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Background: The clinical behaviour and oncologic outcome of diffuse sclerosing papillary thyroid carcinoma (DS-PTC) is poorly understood. The objectives of this study were to compare the clinicopathological characteristics and oncological outcomes of DS-PTC to classic PTC (cPTC) and tall cell PTC (TC-PTC)., Methods: After institutional review board approval, 86 DS-PTC, 2,080 cPTC, and 701 TC-PTC patients treated at MSKCC between 1986 and 2021 were identified. Clinicopathological characteristics were compared by using chi-square test. Kaplan-Meier and log rank were used to compare recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS). DS-PTC patients were propensity matched to cPTC and TC-PTC patients for further comparison., Results: DS-PTC patients were younger with more advanced disease than cPTC and TC-PTC (p < 0.05). Lymphovascular invasion (LVI), extranodal extension, and positive margins were more common in DS-PTC (p < 0.02). Propensity matching confirmed more aggressive histopathological features in DS-PTC. The median number of metastatic lymph nodes was significantly greater and DS-PTC metastases were RAI avid. DS-PTC 5-year RFS was 50.4% compared with 92.4% in cPTC and 88.4% in TC-PTC (p < 0.001). Multivariate analysis confirmed DS-PTC as an independent prognostic factor of recurrence. Ten-year DSS for DS-PTC was 100% compared with 97.1% in cPTC and 91.1% in TC-PTC. Differentiated high-grade, thyroid carcinoma DS had more advanced T-stage and worse 5-year RFS than DS-PTC., Conclusions: DS-PTC presents with more advanced clinicopathological features than cPTC and TC-PTC. Large-volume nodal metastases and LVI are characteristic features. Almost half of patients develop recurrence despite aggressive initial management. Despite this, with successful salvage surgery DSS is excellent., (© 2023. Society of Surgical Oncology.)

Background: The tall cell variant of papillary thyroid carcinoma has traditionally been treated more aggressively than classic papillary thyroid carcinoma. However, this may not be justified in patients with T1/T2 tall cell variant node-negative tumors., Methods: We evaluated well-differentiated thyroid cancers treated surgically between 1985 and 2015 at our institution. We compared patients undergoing lobectomy for node-negative T1/T2 tall cell variant tumors with the same cohort with classic papillary thyroid carcinoma. Patients who underwent early planned completion thyroidectomy were excluded. Tall cell variant tumors were defined as those with ≥30% tall cells. Survival and recurrence outcomes were determined by the Kaplan-Meier method and groups compared using the log-rank test., Results: Thyroid lobectomy was performed for T1/T2 N0X disease in 70 (15%) tall cell cases and 429 (23%) classic papillary thyroid carcinoma cases. There was no significant difference in 10-year overall survival (P = .56) or locoregional recurrence-free probability (P = .52). Disease-specific survival and local or central nodal recurrence-free probability were 100% in both groups. In 9 papillary thyroid carcinoma cases, subsequent contralateral lobe tumors developed, and in 5, lateral neck metastases developed. No recurrences were seen in the tall cell group., Conclusion: T1 node-negative tumors with tall cell histology can be satisfactorily managed with thyroid lobectomy, with equivalent oncological outcomes to classic papillary thyroid carcinoma., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Pediatric thyroid carcinomas (TCs) are rare and mainly approached based on data extrapolated from adults. We retrospectively reviewed 222 pediatric TCs (patient age less than or equal to 21 y). Lymph node (LN) disease volume at presentation was considered high if the largest positive LN measured ≥1 cm and/or >5 LNs were positive. High-grade follicular cell-derived thyroid carcinoma (HGFCTC) were defined by the presence of marked mitotic count and/or tumor necrosis and considered as high-risk histology along with papillary thyroid carcinomas (PTC) diffuse sclerosing variant (DSV). Disease-free survival (DFS) was analyzed. LN involvement at presentation was significantly associated with male sex, larger tumor size, lymphatic invasion, positive surgical margins, and distant metastases at presentation. Five- and 10-year DFS was 84% and 77%, respectively. Only 1 patient with HGFCTC died of disease. Within PTC variants, PTC-DSV was associated with adverse histopathologic parameters and higher regional disease spread, unlike PTC tall cell variant which did not portend worse behavior. The presence of necrosis conferred worse DFS ( P =0.006), while increased mitotic activity did not. While the entire HGFCTC group did not correlate with outcome ( P =0.071), HGFCTC with necrosis imparted worse DFS ( P =0.006). When restricted to PTC-DSV and HGFCTC with necrosis, high-risk histologic classification emerged as an independent prognostic parameter of DFS ( P =0.020). The excellent prognosis of pediatric TCs differs from that of adult TCs showing similar histologic features. While neither increased mitotic activity nor PTC tall cell variant histology predict adverse outcome, PTC-DSV and tumors with necrosis constitute high-risk histologic variants with an increased risk of protracted disease., Competing Interests: Conflicts of Interest and Source of Funding: Supported in part by the Cancer Center Support Grant of the National Institutes of Health/National Cancer Institute under award number P30CA008748. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

This review summarizes the changes in the 5th edition of the WHO Classification of Endocrine and Neuroendocrine Tumors that relate to the thyroid gland. The new classification has divided thyroid tumors into several new categories that allow for a clearer understanding of the cell of origin, pathologic features (cytopathology and histopathology), molecular classification, and biological behavior. Follicular cell-derived tumors constitute the majority of thyroid neoplasms. In this new classification, they are divided into benign, low-risk, and malignant neoplasms. Benign tumors include not only follicular adenoma but also variants of adenoma that are of diagnostic and clinical significance, including the ones with papillary architecture, which are often hyperfunctional and oncocytic adenomas. For the first time, there is a detailed account of the multifocal hyperplastic/neoplastic lesions that commonly occur in the clinical setting of multinodular goiter; the term thyroid follicular nodular disease (FND) achieved consensus as the best to describe this enigmatic entity. Low-risk follicular cell-derived neoplasms include non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), thyroid tumors of uncertain malignant potential, and hyalinizing trabecular tumor. Malignant follicular cell-derived neoplasms are stratified based on molecular profiles and aggressiveness. Papillary thyroid carcinomas (PTCs), with many morphological subtypes, represent the BRAF-like malignancies, whereas invasive encapsulated follicular variant PTC and follicular thyroid carcinoma represent the RAS-like malignancies. This new classification requires detailed subtyping of papillary microcarcinomas similar to their counterparts that exceed 1.0 cm and recommends not designating them as a subtype of PTC. The criteria of the tall cell subtype of PTC have been revisited. Cribriform-morular thyroid carcinoma is no longer classified as a subtype of PTC. The term "Hürthle cell" is discouraged, since it is a misnomer. Oncocytic carcinoma is discussed as a distinct entity with the clear recognition that it refers to oncocytic follicular cell-derived neoplasms (composed of > 75% oncocytic cells) that lack characteristic nuclear features of PTC (those would be oncocytic PTCs) and high-grade features (necrosis and ≥ 5 mitoses per 2 mm 2 ). High-grade follicular cell-derived malignancies now include both the traditional poorly differentiated carcinoma as well as high-grade differentiated thyroid carcinomas, since both are characterized by increased mitotic activity and tumor necrosis without anaplastic histology and clinically behave in a similar manner. Anaplastic thyroid carcinoma remains the most undifferentiated form; squamous cell carcinoma of the thyroid is now considered as a subtype of anaplastic carcinoma. Medullary thyroid carcinomas derived from thyroid C cells retain their distinct section, and there is a separate section for mixed tumors composed of both C cells and any follicular cell-derived malignancy. A grading system for medullary thyroid carcinomas is also introduced based on mitotic count, tumor necrosis, and Ki67 labeling index. A number of unusual neoplasms that occur in the thyroid have been placed into new sections based on their cytogenesis. Mucoepidermoid carcinoma and secretory carcinoma of the salivary gland type are now included in one section classified as "salivary gland-type carcinomas of the thyroid." Thymomas, thymic carcinomas and spindle epithelial tumor with thymus-like elements are classified as "thymic tumors within the thyroid." There remain several tumors whose cell lineage is unclear, and they are listed as such; these include sclerosing mucoepidermoid carcinoma with eosinophilia and cribriform-morular thyroid carcinoma. Another important addition is thyroblastoma, an unusual embryonal tumor associated with DICER1 mutations. As in all the WHO books in the 5th edition, mesenchymal and stromal tumors, hematolymphoid neoplasms, germ cell tumors, and metastatic malignancies are discussed separately. The current classification also emphasizes the value of biomarkers that may aid diagnosis and provide prognostic information., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Aggressive variants of papillary thyroid cancer (PTC) have been described with increasing frequency. These variants include diffuse sclerosing variant, tall cell variant, columnar cell variant, solid variant, and hobnail variant., Methods: We have performed a review of the more aggressive variants of PTC with respect to main characteristics, histological and molecular features, and the consequences that the knowledge of these variants should have in the treatment of the patients., Results: At the present time, we do not know the prognostic value of these aggressive PTC variants. The extent of the surgical treatment and adjuvant therapy necessary should be decided on the basis of the extent of the tumor at presentation and the opinion of experienced clinicians., Conclusion: These aggressive variants should be known by clinicians, to avoid underdiagnosis, and treated according to the latest recommendations in the literature.

In the modern era, a pathology report of thyroid carcinoma requires the inclusion of numerous prognostically relevant histopathological features, e.g. the presence and extent of vascular and capsular invasion, extrathyroidal extension, the surgical margin status and the characteristics of nodal metastasis. These pathological features are crucial components of the initial risk stratification to determine the need for completion thyroidectomy and/or postoperative radioactive iodine ablation therapy. The current review aims to summarise the diagnostic criteria, the controversies, the prognostic impacts and the challenges of these pathological characteristics, focusing specifically on the parameters that are incorporated into the American Joint Committee on Cancer (AJCC) staging system, the College of American Pathologists (CAP) reporting template, the American Thyroid Association (ATA) and the National Comprehensive Cancer Network (NCCN) guidelines., (© 2017 John Wiley & Sons Ltd.)

Background: In 2016, encapsulated follicular variant of papillary thyroid carcinoma without invasion was renamed "noninvasive follicular thyroid neoplasm with papillary-like nuclear features" (NIFTP) in order to reduce overtreatment of this indolent tumor. However, many endocrinologists remain uneasy about managing large (≥4 cm) NIFTP conservatively without radioactive iodine (RAI) therapy. The objectives of this study are to characterize the clinicopathologic characteristics and outcome of large NIFTP in order to assist therapeutic decision making., Methods: The pathology databases of four tertiary hospitals were searched for large (≥4 cm) NIFTP. Cases with separate foci of carcinoma were excluded. Seventy-nine cases fulfilled the inclusion criteria. Among them, 56 (71%) had at least two years of clinical follow-up (FU), and 49 (62%) had four or more years of FU. The clinicopathologic characteristics were reviewed and documented by four endocrine pathologists., Results: The median size of the NIFTP was 4.5 cm (range 4.0-8.0 cm). The entire capsule was sampled in 50 (63%) tumors, while in the remaining 29 (37%) cases, it was submitted representatively, with a median of 2.1 blocks per centimeter of tumor examined. Large NIFTP had a female preponderance with a male:female ratio of 1:1.8, and presented at a median age of 49 years. There were no lymph node metastases at diagnosis in any of the patients, and none of the patients (n = 25) in whom nodal tissue was available for microscopic examination had positive findings. Twenty-six (33%) underwent thyroid lobectomy alone, and 37 (47%) did not receive RAI ablation. No recurrence was observed in the entire cohort, including all 32 patients with two or more years of FU who did not receive RAI therapy (median FU: 6.7 years). Among patients with four or more years of FU, all 25 individuals without RAI therapy did not recur, with a median FU of 11.2 years. Patients with a larger tumor size tended to receive postoperative RAI ablation (p = 0.001)., Conclusions: Similar to their small counterparts, large NIFTP appear to have an extremely low risk of recurrence (zero in this cohort), even when treated conservatively without RAI therapy. Surgical treatment alone, including lobectomy, appears to be adequate for large NIFTP.

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.

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. 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 (131)I 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 statistically nonsignificant 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 at 12-18 months., 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) who 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.

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.

Background: The aggressive nature of medullary thyroid cancer (MTC) is evidenced by its propensity to present early with lymph node (LN) metastases. The clinical significance of sporadic MTC < or =1 cm (micro-MTC) is not clearly defined., Methods: We performed a retrospective review of the clinical, laboratory, and pathologic data for all patients treated or followed at our institution for sporadic micro-MTC from 1987 through 2008., Results: A total of 18 patients met the criteria for inclusion in our study. All tumors were unifocal and C-cell hyperplasia distant from the tumors was uniformly absent. Fourteen (78%) patients underwent total thyroidectomy, and the remaining four (22%) patients with tumors < or =0.5 cm had lobectomy with isthmusectomy alone. Four (22%) patients were found to have LN metastases. However, none of the nine patients with tumors <0.5 cm had clinical evidence of LN metastases. Patients were followed for a median of 3.3 (mean, 4.5) years, and there were no deaths. Postoperative calcitonin levels were available for all patients, of whom 14 had normal levels (range, 0-3.9 pg/ml). The four patients with elevated postoperative calcitonin levels (range, 6.3-644 pg/ml) had tumors ranging from 0.7-0.9 cm in size., Conclusions: Tumors <0.5 cm were associated with a complete absence of clinically detectable nodal disease or elevated postoperative calcitonin levels. The complete absence of multifocal or bilateral disease argues against the need for completion thyroidectomy for sporadic micro-MTC.

Purpose: 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., Methods and Materials: 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%)., Results: 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%)., Conclusion: 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.

Macrofollicular variant of papillary carcinoma (MFPC) is a rare variant of papillary carcinoma in which over 50% of the follicles are represented by macrofollicles. The cytologic features from 7 cases of histologically confirmed MFPC were evaluated. The cytology specimens were evaluated for the following criteria: cellularity, cluster arrangement (micro and macrofollicular), chromatin pattern, nuclear grooves, pseudonuclear inclusions, nuclear shape, nuclear overlap, nucleoli, presence of lymphocytes, macrophages and Hurthle cell, amount and characteristics of background colloid. Most cases were moderately to highly cellular with presence of both microfollicles as well as macrofollicles, but nuclear features of papillary thyroid carcinoma were absent or focal in all cases. MFPC is a variant of papillary carcinoma that can be extremely difficult to diagnose cytologically. The presence of abundant colloid, macrophages, macrofollicular follicular cell arrangement and/or absence of widespread cytologic features associated with papillary carcinoma can lead to an erroneous diagnosis of goiter., ((c) 2007 Wiley-Liss, Inc.)

Background: The tall cell variant (TCV) is a histologic subtype of papillary thyroid carcinoma (PTC) that is more aggressive than "classical" PTC. Most authors believe that TCV's worse prognosis is related to older age at presentation, larger tumor size, and high frequency of extrathyroid tumor extension (ETE). To assess the biologic and clinical behavior of TCV without ETE, we performed a detailed comparative clinicopathologic analysis of classical PTC and TCV without ETE., Methods: TCV was defined as a PTC harboring >50% tall cells, while classical PTC was restricted to those tumors containing >1% papillae and <30% tall cells. Microscopic analysis and chart review identified 62 cases of TCV and 83 classical PTC without ETE. These patients were analyzed for various pathologic, imaging, and clinical parameters including outcome., Results: There was no statistical difference between TCV and classical PTC in relation to age, gender, tumor size, risk stratification, type of therapy, and length of follow-up. TCV displayed more invasion of the tumor capsule and more often infiltrated into the thyroid capsule (p = 0.047 and 0.0004, respectively). Among patients with microscopically assessable regional lymph node (LN), 33 of 49 (67.3%) patients with TCV had LN metastasis at presentation, while only 24 of 60 (40%) classical PTC had positive nodes (p = 0.004). In multivariate analysis, histologic subtype (TCV vs. classical PTC) was the only independent factor associated with LN metastases (p = 0.007). In patients with adequate follow-up, 4 of 62 (6.5%) classical PTC and 7 of the 47 (14.9%) TCV had thyroid cancer recurrence (p = 0.202). TCV recurred at a distant site (3 of 47, 6.4%) while none of the 62 classical PTC developed distant metastases (p = 0.077)., Conclusion: TCV without ETE is biologically a more aggressive tumor than classical PTC without ETE independent of age, gender, and tumor size.

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., (Copyright 2004 Wiley-Liss, Inc.)

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.