225 REVIEW J Clin Pathol: first published as 10.1136/jcp.2003.008474 on 27 February 2004. Downloaded from My approach to oncocytic tumours of the thyroid S L Asa ............................................................................................................................... J Clin Pathol 2004;57:225–232. doi: 11.1036/jcp.2003.008474 The traditional approach to oncocytic thyroid lesions staining. Morphologically, Hu¨rthle cells are characterised by large size, polygonal to square classified these as a separate entity, and applied criteria shape, distinct cell borders, voluminous granular that are somewhat similar to those used for follicular lesions and eosinophilic cytoplasm, and a large, often of the thyroid. In general, the guidelines to distinguish hyperchromatic nucleus with prominent ‘‘cherry pink’’ macronucleoli (fig 1). With the hyperplasia from neoplasia, and benign from malignant Papanicolau stain, the cytoplasm may be orange, were crude and unsubstantiated by scientific evidence. In green, or blue. By electron microscopy, the fact, there is no basis to separate oncocytic lesions from cytoplasmic granularity is produced by large mitochondria filling the cell, consistent with other classifications of thyroid pathology. The factors that oncocytic transformation.23 The diagnosis of an result in mitochondrial accumulation are largely unrelated oncocytic tumour is not usually difficult because to the genetic events that result in proliferation and of these distinctive features, but in borderline or dubious circumstances, mitochondrial markers neoplastic transformation of thyroid follicular epithelial can be used, including the antimitochondrial cells. The concept of classifying oncocytic lesions, including antibody 113-1. follicular variant papillary carcinomas, based on nuclear morphology, immunohistochemical profiles, and molecular ‘‘The proliferation of oncocytes gives rise to markers may pave the way for a better understanding of hyperplastic and neoplastic nodules’’ the biology of oncocytic lesions of the thyroid. In some cases, the degree of oncocytic change ........................................................................... precludes recognition of the cell of origin. In this situation, other markers of differentiation can be he first question that we must ask is ‘‘What applied. Immunohistochemistry of these lesions is oncocytic change?’’. can be confounded by the notorious ‘‘stickiness’’ of oncocytes, which can result in non-specific T staining. In addition they have high endogenous WHAT IS ONCOCYTIC CHANGE peroxidase activity, so that rigorous controls Definition must be performed to enable the results of these http://jcp.bmj.com/ Oncocytic change is defined as cellular enlarge- studies to be interpreted correctly. Using appro- ment characterised by an abundant eosinophilic priate technology, one can apply markers such as granular cytoplasm as a result of the accumula- transcription factors (for example, thyroid tran- tion of altered mitochondria. scription factor 1 (TTF-1)) to distinguish thyroid This is a phenomenon of metaplasia that from parathyroid oncocytic lesions, enzymes and occurs in inflammatory disorders, such as thyr- differentiation proteins (including synaptophy- oiditis, or other situations that result in cellular sin and chromogranins) to distinguish neuroen- 1 stress. The proliferation of oncocytes gives rise to docrine tumours, and hormones (such as on September 25, 2021 by guest. Protected copyright. hyperplastic and neoplastic nodules. thyroglobulin, calcitonin, parathyroid hormone Oncocytic tumours are found in the thyroid (PTH), and other peptide hormones) to char- and other endocrine tissues, including the para- acterise endocrine oncocytomas in the thyroid thyroid, pituitary, adrenal cortex, pancreas, gut, area. and lung. Outside of the endocrine system, there is an oncocytic variant of renal cell carcinoma, Importance and salivary glands, particularly the parotid, In some circumstances, oncocytic change is a develop oncocytic nodules and tumours. This dis- feature of tumours that have a benign behaviour, cussion will concentrate on thyroid nodules, but such as renal cell carcinomas. Parathyroid many of the principles apply to other sites too. tumours with oncocytic change were thought to Oncocytic cells in the thyroid are often called have reduced functional capacity for hormone See end of article for ‘‘Hu¨rthle’’ cells; however, this is a misrepresen- authors’ affiliations production. This has not been substantiated tation because they were initially described by ....................... because there are cases of hormone hypersecre- Askenazy, and the cells that Hu¨rthle described tion in patients with these lesions,4 and immu- Correspondence to: were in fact C cells. Nevertheless, the terminol- Dr S L Asa, 610 University nohistochemical studies show that these lesions ogy has been established in most parts of the Avenue, Suite 4-302, express PTH. In general, however, oncocytic Toronto, Ontario M5G world (with the exception of Germany where the 2M9, Canada; term ‘‘Askenazy cells’’ has persisted). [email protected] ................................................... Accepted for publication Diagnosis Abbreviations: CK, cytokeratin; PTH, parathyroid 28 August 2003 In general, oncocytic change is highly character- hormone; RT-PCR, reverse transcription polymerase chain ....................... istic on conventional haematoxylin and eosin reaction; TTF-1 thyroid transcription factor 1 www.jclinpath.com 226 Asa J Clin Pathol: first published as 10.1136/jcp.2003.008474 on 27 February 2004. Downloaded from Figure 1 Oncocytic follicular cells in the thyroid, known as Hu¨rthle cells, Figure 3 Nodules of oncocytes in the setting of chronic lymphocytic are characterised by large size, polygonal to square shape, distinct cell thyroiditis (as shown) or in nodular hyperplasia may be hyperplastic or borders, voluminous granular and eosinophilic cytoplasm, and a large, neoplastic. The distinction can be extremely difficult or impossible. often hyperchromatic nucleus with prominent ‘‘cherry pink’’ macronucleoli. Hu¨rthle cell lesions.57–13These included capsular and vascular invasion. Moreover, studies showed that the larger the parathyroid tumours tend to be larger than non-oncocytic Hu¨rthle cell lesion, the more likely it is to show invasive tumours with similar concentrations of circulating PTH. characteristics; a Hu¨rthle cell tumour that is 4 cm or greater In the thyroid, Hu¨rthle cells are found in a variety of has an 80% chance of showing histological evidence of conditions and, therefore, are not specific for a particular malignancy.7 Nuclear atypia, which is the hallmark of the disease. Individual cells, follicles, or groups of follicles may Hu¨rthle cell, multinucleation, and mitotic activity were not show Hu¨rthle cell features in irradiated thyroids, in aging considered useful for predicting prognosis. However, there thyroids, in nodular goitre, and in chronic lymphocytic remained a group of Hu¨rthle cell lesions that were not thyroiditis (fig 2), in addition to that seen in long standing invasive and were considered to be Hu¨rthle cell adenomas, autoimmune hyperthyroidism (Graves’ disease). In some of yet they gave rise to lymph node metastases.5 In my opinion, these situations, one can often find an entire nodule these lesions were a reflection of the failure to recognise composed of oncocytes (fig 3), and the distinction of oncocytic follicular variant papillary carcinomas.14 hyperplasia from neoplasia can be problematic. Many Hu¨rthle cell tumours, whether benign or malignant, The identification of oncocytic change in thyroid tumours show papillary change, which is really a pseudopapillary has led to major controversies. Because some lesions that phenomenon, because Hu¨rthle cell tumours have only scant http://jcp.bmj.com/ were called benign developed metastases, there were propo- stroma and may fall apart during manipulation, fixation, and nents of the view that all oncocytic tumours of the thyroid 56 processing. True oxyphilic or Hu¨rthle cell papillary carcinoma should be treated as malignancies. Numerous studies (fig 4) has been reported to comprise from 1% to 11% of all indicated that the criteria that apply to follicular tumours papillary carcinomas.3 15–20 These tumours have a papillary of the thyroid also distinguish malignant from benign on September 25, 2021 by guest. Protected copyright. Figure 2 In chronic lymphocytic thyroiditis, follicular cells can show Figure 4 Oncocytic papillary carcinoma is an accepted diagnosis extensive oncocytic change, which is most pronounced in areas of when the tumour has complex papillary architecture with thin papillae inflammation. The nuclei can exhibit crowding, clearing, irregular that have true fibrovascular cores, and the papillae are lined contours, and grooves, mimicking papillary carcinoma. predominantly or entirely by Hu¨rthle cells. www.jclinpath.com Oncocytic tumours of thyroid 227 architecture, but are composed predominantly or entirely of metastasise,29 explaining the occurrence of malignancy in J Clin Pathol: first published as 10.1136/jcp.2003.008474 on 27 February 2004. Downloaded from Hu¨rthle cells.321The nuclei may exhibit the characteristics of patients with a histopathological diagnosis of adenoma. usual papillary carcinoma,16 22 or they may instead resemble The management of Hu¨rthle cell carcinoma is controver- the pleomorphic nuclei of Hu¨rthle cells, being large, sial.5 11 30–33 In most