assess malignancy risk in indeterminate thyroid nodules (ITNs) classified as Bethesda category III/IV. Our objective was to analyze GEC performance at two institutions with high thyroid cytopathology volumes but differing prevalence of malignancy. Retrospective analysis of all ITNs evaluated with the GEC at Memorial Sloan Kettering Cancer Center (MSK; n = 94) and Mount Sinai Beth Israel (MSBI; n = 71). These institutions have differing prevalences of malignancy in ITNs: 30-38 % (MSK) and 10-19 % (MSBI). Surgical pathology was correlated with GEC findings for each matched nodule. Performance characteristics were estimated using Bayes Theorem. Patient and nodule characteristics were similar at MSK and MSBI. The GEC-benign call rates were 38.3 % (MSK) and 52.1 % (MSBI). Of the GEC-benign nodules, 8.3 % (MSK) and 13.5 % (MSBI) were treated surgically. Surgical pathology indicated that all of GEC-benign nodules were benign. Of the GEC-suspicious nodules, 60.0 % (MSK) and 61.7 % (MSBI) underwent surgery. Positive predictive values (PPVs) for GEC-suspicious results were 57.1 % (95 % CI 41.0-72.3) at MSK and 14.3 % (95 % CI 0.2-30.2) at MSBI. The estimated negative predictive values (NPVs) were 86-92 % at MSK and 95-98 % at MSBI. There were wide variations in the Afirma GEC-benign call rate, PPV, and NPV between MSBI (a comprehensive health system) and MSK (a tertiary referral cancer center), which had differing rates of malignancy in ITNs. The GEC could not routinely alter management in either institution. We believe that this assay would be expected to be most informative in practice settings where the prevalence of malignancy is 15-21 %, such that NPV >95 % and PPV >25 % would be anticipated. Knowing the prevalence of malignancy in ITNs at a particular institution is critical for reliable interpretation of GEC results.
    Annals of Surgical Oncology 04/2015; DOI:10.1245/s10434-015-4486-3 · 3.94 Impact Factor
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    ABSTRACT: Myoepithelial carcinoma (MECA) is an underrecognized rare tumor with a diverse clinical behavior. The histologic features of this tumor are not well characterized, much less its grading, which is controversial. The objective of this study is to provide a better characterization of MECA and its prognostic factors. A total of 48 cases were retrieved from the pathology files. The cases were subjected to a detailed histopathologic, immunohistochemical, statistical, and clinical analysis. Tumors were classified as de novo MECA in 22 cases (46%) and carcinoma ex-pleomorphic adenoma (CA ex-PA) in 26 cases (54%). Tumor necrosis, high mitotic count (≥6/10 high-power fields), and severe pleomorphism were identified in 38%, 33%, and 21%, respectively. Perineural invasion, vascular invasion, and positive margins were noted in 10%, 12%, and 47%, respectively. Median follow-up was 38 months. Four patients had lymph node metastasis at presentation, 9 developed local recurrences, and 12 had distant metastases with the lung being the most common site (83%). The presence of CA ex-PA, necrosis, and vascular invasion correlated significantly with disease-free survival (P=0.02, 0.01, 0.03, respectively). No distant recurrence was noted in all 23 patients lacking necrosis in their neoplasms (median follow-up: 44 mo). MECA is a relatively aggressive tumor that is associated with a high rate of distant metastasis (27%). Compared with de novo MECA, CA ex-PA correlates with worse clinical outcome. A grading system based on the presence of tumor necrosis should be used to identify high-grade MECA and predict its clinical behavior.
    The American journal of surgical pathology 04/2015; 39(7). DOI:10.1097/PAS.0000000000000452 · 4.59 Impact Factor
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    ABSTRACT: Background: Vascular invasion (VI) is an important predictor of distant metastasis and possible radioactive iodine (RAI) benefit in follicular, Hurthle cell, and poorly differentiated thyroid carcinomas, but its role in well-differentiated papillary thyroid cancer (WDTC) remains unclear. Methods: Archived pathological material of all differentiated thyroid carcinoma patients undergoing primary surgical treatment at Memorial Sloan-Kettering Cancer Center between 1986 and 2003 was reviewed by two dedicated thyroid pathologists. Only WDTCs were included in the present study. Standard statistical methods were used to assess the relationship between VI on outcomes of interest, including 10-year disease-specific survival (DSS), regional recurrence-free survival (RRFS), and distant recurrence-free survival (DRFS). Results: VI was present in 47 of 698 WDTC (6.7%). VI was significantly associated with tumor size > 4.0 cm, extrathyroid extension, distant metastasis and RAI treatment. On univariate analysis, VI was predictive of decreased 10-year DRFS, but not DSS, or RRFS. On multivariate analysis, VI was not an independent predictor of DRFS. Univariate survival analysis of 422 RAI-naïve WDTC, showed that both size > 4cm, and VI were predictors of outcome, but only size remained independently predictive on multivariate analysis. Conclusion: The presence of VI is not an independent predictor of outcome in WDTC.
    Thyroid: official journal of the American Thyroid Association 03/2015; 25(5). DOI:10.1089/thy.2015.0052 · 3.84 Impact Factor
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    ABSTRACT: The prognosis of the encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC) and its relationship to encapsulated follicular carcinoma (EFC) and follicular adenoma (FA) is subject to controversy. All EFVPTCs, EFCs, and FAs identified at a single institution between 1981 and 2003 were analyzed microscopically. A cohort of FAs from a different hospital was also examined. EFVPTCs were subdivided into noninvasive EFVPTC (NIEFVPTC) and invasive EFVPTC (IEFVPTC) displaying capsular/vascular invasion. There were 83 EFVPTCs (57 noninvasive, 26 invasive), 14 EFCs, and 52 FAs. Similar to FA, over a median follow-up of 9.5 years, none of the NIEFVPTCs manifested lymph node metastasis (LNM) or recurred. Furthermore, with a median follow-up of 10.5 years, none of 39 NIEFVPTCs without radioactive iodine therapy recurred. Four (15%) of 26 IEFVPTCs and none of 14 EFCs harbored distant metastasis (P = .29). There was no difference in LNM rate and degree of vascular or capsular invasion between IEFVPTC and EFC (P > .1). All 4 IEFVPTCs with adverse behavior presented with distant metastasis and no LNM. Sixteen percent of IEFVPTCs had poor outcome, whereas there was none in the NIEFVPTCs (P = .007). In conclusion, NIEFVPTC seems to behave similarly to FA, whereas IEFVPTC can metastasize and spread like EFC. Thus, invasion rather than nuclear features drives outcome in encapsulated follicular tumors. Non-IEFVPTC could be treated in a conservative manner sparing patients unnecessary total thyroidectomy and radioactive iodine therapy. The position of the EFVPTC in the classification of thyroid neoplasia should be reconsidered. Copyright © 2015 Elsevier Inc. All rights reserved.
    Human Pathlogy 02/2015; 46(5). DOI:10.1016/j.humpath.2015.01.010 · 2.81 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):2755-2755. DOI:10.1158/1538-7445.AM2014-2755 · 9.28 Impact Factor
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    ABSTRACT: Carcinoma ex-pleomorphic adenoma (CA ex-PA) is a malignant salivary gland tumor that arises in association with pleomorphic adenoma (PA). Both PA and CA ex-PA have a broad spectrum of histology and distinction from their histologic mimics may be difficult based on morphology alone. PLAG1 and HMGA2 abnormalities are the most common genetic events in both PA and CA ex-PA; however, the utility of PLAG1 and HMGA2 as adjunct molecular tests has not been well established. FISH for PLAG1 and HMGA2 was performed on 22 CA ex-PA (10 myoepithelial carcinomas (MECA), 10 salivary duct carcinomas (SDC), 1 carcinoma with squamo-glandular features, and 1 mixed MECA-adenocarcinoma not otherwise specified (NOS), 20 de novo carcinomas (11 MECA and 9 SDC), 16 PAs and 11 PA-histologic mimics. All except 3 CAs ex-PA (86%) were positive for PLAG1 or HMGA2 rearrangements/amplifications. In contrast, 18/20 (90%) de novo carcinomas lacked abnormalities in PLAG1 or HMGA2 (p < 0.01). PLAG1 or HMGA2 rearrangements were identified in 6/9 (67%) hypocellular myxoid PAs and in 2/7 (29%) cellular PAs. Furthermore, all morphologic mimics of PA were negative for PLAG1 or HMGA2. PLAG1 and HMGA2 rearrangements are the most common genetic events in CA ex-PA regardless of the histologic subtype. Unlike CA ex-PA, de novo carcinomas were negative for PLAG1 and HMGA2. Interestingly, rearrangements of PLAG1/HMGA2 were identified in the majority of hypocellular PAs but only in a small subset of cellular PAs. FISH for PLAG1 or HMGA2 can be used to distinguish between PA and CA ex-PA and their morphologic mimics.
    Human pathology 09/2014; 46(1). DOI:10.1016/j.humpath.2014.08.017 · 2.81 Impact Factor
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    ABSTRACT: Poorly differentiated tumors of the thyroid gland (PDTC) are generally characterized by a poor prognosis due to their resistance to available therapeutic approaches. The relative rarity of these tumors is a major obstacle to our understanding of the molecular mechanisms leading to tumor aggressiveness and drug resistance, and consequently to the development of novel therapies. By simultaneously activating Kras and deleting p53 in thyroid follicular cells, we have developed a novel mouse model that develops papillary thyroid cancer invariably progressing to PDTC. In several cases, tumors further progress to anaplastic carcinomas. The poorly differentiated tumors are morphologically and functionally similar to their human counterparts and depend on MEK/ERK signaling for proliferation. Using primary carcinomas as well as carcinoma-derived cell lines, we also demonstrate that these tumors are intrinsically resistant to apoptosis due to high levels of expression of the Bcl2 family members Bcl2a1 and Mcl1, and can be effectively targeted by Obatoclax, a small molecule pan-inhibitor of the Bcl2 family. Furthermore, we show that Bcl2 family inhibition synergizes with MEK inhibition as well as with doxorubicin in inducing cell death. Thus, our studies in a novel, relevant mouse model, uncover a promising druggable feature of aggressive thyroid cancers.
    Endocrine Related Cancer 07/2014; 21(5). DOI:10.1530/ERC-14-0268 · 4.91 Impact Factor
  • 05/2014; 117(5):e370-e371. DOI:10.1016/j.oooo.2014.01.149
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    ABSTRACT: Although obesity increases risk and negatively affects survival for many malignancies, the prognostic implications in squamous cell carcinoma (SCC) of the oral tongue, a disease often associated with prediagnosis weight loss, are unknown. Patients with T1-T2 oral tongue SCC underwent curative-intent resection in this single-institution study. All patients underwent nutritional assessment prior to surgery. Body mass index (BMI) was calculated from measured height and weight and categorized as obese (≥ 30 kg/m(2) ), overweight (25-29.9 kg/m(2) ), or normal (18.5-24.9 kg/m(2) ). Clinical outcomes, including disease-specific survival, recurrence-free survival, and overall survival, were compared by BMI group using Cox regression. From 2000 to 2009, 155 patients (90 men, 65 women) of median age 57 years (range, 18-86 years) were included. Baseline characteristics were similar by BMI group. Obesity was significantly associated with adverse disease-specific survival compared with normal weight in univariable (hazard ratio [HR] = 2.65, 95% confidence interval [CI] = 1.07-6.59; P = .04) and multivariable analyses (HR = 5.01; 95% CI = 1.69-14.81; P = .004). A consistent association was seen between obesity and worse recurrence-free survival (HR = 1.87; 95% CI = 0.90-3.88) and between obesity and worse overall survival (HR = 2.03; 95% CI = 0.88-4.65) though without reaching statistical significance (P = .09 and P = .10, respectively) in multivariable analyses. In this retrospective study, obesity was an adverse independent prognostic variable. This association may not have been previously appreciated due to confounding by multiple factors including prediagnosis weight loss. Cancer 2013. © 2013 American Cancer Society.
    Cancer 04/2014; 120(7). DOI:10.1002/cncr.28532 · 4.90 Impact Factor
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    ABSTRACT: Background: While radioactive iodine (RAI) adjuvant therapy is commonly recommended for most papillary thyroid cancer patients presenting with large volume nodal involvement, it remains unclear if such therapy impacts the disease specific recurrence rate and overall survival (1). In this study, we compared the risk of achieving a structural persistent response after low administered activity (100 mCi), intermediate administered activity (150 mCi) and high administered activity (>200 mCi) RAI adjuvant therapy in patients presenting with pathologic N1b disease. Methods: This was a retrospective review of 181 papillary thyroid cancer patients with N1b disease treated with total thyroidectomy, neck dissection, and RAI remnant ablation. Dose response relationships were determined between the administered activity of 131I and the best response to initial therapy. Results: Out of the 181 patients, only 39% achieved no clinical evidence of disease (NED) after initial therapy. Young patients (stage I) had a non-statistically significant trend toward higher rates of NED with increasing dose (34% low activity, 36% intermediate activity, 46% high activity), but there was no evidence of dose response effect with regard to the likelihood of having a structural persistent response to initial therapy or the likelihood of having persistent biochemical evidence of disease. However, analysis of the older patients (Stage IVa) did reveal a trend toward statistically significant dose response relationships with increasing administered activities being associated with lower rates of structural persistent response (46% low activity, 23% intermediate activity, 17% high dose). Unfortunately, the lower rate of structural persistent response only modestly increased the likelihood that patients would be NED but was instead associated with a higher proportion of patients being classified as having biochemical persistent disease. Conclusions: It appears that administering more than 100 mCi of RAI as adjuvant therapy in N1b disease is unlikely to improve the initial response to therapy. This is especially true for the younger (stage I) patients. It is plausible that administered activities of 150-260 mCi may be associated with an improved response to initial therapy in older patients (stage IVa) that are probably at highest risk of having poor outcomes, but the potential benefit from RAI should be balanced against potential adverse effects in those patients.
    Thyroid: official journal of the American Thyroid Association 02/2014; 24(7). DOI:10.1089/thy.2013.0465 · 3.84 Impact Factor
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    ABSTRACT: Background: The Bethesda System for thyroid cytopathology is the standard for interpreting fine needle aspiration (FNA) specimens. The Atypia of Undetermined Significance/Follicular Lesion of Undetermined Significance (AUS/FLUS) category, known as Bethesda Category III, has been ascribed a malignancy risk of 5-15%, but the probability of malignancy in AUS/FLUS specimens remains unclear. Our objective was to determine the risk of malignancy in thyroid FNAs categorized as AUS/FLUS. Methods: The management of 541 AUS/FLUS thyroid nodule patients between 2008-2011 was analyzed. Clinical and radiologic features were examined as predictors for surgery. Target AUS/FLUS nodules were correlated with surgical pathology. Results: Of patients with an FNA initially categorized as AUS/FLUS, 64.7% (350/541) underwent immediate surgery, 17.7% (96/541) had repeat FNA, and 17.6% (95/541) were observed. Repeat FNA cytology was unsatisfactory in 5.2% (5/96), benign in 42.7% (41/96), AUS/FLUS in 38.5% (37/96), suspicious for follicular neoplasm in 5.2% (5/96), suspicious for malignancy in 4.2% (4/96), and malignant in 4.2% (4/96). Of nodules with two consecutive AUS/FLUS diagnoses that were resected, 26.3% (5/19) were malignant. Among all index AUS/FLUS nodules (triaged to surgery, repeat FNA, or observation), malignancy was confirmed on surgical pathology in 26.6% (95% CI, 22.4-31.3). Among AUS/FLUS nodules triaged to surgery, the malignancy rate was 37.8% (95% CI, 33.1-42.8). Incidental cancers were found in 22.3% of patients. On univariate logistic regression analysis, factors associated with triage to surgery were younger patient age (p < 0.0001), increasing nodule size (p < 0.0001), and nodule hypervascularity (p = 0.032). Conclusions: Malignancy rates in nodules with AUS/FLUS cytology are higher than previously estimated, with 26.6-37.8% of AUS/FLUS nodules harboring cancer. These data imply that Bethesda Category III nodules may have a higher risk of malignancy than traditionally believed, and that guidelines recommending repeat FNA or observation merit reconsideration.
    Thyroid: official journal of the American Thyroid Association 12/2013; 24(5). DOI:10.1089/thy.2013.0317 · 3.84 Impact Factor
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    ABSTRACT: Background: The prognostic implications of the diagnosis of a papillary thyroid carcinoma (PTC) with tall cell features (TCF) are unknown. Methods: All PTC patients identified between 1985 and 2005 were analyzed histologically. Classical PTC (cPTC) were defined as having <30% tall cells, PTC TCF (30-49% tall cells), tall cell variant (TCV) (>50% tall cells). All cPTC, PTC TCF and TCV > 1 cm in size were included. Results: 453 patients satisfied the inclusion criteria (288 cPTC, 31 PTC TCF and 134 TCV). cPTC patients were younger than their PTC TCF and TCV counterparts (p<0.0002). There was an increase in tumor size from cPTC to PTC TCF and TCV (p=0.05). Extensive extra-thyroid extension and positive margins were more often present in TCV and PTC TCF than in cPTC . (p=0.0001, 0.03 respectively). Overall pathologic tumor (pT) stage was more advanced in TCV and PTC TCF than in cPTC (p<0.0001). Total thyroidectomy and radioactive iodine therapy were more often performed and administered on TCV patients than on their PTC TCF and cPTC counterparts (p=0.001, p=0.0001 respectively). Median follow up was 9.3 years. 10 year disease specific survival (DSS) was lower in TCV (96%) and PTC TCF (91%) than in cPTC (100%) (p<0.001). 10 year distant recurrence free (RFS) survival was higher in cPTC (98%) than in PTC TCF (89%) and TCV (96%) (p=0.03). In multivariate analysis, the presence of >5 positive nodes and extra-nodal extension were the only independent prognostic factors of neck and distant RFS respectively. Four (2.4%) of 165 PTC with TCF and PTC TCV developed poorly differentiated or anaplastic carcinoma in their recurrence while none of 288 classical PTC transformed into higher grades (p=0.017). Conclusions: 1) PTC TCF and TCV have similar clinico-pathologic features that are more aggressive than cPTC 2) PTC TCF and TCV have similar DSS and distant RFS but poorer than cPTC 3) PTC TCF are currently being treated like cPTC less aggressively than TCV 4) PTC TCF and PTC TCV have a higher rate of high grade transformation than cPTC. 5) Consideration should be given to use a 30% tall cells threshold to diagnose TCV.
    Thyroid: official journal of the American Thyroid Association 11/2013; DOI:10.1089/thy.2013.0503 · 3.84 Impact Factor
  • Ronald A Ghossein, Nora Katabi, Snjezana Dogan
    The American journal of surgical pathology 10/2013; DOI:10.1097/PAS.0000000000000087 · 4.59 Impact Factor
  • Cancer Research 08/2013; 73(8 Supplement):4291-4291. DOI:10.1158/1538-7445.AM2013-4291 · 9.28 Impact Factor
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    ABSTRACT: Background:TERT encodes the reverse transcriptase component of telomerase, which adds telomere repeats to chromosome ends, thus enabling cell replication. Telomerase activity is required for cell immortalization. Somatic TERT promoter mutations modifying key transcriptional response elements were recently reported in several cancers, such as melanomas and gliomas.Objectives:The objectives of the study were: 1) to determine the prevalence of TERT promoter mutations C228T and C250T in different thyroid cancer histological types and cell lines; and 2) to establish the possible association of TERT mutations with mutations of BRAF, RAS, or RET/PTC.Methods:TERT promoter was PCR-amplified and sequenced in 42 thyroid cancer cell lines and 183 tumors: 80 papillary thyroid cancers (PTCs), 58 poorly differentiated thyroid cancers (PDTCs), 20 anaplastic thyroid cancers (ATCs), and 25 Hurthle cell cancers (HCCs).Results:TERT promoter mutations were found in 98 of 225 (44%) specimens. TERT promoters C228T and C250T were mutually exclusive. Mutations were present in 18 of 80 PTCs (22.5%), in 40 of 78 (51%) advanced thyroid cancers (ATC + PDTC) (P < 3 × 10(-4) vs PTC), and in widely invasive HCCs (4 of 17), but not in minimally invasive HCCs (0 of 8). TERT promoter mutations were seen more frequently in advanced cancers with BRAF/RAS mutations compared to those that were BRAF/RAS wild-type (ATC + PDTC, 67.3 vs 24.1%; P < 10(-4)), whereas BRAF-mutant PTCs were less likely to have TERT promoter mutations than BRAF wild-type tumors (11.8 vs 50.0%; P = .04).Conclusions:TERT promoter mutations are highly prevalent in advanced thyroid cancers, particularly those harboring BRAF or RAS mutations, whereas PTCs with BRAF or RAS mutations are most often TERT promoter wild type. Acquisition of a TERT promoter mutation could extend survival of BRAF- or RAS-driven clones and enable accumulation of additional genetic defects leading to disease progression.
    The Journal of Clinical Endocrinology and Metabolism 07/2013; 98(9). DOI:10.1210/jc.2013-2383 · 6.31 Impact Factor
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    ABSTRACT: Inhibitors of RET, a tyrosine kinase receptor encoded by a gene that is frequently mutated in medullary thyroid cancer, have emerged as promising novel therapies for the disease. Rapalogs and other mTOR inhibitors are effective agents in patients with gastro-entero-pancreatic neuroendocrine tumors, which share lineage properties with MTCs. The objective of this study was to investigate the contribution of mTOR activity to RET-induced signaling and cell growth, and to establish whether growth suppression is enhanced by co-targeting RET and mTOR kinase activities. Treatment of the RET mutant cell lines TT, TPC-1 and MZ-CRC-1 with AST487, a RET kinase inhibitor, suppressed growth and showed profound and sustained inhibition of mTOR signaling, which was recapitulated by siRNA-mediated RET knockdown. Inhibition of mTOR with INK128, a dual mTORC1 and mTORC-2 kinase inhibitor, also resulted in marked growth suppression, to levels comparable to those seen with RET blockade. Moreover, combined treatment with AST487 and INK128 at low concentrations suppressed growth and induced apoptosis. These data establish mTOR as a key mediator of RET-mediated cell growth in thyroid cancer cells, and provide rationale for combinatorial treatments in thyroid cancers with oncogenic RET mutations.
    Endocrine Related Cancer 07/2013; 20(5). DOI:10.1530/ERC-13-0085 · 4.91 Impact Factor

Publication Stats

4k Citations
761.16 Total Impact Points

Institutions

  • 1994–2015
    • Memorial Sloan-Kettering Cancer Center
      • • Department of Pathology
      • • Head and Neck Service
      New York, New York, United States
  • 2006
    • The Rockefeller University
      New York, New York, United States
  • 1998
    • Yale-New Haven Hospital
      • Department of Pathology
      New Haven, Connecticut, United States
  • 1997
    • Dana-Farber Cancer Institute
      Boston, Massachusetts, United States