Heritable forms of primary hyperparathyroidism: a current perspective.

Primary hyperparathyroidism (PHPT) is one of the most common of all endocrine disorders encountered by the practising histopathologist. The vast majority of lesions are sporadic in nature, approximately 85% of which are parathyroid adenomas, while hyperplasia and carcinoma account for 10-15% and fewer than 1%, of cases, respectively. Heritable forms of PHPT are much less common and present challenges both to clinicians and pathologists, particularly when they are the presenting feature of an endocrine syndrome. In such instances, pathologists play a key role in alerting physicians to the possibility of an underlying heritable endocrine syndrome and the potential for extra-endocrine manifestations. Therefore, a working knowledge of these disorders is essential for providing guidance to treating physicians. The aim of this update is to review the clinicopathological features, genetic bases and current management for patients with PHPT associated with multiple endocrine neoplasia (MEN) types 1, 2A and 4 and hyperparathyroidism-jaw tumour (HPT-JT) syndrome in the context of the 2017 World Health Organization (WHO) Classification of Tumours of the Endocrine Organs. Additionally, familial isolated hyperparathyroidism, familial hypocalciuric hypercalcaemia and neonatal severe hyperparathyroidism are discussed.

Role of Rac1 in regulation of NOX5-S function in Barrett's esophageal adenocarcinoma cells.

We have shown that a novel NADPH oxidase isoform, NOX5-S, is the major isoform of NADPH oxidases in an esophageal adenocarcinoma (EA) cell line, FLO, and is overexpressed in Barrett's mucosa with high-grade dysplasia. NOX5-S is responsible for acid-induced reactive oxygen species production. In this study, we found that mRNA levels of NOX5-S were significantly higher in FLO EA cells than in the normal human esophageal squamous cell line HET-1A or in a Barrett cell line, BAR-T. The mRNA levels of NOX5-S were also significantly increased in EA tissues. The data suggest that NOX5-S may be important in the development of EA. Mechanisms of functional regulation of NOX5-S are not fully understood. We show that small G protein Rac1 was present in HET-1A cells, BAR-T cells, and EA cell lines FLO and OE33. Rac1 protein levels were significantly higher in FLO and OE33 cells than in HET-1A or BAR-T cells. Knockdown of Rac1 with Rac1 small interfering RNA significantly decreased acid-induced increase in H(2)O(2) production in FLO EA cells. Overexpression of constitutively active Rac1 significantly increased H(2)O(2) production, an increase that was blocked by knockdown of NOX5-S. By immunofluorescence staining and immunoprecipitation, we found that NOX5-S was present in the cytosol of FLO EA cells and colocalized with Rac1 and SERCA1/2 Ca(2+)-ATPase which is located in the endoplasmic reticulum membrane. We conclude that Rac1 may be important in activation of NOX5-S in FLO EA cells.

Parathyroid tumors and related disorders.

Primary hyperparathyroidism (P-HPT) is a common endocrine disorder that occurs as a result of adenomas (80-85%), hyperplasias (10-15%) or carcinomas (<1%) of the parathyroid glands. Molecular genetic analyses of heritable P-HPT syndromes have provided considerable insight into the understanding of sporadic parathyroid tumors and hyperplasias. This review will focus on the criteria for classification of parathyroid proliferative disorders and will highlight our understanding of these lesions at the molecular level. Advances in radiological imaging techniques together with the rapid intraoperative parathyroid hormone assay will be reviewed with respect to current treatment approaches for P-HPT.

Nonshadowing echogenic foci in thyroid nodules: are certain appearances enough to avoid thyroid biopsy?

OBJECTIVES: The purpose of this study was to further classify nonshadowing echogenic foci and examine the association with malignancy. METHODS: This study received Institutional Review Board approval and was Health Insurance Portability and Accountability Act compliant. A total of 371 consecutive thyroid nodules were evaluated in 189 patients (177 female and 12 male; mean age, 59 years; range, 21-92 years). Eighty-six nodules (23%) measured 5 mm or larger and contained nonshadowing echogenic foci with a mean nodule diameter of 16 mm (5-66 mm). Blinded review of these nodules 12 months later was performed. Echogenic foci were classified as follows: showing a comet tail artifact (type 1), linear and brightly echogenic (type 2), round and indeterminate (type 3), and microcalcifications (type 4). All available thyroid sonograms and pathologic data were then reviewed. RESULTS: Nineteen nodules (22%) showed a classic comet tail artifact, with malignancy in 0 of 19. Six (32%) had negative pathologic results, and 9 (47%) had stable imaging follow-up (mean, 37 months). Twenty-nine nodules (34%) showed linear and brightly echogenic foci, with malignancy in 0 of 29. Fifteen (52%) had negative pathologic results, and 11 (38%) had stable imaging follow-up (mean, 34 months). Twenty-four nodules (28%) showed round and indeterminate echogenic foci, with 1 of 24 (4%) containing papillary carcinoma. Thirteen (54%) had negative pathologic results, and 8 (33%) had stable imaging follow-up (mean, 24 months). Fourteen nodules (16%) contained microcalcifications, with 4 of 14 (29%) containing papillary thyroid cancer. Nine (64%) had negative pathologic results, and 1 (7%) had stable imaging follow-up (63 months). CONCLUSIONS: Nonshadowing brightly echogenic linear foci with or without a comet tail artifact may be a benign finding. Confirmatory studies are needed for this result to be applied clinically.

Role of a novel bile acid receptor TGR5 in the development of oesophageal adenocarcinoma.

BACKGROUND AND AIMS: Mechanisms of the progression from Barrett's oesophagus to oesophageal adenocarcinoma (OA) are not fully understood. Bile acids may have an important role in this progression. This study aimed at examining the role of NADPH oxidase NOX5-S and a novel bile acid receptor TGR5 in taurodeoxycholic acid (TDCA)-induced increase in cell proliferation. METHODS: Human Barrett's cell line BAR-T and OA cell line FLO were transfected by the Lipofectamine 2000 or Amaxa-Nucleofector-System. mRNAs were measured by real-time PCR. H(2)O(2) was measured by a fluorescent assay. Cell proliferation was determined by measurement of thymidine incorporation. RESULTS: NOX5-S was present in FLO cells. TDCA significantly increased NOX5-S expression, H(2)O(2) production and thymidine incorporation in FLO and BAR-T cells. This increase in thymidine incorporation was significantly reduced by knockdown of NOX5-S. TGR5 mRNA and protein levels were significantly higher in OA tissues than in normal oesophageal mucosa or Barrett's mucosa. Knockdown of TGR5 markedly inhibited TDCA-induced increase in NOX5-S expression, H(2)O(2) production and thymidine incorporation in FLO and BAR-T cells. Overexpression of TGR5 significantly enhanced the effects of TDCA in FLO cells. TGR5 receptors were coupled with Galphaq and Galphai3 proteins, but only Galphaq mediated TDCA-induced increase in NOX5-S expression, H(2)O(2) production and thymidine incorporation in FLO cells. CONCLUSIONS: TDCA-induced increase in cell proliferation depends on upregulation of NOX5-S expression in BAR-T and FLO cells. TDCA-induced NOX5-S expression may be mediated by activation of the TGR5 receptor and Galphaq protein. These data may provide potential targets to prevent and/or treat Barrett's OA.

Modifying phrases in surgical pathology reports: introduction of Standardized Scheme of Reporting Certainty in Pathology Reports (SSRC-Path).

Pathologists often incorporate modifying phrases in their diagnosis to imply varying levels of diagnostic certainty; however, what is implied by the pathologists is not equivalent with what is perceived by the referring physicians and patients. This discordance can have significant implications in management, safety, and cost. We intend to identify lack of consistency in interpretation of modifying phrases by comparing perceived level of certainty by pathologists and non-pathologists, and introduce a standard scheme for reporting uncertainty in pathology reports using the experience with imaging reporting and data systems. In this study, a list of 18 most commonly used modifying phrases in pathology reports was distributed among separate cohorts of pathologists (N = 17) and non-pathology clinicians (N = 225) as a questionnaire survey, and the participants were asked to assign a certainty level to each phrase. All the participants had practice privileges in Brown University-affiliated teaching hospitals. The survey was completed by 207 participants (17 pathologists, 190 non-pathologists). It reveals a significant discordance between the interpretations of the modifying phrases between the two cohorts, with significant variations in subgroups of non-pathology clinicians. Also there is disagreement between pathologists and other clinicians regarding the causes of miscommunication triggered by pathology reports. Pathologists and non-pathology clinicians should be mindful of the potential sources of misunderstanding of pathology reports and take necessary actions to prevent and clarify the uncertainties. Using a standard scheme for reporting uncertainty in pathology reports is recommended.

Acid-induced p16 hypermethylation contributes to development of esophageal adenocarcinoma via activation of NADPH oxidase NOX5-S.

Inactivation of tumor suppressor gene p16 may play an important role in the progression from Barrett's esophagus (BE) to esophageal adenocarcinoma (EA). Hypermethylation of p16 gene promoter is an important mechanism inactivating p16. However, the mechanisms of p16 hypermethylation in EA are not known. Therefore, we examined whether acid increases methylation of p16 gene promoter and whether NADPH oxidase NOX5-S mediates acid-induced p16 hypermethylation in a Barrett's cell line BAR-T and an EA cell line OE33. We found that NOX5-S was present in BAR-T and OE33 cells. Acid-induced increase in H(2)O(2) production and cell proliferation was significantly reduced by knockdown of NOX5-S. Exogenous H(2)O(2) remarkably increased p16 promoter methylation and cell proliferation. In addition, acid treatment significantly increased p16 promoter methylation and decreased p16 mRNA level. Knockdown of NOX5-S significantly increased p16 mRNA, inhibited acid-induced downregulation of p16 mRNA, and blocked acid-induced increase in p16 methylation and cell proliferation. Conversely, overexpression of NOX5-S significantly decreased p16 mRNA and increased p16 methylation and cell proliferation. In conclusion, NOX5-S is present in BAR-T cells and OE33 cells and mediates acid-induced H(2)O(2) production and cell proliferation. NOX5-S is also involved in acid-induced hypermethylation of p16 gene promoter and downregulation of p16 mRNA. It is possible that acid reflux present in BE patients may activate NOX5-S and increase production of reactive oxygen species, which in turn increase p16 promoter methylation, downregulate p16 expression, and increase cell proliferation, thereby contributing to the progression from BE to EA.

ColXα1 is a stromal component that colocalizes with elastin in the breast tumor extracellular matrix.

The tumor microenvironment regulates tissue development and homeostasis, and its dysregulation contributes to neoplastic progression. Increased expression of type X collagen α-1 (ColXα1) in tumor-associated stroma correlates with poor pathologic response to neoadjuvant chemotherapy in estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2)-positive breast cancers. Evaluation of ColXα1 expression patterns suggests a potential connection with elastin fibers. To investigate the possible interaction between ColXα1 and elastin, we evaluated the expression of ColXα1 in relation to elastin fibers in normal breast tissue, ductal carcinoma in situ, and invasive breast carcinomas at cellular and subcellular levels. Our findings demonstrate that ColXα1 colocalizes with elastin in invasive breast cancer-associated stroma by immunohistochemistry, immunofluorescence, and electron microscopy. In 212 invasive breast carcinomas, this complex was aberrantly and selectively expressed in tumor extracellular matrix in 79% of ER+/HER2-, 80% of ER+/HER2+, 76% of ER-/HER2+, and 58% of triple negative breast cancers. In contrast, ColXα1 was generally absent, while elastin was present perivascularly in normal breast tissue. ColXα1 and elastin were coexpressed in 58% of ductal carcinoma in situ (DCIS) in periductal areas. In mass-forming DCIS with desmoplastic stroma, the complex was intensely expressed in periductal areas as well as within the tumor-associated stroma in all cases. Our data suggest that the breast carcinoma neoplastic process may involve aberrant expression of ColXα1 and elastin in the tumor microenvironment emerging early at the DCIS stage. Enrichment of these complexes in tumor-associated stroma may represent a stromal signature indicative of intrinsic differences between breast cancers. These findings shed light on investigation into the role of aberrant collagen complex expression in tumorigenesis and tumor progression which may be leveraged in therapeutic and theranostic applications.

The diagnostic and prognostic utility of claudin expression in renal cell neoplasms.

This study evaluated the expression patterns of claudins 1, 3, 4, 7, and 8 in human renal cell carcinomas and oncocytomas and correlated expression with patient prognosis. Tissue microarrays were created from paraffin-embedded tissue samples from 141 patients with renal cell carcinomas or oncocytoma (90 clear cell, 22 papillary, 17 chromophobe renal cell carcinomas, and 12 oncocytomas). The staining pattern for claudins 3, 4, 7, and 8 was membranous and/or cytoplasmic, whereas claudin 1 was predominantly membranous in both nonneoplastic renal tissue and tumors. Negative to weak claudin 3 staining was predominantly detected in Fuhrman's grade 1 and 2 clear cell renal cell carcinomas (78%; P=0.016), suggesting that upregulation of claudin 3 potentially occurs concomitantly with increasing grade of clear cell renal cell carcinomas. In addition, Kaplan-Meier univariate analysis showed a significant inverse correlation between moderate to strong claudin 3 and 4 expression with overall survival in clear cell renal cell carcinomas (P=0.038 and P=0.031). Moderate to strong claudin 7 expression was significantly more common in chromophobe renal cell carcinomas (94%) than in oncocytomas (55%; P=0.041). Claudin 8 staining was moderate to strong in 92% of oncocytomas, which differentiated them from papillary and clear cell renal cell carcinomas (14 and 12%; both P<0.0001). Only negative to weak claudin 8 staining was detected in all chromophobe renal cell carcinomas, whereas there were no claudin 8 negative oncocytomas and 8% exhibited a weak staining pattern (P<0.0001). Due to their distinctive expression patterns, claudins 7 and 8 can be used as useful immunohistochemical markers for the separation of chromophobe renal cell carcinomas from oncocytomas, whereas claudins 3 and 4 may serve as indicators of prognosis in clear cell renal cell carcinomas.

Challenging lesions in the differential diagnosis of endocrine tumors: parathyroid carcinoma.

Parathyroid neoplasms encompass a spectrum of proliferative lesions that include adenomas, atypical adenomas, and carcinomas. While the diagnosis of adenomas is usually straightforward, parathyroid carcinomas (PTCAs) often present considerable diagnostic challenges. Fibrosis and mitotic activity are common in PTCAs, but these features are not specific for malignancy. An unequivocal diagnosis of PTCA should be restricted to those tumors that invade adjacent soft tissues, thyroid gland, blood vessels, or perineural spaces or to those cases with documented metastases. Atypical adenomas include those tumors that share some of the features of PTCA but lack evidence of invasive growth. A variety of genetic abnormalities, including HRPT2 mutations, occur in PTCAs. Mutations of the HRPT2 gene, which encodes parafibromin, are responsible for the development of the hyperparathyroidism-jaw tumor syndrome and have also been implicated in the development of a high proportion of sporadic PTCAs. Correlative immunohistochemical studies have revealed nuclear parafibromin immunoreactivity in adenomas but absence or partial loss of staining in PTCAs. While parafibromin immunohistochemistry represents an important step in the ability to diagnose PTCA, additional studies will be required to test the validity of this approach and to determine the roles of other genes in the development of these tumors.

Plasma Cell Granuloma of the Thyroid: Review of an Uncommon Entity.

Plasma cell granuloma (PCG) is characterized by proliferation of polyclonal plasma cells with associated fibrosis and is often considered part of the heterogeneous group of inflammatory myofibroblastic tumors (IMTs). The thyroid is rarely affected by PCG. A patient having PCG associated with Hashimoto thyroiditis (HT) prompted our literature search that revealed 18 cases of PCG, 55% (n = 10) of which occurred together with HT. The etiopathogenesis of PCG is unknown and there is no specific treatment except surgical excision for compressive symptoms. This entity has an excellent prognosis with no evidence of recurrence or metastasis. Lesions of the thyroid with infiltrating plasma cells include HT, fibrous variant of HT, plasmacytoma, plasma cell myeloma, Riedel thyroiditis, IgG4 (immunoglobulin G4)-related disease, IMT, and PCG. Inflammatory myofibroblastic tumor has ALK gene rearrangements and is considered a neoplasm as opposed to PCG, which is a reactive polyclonal plasma cell proliferation. We believe IMT and PCG are distinct entities and consensus definitions are required for avoiding confusion in the literature.

The AFIP/ARP Atlases of Pathology Past, Present, and Future.

The AFIP (Armed Forces Institute of Pathology) Atlases (Fascicles) have been in continuous publication for nearly 75 years and have enjoyed a highly regarded reputation for their excellence. Throughout this time period, more than 130 volumes, encompassing the 1st to 4th series have been published. Since their inception in the 1940's, the Fascicles have evolved from loose-leafed atlases illustrated with black and white images, to hardbound monographs with full color images and expansion of scope, including relevant clinical information, cytopathology, and the most recent advances in immunohistochemistry and molecular diagnostics. Each of the volumes undergoes a rigorous review process by the Editor-in-Chief, Associate Editors, members of the Editorial Advisory Board, and external reviewers. The 5th series, under the editorial direction of Drs. Elizabeth Montgomery and Jason Hornick, is well underway and will include an Epub version and a virtual slide box, in addition to the hardbound book. The Atlases of Nontumor Pathology will also continue to be published. With the closure of the AFIP in 2011, the American Registry of Pathology (ARP) has assumed full responsibility for the publication of both the Tumor and Nontumor Fascicles.

Analysis of T-cell clonality using laser capture microdissection and high-resolution microcapillary electrophoresis.

Identification of clonal lymphocytic populations by polymerase chain reaction may be difficult in cases with scant cellular infiltrates or those with a heterogeneous population of cells. Here, we assessed the diagnostic utility of laser capture microdissection (LCM) and high-resolution microcapillary electrophoresis in the analysis of clonality of small biopsy specimens. Clonality was determined in 24 cases: five reactive tonsils, five reactive lymph nodes, six inflammatory skin lesions, and eight T-cell lymphomas. CD3-positive T lymphocytes were captured by LCM from paraffinized immunohistochemically stained sections. Genomic DNA was analyzed for T-cell receptor-gamma gene rearrangement by polymerase chain reaction followed by high-resolution microcapillary electrophoresis with the DNA 500 LabChip and the Agilent Bioanalyzer. In the reactive specimens, T-cell receptor-gamma polymerase chain reaction revealed monoclonal bands when 10 to 1000 cells were captured. This pattern changed to polyclonal when higher numbers of cells were microdissected (2000 to 10,000 cells). In contrast, lymphoma cells were consistently monoclonal whether low or high numbers were microdissected. Microcapillary electrophoresis coupled with LCM facilitated clonality analysis in equivocal cases. In two of eight lymphoma cases, LCM revealed diagnostic monoclonal bands, whereas routine T-cell receptor-gamma assessment of whole tissue sections with 10% polyacrylamide gel electrophoresis demonstrated only minor clonal bands. We conclude that clonality determined by LCM is cell number-dependent. Biopsy specimens containing low numbers of reactive polyclonal T cells may produce pseudomonoclonal bands and therefore should be interpreted with great caution.

Diagnostic yield of 58 consecutive imaging-guided biopsies of solid renal masses: should we biopsy all that are indeterminate?

OBJECTIVE: The purpose of our study was to report the diagnostic yield of 58 consecutive imaging-guided biopsies of solid renal masses. MATERIALS AND METHODS: We retrospectively reviewed all percutaneous renal biopsies of solid masses performed at our institution over 83 consecutive months from May 1998 to March 2005 through a query of our radiology department procedure database. Fifty-five CT and three sonographic biopsies were performed at our institution during this time. A solid renal mass was documented prior to biopsy by contrast-enhanced CT (n = 48), gadolinium-enhanced MRI (n = 6), or sonography (solid noncystic masses, n = 4). The average maximal mass diameter was 3.1 cm (range, 1.0-11.0 cm). Forty-seven (81%) of the 58 biopsies were performed immediately before percutaneous ablation. Forty-four (76%) of the biopsies were performed using a coaxial technique with side-cutting automated biopsy needles (16-20 gauge), and 14 (24%) were fineneedle aspirations with a Franseen needle (20 gauge) using a tandem technique. In 19 cases, immunohistochemistry or histochemistry (Hale colloidal iron stain) was used to establish or confirm the diagnosis. Medical records and radiology and pathology reports were reviewed for all patients. RESULTS: An adequate sample size was obtained in 55 (95%) of 58 renal masses and led to a definitive diagnosis in 52 (90%) of the 58. Renal cell carcinoma accounted for 36 (69%) of 52 diagnostic biopsies. The diagnosis of a benign lesion was made in 14 (27%) of 52 biopsies. Lymphoma (1/58) and metastatic disease (1/58) accounted for the remaining two diagnostic biopsies. Three biopsy samples obtained inadequate sample volumes, and an additional three samples were thought to have adequate sample volume but were not diagnostic. A single false-negative biopsy result was identified after growth was seen on follow-up imaging and subsequent nephrectomy revealed renal cell carcinoma. CONCLUSION: Imaging-guided biopsy of a solid enhancing renal mass was diagnostic in 52 (90%) of 58 consecutive biopsies. The diagnosis of a benign lesion was made in 27% of diagnostic biopsies. Because of the advances in biopsy and histology techniques, the role of imaging-guided biopsy should be reconsidered.

Distribution of GPR30, a seven membrane-spanning estrogen receptor, in primary breast cancer and its association with clinicopathologic determinants of tumor progression.

PURPOSE: The seven transmembrane receptor, GPR30, is linked to estrogen binding and heparan-bound epidermal growth factor release. Here, the significance of GPR30 in human breast cancer was evaluated by comparing its relationship to steroid hormone receptor expression and tumor progression variables. EXPERIMENTAL DESIGN: Immunohistochemical analysis of a National Cancer Institute-sponsored tumor collection comprised of 361 breast carcinomas obtained at first diagnosis (321 invasive and 40 intraductal tumors). Biopsies from 12 reduction mammoplasties served as controls. The distribution pattern of GPR30, estrogen receptor (ER), and progesterone receptor (PR) was correlated with clinicopathologic variables obtained at diagnosis. RESULTS: GPR30, ER, and PR were positive in all 12 normal controls. In contrast, GPR30 expression varied in breast tumors, in which 62% (199 of 321) of invasive tumors and 42% (17 of 40) of intraductal tumors were positive. Codistribution of ER and GPR30 was measured in 43% (139 of 321) of invasive breast tumors, whereas both receptors were lacking (ER-GPR30-) in 19% (61 of 321) of the tumors analyzed, indicating a significant association between ER and GPR30 (P<0.05). The coexpression of PR and ER did not influence GPR30 expression, yet coexpression of GPR30 and ER was linked to PR positivity. Unlike ER, which varied inversely with HER-2/neu and tumor size, GPR30 positively associated with HER-2/neu and tumor size. In addition, GPR30 showed a positive association with metastasis (P=0.014; odds ratio, 1.9). CONCLUSIONS: GPR30 and ER exhibited distinct patterns of association with breast tumor progression variables, including HER-2/neu, tumor size, and metastatic disease. Thus, these results support the hypothesis that GPR30 and ER have an independent influence on estrogen responsiveness in breast carcinoma.

Observer variation of encapsulated follicular lesions of the thyroid gland.

Although histologic definition of follicular thyroid lesions is readily available, application of the diagnostic criteria and personal experience may lead to disagreement among pathologists. To investigate interobserver variation in assessment of encapsulated follicular lesions, eight pathologists (four American and four Japanese) reviewed the same hematoxylin and eosin-stained slide of each of 21 cases of thyroid lesions showing encapsulation and follicular growth pattern. In 10% of the cases, there was complete agreement. At least seven pathologists agreed on the diagnosis in 29% of the cases, and at least six in 76% of the cases. American and Japanese pathologists agreed among themselves in 33% and 52% of cases, respectively. The frequency of diagnosis of adenomatous goiter among Japanese pathologists (31%) was considerably higher than that among American pathologists (6%). In contrast, the frequency of diagnosis (25%) of papillary carcinoma among American pathologists was considerably higher than that (4%) among Japanese pathologists. Our analysis revealed three main factors affecting observer variation: 1) interpretation of the significance of microfollicles intimately related to capillaries within the tumor capsule, 2) evaluation of what constituted the type of nuclear clearing indicative of papillary carcinoma, and 3) absence of clear morphologic criteria for separation of adenomatous goiter and follicular adenoma. To reduce observer variation of encapsulated follicular lesions, it will be necessary to provide more explicit criteria for diagnosis.

Observer variation in the diagnosis of follicular variant of papillary thyroid carcinoma.

The histopathologic diagnosis of follicular variant of papillary thyroid carcinoma (FVPCA) can be difficult. Recent reports have suggested that this neoplasm may be frequently overdiagnosed by pathologists. We examined the observer variation in the diagnosis of FVPCA in 87 tumors by 10 experienced thyroid pathologists. The criteria that the reviewers considered most helpful for making a diagnosis of FVPCA were also assessed. A concordant diagnosis of FVPCA was made by all 10 reviewers with a cumulative frequency of 39%. In this series, 24.1% of the patients had metastatic disease (n = 21). In the cases with metastatic disease, a diagnosis of FVPCA was made by all 10 reviewers with a cumulative frequency of 66.7%, and 7 of the reviewers made a diagnosis of FVPCA with a cumulative frequency of 100%. The most important criteria used to diagnose FVPCA included the presence of cytoplasmic invaginations into the nucleus (pseudo-inclusions), abundant nuclear grooves, and ground glass nuclei. These results suggest that although the diagnosis of FVPCA is variable even among experienced thyroid pathologists, most reviewers agreed on this diagnosis for patients with metastatic disease. The use of well-defined histopathologic features should improve the consistency in diagnosing FVPCA. Since most cases with metastatic disease had obvious invasion, caution should be used in making a diagnosis of FVPCA in the absence of the major histopathologic features or clear-cut invasive growth.