Abstract
Hurthle cell lesion is one of the most questionable clinico-pathological entities in most of its aspects. Literature has used the terms oncocytic, oxyphilic, Hurthle, and Ashkanazy interchangeably; what does each term denote? Who first described these cells? What is the cell of origin? How much Hurthle cells should be present to define the lesion as Hurthle cell one? Is it possible to differentiate hyperplastic from neoplastic and benign from malignant Hurthle cell lesion on a non-histopathologic ground? Does it belong to follicular or to papillary neoplasms or should it be classified separately? Can we anticipate its clinical behavior or predict its outcome? How can we manage? We will try to answer these questions in light of the ongoing relevant arguments with the aim of resolving some uncertainties and suggesting how to solve others.
Keywords: Hurthle, Oncocytic, Oxyphilic, Thyroid
Introduction
Since its description in nineteenth century to date, Hurthle cell lesion has been a subject of continuing and evolving conflicts in nearly all of its aspects, starting from its nomenclature to its management. Numerous studies, many of which are very recent, have pointed to important facts relevant to these lesions and have proposed several clinical and non clinical tools which may help managing them. However, only few facts are established while controversies, challenges, and debates still encompass most of its spectrum. In this article, we aim to emphasize established concepts, display the ongoing arguments with a view of clarifying some uncertainties, and make suggestions which may contribute to further resolving others. In order to approach this, we reviewed the literature published in the last 20 years by using the search terms “Hurthle cell lesions” “Hurthle cell tumors” and “Oncocytic tumors” in the bibliographic database, mainly of “PubMed” and “ScienceDirect” and we retrieved 89 published manuscripts from which we constructed this narrative review.
Nomenclature Controversy: Oncocytic, Oxyphilic, Hurthle, or Ashkanazy?
An oncocyte is an epithelial cell defined by the presence of numerous mitochondria imparting a deeply eosinophilic finely granular appearance to the cytoplasm [1]. Mitochondrial proteins, being of basic nature, have avidity to bind acidic dyes like eosin. Because of this staining feature, oncocytes have also been termed oxyphils. Oncocytes have been found to arise in various tissues, including endocrine glands (thyroid, parathyroid, and pituitary glands), exocrine glands (salivary, lacrimal glands, pancreas, and liver), and secretory epithelia (nasal cavities, buccal mucosa, and larynx) [2, 3]. In the thyroid gland, these cells have also been termed Hurthle cells (HCs) or Ashkanazy cells [1, 4] after the names of these two scientists.
Historical Controversy: Hurthle or Ashkanazy?
In 1894, Karl Hurthle talked about parafollicular cell in the thyroid of dogs [5]. The oncocytic cells derived from thyroid follicular epithelium were, in fact, first described in 1898 by Max Ashkanazy in patients with Graves’ disease [6]. Despite this historical fact, the term “Hurthle cell” has continued to be used in the literature to refer to thyroid follicular cells with oncocytic features, except in Germany where the term “Askkanazy cells” is in use.
Controversy of Origin: Follicular or Parafollicular Cells?
Hurthle cells are generally thought to arise from thyroid follicular cells, based on detection of thyroglobulin immunoreactivity [7] and TSH receptor adenylate cyclase system [8]. On the other hand, parafollicular cell origin was reported [9] based on the more frequent lymphatic metastasis [10], lower radioactive iodine (RAI) avidity [11], and different oncogene expression when compared to follicular thyroid cancer (FTC) [12]. However, given that the hallmark of oncocytic change is mitochondrial proliferation as an adaptive process to a primary nuclear abnormality [4, 13], it can occur in follicular as well as in parafollicular cells [14].
Controversy of Definition: Is It a Hurthle Cell Lesion?
A Hurthle cell lesion (HCL) has been defined as a discrete lesion composed mainly of HCs. However, percentage of HCs required for the lesion to be diagnosed as HCL has been controversial. Most literature defined the lesion as HCL when oncocytes are making 75 % or more [4, 15, 16]. Some authors considered it a HCL when oncocytes exceed 50 % of follicular cells in fine-needle aspiration biopsy (FNAB) [17–19]. However, most authors used the figures 75 [20–25] and 50 % [9, 26–30] to refer to neoplastic rather than non-neoplastic HCL. Others required more than 90 % oncocytes to define the lesion as oncocytic neoplasm [26, 31].
Hurthle Cell Lesion: the Challenge of Neoplastic or Non-neoplastic?
Approximately, 15–30 % of FNA specimens are reported as “indeterminate” [32]. For these indeterminate cases in which HCs predominate, the more specific term “Hurthle cell lesion” is often reported [33]. It encompasses a variety of neoplastic as well as non-neoplastic thyroid follicular lesions. Non-neoplastic conditions in which HCs may be present include autoimmune thyroiditis (Hashimoto’s and Graves’), multinodular goiter (MNG) (with oncocytic metaplasia) as well as aging and irradiated thyroids. In such “indeterminate cases,” FNAB cannot reliably diagnose neoplasia vs hyperplasia and carcinoma vs adenoma. In addition, demographic (age and sex), clinical (nodule size), and laboratory (thyroid function) data were found unhelpful to differentiate neoplastic from non-neoplastic cases [34]. Many of these pathologies may be managed conservatively if neoplasia can be excluded. Thus, a challenging clinical situation may arise if HCs are detected in FNABs. A distinction between neoplastic and non-neoplastic HCLs should be made in order to segregate patients for whom surgery is indicated from those who may be managed conservatively. Pathologists have suggested criteria to solve this challenge; abundance of HCs, dyscohesive pattern, non-macrofollicular pattern, absent or scanty colloid, and absence of background chronic inflammation are FNA features suggesting Hurthle cell neoplasm (HCN) [17, 35–37]. On the other hand, presence of HCs in cohesive flat sheets or presence of watery colloid suggests MNG with oncocytic metaplasia, while a background of lymphocytes and plasma cells usually indicates chronic lymphocytic thyroiditis [36]. Intracytoplasmic lumina and transgressing vessels may help to differentiate neoplastic from non-neoplastic HCLs with their presence favors the diagnosis of neoplastic one [17, 21, 38]. Molecular biology techniques may offer another tool; RET/PTC activation was detected in a significant number of neoplastic cases but not in hyperplastic nodules [39].
Hurthle Cell Neoplasm (HCN): the Challenge of Benign or Malignant?
The incidence of HCN varies between 3 and 10 % in all thyroid nodules [20, 22, 40]. These HCNs have been classified into Hurthle cell adenoma (HCA) and Hurthle cell carcinoma (HCC) [23]. In the absence of metastasis, a controversy arises regarding the nature of HCN as whether it is benign or malignant since cytological criteria diagnostic of malignancy, like cellular atypia and architectural distortion, may be found in benign HCNs [41]. In this context, FNAB usually reports “HCL/HCN” [1]. Moreover, intraoperative frozen section examination was consistently reported to be unhelpful [13, 27, 29, 42]. Thus, the sole distinction is based on presence or absence of capsular invasion (CI) and vascular invasion (VI) which can only be reliably identified in paraffin section. Given the aggressive behavior of histologically proven malignant HCN reported by some investigators [23], such indeterminate findings impose a challenging situation in which clinicians tend to follow a more aggressive surgical approach. However, the incidence of malignancy among nodules, which are cytologically suspicious for HCN, was found, by histopathology, to range from 5 to 35 % [22, 27, 33]. This means that a considerable proportion of these patients is unnecessarily exposed to the risk of surgical complications. Stemming from this, investigators have tried to employ demographic (age, gender, race, ethnicity), clinico-pathological criteria (tumor size, radiation history, family history, multifocality, and coexisting thyroid pathology) to better predict the risk of malignancy in HCN. Older age was found to be significantly associated with malignancy in some studies [43, 44]; however, others found no significant association [16, 22, 45, 46]. Similarly, contradictory findings were reported concerning gender association [20, 27, 47, 48]. Larger tumors were found, by some authors, to be associated with higher malignancy rates [29, 49] while others did not find a significant association [19, 28]. Laboratory data, like preoperative thyroglobulin (Tg) concentration, were also sought; some authors found no significant difference between malignant and benign HCNs [45, 47]. However, in 2014, Petric et al. have found that preoperative Tg concentration was a predicting factor for malignancy in HCNs [50]. Similarly, sonographic criteria were investigated; hypoechogenicity [22, 46] and hyperechogenicity were significantly associated with malignancy while iso-echogenicity could significantly predict benignity [46], albeit Maizlin et al. previously found that the sonographic appearance of HCNs varied from hypo- to iso- and hyperechoic regardless of their pathology, thus precluding sonography for characterization of HCNs [25]. Literature published in the last 15 years for studies evaluating these factors is plentiful (Table 1), and it is noticeable that the discrepancy in the results is so obvious that no single factor has maintained consistency throughout all studies; this may be attributed to the retrospective and single institutional nature in all of them. This subsequently calls the need for prospective multi-institutional studies to better evaluate these factors for preoperative sorting of malignant from benign cases. In continuing trials to resolve this challenge, Arduc et al., in 2014, have found that larger body mass index and waist circumference were associated with higher malignancy risk in patients with FNAB diagnosis of HCN [51]. In addition, pathologists tried to refine the FNAB results by finding specific microscopical features; a microfollicular pattern with marked nuclear atypia in a background of HCs was found to be a significant predictor of malignancy [20]. Immunohistochemistry may provide an ancillary tool; expression of cell cycle proteins (Ki67 [24, 52] and Cyclin D1 [52]) has been shown to be significantly higher in HCC than in HCA.
Table 1.
Studies evaluating demographic, clinico-pathologic, sonographic, and laboratory criteria in Hurthle cell neoplasms
Year | Author | Sample size | Significant association with malignancy? | |
---|---|---|---|---|
Yes | No | |||
1998 | Chen et al. [29] | 57 | Larger tumor size | Age, gender and radiation history |
1999 | McHenry et al. [19] | 75 | Age, gender, radiation history and tumor size | |
2001 | Sugino et al. [47] | 188 | Male gender | Age, tumor size and Tg concentration |
2003 | Lopez-Penabard et al. [43] | 127 | Older age and larger tumor size | Gender and radiation history |
2005 | Chao et al. [28] | 163 | Age, gender, tumor size and location | |
2006 | Paunovic et al. [49] | 199 | Larger tumor size | Age |
2006 | Melck et al. [27] | 27 | Male gender and larger tumor size | Age and gland nodularity |
2008 | Sippel et al. [48] | 57 | Larger tumor size | Age, gender, radiation history, family history and presence of thyroiditis |
2008 | Zhang et al. [44] | 55 | Older age and larger tumor size | Gender and gland nodularity |
2010 | Pisanu et al. [20] | 57 | Larger tumor size and multifocality | Age and gender |
2010 | Suh et al. [45] | 39a | Age, gender, tumor size, radiation history, family history and Tg concentration | |
2013 | Parikh et al. [46] | 84 | Hypo- or hyperechogeniciy in the US | Age, gender, race, ethnicity, presence of thyroiditis and other sonographic criteria. |
2013 | Lee at al. [22] | 75 | Larger tumor size and hypoechogenicity in the US | Age, gender and other sonographic criteria |
2014 | Kroeker et al. [16] | 78 | Age, gender, tumor size, history of head and neck radiation, family history of thyroid cancer and calcifications in the US | |
2014 | Petric et al. [50] | 244a | Male gender and higher preoperative Tg concentrationb | Age and tumor size |
aSample included follicular neoplasms in addition to HCNs
bCut-off point for serum thyroglobulin concentration is 80 ng/ml
Hurthle Cell Neoplasm: Controversies of Pathological Classification
Traditionally, HCNs have been classified into benign (HCA) and malignant (HCC) [23]. Based on histopathologic features, Erickson et al., in 2000, added a third category; HCN of uncertain malignant behavior (UMB), characterized by equivocal CI with absent VI [52]. In the same year, Cheung et al. classified HCNs into HCA, HCC, and Hurthle cell papillary carcinoma (HCPC) based on data from molecular studies [53]. In fact, demonstration of oncocytic features in certain variants of papillary thyroid cancer (PTC) has been long recognized and reported [54]. However, the diagnosis of this entity is in itself another controversy. Some authors required the demonstration of classic nuclear features of PTC, in addition to the presence of oxyphilic cells with or without papillary growth pattern [31, 55–57]. Others necessitate the detection of a papillary architecture, with or without recognizing the diagnostic nuclear features of PTC; as these may be obscured by the nuclear hyperchromasia of HCs [15]. Recently, detection of RET/PTC rearrangement, that was thought to be specific to conventional PTC, in some HCNs has expanded the diagnosis of HCPC to include a subgroup of cancer that shows this molecular event even without detecting any of the characteristic cyto-architectural features [53, 58, 59].
Hurthle cell carcinoma has been long considered as a subgroup of follicular thyroid cancer (FTC) and was classified as such by the World Health Organization (WHO) [60] based on similar clinical behavior reported in some literature [10, 11, 61, 62]. However, stemming from the apparently more aggressive clinical behavior reported by others [63], different oncogene expression [12], and specific molecular pathogenesis [64–66], HCC has been considered by some authors to be a distinctive subset of differentiated thyroid cancer (DTC), different from FTC [23, 63, 67]. Moreover, molecular studies [53, 58, 59] have suggested that HCC would be more appropriately sub-classified under PTC [27] or at least closer to PTCs than was originally believed. However, more recently and perpetuating the enigma, data by Finely et al. have shown that the molecular signature of HCCs is most similar to FTC [68].
Based on the degree of CI and VI, HCC has been sub-classified into two groups: minimally invasive (miHCC) and widely invasive Hurthle cell carcinoma (wiHCC); however, another controversy exists in the literature concerning definition of miHCC. Chindris et al. defined it as HCC with four or less foci of CI or with less than four foci of VI [69], while Stojadinovic et al. defined it as HCC with a single focus of complete CI or a single focus of any VI or both [41]. On the other hand, Monotone opined that angioinvasion should be removed from the definition of miHCC [31]. In their series, Barnabei et al. distinguished HCC as miHCC if only CI was reported [18] while Sanders et al. included only cases with minimal CI [11].
Two relevant concepts remain. Initially, because dedifferentiation is well documented in DTC [60], an oncocytic poorly differentiated thyroid cancer has also been described [4, 15, 70]. Additionally, oncocytic change can also occur in parafollicular cells resulting in oncocytic medullary thyroid carcinoma (MTC) [71]. As a result, Sobrinho et al. stated that with the exception of undifferentiated carcinoma, every type of benign or malignant thyroid tumor has its oncocytic variant [72]. These data support the classification system proposed by Asa [15] in which malignant HCNs are categorized into HCPC, Hurthle cell follicular carcinoma, Hurthle cell poorly differentiated carcinoma, and oncocytic medullary carcinoma.
Controversies of Clinical Behavior
By definition, an indolent course lacking recurrence or metastasis is the clinical hallmark of benign tumors. However, for HCNs, this concept is confused by the occasional reports of recurrence or metastasis in histologically proven HCAs [73]. Asa suggested that such lesions may be unrecognized cases of HCPC [15]. To resolve this confusion, HCA has been suggested to be restricted to HCNs, not only lacking CI and VI, but also lacking RET/PTC rearrangement; HCNs showing this molecular event would be considered HCPC [58].
There has also been a considerable controversy in the literature as to whether HCC has a similar or more aggressive clinical behavior to FTC. Some authors found that they both behave in an identical fashion [61, 74] as there was no statistically significant difference between both in terms of size, extrathyroidal extension, nodal or distant metastasis, local recurrence, and patient survival [10, 11, 62, 75]. Others suggested that HCCs are more aggressive [63, 67] based on the facts of more frequent nodal [10, 76] and distal metastasis [77, 78], less RAI avidity [11, 76, 79], and greater likelihood of local recurrence [10, 23]. In a study by Shaha et al. [80], Hurthle variety categorized FTC into higher risk groups. Similarly, the clinical behavior of HCPC is controversial; some reported a behavior identical to conventional type PTC [55] while others reported a more aggressive behavior with higher rates of recurrence and cause-specific mortality [81].
Controversies of Prognosis
Age, metastasis, extrathyroid extension, and size (AMES) prognostic index, which has been long used to predict outcome of DTC, was also validated to stratify HCC into high and low risk groups and was subsequently found to correlate significantly with survival and to predict recurrence risk [11, 82]. However, as with other aspects of this tumor, controversy is evident. Some authors found that advancing age significantly correlated with poor outcome [74] while contradictory findings were concluded by others [41, 62, 63, 83]. Similar contradiction exists regarding gender-outcome correlation [62, 63]. Likewise, larger tumor size was found to adversely impact the outcome [63, 74, 83] while others found no significant association [41, 62]. Extrathyroid extension was shown to significantly compromise survival [41, 83]; however, this was found to be insignificant in a study by Barnabei et al. [18]. With the exception of few studies [11, 18, 80], nodal metastasis was correlated with adverse prognosis [41, 63, 83] while distant metastasis always caused dismal outcome [63, 83]. The microscopic morphology appears also to correlate with outcome; in a histopathological appraisal by Stojadinovic et al. [41], all patients with miHCC exhibited a benign clinical course with no cause-specific mortality while considerable proportions of wiHCC patients developed metastasis, recurrence, or died [41], in concordant with findings reported by Sanders [11] and Chindris et al. [69]. On the other hand, Barnabei et al. stated that VI, the hallmark of wiHCC, was not associated with worse survival [18], and Goldstein et al. reported no statistically significant difference in the number of CI or VI foci between metastatic and non-metastatic HCCs [84].
Debates in Management
It is well known that surgery is an important line for managing thyroid pathologies. For HCLs, however, prudency of surgical decision, appropriateness of surgery extent, and post operative management are debatable. The first debate is whether or not to operate. Given the high incidence of malignancy in their series, Azidan et al. [85] concluded that the cytological detection of HCs in FNAB was an indication for surgery after excluding Hashimoto’s thyroiditis. On the contrary, subsequent studies suggested that the percentage, rather than the mere detection, of HCs should guide the operative decision with the detection of more than 50 % HCs being an adequate criterion for opting surgery [30, 86]. The second debate is, if to operate, how much to resect. Several issues stand behind such debate. Firstly, based on the relative rarity of HCNs in general [9] and of HCCs in particular [61], single institutional experience is usually not sufficient to define an ultimate management plan. Secondly, inability to preoperatively differentiate malignancy from benignity or even to predict clinical behavior or outcome usually affect treatment decision in a way that, given a presumed aggressive nature, more radical surgery is preferable. Thirdly, most studies evaluating the outcome of surgery were retrospective studies confounded by non-matching of variables (age, gender, and tumor size) which also influence the outcome. Given the relatively small proportion of HCCs among HCN nodules and benign course identified in most miHCC, Kroeker et al. [16], in agreement with previous reports of Parikh et al. [46], Melck et al. [27], and McHenry et al. [19], have advocated thyroid lobectomy for initial management of HCNs keeping in mind two possibilities. Firstly, proceeding to total thyroidectomy may be decided immediately if extrathyroidal extension or lymphadenopathy was detected intraoperatively. Secondly, completion thyroidectomy may be planned shortly after initial surgery if HCC was revealed on paraffin sections. Additionally, in his large series, Haigh et al. found no significant association between extent of thyroidectomy and survival [61]. On the other hand, total thyroidectomy, as an initial surgery, was supported by Mills et al. [23], Paunovic et al. [49], and Khafif et al. [62] as they noticed favorable outcomes associated with assertive resection. Moreover, a lower threshold for selecting initial radical surgery was advocated by Chen et al. [29], Sippel et al. [48], and Zhang et al. [44] in large size tumors since they detected significant correlation with malignancy. In fact, the latter opinion is fueled by several facts; the aggressive course identified in some reports [63, 67], the low avidity for RAI [11], the low incidence of complications in experienced hands [29, 49], which substantially increase in re-operative surgery, the availability of replacement therapy, the privilege of using thyroglobulin as a marker for recurrence, and the potential use of RAI for ablating a possible remnant [28]. The third debate is whether or not to use RAI. Although HCC generally fail to concentrate RAI [76], its controversial role in management is fueled by the varying results published in the literature. Lopez et al. reported a survival benefit when used for remnant ablation but not in metastatic disease [43]. On the other hand, in their series, Sanders et al. stated that using RAI did not improve outcome [11]. Moreover, Mills et al. reported a worse disease free survival (DFS) conferred by RAI ablation and therapy [23]. However, National Comprehensive Cancer Network (NCCN) 2013 guidelines have considered RAI ablation for suspected or proven thyroid bed uptake and RAI treatment for suspected or proven RAI responsive residual tumor in postoperative management of histologically proven HCC [87].
In our opinion, standardizing a management plan needs a two-pronged approach. First, starting prospectively designed randomized controlled clinical trials (RCCTs) evaluating the efficacy of different management plans on large sample of patients, which given the rarity and long natural history of the disease, would appropriately be multi-institutional. Second, employing molecular biology techniques and advanced imaging tools would resolve much of the diagnostic controversy and subsequently the management debate; for example, a recently described gene expression classifier has achieved 92 % sensitivity in detecting “suspicious” nodules which were cytologically “indeterminate” [88]. In addition, sonographic elastography scoring may contribute to better characterization of HCLs [89].
Conclusion
Despite many studies investigating HCLs in general and HCNs in particular, only few facts are established while uncertainties still obscure much of the disease spectrum. Further research, with implementation of advanced diagnostic aids and conduction of RCCTs, is needed to fix its riddle.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no competing interests.
References
- 1.Wakely PE., Jr Oncocytic and oncocyte-like lesions of the head and neck. Ann Diagn Pathol. 2008;12(3):222–230. doi: 10.1016/j.anndiagpath.2008.04.007. [DOI] [PubMed] [Google Scholar]
- 2.Kontaxis A, Zanarotti U, Kainz J, Beham A. Die diffuse Onkozytose der Glandula Parotidea. Laryngo-Rhino-Otologie. 2004;83(03):185–188. doi: 10.1055/s-2004-814267. [DOI] [PubMed] [Google Scholar]
- 3.Prabakaran SS, Chen F, Aguirre A. Oncocytoma of the parotid gland and its mimickers: a comprehensive review. N Am J Med Sci. 2010;3:171–180. doi: 10.7156/v3i4p171. [DOI] [Google Scholar]
- 4.Mete O, Asa SL. Oncocytes, oxyphils, Hurthle, and Askanazy cells: morphological and molecular features of oncocytic thyroid nodules. Endocr Pathol. 2010;21(1):16–24. doi: 10.1007/s12022-009-9102-2. [DOI] [PubMed] [Google Scholar]
- 5.Hurthle K. BeitrÃgezurKenntniss des Secretionsvorgangs in der. SchilddrÃse. Pflugers Arch Physiol. 1894;56:10–44. doi: 10.1007/BF01662011. [DOI] [Google Scholar]
- 6.Ashkanazy M. Pathologisch-anatomischeBeitrÃgezurKenntniss des. MorbusBasedowii, insbesondere über die dabeiauftretendeMuskelerkrankung. Dtsch Arch Klin Med. 1898;61:118–186. [Google Scholar]
- 7.Johnson TL, Lloyd RV, Burney RE, Thompson NW. Hurthle cell thyroid tumors. An immunohistochemical study. Cancer. 1987;59(1):107–112. doi: 10.1002/1097-0142(19870101)59:1<107::AID-CNCR2820590123>3.0.CO;2-U. [DOI] [PubMed] [Google Scholar]
- 8.Clark OH, Gerend PL. Thyrotropin receptor-adenylate cyclase system in Hurthle cell neoplasms. J Clin Endocrinol Metab. 1985;61(4):773–778. doi: 10.1210/jcem-61-4-773. [DOI] [PubMed] [Google Scholar]
- 9.Chen H, Udelsman R. Chapter 14 - Hürthle cell adenoma and carcinoma. In: Kebebew OHC-YD, editor. Textbook of endocrine surgery. 2. Philadelphia: W.B. Saunders; 2005. pp. 123–128. [Google Scholar]
- 10.Evans HL, Vassilopoulou-Sellin R. Follicular and Hurthle cell carcinomas of the thyroid: a comparative study. Am J Surg Pathol. 1998;22(12):1512–1520. doi: 10.1097/00000478-199812000-00008. [DOI] [PubMed] [Google Scholar]
- 11.Sanders LE, Silverman M. Follicular and Hürthle cell carcinoma: predicting outcome and directing therapy. Surgery. 1998;124(6):967–974. doi: 10.1016/S0039-6060(98)70036-4. [DOI] [PubMed] [Google Scholar]
- 12.Masood S, Auguste L-J, Westerband A, et al. Differential oncogenic expression in thyroid follicular and Hürthle cell carcinomas. Am J Surg. 1993;166(4):366–368. doi: 10.1016/S0002-9610(05)80334-4. [DOI] [PubMed] [Google Scholar]
- 13.Stankov K, Romeo G. Oxyphilic carcinoma of the thyroid gland. Arch Oncol. 2003;11(2):81–89. doi: 10.2298/AOO0302081S. [DOI] [Google Scholar]
- 14.Rosai J, Kuhn E, Carcangiu ML. Pitfalls in thyroid tumour pathology. Histopathology. 2006;49(2):107–120. doi: 10.1111/j.1365-2559.2006.02451.x. [DOI] [PubMed] [Google Scholar]
- 15.Asa S. My approach to oncocytic tumours of the thyroid. J Clin Pathol. 2004;57(3):225–232. doi: 10.1136/jcp.2003.008474. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Kroeker T, Prisman E, Shah M, et al. Hurthle cell lesions-a retrospective review of final surgical pathology. Thyroid Disord Ther. 2014;3(155):2. [Google Scholar]
- 17.Elliott DD, Pitman MB, Bloom L, Faquin WC. Fine-needle aspiration biopsy of Hurthle cell lesions of the thyroid gland: a cytomorphologic study of 139 cases with statistical analysis. Cancer. 2006;108(2):102–109. doi: 10.1002/cncr.21716. [DOI] [PubMed] [Google Scholar]
- 18.Barnabei A, Ferretti E, Baldelli R, et al. Hurthle cell tumours of the thyroid. Personal experience and review of the literature. Acta Otorhinolaryngol Ital. 2009;29(6):305–311. [PMC free article] [PubMed] [Google Scholar]
- 19.McHenry CR, Thomas SR, Slusarczyk SJ, Khiyami A. Follicular or Hu ¨rthle cell neoplasm of the thyroid: can clinical factors be used to predict carcinoma and determine extent of thyroidectomy? Surgery. 1999;126(4):798–804. doi: 10.1016/S0039-6060(99)70138-8. [DOI] [PubMed] [Google Scholar]
- 20.Pisanu A, Di Chiara B, Reccia I, Uccheddu A. Oncocytic cell tumors of the thyroid: factors predicting malignancy and influencing prognosis, treatment decisions, and outcomes. World J Surg. 2010;34(4):836–843. doi: 10.1007/s00268-009-0357-z. [DOI] [PubMed] [Google Scholar]
- 21.Yang YJ, Khurana KK. Diagnostic utility of intracytoplasmic lumen and transgressing vessels in evaluation of Hurthle cell lesions by fine-needle aspiration. Arch Pathol Lab Med. 2001;125(8):1031–1035. doi: 10.5858/2001-125-1031-DUOILA. [DOI] [PubMed] [Google Scholar]
- 22.Lee KH, Shin JH, Ko ES, et al. Predictive factors of malignancy in patients with cytologically suspicious for Hurthle cell neoplasm of thyroid nodules. Int J Surg. 2013;11(9):898–902. doi: 10.1016/j.ijsu.2013.07.010. [DOI] [PubMed] [Google Scholar]
- 23.Mills SC, Haq M, Smellie WJ, Harmer C. Hurthle cell carcinoma of the thyroid: retrospective review of 62 patients treated at the Royal Marsden Hospital between 1946 and 2003. Eur J Surg Oncol. 2009;35(3):230–234. doi: 10.1016/j.ejso.2008.06.007. [DOI] [PubMed] [Google Scholar]
- 24.Hoos A, Stojadinovic A, Singh B, et al. Clinical significance of molecular expression profiles of Hurthle cell tumors of the thyroid gland analyzed via tissue microarrays. Am J Pathol. 2002;160(1):175–183. doi: 10.1016/S0002-9440(10)64361-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Maizlin ZV, Wiseman SM, Vora P, et al. Hurthle cell neoplasms of the thyroid: sonographic appearance and histologic characteristics. J Ultrasound Med. 2008;27(5):751–757. doi: 10.7863/jum.2008.27.5.751. [DOI] [PubMed] [Google Scholar]
- 26.Cannon J. The significance of Hürthle cells in thyroid disease. Oncologist. 2011;16(10):1380–1387. doi: 10.1634/theoncologist.2010-0253. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Melck A, Bugis S, Baliski C, et al. Hemithyroidectomy: the preferred initial surgical approach for management of Hurthle cell neoplasm. Am J Surg. 2006;191(5):593–597. doi: 10.1016/j.amjsurg.2006.02.007. [DOI] [PubMed] [Google Scholar]
- 28.Chao T-C, Lin J-D, Chen M-F. Surgical treatment of Hurthle cell tumors of the thyroid. World J Surg. 2005;29(2):164–168. doi: 10.1007/s00268-004-7669-9. [DOI] [PubMed] [Google Scholar]
- 29.Chen H, Nicol TL, Zeiger MA, et al. Hurthle cell neoplasms of the thyroid: are there factors predictive of malignancy? Ann Surg. 1998;227(4):542–546. doi: 10.1097/00000658-199804000-00015. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Hudak K, Mazeh H, Sippel RS, Chen H. Hürthle cell metaplasia on fine-needle aspiration biopsy is not by itself an indication for thyroid surgery. Am J Surg. 2012;203(3):287–291. doi: 10.1016/j.amjsurg.2011.09.019. [DOI] [PubMed] [Google Scholar]
- 31.Montone KT, Baloch ZW, LiVolsi VA. The thyroid Hurthle (oncocytic) cell and its associated pathologic conditions: a surgical pathology and cytopathology review. Arch Pathol Lab Med. 2008;132(8):1241–1250. doi: 10.5858/2008-132-1241-TTHOCA. [DOI] [PubMed] [Google Scholar]
- 32.Cooper DS, Doherty GM, Haugen BR, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2009;19(11):1167–1214. doi: 10.1089/thy.2009.0110. [DOI] [PubMed] [Google Scholar]
- 33.Pu RT, Yang J, Wasserman PG, et al. Does Hurthle cell lesion/neoplasm predict malignancy more than follicular lesion/neoplasm on thyroid fine-needle aspiration? Diagn Cytopathol. 2006;34(5):330–334. doi: 10.1002/dc.20440. [DOI] [PubMed] [Google Scholar]
- 34.Alaedeen DI, Khiyami A, McHenry CR. Fine-needle aspiration biopsy specimen with a predominance of Hürthle cells: a dilemma in the management of nodular thyroid disease. Surgery. 2005;138(4):650–657. doi: 10.1016/j.surg.2005.06.047. [DOI] [PubMed] [Google Scholar]
- 35.Galera-Davidson H, González-Cámpora R. Chapter 23 - thyroid. In: Wilbur MB, editor. Comprehensive cytopathology. 3. Edinburgh: W.B. Saunders; 2008. pp. 633–670. [Google Scholar]
- 36.Clark D, Faquin W. Hurthle cell lesions. Thyroid cytopathology. US: Springer; 2010. pp. 93–107. [Google Scholar]
- 37.Kasper K, Stewart J, III, Das K. Fine needle aspiration cytology of thyroid nodules with Hürthle cells: cytomorphologic predictors for neoplasms, improving diagnostic accuracy and overcoming pitfalls. J Am Soc Cytopathol. 2012;1(1):S62–S63. doi: 10.1016/j.jasc.2012.08.136. [DOI] [PubMed] [Google Scholar]
- 38.Baloch ZW, LiVolsi VA, Asa SL, et al. Diagnostic terminology and morphologic criteria for cytologic diagnosis of thyroid lesions: a synopsis of the National Cancer Institute Thyroid Fine-Needle Aspiration State of the Science Conference. Diagn Cytopathol. 2008;36(6):425–437. doi: 10.1002/dc.20830. [DOI] [PubMed] [Google Scholar]
- 39.Chiappetta G, Toti P, Cetta F, et al. The RET/PTC oncogene is frequently activated in oncocytic thyroid tumors (Hurthle cell adenomas and carcinomas), but not in oncocytic hyperplastic lesions. J Clin Endocrinol Metab. 2002;87(1):364–369. doi: 10.1210/jcem.87.1.8180. [DOI] [PubMed] [Google Scholar]
- 40.Zhang YW, Greenblatt DY, Repplinger D, et al. QS264. Factors that predict malignancy in Hürthle cell neoplasms of the thyroid. J Surg Res. 2008;144(2):371–372. doi: 10.1016/j.jss.2007.12.512. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Stojadinovic A, Ghossein RA, Hoos A, et al. Hurthle cell carcinoma: a critical histopathologic appraisal. J Clin Oncol. 2001;19(10):2616–2625. doi: 10.1200/JCO.2001.19.10.2616. [DOI] [PubMed] [Google Scholar]
- 42.Pisanu A, Sias L, Uccheddu A. Factors predicting malignancy of Hürthle cell tumors of the thyroid: influence on surgical treatment. World J Surg. 2004;28(8):761–765. doi: 10.1007/s00268-004-7312-9. [DOI] [PubMed] [Google Scholar]
- 43.Lopez-Penabad L, Chiu AC, Hoff AO, et al. Prognostic factors in patients with Hurthle cell neoplasms of the thyroid. Cancer. 2003;97(5):1186–1194. doi: 10.1002/cncr.11176. [DOI] [PubMed] [Google Scholar]
- 44.Zhang Y, Greenblatt D, Repplinger D, et al. Older age and larger tumor size predict malignancy in Hürthle cell neoplasms of the thyroid. Ann Surg Oncol. 2008;15(10):2842–2846. doi: 10.1245/s10434-008-0079-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45.Suh I, Vriens MR, Guerrero MA, et al. Serum thyroglobulin is a poor diagnostic biomarker of malignancy in follicular and Ḧurthle-cell neoplasms of the thyroid. Am J Surg. 2010;200(1):41–46. doi: 10.1016/j.amjsurg.2009.08.030. [DOI] [PubMed] [Google Scholar]
- 46.Parikh PP, Allan BJ, Lew JI. Surgeon-performed ultrasound predictors of malignancy in patients with Hürthle cell neoplasms of the thyroid. J Surg Res. 2013;184(1):247–252. doi: 10.1016/j.jss.2013.03.005. [DOI] [PubMed] [Google Scholar]
- 47.Sugino K, Ito K, Mimura T, et al. Hürthle cell tumor of the thyroid: analysis of 188 cases. World J Surg. 2001;25(9):1160–1163. doi: 10.1007/BF03215865. [DOI] [PubMed] [Google Scholar]
- 48.Sippel RS, Elaraj DM, Khanafshar E, et al. Tumor size predicts malignant potential in Hurthle cell neoplasms of the thyroid. World J Surg. 2008;32(5):702–707. doi: 10.1007/s00268-007-9416-5. [DOI] [PubMed] [Google Scholar]
- 49.Paunovic I, Krgovic K, Tatic S, et al. Surgery for thyroid Hürthle cell tumours—a single institution experience. Eur J Surg Oncol. 2006;32(4):458–461. doi: 10.1016/j.ejso.2005.11.023. [DOI] [PubMed] [Google Scholar]
- 50.Petric R, Besic H, Besic N. Preoperative serum thyroglobulin concentration as a predictive factor of malignancy in small follicular and Hürthle cell neoplasms of the thyroid gland. World J Surg Oncol. 2014;12(1):1–7. doi: 10.1186/1477-7819-12-282. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 51.Arduc A, Dogan BA, Tuna MM, et al (2015) Higher body mass index and larger waist circumference may be predictors of thyroid carcinoma in patients with Hurthle-cell lesion/neoplasm fine-needle aspiration diagnosis. Clin Endocrinol (Oxf) 83(3):405–411 [DOI] [PubMed]
- 52.Erickson LA, Jin L, Goellner JR, et al. Pathologic features, proliferative activity, and cyclin D1 expression in Hurthle cell neoplasms of the thyroid. Mod Pathol. 2000;13(2):186–192. doi: 10.1038/modpathol.3880034. [DOI] [PubMed] [Google Scholar]
- 53.Cheung CC, Ezzat S, Ramyar L, et al. Molecular basis of Hurthle cell papillary thyroid carcinoma. J Clin Endocrinol Metab. 2000;85(2):878–882. doi: 10.1210/jcem.85.2.6404. [DOI] [PubMed] [Google Scholar]
- 54.Histopathology A. Histopathology of thyroid tumors. An overview. Hormones. 2004;3(2):100–110. doi: 10.14310/horm.2002.11118. [DOI] [PubMed] [Google Scholar]
- 55.Berho M, Suster S. The oncocytic variant of papillary carcinoma of the thyroid: a clinicopathologic study of 15 cases. Hum Pathol. 1997;28(1):47–53. doi: 10.1016/S0046-8177(97)90278-1. [DOI] [PubMed] [Google Scholar]
- 56.Sabino de Matos P. Thyroid epithelial tumours. Diagn Histopathol. 2008;14(5):236–246. doi: 10.1016/j.mpdhp.2008.03.005. [DOI] [Google Scholar]
- 57.Lloyd RV, Buehler D, Khanafshar E. Papillary thyroid carcinoma variants. Head Neck Pathol. 2011;5(1):51–56. doi: 10.1007/s12105-010-0236-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 58.Belchetz G, Cheung CC, Freeman J, et al. Hürthle cell tumors: using molecular techniques to define a novel classification system. Arch Otolaryngol Head Neck Surg. 2002;128(3):237–240. doi: 10.1001/archotol.128.3.237. [DOI] [PubMed] [Google Scholar]
- 59.Musholt PB, Imkamp F, von Wasielewski R, et al. RET rearrangements in archival oxyphilic thyroid tumors: new insights in tumorigenesis and classification of Hürthle cell carcinomas? Surgery. 2003;134(6):881–889. doi: 10.1016/j.surg.2003.08.003. [DOI] [PubMed] [Google Scholar]
- 60.Nikiforov YE, Biddinger PW, Thompson LDR. Diagnostic pathology and molecular genetics of the thyroid: a comprehensive guide for practicing thyroid pathology. Wolters Kluwer Health: USA; 2012. [Google Scholar]
- 61.Haigh PI, Urbach DR. The treatment and prognosis of Hürthle cell follicular thyroid carcinoma compared with its non-Hürthle cell counterpart. Surgery. 2005;138(6):1152–1158. doi: 10.1016/j.surg.2005.08.034. [DOI] [PubMed] [Google Scholar]
- 62.Khafif A, Khafif RA, Attie JN. Hürthle cell carcinoma: a malignancy of low-grade potential. Head Neck. 1999;21(6):506–511. doi: 10.1002/(SICI)1097-0347(199909)21:6<506::AID-HED2>3.0.CO;2-M. [DOI] [PubMed] [Google Scholar]
- 63.Kushchayeva Y, Duh Q-Y, Kebebew E, et al. Comparison of clinical characteristics at diagnosis and during follow-up in 118 patients with Hurthle cell or follicular thyroid cancer. Am J Surg. 2008;195(4):457–462. doi: 10.1016/j.amjsurg.2007.06.001. [DOI] [PubMed] [Google Scholar]
- 64.Dettori T, Frau DV, Lai ML, et al. Aneuploidy in oncocytic lesions of the thyroid gland: diffuse accumulation of mitochondria within the cell is associated with trisomy 7 and progressive numerical chromosomal alterations. Genes Chromosom Cancer. 2003;38(1):22–31. doi: 10.1002/gcc.10238. [DOI] [PubMed] [Google Scholar]
- 65.Wada N, Duh QY, Miura D, et al. Chromosomal aberrations by comparative genomic hybridization in hurthle cell thyroid carcinomas are associated with tumor recurrence. J Clin Endocrinol Metab. 2002;87(10):4595–4601. doi: 10.1210/jc.2002-020339. [DOI] [PubMed] [Google Scholar]
- 66.Máximo V, Soares P, Lima J, et al. Mitochondrial DNA somatic mutations (point mutations and large deletions) and mitochondrial DNA variants in human thyroid pathology: a study with emphasis on Hürthle cell tumors. Am J Pathol. 2002;160(5):1857–1865. doi: 10.1016/S0002-9440(10)61132-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 67.Carcangiu ML, Bianchi S, Savino D, et al. Follicular Hurthle cell tumors of the thyroid gland. Cancer. 1991;68(9):1944–1953. doi: 10.1002/1097-0142(19911101)68:9<1944::AID-CNCR2820680917>3.0.CO;2-I. [DOI] [PubMed] [Google Scholar]
- 68.Finley DJ, Zhu B, Fahey Iii TJ. Molecular analysis of Hurthle cell neoplasms by gene profiling. Surgery. 2004;136(6):1160–1168. doi: 10.1016/j.surg.2004.05.061. [DOI] [PubMed] [Google Scholar]
- 69.Chindris A-M, Casler JD, Bernet VJ, et al (2014) Clinical and molecular features of Hürthle cell carcinoma of the thyroid. J Clin Endocrinol Metab 0(0):jc.2014-1634 [DOI] [PubMed]
- 70.Papotti M, Torchio B, Grassi L, et al. Poorly differentiated oxyphilic (Hurthle cell) carcinomas of the thyroid. Am J Surg Pathol. 1996;20(6):686–694. doi: 10.1097/00000478-199606000-00005. [DOI] [PubMed] [Google Scholar]
- 71.Dedivitis RA, Di Giovanni JH, Silva GF, et al. Oncocytic variant of medullary thyroid carcinoma: case report. Arq Bras Endocrinol Metabol. 2004;48(2):315–317. doi: 10.1590/S0004-27302004000200017. [DOI] [PubMed] [Google Scholar]
- 72.Sobrinho-Simões M, Magalhães J, Fonseca E, Amendoeira I. Diagnostic pitfalls of thyroid pathology. Curr Diagn Pathol. 2005;11(1):52–59. doi: 10.1016/j.cdip.2004.07.007. [DOI] [Google Scholar]
- 73.Ain K. Unusual types of thyroid cancer. Rev Endocr Metab Disord. 2000;1(3):225–231. doi: 10.1023/A:1010039317050. [DOI] [PubMed] [Google Scholar]
- 74.Bhattacharyya N. Survival and prognosis in Hürthle cell carcinoma of the thyroid gland. Arch Otolaryngol Head Neck Surg. 2003;129(2):207–210. doi: 10.1001/archotol.129.2.207. [DOI] [PubMed] [Google Scholar]
- 75.Ozlem Kucuk N, Kulak H, Tokmak E, et al. Hurthle cell carcinoma: a clinicopathological study of thirteen cases. Nucl Med Commun. 2006;27(4):377–379. doi: 10.1097/01.mnm.0000202862.74917.0c. [DOI] [PubMed] [Google Scholar]
- 76.Yutan E, Clark O. Hürthle cell carcinoma. Curr Treat Options in Oncol. 2001;2(4):331–335. doi: 10.1007/s11864-001-0026-4. [DOI] [PubMed] [Google Scholar]
- 77.Shaha AR, Shah JP, Loree TR. Patterns of nodal and distant metastasis based on histologic varieties in differentiated carcinoma of the thyroid. Am J Surg. 1996;172(6):692–694. doi: 10.1016/S0002-9610(96)00310-8. [DOI] [PubMed] [Google Scholar]
- 78.Ruegemer JJ, Hay ID, Bergstralh EJ, et al. Distant metastases in differentiated thyroid carcinoma: a multivariate analysis of prognostic variables. J Clin Endocrinol Metab. 1988;67(3):501–508. doi: 10.1210/jcem-67-3-501. [DOI] [PubMed] [Google Scholar]
- 79.Schneider DF, Chen H. New developments in the diagnosis and treatment of thyroid cancer. CA Cancer J Clin. 2013;63(6):373–394. doi: 10.3322/caac.21195. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 80.Shaha AR, Loree TR, Shah JP. Prognostic factors and risk group analysis in follicular carcinoma of the thyroid. Surgery. 1995;118(6):1131–1138. doi: 10.1016/S0039-6060(05)80124-2. [DOI] [PubMed] [Google Scholar]
- 81.Herrera M, Hay I, Wu PC, et al. Hürthle cell (oxyphilic) papillary thyroid carcinoma: a variant with more aggressive biologic behavior. World J Surg. 1992;16(4):669–674. doi: 10.1007/BF02067351. [DOI] [PubMed] [Google Scholar]
- 82.McDonald MP, Sanders LE, Silverman ML, et al. Hürthle cell carcinoma of the thyroid gland: prognostic factors and results of surgical treatment. Surgery. 1996;120(6):1000–1005. doi: 10.1016/S0039-6060(96)80046-8. [DOI] [PubMed] [Google Scholar]
- 83.Stojadinovic A, Hoos A, Ghossein R, et al. Hürthle cell carcinoma: a 60-year experience. Ann Surg Oncol. 2002;9(2):197–203. doi: 10.1007/BF02557374. [DOI] [PubMed] [Google Scholar]
- 84.Goldstein NS, Czako P, Neill JS. Metastatic minimally invasive (encapsulated) follicular and Hurthle cell thyroid carcinoma: a study of 34 patients. Mod Pathol. 2000;13(2):123–130. doi: 10.1038/modpathol.3880023. [DOI] [PubMed] [Google Scholar]
- 85.Azadian A, Rosen IB, Walfish PG, Asa SL. Management considerations in Hürthle cell carcinoma. Surgery. 1995;118(4):711–715. doi: 10.1016/S0039-6060(05)80039-X. [DOI] [PubMed] [Google Scholar]
- 86.Kauffmann PR, Dejax C, de Latour M, Dauplat J. The meaning and predictivity of Hürthle cells in fine needle aspiration cytology for thyroid nodular disease. Eur J Surg Oncol. 2004;30(7):786–789. doi: 10.1016/j.ejso.2004.05.017. [DOI] [PubMed] [Google Scholar]
- 87.Gallagher L, Hughes M, McMillian L (2013) National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Thyroid Carcinoma Version 2. 2013. Available from: http://www.nccn.org/professionals/physician_gls/pdf/thyroid.pdf
- 88.Alexander EK, Kennedy GC, Baloch ZW, et al. Preoperative diagnosis of benign thyroid nodules with indeterminate cytology. N Engl J Med. 2012;367(8):705–715. doi: 10.1056/NEJMoa1203208. [DOI] [PubMed] [Google Scholar]
- 89.Tuzun D, Ersoy R, Kilicyazgan A, et al (2014) Elastosonography scoring and strain index of thyroid nodules with Hurthle cells. Minerva Endocrinol [Epub ahead of print] [PubMed]