Michael Rivera

Mayo Clinic - Rochester, Рочестер, Minnesota, United States

Are you Michael Rivera?

Claim your profile

Publications (22)129.14 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Vascular invasion (VI) is an important predictor of distant metastasis and possible radioactive iodine (RAI) benefit in follicular, Hürthle 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 and 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, extrathyroidal 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 >4 cm 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.
    No preview · Article · Mar 2015 · Thyroid: official journal of the American Thyroid Association
  • [Show abstract] [Hide abstract]
    ABSTRACT: Context and objective: Oncocytic thyroid carcinoma, also known as Hürthle cell thyroid carcinoma, accounts for only a small percentage of all thyroid cancers. However, this malignancy often presents at an advanced stage and poses unique challenges to patients and clinicians. Surgical resection of the tumor accompanied in some cases by radioactive iodine treatment, radiation, and chemotherapy are the established modes of therapy. Knowledge of the perturbed oncogenic pathways can provide better understanding of the mechanism of disease and thus opportunities for more effective clinical management. Design and patients: Initially, two oncocytic thyroid carcinomas and their matched normal tissues were profiled using whole genome sequencing. Subsequently, 72 oncocytic thyroid carcinomas, one cell line, and five Hürthle cell adenomas were examined by targeted sequencing for the presence of mutations in the multiple endocrine neoplasia I (MEN1) gene. Results: Here we report the identification of MEN1 loss-of-function mutations in 4% of patients diagnosed with oncocytic thyroid carcinoma. Whole genome sequence data also revealed large regions of copy number variation encompassing nearly the entire genomes of these tumors. Conclusion: Menin, a ubiquitously expressed nuclear protein, is a well-characterized tumor suppressor whose loss is the cause of MEN1 syndrome. Menin is involved in several major cellular pathways such as regulation of transcription, control of cell cycle, apoptosis, and DNA damage repair pathways. Mutations of this gene in a subset of Hürthle cell tumors point to a potential role for this protein and its associated pathways in thyroid tumorigenesis.
    No preview · Article · Jan 2015 · Journal of Clinical Endocrinology & Metabolism
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Here, we describe the genomic landscape of 496 PTCs. We observed a low frequency of somatic alterations (relative to other carcinomas) and extended the set of known PTC driver alterations to include EIF1AX, PPM1D, and CHEK2 and diverse gene fusions. These discoveries reduced the fraction of PTC cases with unknown oncogenic driver from 25% to 3.5%. Combined analyses of genomic variants, gene expression, and methylation demonstrated that different driver groups lead to different pathologies with distinct signaling and differentiation characteristics. Similarly, we identified distinct molecular subgroups of BRAF-mutant tumors, and multidimensional analyses highlighted a potential involvement of oncomiRs in less-differentiated subgroups. Our results propose a reclassification of thyroid cancers into molecular subtypes that better reflect their underlying signaling and differentiation properties, which has the potential to improve their pathological classification and better inform the management of the disease.
    Full-text · Article · Oct 2014 · Cell
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Context: Hürthle cell cancer [HCC] of the thyroid remains the subject of controversy with respect to natural course, treatment, and follow-up. Objective: To evaluate the clinical and molecular features associated with outcome in HCC. Design: A review of 173 HCC cases treated at Mayo Clinic over 11 years with a median 5.8 years follow-up. Results: None of the patients with minimally invasive histology had persistent disease, clinical recurrence, or disease-related death. Male gender and TNM stage were independently associated with increased risk of clinical recurrence or death in widely invasive patients. The 5-year cumulative probability of clinical recurrence or death was higher in patients with TNM stage III-IV (females=74%, males=91%) compared with patients with TNM stage I-II (females=0%, males=17%). Pulmonary metastases were best identified by computed tomography while radioactive iodine [RAI] scans were positive in only 2 of 27 cases. Thyroglobulin was detectable in patients with clinical disease with the notable exception of 5 patients with distant metastases. The common TERT C228T promoter mutation was detected in both widely invasive and minimally invasive tumors. TERT mRNA was below the limits of detection in all samples. Conclusion: Widely invasive HCC with TNM stage III-IV is aggressive with low probability of recurrence-free survival. Males have worse outcomes than females. Minimally invasive HCC appears to be considerably less aggressive. RAI scan performs poorly in detecting distant disease. Although the TERT gene is mutated in HCC, the role of this mutation remains to be demonstrated.
    Full-text · Article · Sep 2014 · Journal of Clinical Endocrinology & Metabolism
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Context:The BRAF V600E mutation (BRAF-MUT) confers an aggressive phenotype in papillary thyroid carcinoma, but unidentified additional genomic abnormalities may be required for full phenotypic expression.Objective:RNA sequencing (RNA-Seq) was performed to identify genes differentially expressed between BRAF-MUT and BRAF wild-type (BRAF-WT) tumors and to correlate changes to patient clinical status.Design:BRAF-MUT and BRAF-WT tumors were identified in patients with T1N0 and T2-3N1 tumors. Gene expression levels were determined (RNA-Seq) and fusion transcripts were detected. Multiplexed capture/detection and digital counting of mRNA transcripts (nCounter, NanoString Technologies) validated RNA-Seq data for immune system-related genes.Setting:Referral medical center.Patients:BRAF-MUT patients included nine women, three men; nine were TNM stage I and three were stage III. Three (25%) had tumor infiltrating lymphocytes. BRAF-WT included five women, three men; all were stage I, and five (62.5%) had tumor infiltrating lymphocytes.Results:RNA-Seq identified 560 of 13 t085 genes differentially expressed between BRAF-MUT and BRAF-WT tumors. Approximately 10% of these genes were related to MetaCore immune function pathways; 51 were underexpressed in BRAF-MUT tumors, whereas 4 (HLAG, CXCL14, TIMP1, IL1RAP) were overexpressed. The four most differentially overexpressed immune genes in BRAF-WT tumors (IL1-B; CCL19; CCL21; CXCR4) correlated with lymphocyte infiltration. nCounter confirmed the RNA-Seq expression level data. Eleven different high-confidence fusion transcripts were detected (four interchromosomal; seven intrachromosomal) in 13 of 20 tumors. All in-frame fusions were validated by RT-PCR.Conclusion:BRAF-MUT papillary thyroid cancers have reduced expression of immune/inflammatory response genes compared with BRAF-WT tumors and correlate with lymphocyte infiltration. In contrast, HLA-G and CXCL14 are overexpressed in BRAF-MUT tumors. Sixty-five percent of tumors had between one and three fusion transcripts. Functional studies will be required to determine the potential role of these newly identified genomic abnormalities in contributing to the aggressiveness of BRAF-MUT and BRAF-WT tumors.
    Full-text · Article · Dec 2013 · The Journal of Clinical Endocrinology and Metabolism
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: The prognostic implications of the diagnosis of a papillary thyroid carcinoma (PTC) with tall-cell features are unknown. Methods: All PTC patients identified between 1985 and 2005 were analyzed histologically. Classical PTC cases were defined as having <30% tall cells, PTC with tall-cell features (PTC TCF) as 30%-49% tall cells, and tall-cell variant of PTC (TCV) as ≥ 50% tall cells. All classical PTC, PTC TCF, and TCV ≥ 1 cm in size were included. Results: A total of 453 patients satisfied the inclusion criteria (288 classical PTC, 31 PTC TCF, and 134 TCV). Classical PTC patients were younger than their PTC TCF and TCV counterparts (p<0.0002). There was an increase in tumor size from classical PTC to PTC TCF and TCV (p=0.05). Extensive extrathyroid extension and positive margins were more often present in TCV and PTC TCF than in classical PTC (p=0.0001 and p=0.03 respectively). Overall pathologic tumor (pT) stage was more advanced in TCV and PTC TCF than in classical PTC (p<0.0001). Total thyroidectomy and radioactive iodine therapy were more often performed and administered in TCV patients than in their PTC TCF and classical PTC counterparts (p=0.001 and p=0.0001 respectively). Median follow-up was 9.3 years. Ten-year disease-specific survival (DSS) was lower in TCV (96%) and PTC TCF (91%) than in classical PTC (100%; p<0.001). Ten-year distant recurrence-free survival (RFS) was higher in classical PTC (98%) than in PTC TCF (89%) and TCV (96%; p=0.03). In multivariate analysis, the presence of more than five positive nodes and extranodal extension were the only independent prognostic factors of neck and distant RFS respectively. Four (2.4%) of 165 PTC TCF and PTC TCV developed poorly differentiated or anaplastic carcinoma in their recurrence, while none of the 288 classical PTC transformed into higher grades (p=0.017). Conclusions: PTC TCF and TCV have similar clinicopathologic features that are more aggressive than classical PTC. PTC TCF and TCV have similar DSS and distant RFS but poorer outcomes than classical PTC. PTC TCF are currently being treated like classical PTC, that is, less aggressively than TCV. PTC TCF and TCV TCV have a higher rates of high-grade transformation than classical PTC. Consideration should be given to using a 30% tall-cell threshold to diagnose TCV.
    No preview · Article · Nov 2013 · Thyroid: official journal of the American Thyroid Association
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: There continues to be controversy regarding which clinicopathological features confer a higher risk of adverse outcome in papillary microcarcinomas (PMC). The aim of this study was to assess the prognostic value of a meticulous histologic examination in PMC. Method: All papillary thyroid carcinoma <1 cm in size without associated larger thyroid carcinomas, identified between 1977 and 2002, were categorized as PMC and subjected to a meticulous histopathologic examination by 2 thyroid pathologists. Results: 148 PMC patients fulfilled the inclusion criteria. Within PMC, young age, male sex, tumor multicentricity, extrathyroidal extension, and infiltrative and larger tumor (≥0.5 cm) correlated with the presence of >1 cm metastatic node (MN) or >3 MN at presentation (p<0.05). With a median follow-up of 9.9 years, only 1 (0.7%) of 134 PMC patients died of thyroid carcinomas and 3 (2.2%) had recurrences in the neck. The patient who died had harbored a poorly differentiated carcinoma in his MN. The presence of MN and especially a large MN (>1 cm) correlated with worse recurrence-free survival (p=0.005 and p<0.0001, respectively). Except for one, all individuals with clinically adverse outcomes had >1 cm MN. Patients whose MNs were predominantly composed of poorly differentiated carcinoma or tall cell variant papillary thyroid carcinoma had a significant shorter recurrence-free survival (p<0.0001). Only 1 of 80 radioactive iodine-naïve PMC patients with absent or small MN (≤1 cm) had recurrence with a median follow-up of 9.2 years. Conclusions: (i) The size and histotype of the MN are predictors of outcome in PMC and should be recorded. (ii) The very rare PMC patients who suffer recurrence or even die of disease have usually aggressive histopathologic features at presentation. (iii) PMC patients with nodal disease that is small or absent at presentation are at a very low risk of recurrence and may be spared radioactive iodine therapy.
    No preview · Article · Jun 2013 · Thyroid: official journal of the American Thyroid Association
  • [Show abstract] [Hide abstract]
    ABSTRACT: Papillary thyroid carcinoma (PTC) patients presenting with cervical lymph nodes (LN) metastases (M) have a variable outcome. The objective of this study is to assess the value of meticulous histopathologic examination and genotyping in stratifying these patients into clinically relevant prognostic subgroups. This was a retrospective clinical and histopathological review of PTC patients with lymph node metastases at presentation identified between 1980 and 2002 in a single institution. Primary tumors from patients who later recurred were matched to a group of patients who did not recur and subjected to mass spectrometry genotyping encompassing the most significant oncogenes in thyroid carcinomas. There were 246 patients who satisfied the inclusion criteria. The median follow-up was 10.8 years. The presence of >3 metastatic nodes was an independent predictor of decreased recurrence free survival (p=0.03). In patients <45 years, none of 45 with 1-2 metastatic LN recurred, including 26 patients followed for a median of 13 years without radioactive iodine (RAI) therapy. BRAF mutations were found in 28 (78%) of 36 genotyped tumors. Combined positivity for BRAF and extra-nodal extension was much stronger in predicting disease specific survival (DSS) (p=0.004) than the single analysis of BRAF (p=0.12) or extra-nodal extension (p=0.02). (i) The number of metastatic LN is an independent predictor of recurrence in all age groups and identifies a subset of young patients with excellent prognosis who may not benefit from RAI therapy. (ii) Combined positivity for BRAF and extra-nodal extension has additive prognostic value in predicting DSS. (iii) Classification systems that assign the same magnitude of risk for recurrence or death to all patients with N1 disease should be revisited.
    No preview · Article · Apr 2012 · Thyroid: official journal of the American Thyroid Association
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Papillary thyroid carcinoma (PTC) patients presenting with cervical lymph nodes (LN) metastasis (M) have a variable outcome. The objective of this study is to assess the value of meticulous histopathologic examination and genotyping in stratifying these patients into clinically relevant prognostic subgroups. Methods: Retrospective clinical and histopathological review of PTC patients with LNM at presentation identified between 1980 and 2002 in a single institution. Primary tumors from patients who later recurred were matched to a group of patients who did not recur and subjected to mass spectrometry genotyping encompassing the most significant oncogenes in thyroid carcinomas. Results: 246 patients satisfied the inclusion criteria. Median follow up was 10.8 years. The presence of >3 metastatic nodes was an independent predictor of decreased recurrence free survival (p=0.03). In patients < 45 years, none of 45 cases with 1-2 metastatic LN recurred, including 26 patients followed for a median of 13 years without radioactive iodine (RAI) therapy. BRAF mutations were found in 28 (78%) of 36 genotyped tumors. Combined positivity for BRAF and extra-nodal extension was much stronger in predicting disease specific survival (DSS) (p=0.004) than the single analysis of BRAF (p=0.12) or extra-nodal extension (p=0.02). Conclusions: 1) The number of metastatic LN is an independent predictor of recurrence in all age groups and identifies a subset of young patients with excellent prognosis who may not benefit from RAI therapy. 2) Combined positivity for BRAF and extra-nodal extension has additive prognostic value in predicting DSS. 3) Classification systems that assign the same magnitude of risk for recurrence or death to all patients with N1 disease should be revisited.
    No preview · Article · Dec 2011 · Thyroid: official journal of the American Thyroid Association
  • [Show abstract] [Hide abstract]
    ABSTRACT: Anaplastic thyroid carcinoma (ATC) is a rare, aggressive malignancy. The potential for pathologic misclassification complicates interpretation of published data. One standard treatment option for locoregionally advanced disease is weekly low-dose doxorubicin with concurrent radiation therapy, and was previously developed at our institution. We evaluated our more recent experience with this approach, which included pathologic confirmation of all cases. A retrospective review was performed on patients identified through the Memorial Sloan-Kettering Cancer Center (MSKCC) Cancer Database. Inclusion criteria: pathologically confirmed ATC; locoregional disease encompassable within a radiation portal; treatment with curative intent at MSKCC with planned weekly doxorubicin (10 mg/m(2)) and concurrent radiation. Principle outcomes assessed were locoregional progression-free survival (LR-PFS) and overall survival (OS). Thirty-seven patients were included. Median radiotherapy dose was 57.6 Gy, and was ≥ 50Gy in 29 (78%), administered through hyperfractionated or once-daily schedules. One-year outcomes were LR-PFS, 45%; OS, 28%. The prognosis of patients with ATC remains grim and our current results appear inferior to those reported previously by our institution. More accurate histologic diagnoses and patient selection in the present series compared to the prior one may be responsible in part. Better therapy is desperately needed for this aggressive disease.
    No preview · Article · Dec 2011 · Radiotherapy and Oncology
  • [Show abstract] [Hide abstract]
    ABSTRACT: The impact of varying degrees of extrathyroid extension (ETE), especially microscopic ETE (METE), on survival in thyroid carcinomas (TC) has not been well established. Our objective was to analyze ETE at the molecular and histologic levels and assess the effect of its extent on outcome. All cases of TC with ETE but without nodal metastases at presentation (NMP) were identified over a 20-year period and grouped into gross and METE. Twelve papillary thyroid carcinomas (PTCs) without ETE and NMP were also analyzed. Cases with paraffin tissues were subjected to mass spectrometry genotyping encompassing the most significant oncogenes in TC: 111 mutations in RET, BRAF, NRAS, HRAS, KRAS, PIK3CA, and AKT1, and other related genes were surveyed. Eighty-one (10%) of 829 patients in the database had ETE and no NMP. There was a much higher frequency of poorly differentiated and anaplastic carcinomas (12/29, 41%) in patients with gross ETE than in those with METE (3/52, 6%) (p < 0.01). There was a higher disease-specific survival (DSS) in patients with METE than in those with gross ETE (p < 0.0001). Except for an anaplastic case, no recurrences were detected in 45 patients with METE, including 23 PTC patients followed up for a median of 10 years without radioactive iodine therapy. Within patients with gross invasion into trachea/esophagus, tumors with high mitotic activity and/or tumor necrosis correlated with worse DSS (p < 0.05). Fifty-six cases with ETE were genotyped as follows: BRAFV600E, 39 (70%); BRAFV600E-AKT1, 1 (1.8%); NRAS, 1 (1.8%); KRAS, 1 (1.8%); RET/PTC, 3 (5%); wild type, 11 (19.6%). Within PTCs, BRAF positivity rate increased the risk of ETE (p = 0.01). If PTC follicular variants are excluded, BRAF positivity does not correlate with ETE status within classical/tall cell PTC. (i) PTCs with METE without NMP have an extremely low recurrence rate in contrast to tumors with gross ETE. (ii) High mitotic activity and/or tumor necrosis confers worse DSS even in patients stratified for gross ETE in trachea/esophagus. (iii) BRAF positivity correlates with the presence of ETE in PTC, but this relationship is lost within classical/tall cell PTC if follicular variants are excluded from the analysis.
    No preview · Article · Oct 2010 · Thyroid: official journal of the American Thyroid Association
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The follicular variant of papillary thyroid carcinoma usually presents as an encapsulated tumor and less commonly as a partially/non-encapsulated infiltrative neoplasm. The encapsulated form rarely metastasizes to lymph node, whereas infiltrative tumor often harbors nodal metastases. The molecular profile of the follicular variant was shown to be close to the follicular adenoma/carcinoma group of tumors with a high RAS and very low BRAF mutation rates. A comprehensive survey of oncogenic mutations in the follicular variant of papillary thyroid carcinoma according to its encapsulated and infiltrative forms has not been performed. Paraffin tissue from 28 patients with encapsulated and 19 with infiltrative follicular variant were subjected to mass spectrometry genotyping encompassing the most significant oncogenes in thyroid carcinomas: 111 mutations in RET, BRAF, NRAS, HRAS, KRAS, PIK3CA, AKT1 and other related genes. There was no difference in age, gender, tumor size and angioinvasion between encapsulated or infiltrative tumors. Infiltrative carcinomas had a much higher frequency of extrathyroid extension, positive margins and nodal metastases than encapsulated tumors (P<0.05). The BRAF 1799T>A mutation was found in 5 of 19 (26%) of the infiltrative tumor and in none of the encapsulated carcinomas (P=0.007). In contrast, RAS mutations were observed in 10 of 28 (36%) of the encapsulated group (5 NRAS_Q61R, 3 HRAS_Q61, 1 HRAS_G13C and 1 KRAS_Q61R) and in only 2 of 19 (10%) of infiltrative tumors (P=0.09). One encapsulated carcinoma showed a PAX8/PPARgamma rearrangement, whereas two infiltrative tumors harbored RET/PTC fusions. Encapsulated follicular variant of papillary thyroid carcinomas have a molecular profile very close to follicular adenomas/carcinomas (high rate of RAS and absence of BRAF mutations). Infiltrative follicular variant has an opposite molecular profile closer to classical papillary thyroid carcinoma than to follicular adenoma/carcinoma (BRAF>RAS mutations). The molecular profile of encapsulated and infiltrative follicular variant parallels their biological behavior (ie, metastatic nodal and invasive patterns).
    Preview · Article · Sep 2010 · Modern Pathology
  • [Show abstract] [Hide abstract]
    ABSTRACT: To evaluate the morphologic findings most encountered in anaplastic thyroid carcinomas (ATCs) and evaluate for the expression of PAX-8. The cytology specimens from 21 cases of ATC were evaluated for the following several cytologic criteria: cell morphology, pleomorphism, presence or absence of multinucleated cells, colloid, neutrophilic infiltrate and well-differentiated component. Immunohistochemical studies for PAX-8 were performed on cell blocks in selected cases. The most common morphology present was epithelioid, followed by spindle, multinucleated giant cell and rhabdoid, with 75% demonstrating more than 1 cell morphology. Marked pleomorphism (81%), neutrophilic infiltrate (90%) and necrosis (63%) were frequent. No nuclear grooves, colloid or well-differentiated component was identified in any case. Immunocytochemical stains for PAX-8 were negative in 5 cases in which a cell block was available. ATC is a tumor with diverse morphologic characteristics, and more than 1 cell morphology is usually present. A neutrophilic infiltrate is a common finding and represents a clue to the correct diagnosis.
    No preview · Article · Sep 2010 · Acta cytologica
  • [Show abstract] [Hide abstract]
    ABSTRACT: Encapsulated thyroid tumors of follicular cell origin with high-grade features (EFHG) are unusual neoplasms. In current classification schemes, they are called atypical adenomas or follicular, papillary, or poorly differentiated carcinoma. When noninvasive, EFHG create a major therapeutic/diagnostic dilemma stemming from their rarity, low-stage, high-grade appearance, and lack of long-term follow-up studies. All cases of EFHG were defined as encapsulated tumors of follicular cell origin with at least 5 mitoses per 10 high-power fields and/or tumor necrosis. Available tissues were subjected to a thyroid carcinoma platform for mass spectrometry high-throughput genotyping, which consisted of 111 known mutations in 16 different genes: BRAF, RET, NRAS, HRAS, KRAS, PIK3CA, AKT1, and other related genes. Twenty-five cases met the selection criteria. Tumor necrosis was present in 56.0% (n = 14). Extensive vascular invasion was identified in 24.0% (n = 6). Eight (32%) of 25 tumors were noninvasive. Twenty-two patients (88%) were free of disease (median follow up: 8.5 years). All 8 noninvasive tumor did not recur despite focal/extensive tumor necrosis in 3 cases and a median follow-up of 11.9 years. EFHG with no vascular invasion did not recur. In patients without distant metastases at presentation (n = 24), 33% (2/6) of patients with extensive angioinvasion relapsed, whereas none of 18 with absent/focal vascular invasion recurred (P = .054). Mutations were found in 10 (45%) of 22 cases tested: 8 had NRAS codon 61, 1 KRAS codon 61, and 1 had coexistent BRAF V600E and AKT1. There was a higher frequency of RAS (9/22, 41%) than BRAF mutations (1/22, 4.5%) (P = .009). Noninvasive EFHG have an indolent behavior even in the presence of extensive tumor necrosis. EFHG with absent vascular invasion have an excellent prognosis despite the frequent occurrence of tumor necrosis. NRAS mutations are the most frequent oncogenic event in EFHG.
    No preview · Article · Nov 2009 · Human pathology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Patients with poorly differentiated thyroid cancers (PDTC), anaplastic thyroid cancers (ATC), and radioactive iodine-refractory (RAIR) differentiated thyroid cancers have a high mortality, particularly if positive on [(18)F]fluorodeoxyglucose (FDG)-positron emission tomography (PET). To obtain comprehensive genetic information on advanced thyroid cancers, we designed an assay panel for mass spectrometry genotyping encompassing the most significant oncogenes in this disease: 111 mutations in RET, BRAF, NRAS, HRAS, KRAS, PIK3CA, AKT1, and other related genes were surveyed in 31 cell lines, 52 primary tumors (34 PDTC and 18 ATC), and 55 RAIR, FDG-PET-positive recurrences and metastases (nodal and distant) from 42 patients. RAS mutations were more prevalent than BRAF (44 versus 12%; P = 0.002) in primary PDTC, whereas BRAF was more common than RAS (39 versus 13%; P = 0.04) in PET-positive metastatic PDTC. BRAF mutations were highly prevalent in ATC (44%) and in metastatic tumors from RAIR PTC patients (95%). Among patients with multiple metastases, 9 of 10 showed between-sample concordance for BRAF or RAS mutations. By contrast, 5 of 6 patients were discordant for mutations of PIK3CA or AKT1. AKT1_G49A was found in 9 specimens, exclusively in metastases. This is the first documentation of AKT1 mutation in thyroid cancer. Thus, RAIR, FDG-PET-positive metastases are enriched for BRAF mutations. If BRAF is mutated in the primary, it is likely that the metastases will harbor the defect. By contrast, absence of PIK3CA/AKT1 mutations in one specimen may not reflect the status at other sites because these mutations arise during progression, an important consideration for therapies directed at phosphoinositide 3-kinase effectors.
    Full-text · Article · Jul 2009 · Cancer Research
  • [Show abstract] [Hide abstract]
    ABSTRACT: Struma ovarii (SO) infrequently harbor carcinomas that are histologically similar to those arising in the eutopic thyroid. We identified 10 such cases in our files. Eight patients presented with pelvic-related symptoms whereas 2 were incidentally discovered during pregnancy, all with disease confined to the ovary. There were 8 papillary thyroid carcinomas (PTCs) (2 classic and 6 follicular variant) and 2 poorly differentiated thyroid carcinomas. Two of the 10 thyroid carcinomas relapsed after an initial diagnosis of "benign" struma. Both occurred in young women with ovarian cysts discovered during pregnancy. The cystectomy from 1 patient showed thyroid follicles with nuclear features of the follicular variant of PTC whereas the cyst from the second patient showed thyroid follicles with subtle nuclear features, suggestive but not diagnostic of PTC. Both patients presented with disseminated PTC 3 and 4 years after the initial diagnosis, involving the pelvis in both cases and also the liver parenchyma in 1 case. The 2 patients received radioactive iodine therapy after thyroidectomy and are both alive with disease 6 years after diagnosis. The criteria separating hyperplastic nodules from well-differentiated follicular variant of PTC in the thyroid gland seem to be applicable to thyroid-type carcinomas arising in SO. The propensity for adverse clinical behavior does not seem to be related to the grade or histologic type of carcinoma in this small series. The hormonal milieu during pregnancy may lead to progression of malignant SO and such patients should be closely followed, particularly if their treatment consists of cystectomy alone.
    No preview · Article · Jun 2009 · International journal of gynecological pathology: official journal of the International Society of Gynecological Pathologists
  • [Show abstract] [Hide abstract]
    ABSTRACT: 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. All cases of thyroid carcinomas treated at our institution between 1980 and 2000 were reviewed and reclassified according to current histopathologic criteria. 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). 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.
    No preview · Article · Mar 2009 · Thyroid: official journal of the American Thyroid Association
  • [Show abstract] [Hide abstract]
    ABSTRACT: External beam radiotherapy (EBRT) plays a controversial role in the management of nonanaplastic thyroid cancer. We reviewed our institution's outcomes in patients treated with EBRT for advanced or recurrent nonanaplastic thyroid cancer. Between April 1989 and April 2006, 76 patients with nonanaplastic thyroid cancer were treated with EBRT. The median follow-up for the surviving patients was 35.3 months (range, 4.2-178.4). The lesions were primarily advanced and included Stage T2 in 5 (7%), T3 in 5 (7%), and T4 in 64 (84%) patients. Stage N1 disease was present in 60 patients (79%). Distant metastases before EBRT were identified in 27 patients (36%). The median total EBRT dose delivered was 6,300 cGy. The histologic features examined included medullary in 12 patients (16%) and nonmedullary in 64 (84%). Of the 76 patients, 71 (93%) had undergone surgery before RT, and radioactive iodine treatment was used in 56 patients (74%). The 2- and 4-year overall locoregional control rate for all histologic types was 86% and 72%, respectively, and the 2- and 4-year overall survival rate for all patients was 74% and 55%, respectively. No significant differences were found in locoregional control, overall survival, or distant metastases-free survival for patients with complete resection, microscopic residual disease, or gross residual disease. Grade 3 acute mucositis and dysphagia occurred in 14 (18%) and 24 (32%) patients, respectively. Late adverse toxicity was notable for percutaneous endoscopic gastrostomy tube use in 4 patients (5%). The results of our study have shown that EBRT is effective for locoregional control of selected locally advanced or recurrent nonanaplastic thyroid malignancies, with acceptable acute toxicity.
    No preview · Article · Sep 2008 · International journal of radiation oncology, biology, physics
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Radioactive iodine-refractory (RAIR) 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) positive thyroid carcinomas represent the major cause of deaths from thyroid carcinomas (TC) and are therefore the main focus of novel target therapies. However, to the authors' knowledge, the histology of FDG-PET-positive RAIR metastatic thyroid carcinoma has not been described to date. Metastatic tissue from RAIR PET-positive patients identified between 1996 and 2003 at the study institution were selected for histologic examination. The biopsied metastatic site corresponded to a FDG-PET positive lesion sampled within 2 years (87% of which were sampled within 1 year) of the PET scan. Detailed microscopic examination was performed on the metastatic deposit and the available primary tumors. Poorly differentiated thyroid carcinomas (PDTC) were defined on the basis of high mitotic activity (> or =5 mitoses/10 high-power fields) and/or tumor necrosis. Other types of carcinomas were defined by conventional criteria. The histology of the metastases and primary were analyzed, with disease-specific survival (DSS) as the endpoint. A total of 70 patients satisfied the selection criteria, 43 of whom had primary tumors available for review. Histologic characterization of the metastasis/recurrence in 70 patients revealed that 47.1% (n = 33 patients) had PDTC, 20% (n = 14 patients) had the tall cell variant (TCV) of papillary thyroid carcinoma, 22.9% (n = 16 patients) had well-differentiated papillary thyroid carcinoma (WDPTC), 8.6% (n = 6 patients) had Hurthle cell carcinoma (HCC), and 1.4% (n = 1 patient) had anaplastic carcinomas. The histopathologic distribution of the tumor in the primaries was: PDTC, 51%; TCV, 19%; WDPTC, 23%; and widely invasive HCC, 7%. A differing histology between the primary tumor and metastasis was observed in 37% of cases (n = 16 patients). In the majority of instances (63%; 10 of 16 patients) this was noted as transformation to a higher grade. Of the primary tumors classified as PTC, 70% progressed to more aggressive histotypes in the metastasis. Tumor necrosis and extensive extrathyroid extension in the primary tumor were found to be independent predictors of poorer DSS in this group of patients (P = .015). Approximately 68% of the PDTC primary tumors were initially classified by the primary pathologist as better-differentiated tumors on the basis of the presence of papillary and/or follicular architecture or the presence of typical PTC nuclear features. Several observations can be made based on the results of the current study. The majority of metastases in patients with RAIR PET-positive metastases are of a histologically aggressive subtype. However, well-differentiated RAIR metastatic disease is observable. Poorly differentiated disease is underrecognized in many cases if defined by architectural and nuclear features alone. The presence of tumor necrosis was found to be a strong predictor of aggressive behavior, even within this group of clinically aggressive tumors. Finally, there is a significant amount of histologic plasticity between primary tumors and metastases that may reflect the genetic instability of these tumors.
    Preview · Article · Jul 2008 · Cancer
  • Michael Rivera · Satish K Tickoo · Anjali Saqi · Oscar Lin
    [Show abstract] [Hide abstract]
    ABSTRACT: Renal tumors may arise in the setting of end-stage renal cell disease. The risk is 100 times that of the normal population with an incidence ranging from 3-7%. The most common malignant tumor to arise in the setting of acquired cystic disease of the kidney is the acquired cystic disease-associated renal cell carcinoma (ACD-associated RCC). The cytomorphologic features of ACD-associated RCC, which has not been described previously, show moderately cellular specimens composed of clusters of cells with papillary configuration. The cells ranged from polygonal to columnar and contained abundant eosinophilic granular cytoplasm. The nuclei were round and centrally located, and the chromatin was finely granular with prominent central nucleoli that corresponded to Fuhrman's grade 3 nucleolar size. The main differential diagnosis is type 2 papillary renal cell carcinoma, from which it can be distinguished based on clinical findings only at this moment.
    No preview · Article · May 2008 · Diagnostic Cytopathology

Publication Stats

843 Citations
129.14 Total Impact Points

Institutions

  • 2013-2015
    • Mayo Clinic - Rochester
      • Department of Laboratory Medicine & Pathology
      Рочестер, Minnesota, United States
  • 2014
    • National Cancer Institute (USA)
      베서스다, Maryland, United States
  • 2007-2013
    • Memorial Sloan-Kettering Cancer Center
      • Department of Pathology
      New York, New York, United States