Psammomatous calcifications in thyroid oncocytic (Hürthle cell) follicular tumors

Concentric calcifications, also known as psammoma bodies, are a relatively frequent finding in certain types of tumors, particularly papillary thyroid carcinoma (PTC). In the thyroid, they have been assigned a significant role in the diagnosis of PTC and in distinguishing between these tumors and other types of thyroid neoplasms. Concentric calcifications have also less commonly been noted in other processes in the thyroid, such as in tumors characterized by cells containing abundant oxyphilic cytoplasm (i.e., Hürthle cells). We have studied 12 patients with oncocytic thyroid follicular tumors that contained scattered psammomatous calcifications that led to difficulties in diagnosis. The patients were 9 women and 3 men, aged 34 to 63 years. 10 cases corresponded to benign, non-invasive oncocytic tumors and 2 cases were minimally invasive follicular carcinomas of oncocytic (so called Hürthle cell) type. The psammomatous calcifications were randomly scattered throughout the lesions and were present as a focal, incidental finding in 8 cases and were diffuse in 4 cases. They were composed of concentrically laminated deposits of dense basophilic material closely resembling psammoma bodies, often associated with more homogeneous deposits of lightly eosinophilic material without concentric lamination that were interpreted as precipitated thyroglobulin. Seven patients with clinical follow-up, including one with minimally invasive carcinoma, were alive and well between 5 and 12 years after diagnosis. Concentric laminated calcifications may be encountered in oncocytic (Hürthle cell) follicular tumors and should not be interpreted as indicative of PTC in the context of oncocytic neoplasms of the thyroid.     

Hürthle (oncocytic) cell tumors of thyroid: etiopathogenesis, diagnosis and clinical significance

The etiopathogenesis and the classification of oncocytic (Hürthle cell) tumors of the thyroid is reviewed with an emphasis on the role played by mitochondrial and nuclear genetic abnormalities that interfere with mitochondrial function. Oxyphilia is classified into primary or secondary and the so-called Hürthle cell carcinoma is divided into oncocytic (Hürthle cell) variants of papillary and follicular carcinoma.     

Molecular Characterization of an Endometrial Endometrioid Adenocarcinoma Metastatic to a Thyroid Hürthle Cell Adenoma Showing Cancerization of Follicles

Tumor-to-tumor metastasis is rare. Herein, we present a unique case of endometrial endometrioid adenocarcinoma metastatic to a thyroid Hürthle cell adenoma 9 years after initial diagnosis. On histologic examination of the thyroid, the malignant endometrioid glands and single cells (donor tumor) were dispersed within the Hürthle cell adenoma (recipient tumor). In several sections of the adenoma with still preserved microfollicular architecture, malignant endometrial adenocarcinoma cells were admixed within oncocytic adenomatous epithelium (so-called “cancerization of the follicles”). This unusual phenomenon, to our knowledge, is a novel finding in the thyroid gland. Immunohistochemistry, subsequently elicited clinical history, and morphologic comparison of the tumor in the thyroid to the primary endometrial tumor confirmed the origin of the donor tumor cells. Molecular analysis of both the metastatic and primary endometrial tumors demonstrated PIK3CA and PTEN mutations in both tumors, as is characteristic of well-differentiated endometrioid tumors of the endometrium. Amplification of chromosome 1q was detected in both sites; however, only the metastatic tumor showed loss of chromosomes 2, 9, and 22. The morphologic differential diagnosis of metastatic endometrioid adenocarcinoma in the thyroid includes columnar cell variant of papillary thyroid carcinoma (CCVPTC) arising in a preexisting adenoma, endocrine glandular atypia within an adenoma, and metastasis from other anatomic sites. Histomorphologic differences among these entities may be subtle; therefore, knowledge of and morphologic comparison with prior malignancies and immunohistochemistry can be helpful in rendering the correct diagnosis.     

Diagnostic criteria in well-differentiated thyroid carcinomas

The criteria used for the differential diagnosis of well-differentiated thyroid tumors derived from follicular cells are reviewed taking into account the architectural characteristics together with the immunohistochemical and molecular features. The review is focused on follicular carcinoma, papillary carcinoma, follicular variant of papillary carcinoma, and oncocytic (Hürthle cell) tumors, as well as on the recently described borderline lesions: follicular and well-differentiated tumors of uncertain malignant potential, and well-differentiated carcinoma, not otherwise specified.     

Combined tall cell carcinoma and Hürthle cell carcinoma (collision tumor) of the thyroid

Tall cell carcinoma and Hürthle cell carcinoma are 2 aggressive forms of differentiated follicular-derived thyroid carcinomas. We present a case where these malignant tumors of thyroid coexisted. The tumor originated in the thyroid as a mixed tumor and metastasized as a tall cell tumor to the lymph nodes and as a Hürthle cell carcinoma to lungs. The coexistence of these tumor types is rare and sheds light on the histogenesis of Hürthle cell tumors and the metastatic behavior of combined tumors.     

Oncocytic thyroid neoplasms: from histology to molecular biology

The recent update of the 4th edition of the World Health Organization's Classification of Tumors of Endocrine Organs introduced important changes in the nomenclature of follicular-cell thyroid tumors, namely, regarding mitochondrion-rich neoplasms (In this review, for the practical purposes, the words Hürthle and oncocytic are synonymous in the field of thyroid pathology.) According to the last edition, oncocytic thyroid neoplasms, with follicular architecture and no typical nuclei of papillary carcinoma, – are now included in a separate group - the Hürthle cell neoplasms. Whenever thus categorized-while keeping oncocytic variant of papillary, medullary and poorly differentiated carcinoma-, a sort of tidal phenomenon has occurred about oncocytic tumors known for decades. Through this categorization, pathologists and researchers need to progress in the discussion about etiopathogenesis of oncocytic neoplasms (ONs). This review provides an attempt to balance the facts and doubts by questioning the recent changes based on what is known about oncocytic tumors.     

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

Oncocytic cells are characterized by a greatly increased number of mitochondria that distend the cell cytoplasm and result in a distinctive granular appearance of the cell on conventional histology sections. Oncocytes are frequently found in metabolically active human tissues including the thyroid gland, and, as a general rule, when their proportion in a thyroid tumor is greater than 75% the tumor is referred to as oncocytic (Hürthle cell) adenoma or carcinoma. Such tumors represent a subset of thyroid lesions, and recently, both interphase fluorescence in situ hybridization (FISH) and comparative genomic hybridization (CGH) studies reported that they may show aneuploidy, with widespread numerical chromosomal alterations. In contrast, very few cases have been studied by conventional cytogenetic analysis. Whether the cells with chromosomal changes are the same as those with mitochondrial accumulation or whether lesions only partially composed of oncocytic cells also have cytogenetic alterations is unclear. To investigate the relationship between acquisition of the oncocytic phenotype and numerical chromosomal changes, we analyzed a random selection of thyroid lesions with (18 cases) and without (11 cases) morphological evidence of oncocytic differentiation. Lesions with oncocytes included hyperplastic nodules, adenomas, Hürthle cell tumors, and papillary carcinomas with lymphocytic stroma (Whartin-like tumors of the thyroid). Karyotypic changes were analyzed by cytogenetic analysis, FISH, or CGH, and the results were compared with in situ analysis of mitochondrial accumulation by immunofluorescence. A striking correlation between the presence of oncocytes and the presence of aneuploid katyotypes was seen in the oncocytic follicular thyroid nodules, but not in the oncocytic papillary tumors. Structural chromosome changes or normal karyotypes were observed in the lesions lacking oncocytic features. Extending the FICTION technique to the evaluation of a cytoplasmic antigen (mitochondrial membrane antigen), we pursued the simultaneous visualization of both mitochondrial increase and numerical chromosomal alterations, and showed that oncocytes of follicular lesions are prone to become aneuploid. Our data support the contention that follicular tumors composed of oncocytes should be regarded as a distinct subset.     

Immunohistochemical expression of galectin-3 in benign and malignant thyroid lesions

CONTEXT: The expression of galectin-3, a human lectin, has been shown to be highly associated with malignant behavior of thyroid lesions. DESIGN: We studied the immunohistochemical expression pattern of galectin-3 in a variety of follicular-derived thyroid lesions (13 benign and 62 malignant), including Hürthle cell and follicular carcinoma, papillary carcinomas and variants, and anaplastic and poorly differentiated carcinomas. RESULTS: Immunoreactivity was strongest in papillary thyroid carcinomas, whereas staining was less intense in Hürthle cell and anaplastic carcinomas, and even weaker in the follicular variant of papillary thyroid carcinoma. Staining was absent or weak in the 3 follicular thyroid carcinomas and was negative in both insular carcinomas. In several tumors, staining was stronger at the advancing invasive edge of the lesion than in the central portion of the tumor. Galectin-3 was also expressed focally and weakly in reactive follicular epithelium and entrapped follicles in chronic lymphocytic thyroiditis. A variety of thyroid lesions showed prominent endogenous, biotin-like activity, which could cause flaws in interpretation if a biotin-detection system were used. CONCLUSION: We conclude that galectin-3 immunostaining, when used in biotin-free detection systems, may be useful as an adjunct to distinguish benign from malignant thyroid lesions.     

Warthin-like papillary carcinoma of the thyroid

BACKGROUND: Warthin-like papillary carcinoma of thyroid is characterized by distinct papillary formations lined by tumor cells with oncocytic cytoplasm, nuclear features of papillary carcinoma, and brisk lymphoplasmacytic infiltrates in the papillary stalks. This tumor derives its name from its close resemblance to Warthin tumor of major salivary glands. DESIGN: The clinicopathologic features of 17 patients with Warthin-like papillary carcinoma were studied. RESULTS: Fifteen tumors occurred in women and 2 arose in men (age range, 23-63 years). The lesions ranged in size from 3 mm to 2.5 cm. Fine-needle aspiration biopsies were performed in 7 cases; 4 were diagnosed as papillary carcinoma, 2 as consistent with lymphocytic thyroiditis, and 1 as atypical cells. All 17 tumors were confined to the thyroid; 6 showed prominent cyst formation and the remaining tumors were solid. In each case, the tumor arose in a background of lymphocytic thyroiditis. Nodal metastases were identified in 3 cases; however, none showed distant metastases. In 7 cases, foci of papillary microcarcinoma and follicular variant of papillary carcinoma were found in other areas of the thyroid. CONCLUSIONS: Warthin-like tumors can be mistaken for benign lymphoepithelial lesions of the thyroid, Hürthle cell carcinoma, and tall cell variant of papillary carcinoma in both fine-needle aspiration and histology specimens. Follow-up information on the previously reported cases has suggested that these tumors behave similarly to usual papillary carcinoma. The extensive lymphocytic infiltration in these tumors and their association with chronic lymphocytic thyroiditis may suggest a role for immunological mechanisms in the pathogenesis of thyroid tumors.     

Oncocytic neoplasms of the thyroid gland.

Among well differentiated thyroid tumors, oncocytic neoplasms feature a distinctive set of clinical, morphologic and biologic characteristics, some of which have been a matter of controversy. The world literature on this subject has been reviewed to show that: 1) Morphology accurately predicts the behavior of Hürthle cell tumors assuming that the specimen has been adequately sampled; 2) Capsular and/or vascular invasion is the sine qua non condition for a diagnosis of malignancy; 3) "Indeterminate" or "possibly malignant" categories are useless because in the absence of invasion these neoplasms almost invariably behave in a benign fashion; 4) Among cases histologically classified as malignant, a clinically aggressive behavior is to be expected in a high percentage of cases; 5) Size alone cannot be used as a criterion of malignancy; 6) Less than total thyroidectomy provides an adequate treatment for histologically benign tumors; aggressive surgical procedures (i.e. total thyroidectomy) do not diminish the incidence of metastasis; 7) Analysis of DNA content may be helpful in defining subsets of patients with Hürthle cell carcinomas having a particularly poor prognosis; 8) Mitochondrial and/or nuclear DNA abnormalities probably play an important role in the cellular alterations which characterize the phenotype of oncocytes.     

Retinoblastoma expression in thyroid neoplasms.

Retinoblastoma (Rb) mutation in thyroid neoplasia has been identified in a few molecular studies; however, the utility of Rb immunohistochemistry in distinguishing benign and malignant thyroid lesions has not been documented in formalin-fixed, paraffin-embedded tissues. The present study investigated Rb immunohistochemistry in a series of 111 formalin-fixed, paraffin-embedded benign and malignant thyroid lesions. All of the major histologic subtypes were included to detect any heterogeneity in Rb-1 expression that might influence the diagnostic utility of this technique or further elucidate the pathogenesis of thyroid neoplasia among the categories. Altogether, 34 follicular adenomas, 9 follicular carcinomas, 7 Hürthle cell adenomas, 5 Hürthle cell carcinomas, 23 papillary carcinomas (8 of which were follicular variants), 4 insular carcinomas, 4 anaplastic carcinomas, 6 medullary carcinomas, and 19 nodular goiters were analyzed. Avidinbiotin immunohistochemistry was performed using the Dako Rb-1 clone. Pronase digestion was introduced into the epitope retrieval protocol to eliminate false-positive cytoplasmic stainig. Nuclear immunoreactivity was assessed as positive if 10% or more of thyroid epithelial nuclei stained positively, and conversely as negative. The majority of benign non-Hürthle thyroid lesions, whether hyperplastic or neoplastic, retained Rb nuclear immunopositivity in most cells (51 of 53 cases [96%]). Conversely, malignant thyroid neoplasms lacked Rb immunoreactivity in the majority (42 of 51 cases [82%]), including all papillary carcinomas (23 of 23) and almost all follicular carcinomas (8 of 9 [89%]). Virtually all Hürthle cell neoplasms were negative (11 of 12 [92%]), whether benign or malignant. In conclusion, Rb immunohistochemistry can aid in the distinction between benign and malignant thyroid lesions in conjunction with morphology. This seems to be most applicable to the often problematic differentiation between follicular adenoma and the follicular variant of papillary carcinoma (P < .0001; sensitivity and specificity, 100%) or minimally invasive follicular carcinoma (P = .0007; sensitivity, 89%; specificity, 100%).     

Clinical Significance of Molecular Expression Profiles of Hürthle Cell Tumors of the Thyroid Gland Analyzed via Tissue Microarrays

Hürthle cell tumors are rare thyroid neoplasms for which disease biology is poorly understood and diagnosis of carcinoma can be challenging. The aim of the study was to characterize molecular expression profiles of Hürthle cell tumors and to determine the clinical significance of identified phenotypes. Paraffin-embedded tissue cores of normal thyroid (n = 18), and histopathologically well-defined Hürthle cell adenomas (n = 27), Hürthle cell tumors of unknown malignant behavior (n = 7), and minimally (n = 14) and widely (n = 21) invasive Hürthle cell carcinomas were arrayed in triplicate on tissue microarrays. Expression profiles of p53, mdm-2, p21, Bcl-2, cyclin D1, and Ki-67 were detected by immunohistochemistry and correlated with clinicopathological data and patient outcome using standard statistical methodology. Median follow-up time was 8 years. High Ki-67 proliferative index was evident only in the clinically aggressive widely invasive Hürthle cell carcinomas and was associated with significantly reduced relapse-free (P = 0.001) and disease-specific (P < 0.001) survival. The molecular phenotype of Hürthle cell tumors, independent of histopathological subtype diagnosis, was characterized by p53(-), mdm-2(+), p21(+/-), cyclin D1(-), and Bcl-2(+/-). Normal thyroid tissue demonstrated a p53(-), mdm-2(-), p21(-), cyclin D1(-), and Bcl-2(+) phenotype. The Bcl-2(+) phenotype was associated with improved relapse-free survival (P = 0.04) and disease-specific survival (P = 0.01) in widely invasive carcinomas and the Ki-67(+)/Bcl-2(-) phenotype was associated with the diagnosis of widely invasive Hürthle cell carcinoma (P < 0.001). This study demonstrates that tissue microarray-based profiling allows identification of molecular markers that are associated with patient prognosis. High Ki-67 proliferative index was associated with adverse outcome in Hürthle cell neoplasms. Together with down-regulation of Bcl-2, high Ki-67 proliferative index may be useful for diagnosing widely invasive Hürthle cell carcinomas. Molecular alterations in the p53 pathway play a role in Hürthle cell tumorigenesis, but other unidentified molecular changes seem to be required to induce the malignant phenotype.     

Granular cell tumor of the thyroid: a case report

We report a rare case of granular cell tumor (GCT) arising within the thyroid parenchyma. The differential diagnosis of GCT in thyroid includes all oncocytic/Hürthle cell lesions of the thyroid, medullary carcinoma and metastasis. The classic histomorphologic features and immunohistochemistry are helpful in arriving at the correct diagnosis.     

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

In an attempt to progress in the understanding of the relationship of mitochondrial DNA (mtDNA) alterations and thyroid tumorigenesis, we studied the mtDNA in 79 benign and malignant tumors (43 Hürthle and 36 non-Hürthle cell neoplasms) and respective normal parenchyma. The mtDNA common deletion (CD) was evaluated by semiquantitative polymerase chain reaction. Somatic point mutations and sequence variants of mtDNA were searched for in 66 tumors (59 patients) and adjacent parenchyma by direct sequencing of 70% of the mitochondrial genome (including all of the 13 OXPHOS system genes). We detected 57 somatic mutations, mostly transitions, in 34 tumors and 253 sequence variants in 59 patients. Follicular and papillary carcinomas carried a significantly higher prevalence of non-silent point mutations of complex I genes than adenomas. We also detected a significantly higher prevalence of complex I and complex IV sequence variants in the normal parenchyma adjacent to the malignant tumors. Every Hürthle cell tumor displayed a relatively high percentage (up to 16%) of mtDNA CD independently of the lesion's histotype. The percentage of deleted mtDNA molecules was significantly higher in tumors with D-loop mutations than in mtDNA stable tumors. Sequence variants of the ATPase 6 gene, one of the complex V genes thought to play a role in mtDNA maintenance and integrity in yeast, were significantly more prevalent in patients with Hürthle cell tumors than in patients with non-Hürthle cell neoplasms. We conclude that mtDNA variants and mtDNA somatic mutations of complex I and complex IV genes seem to be involved in thyroid tumorigenesis. Germline polymorphisms of the ATPase 6 gene are associated with the occurrence of mtDNA CD, the hallmark of Hürthle cell tumors.     

Hurthle cell carcinoma arising from thyroid papillary carcinoma

Hürthle cell carcinoma of the thyroid is generally considered to be a subtype of follicular carcinoma. We report a case of a small solitary usual-type papillary carcinoma of the thyroid, with metastatic tumor in cervical lymph nodes. The lymph node tumor consisted of both tall-cell papillary carcinoma and Hürthle cell carcinoma. This suggests a closer relationship between papillary cell carcinoma and Hürthle cell tumors than previously appreciated.     

Diagnostic value of neutrophil gelatinase-associated lipocalin (NGAL) immunoexpression in follicular-patterned lesions of the thyroid gland

Neutrophil gelatinase-associated lipocalin (NGAL) is a protein which participates in iron trafficking and which is involved in cancerogenesis and cancer progression. Since its over-expression has been documented in thyroid malignancies in comparison to thyroid normal gland, in the present study, we aimed to determine whether the evaluation of NGAL immunoexpression may be of help in the differential diagnosis of follicular-patterned thyroid lesions. Our additional aim was to test the possible interference of endogenous biotin on the immunohistochemical findings. Thus, all the immunohistochemical procedures, carried out with labeled streptavidin biotin method, were doubly performed, with or without the preliminary inhibition of endogenous biotin. No NGAL staining was found in the normal thyroid gland nor in the nodular colloid goiters or in Hashimoto's thyroiditis. NGAL expression appeared to be significantly more frequent in the malignant tumors in comparison to benign ones (P < 0.000001). Even more, NGAL expression appeared to be specific (specificity 93%) for carcinoma and represented a sensitive method (sensitivity 84%), with high negative (88%) and positive (94%) predictive values, as well as high diagnostic accuracy (88%), in the identification of follicular-patterned thyroid malignant tumors. The specificity, positive predictive value and diagnostic accuracy lowered when biotin was not preliminary inhibited, due to the presence of false positives among benign Hürthle cell tumors. In conclusion, the immunohistochemical detection of NGAL may be helpful in the differential diagnosis between malignant and benign follicular-patterned lesions of the thyroid. The use of biotin free system or the preliminary biotin inhibition is warranted for the detection of NGAL in thyroid samples, especially when dealing with Hürthle cell tumors.     

Flow cytometric analysis of DNA content in Hürthle cell adenomas and carcinomas of the thyroid

Paraffin-embedded surgical biopsy material from 17 Hürthle cell tumors of the thyroid was examined for DNA content by flow cytometry to assess the diagnostic and prognostic utility of ploidy determinations in these rare tumors. Both adenomas (11 cases) and carcinomas (6 cases) were studied. As a control for methods, ten randomly selected normal autopsy thyroids were analyzed, all of which demonstrated normal diploid DNA content. Among the Hürthle cell tumors, however, aneuploid peaks were present in six adenomas (55%) and in four carcinomas (67%). Similarly, polyploid DNA peaks in the absence of other aneuploid peaks were present in two adenomas and two carcinomas (18% and 33%, respectively). These findings demonstrate the limited value of aneuploidy or polyploidy as diagnostic features for malignancy in Hürthle cell tumors of the thyroid. As for prognosis, there does not appear to be any unfavorable prognostic significance for abnormal DNA content in histologically benign Hürthle cell tumors treated by surgical excision because no metastases or recurrences occurred in this group at a mean disease-free follow-up of 50 +/- 19 months for six aneuploid lesions and 19 +/- 7 months for two polyploid adenomas. Preliminary data suggest that aneuploidy may, however, have an important prognostic value for histologically defined Hürthle cell carcinomas, because the only patient to die from the tumor in this series had an aneuploid Hürthle carcinoma. Thus, the authors' data indicate that the diagnostic utility of DNA content in Hürthle cell tumors is extremely limited and that there does not appear to be any negative prognostic significance for aneuploidy in histologically defined Hürthle cell adenomas.     

Frequent chromosomal DNA unbalance in thyroid oncocytic (Hürthle cell) neoplasms detected by comparative genomic hybridization.

Thyroid oncocytic (Hürthle cell) neoplasms represent a distinct subset of follicular thyroid tumors characterized by abnormal accumulation of mitochondria, whose chromosomal abnormalities have never been systematically analyzed. We have used comparative genomic hybridization to investigate chromosomal DNA alterations in 11 thyroid oncocytic tumors (7 adenomas and 4 carcinomas). Unbalanced chromosomal DNA profiles were detected in 6 of 7 adenomas and 3 of 4 carcinomas, numerical chromosomal aberrations being the dominant feature. Comparative genomic hybridization findings are compatible with two separate groups of tumors with karyotypic abnormalities, one characterized by multiple chromosomal gains with polysomy of chromosomes 5 and 7, the other by loss of chromosome 2. Pathologic and clinical features were similar in the two groups with no difference observed between adenomas and carcinomas. Activating H-, K-, or N-Ras mutations are commonly detected in follicular adenomas and carcinomas of the thyroid gland. However, Ras mutational analysis demonstrated that only one of the tumors in this series, an oncocytic carcinoma with a balanced karyotype, had activating Ras mutations (at codon 13 of K-Ras). The lack of Ras mutations in the 9 oncocytic neoplasms exhibiting chromosomal aneuploidy indicates that numerical chromosomal abnormalities are independent of activating Ras mutations in oncocytic tumors.     

Reduced HBME-1 immunoreactivity of papillary thyroid carcinoma and papillary thyroid carcinoma-related neoplastic lesions with Hürthle cell and/or apocrine-like changes

BACKGROUND: We have recently observed that Hürthle cell tumours and papillary thyroid carcinoma with tumour cells showing decapitation of luminal portion of the cytoplasm (apocrine-like changes) display negative or decreased immunoreactivity for HBME. The purpose of this study is to correlate papillary thyroid carcinoma with positive and negative immunoreactivity for HBME with the histopathological features. METHODS AND RESULTS: Two hundred and five thyroid neoplasms including carcinoma and adenomas were grouped into Hürthle cell tumours, tumours with or without some features of Hürthle cells, tumours with apocrine-like changes and adenomas with or without limited nuclear features of papillary thyroid carcinoma but not diagnostic for papillary thyroid carcinoma. All neoplasms were submitted for immunostaining with cytokeratin 19 (CK19) and HBME. Papillary thyroid carcinoma, follicular carcinoma and follicular adenoma that have areas of limited nuclear features but not diagnostic for papillary thyroid carcinoma showed stronger immunostaining for HBME than their respective counterparts with Hürthle cell changes. All Hürthle cell tumours showed negative to focal reactivity. This decrease of reactivity for HBME was proportional to the levels of Hürthle cell changes. In addition, focal to extensive apocrine-like changes were seen in most Hürthle cell neoplasms and rarely seen in non-Hürthle cell neoplasms. Apocrine-like changes abolished or decreased HBME immunoreactivity of papillary thyroid carcinoma and tumours with limited nuclear features. Immunostaining for cytokeratin AE3 was not affected by Hürthle cell or apocrine-like changes. CONCLUSIONS: All papillary thyroid carcinomas without Hürthle cell or apocrine-like differentiation are reactive for HBME. Hürthle cell tumours and tumours with Hürthle cell or apocrine-like changes show negative or focal reactivity for HBME. Except for this limitation, HBME is a sensitive marker for papillary thyroid carcinoma and tumours with limited nuclear features.