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.

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.

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.

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.

Expression of S100A4 in renal epithelial neoplasms.

Expression of S100A4 has been associated with progression and poor clinical outcome in a variety of malignancies including those of the breast, pancreas, bladder, and thyroid. To date, the expression of S100A4 protein in renal epithelial neoplasms is poorly understood. In this study, we evaluated the expression of S100A4 protein and mRNA in the nontumoral kidney and renal epithelial neoplasms of different types and correlated its expression with patient outcome. The study population included 155 clear cell renal cell carcinomas (cRCC), 22 papillary renal cell carcinomas (pRCC), 13 chromophobe renal cell carcinomas and 13 oncocytomas. In nontumoral kidney, nuclear and cytoplasmic S100A4 staining was detected in the glomerular epithelium and endothelium, distal tubules and collecting ducts, and loops of Henle. A different expression pattern was noted in the various neoplasms. S100A4 expression was significantly increased in the stromal cells in cRCC (83%) and pRCC (73%) compared with paired nontumoral kidney tissue (P<0.001). There was no increased stromal cell expression of S100A4 in oncocytomas and chromophobe carcinomas. Positive epithelial staining was more common in pRCC (58%) than cRCC (11%) (P=0.01). The level of mRNA detected by reverse transcription-polymerase chain reaction was significantly higher in the tumor as opposed to normal tissue in cRCC but not in the other neoplasms (P=0.03). Multivariate analysis revealed that epithelial S100A4 protein expression is an independent poor prognostic factor along with grade and stage only in cRCC (P<0.01). Although S100A4 protein was expressed in a minority of cRCC, its expression was associated with shorter overall patient survival.

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.

Expression of the glucocorticoid receptor in renal cell neoplasms: an immunohistochemical and quantitative reverse transcriptase polymerase chain reaction study.

Glucocorticoid receptors mediate the action of steroid hormones in a variety of tissues, including the kidney. Our goal was to determine the expression pattern and prognostic significance of glucocorticoid receptor in renal cell neoplasms. Paraffin-embedded microarrays from 200 patients with RCNs including 147 clear cell renal cell carcinomas, 23 papillary, 16 chromophobe renal cell carcinoma, and 14 oncocytomas were analyzed for glucocorticoid receptor expression by immunohistochemistry. Glucocorticoid receptor expression was also quantitated by real-time reverse transcriptase polymerase chain reaction in 45 cases (33 clear cell renal cell carcinomas, 5 chromophobe renal cell carcinomas, and 3 oncocytomas). Strong nuclear glucocorticoid receptor expression was present in normal glomeruli and in the proximal convoluted tubules. Nuclear glucocorticoid receptor expression was found in most clear cell renal cell carcinomas (66%), in 26% of papillary renal cell carcinomas, and in only 6% of chromophobe renal cell carcinomas and 14% of oncocytoma (P < .005). Within the clear cell renal cell carcinoma group, most positive cases (87%) demonstrated strong immunoreactivity (2+ and 3+), whereas only 1 papillary renal cell carcinoma, 1 chromophobe renal cell carcinoma, and none of the oncocytomas showed strong expression. Glucocorticoid receptor α messenger RNA expression was significantly higher in clear cell renal cell carcinoma than in chromophobe renal cell carcinoma, oncocytoma, or in the normal kidney. Significantly more frequent glucocorticoid receptor expression was associated with tumors of low nuclear grade (Fuhrman grade 1 and 2) and low stage (stages 1 and 2; P = .0068 and P = .0002). Survival analysis revealed a significant direct correlation between glucocorticoid receptor expression and overall survival in clear cell renal cell carcinoma (P = .01). In summary, strong glucocorticoid receptor expression was most commonly seen in clear cell renal cell carcinoma and only rarely seen in other subtypes. The glucocorticoid receptor expression pattern in RCNs seems to reflect the histogenetic origin of clear cell renal cell carcinoma from the proximal nephron. Finally, glucocorticoid receptor expression proved to be a marker of less aggressive behavior in clear cell renal cell carcinoma.

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.

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.

Spindle cell foci in the thyroid gland: an immunohistochemical analysis.

Spindle cell proliferations of the thyroid gland are uncommon lesions that encompass a wide spectrum of reactive, hyperplastic, and neoplastic processes. Spindle cells may occur in subsets of papillary carcinomas and follicular adenomas where they are thought to represent metaplastic foci. The goals of the present study are to further characterize the metaplastic nature of spindle cell foci of the thyroid (SCFT), to define their immunohistochemical profiles and to review their differential diagnoses. The study group included: multinodular goiter (2), follicular adenoma (2), and minimally invasive follicular carcinoma (2). SCFTs were composed of elongate cells with thin or slightly plump nuclei with finely granular chromatin and inconspicuous nucleoli. Rare mitotic figures were present but there was no necrosis or inflammation. All cases were positive for thyroglobulin, thyroid transcription factor (TTF)-1, and TTF-2. TTF-1 and TTF-2 had a characteristic nuclear localization although the intensity of staining for TTF-1 was consistently greater than that of TTF-2. Each of the 6 cases was positive for vimentin whereas 5 of the 6 cases were positive for broad-spectrum cytokeratins. None of the cases was positive for high molecular weight cytokeratin, cytokeratin-19, smooth muscle actin, desmin, calcitonin, chromogranin, or synaptophysin. The proliferative rate was less than 1% in all cases. Staining for TTF-1 and TTF-2 provided high specificity for identification of SCFT since these markers were not subject to the same diffusion artifact inherent in thyroglobulin-stained sections. The results of this study further support the hypothesis that SCFT result from metaplastic transformation of follicular cells.

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.

Bile acid reflux contributes to development of esophageal adenocarcinoma via activation of phosphatidylinositol-specific phospholipase Cgamma2 and NADPH oxidase NOX5-S.

Gastroesophageal reflux disease complicated by Barrett's esophagus (BE) is a major risk factor for esophageal adenocarcinoma (EA). However, the mechanisms of the progression from BE to EA are not fully understood. Besides acid reflux, bile acid reflux may also play an important role in the progression from BE to EA. In this study, we examined the role of phosphatidylinositol-specific phospholipase C (PI-PLC) and a novel NADPH oxidase NOX5-S in bile acid-induced increase in cell proliferation. We found that taurodeoxycholic acid (TDCA) significantly increased NOX5-S expression, hydrogen peroxide (H(2)O(2)) production, and cell proliferation in EA cells. The TDCA-induced increase in cell proliferation was significantly reduced by U73122, an inhibitor of PI-PLC. PI-PLCbeta1, PI-PLCbeta3, PI-PLCbeta4, PI-PLCgamma1, and PI-PLCgamma2, but not PI-PLCbeta2 and PI-PLCdelta1, were detectable in FLO cells by Western blot analysis. Knockdown of PI-PLCgamma2 or extracellular signal-regulated kinase (ERK) 2 mitogen-activated protein (MAP) kinase with small interfering RNAs (siRNA) significantly decreased TDCA-induced NOX5-S expression, H(2)O(2) production, and cell proliferation. In contrast, knockdown of PI-PLCbeta1, PI-PLCbeta3, PI-PLCbeta4, PI-PLCgamma1, or ERK1 MAP kinase had no significant effect. TDCA significantly increased ERK2 phosphorylation, an increase that was reduced by U73122 or PI-PLCgamma2 siRNA. We conclude that TDCA-induced increase in NOX5-S expression and cell proliferation may depend on sequential activation of PI-PLCgamma2 and ERK2 MAP kinase in EA cells. It is possible that bile acid reflux present in patients with BE may increase reactive oxygen species production and cell proliferation via activation of PI-PLCgamma2, ERK2 MAP kinase, and NADPH oxidase NOX5-S, thereby contributing to the development of EA.

Comparison of thyroid transcription factor-1 expression by 2 monoclonal antibodies in pulmonary and nonpulmonary primary tumors.

Thyroid transcription factor-1 (TTF-1) is a transcription factor that plays a role in the development and physiology of the thyroid and lungs. Expression of TTF-1 is used as a marker of lung and thyroid clinically. Commercially available clones of TTF-1 monoclonal antibodies, 8G7G3/1 and SPT24, have been reported to have different sensitivities for the detection of neoplasms of different origins. Although they are used extensively in daily practice, a comprehensive comparative study of these antibodies in a wide variety of neoplasms is lacking. We examined TTF-1 expression in primary tumors of the lung, prostrate, pancreas, stomach, salivary glands, breast, bladder, colon, and squamous cell carcinoma of the head and neck and compared the results obtained with both TTF-1 clones. The SPT24 clone detected more primary lung tumors of all histologic subtypes. Importantly, the SPT24 clone detected a significantly higher number of squamous cell carcinomas and carcinoid tumors of the lung. Among nonpulmonary primary tumors, a significant number of invasive urothelial carcinoma of the bladder (5.1%) was TTF-1 positive. In addition, a small proportion of prostate (1.2%), stomach (0.9%), salivary gland (1.8%), and colon (2.5%) carcinomas were positive with both clones. Of note, both clones stained the same nonpulmonary tumors with similar intensity and distribution. Carcinomas of the pancreas, breast, and squamous cell carcinomas of the head and neck were negative with both clones. In summary, the SPT24 clone detected a higher number of pulmonary non-small cell tumors of all histologic subtypes whereas both clones stained a similar proportion of nonpulmonary tumors.

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.