Do ACR TI-RADS scores demonstrate unique thyroid molecular profiles?

PURPOSE: The present study aimed to examine the molecular profiles of cytologically indeterminate thyroid nodules stratified by American College of Radiology Thyroid Imaging Reporting and Data System (TI-RADS) categories and to determine whether certain ultrasonographic features display particular molecular alterations. METHODS: A retrospective review was conducted of cases from January 1, 2016 to April 1, 2018. Cases with in-house ultrasonography, fine-needle aspiration Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) diagnoses, molecular testing, and surgery were included. All cases were diagnosed as TBSRTC indeterminate categories. The ultrasound studies were retrospectively reviewed and assigned TI-RADS scores (TR1-TR5) by board-certified radiologists. The final diagnoses were determined based on the surgical resection pathology. Binary logistic regression analysis was used to study whether demographic characteristics, TI-RADS levels, and TBSRTC diagnoses were associated with ThyroSeq molecular results. RESULTS: Eighty-one cases met the inclusion criteria. RAS mutations were the most common alteration across all TI-RADS categories (TR2 2/2; TR3 10/19, TR4 13/44, and TR5 8/16), and did not stratify with any particular TI-RADS category. Only TR4 and TR5 categories displayed more aggressive mutations such as BRAFV600E and TERT. ThyroSeq results were positively correlated with thyroid malignancy when non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was categorized in the malignant category (odds ratio [OR], 6.859; P<0.01), but not when NIFTP was removed from the malignancy category. Echogenicity scores were found to be negatively correlated with ThyroSeq results in thyroid nodules (OR, 0.162; P<0.01). CONCLUSION: Higher-risk molecular alterations tended to stratify with the higher TI-RADS categories.

Flat epithelial atypia on breast needle core biopsy: a retrospective study with clinical-pathological correlation.

There are limited data to guide clinical management when flat epithelial atypia (FEA) is identified in breast needle core biopsies (NCBs). Our objectives were to determine the frequency of malignancy in subsequent breast excisions following NCB diagnosis of FEA, and to characterize the pathological and clinical features of associated tumors. Two hundred and fifty-six breast NCBs from a retrospective search (January 1999-July 2007) were blindly reviewed for FEA/other columnar cell lesions (CCLs). NCBs with co-existing carcinoma were excluded. The study included 211 NCBs: 116 (55%) with CCLs without atypia; 40 (19%) with CCLs with atypical ductal hyperplasia (ADH), 15 (7%) with FEA and 40 (19%) with FEA and ADH; 94 cases had follow-up excisions. Ductal carcinoma in situ and/or invasive carcinoma were present in: 4/26 (15%) excisions with CCLs on NCB, 11/30 (37%) with CCLs + ADH, 1/7 (14%) with FEA alone, and 9/31 (29%) with FEA + ADH. (a) FEA was more frequently seen with ADH, than without ADH in NCBs, (b) FEA and CCLs were more frequently associated with malignancy when with ADH, and (c) tumors excised following NCB diagnosis of FEA+/-ADH had favorable prognostic factors. A conservative excision is warranted following a NCB diagnosis of FEA and ADH, and may be warranted for FEA alone.

Pattern recognition of benign nodules at ultrasound of the thyroid: which nodules can be left alone?

OBJECTIVE: The purpose of this study was to evaluate morphologic features predictive of benign thyroid nodules. MATERIALS AND METHODS: From a registry of the records of 1,232 fine-needle aspiration biopsies performed jointly by the cytology and radiology departments at a single institution between 2005 and 2007, the cases of 650 patients were identified for whom both a pathology report and ultrasound images were available. From the alphabetized list generated, the first 500 nodules were reviewed. We analyzed the accuracy of individual sonographic features and of 10 discrete recognizable morphologic patterns in the prediction of benign histologic findings. RESULTS: We found that grouping of thyroid nodules into reproducible patterns of morphology, or pattern recognition, rather than analysis of individual sonographic features, was extremely accurate in the identification of benign nodules. Four specific patterns were identified: spongiform configuration, cyst with colloid clot, giraffe pattern, and diffuse hyperechogenicity, which had a 100% specificity for benignity. In our series, identification of nodules with one of these four patterns could have obviated more than 60% of thyroid biopsies. CONCLUSION: Recognition of specific morphologic patterns is an accurate method of identifying benign thyroid nodules that do not require cytologic evaluation. Use of this approach may substantially decrease the number of unnecessary biopsy procedures.

Does noninvasive follicular thyroid neoplasm with papillary-like nuclear features have distinctive features on sonography?

BACKGROUND: The noninvasive encapsulated follicular variant of papillary carcinoma (nEFVPTC) has recently been reclassified to "noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP)," removing this entity from the malignant category. This re-categorization has had major implications for clinical management. NIFTP has overlapping cytohistologic features with papillary thyroid carcinoma (PTC) and with follicular adenomas (FA), but sonographic data comparing NIFTP to PTC and FA is lacking. Our study examines the sonographic features of NIFTP as compared with PTC and FA. METHODS: Ultrasound scans and Doppler blood flow from subjects who had pre-surgical sonograms and fine needle aspiration biopsies with final surgical pathology diagnoses of NIFTP/nEFVPTC, classical PTC, and FA between 01/2013-08/2016 were assessed. Sonographic and Doppler features as well as Bethesda System (TBS) diagnoses were recorded and analyzed. RESULTS: 40 NIFTP, 58 classical PTC, and 23 FA cases were included. The most common NIFTP pre-surgical TBS cytology diagnosis was Atypia of Undetermined Significance (AUS/FLUS) (40%). NIFTP cases predominantly displayed wider-than-tall shape (100%), smooth borders (75%), occurrence in multinodular glands (82.5%), heterogeneous echogenicity (50%), both perinodular and intranodular Doppler flow patterns (70%), minimal Doppler flow grade (62.5%), and no calcifications (90%). CONCLUSIONS: Our study demonstrates that NIFTP, PTC, and FA display several distinguishing and overlapping sonographic and Doppler features. Sonographic features appear to complement cytology findings and may help raise pre-operative concern for NIFTP in the proper clinical setting, potentially leading to a more conservative management approach.

Renal angiosarcoma: a case report and literature review.

PURPOSE: In adults renal cell carcinoma (RCC) accounts for over 85% of all diagnosed renal cancers. A much more rare and aggressive malignant tumor of the kidney is angiosarcoma (AS) with less than 25 cases described internationally. Both RCC and AS have similar radiological appearances and thus require histological evaluation for definitive diagnosis. We present a case of renal AS in a 63-year old male who was initially radiologically diagnosed as RCC, and review the current renal AS literature. METHODS: The current English literature from 1981 and onwards on renal AS was reviewed and compared to our current case. RESULTS: The median age and sex of patients with renal AS at presentation was 63 years old (mean 61 years) and common in males with a left kidney predominance. Symptoms included flank pain, palpable mass, and hematuria with imaging suggestive of RCC. Hematogenous metastatic spread often occurred with median survival time of 3.5 months from time of diagnosis (mean 5.8 months). Histologically, the tumors have classical features of angiosarcoma with numerous blood-filled vascular spaces lined by plump pleomorphic endothelial cells with CD31 and CD34 staining positivity. Overall treatment was radical nephrectomy with radiation therapy for local control and metastases. The use of chemotherapy was not consistent. CONCLUSION: Although RCC accounts for the majority of malignant renal tumors, the poor prognosis of AS and its similar radiological appearance to RCC imparts the importance of histological evaluation and the potential radiological mimicry of AS.

Mechanical stretch regimen enhances the formation of bioengineered autologous cardiac muscle grafts.

BACKGROUND: Surgical repair of congenital and acquired cardiac defects may be enhanced by the use of autologous bioengineered muscle grafts. These tissue-engineered constructs are not optimal in their formation and function. We hypothesized that a mechanical stretch regimen applied to human heart cells that were seeded on a three-dimensional gelatin scaffold (Gelfoam) would improve tissue formation and enhance graft strength. METHODS AND RESULTS: Heart cells from children undergoing repair of Tetralogy of Fallot were isolated and cultured. Heart cells were seeded on gelatin-matrix scaffolds (Gelfoam) and subjected to cyclical mechanical stress (n=7) using the Bio-Stretch Apparatus (80 cycles/minute for 14 days). Control scaffolds (n=7) were maintained under identical conditions but without cyclical stretch. Cell counting, histology, and computerized image analysis determined cell proliferation and their spatial distribution within the tissue-engineered grafts. Collagen matrix formation and organization was determined with polarized light and laser confocal microscopy. Uniaxial tensile testing assessed tissue-engineered graft function. Human heart cells proliferated within the gelatin scaffold. Remarkably, grafts that were subjected to cyclical stretch demonstrated increased cell proliferation and a marked improvement of cell distribution. Collagen matrix formation and organization was enhanced by mechanical stretch. Both maximal tensile strength and resistance to stretch were improved by cyclical mechanical stretch. CONCLUSION: The cyclical mechanical stretch regimen enhanced the formation of a three-dimensional tissue-engineered cardiac graft by improving the proliferation and distribution of seeded human heart cells and by stimulating organized matrix formation resulting in an order of magnitude increase in the mechanical strength of the graft.

Microfilaments and microtubules maintain endothelial integrity.

The endothelium is a highly metabolic monolayer of cells regulating numerous physiological and pathological functions that maintain the permeability and thromboresistant functions of the endothelium. The structure and function of the endothelial cytoskeleton prevents vascular disease by regulating the structure of the endothelium to act as a resting molecular barrier to atherogenic proteins and by becoming an activated layer of migrating cells to repair denuding injuries. The purpose of this review is to examine the structure of the endothelial cytoskeleton and its roles in cell-cell and cell-substratum adhesion, cell signaling, and regulation of wound repair. Studies focused on the cellular and molecular biology of the structure and function of the endothelial cytoskeleton and in wound repair are reviewed. The cytoskeleton is a key regulator in maintaining endothelial integrity and in restoring integrity following injurious denudation, such as those that occur in the pathogenesis of atherosclerosis. Actin microfilaments and their associated adherens junctions and focal adhesions are important regulators of cell signaling, cell locomotion, cell adhesion, and wound repair mechanisms. Various proteins have been implicated in controlling cytoskeletal-based endothelial function and repair such as tyrosine kinases/phosphatases and the Rho family of proteins. The normal function of the endothelium is highly dependent on the endothelial cytoskeleton. Disruption and dysfunction of the cytoskeleton may result in impairment of endothelial function, subsequently tipping the balance towards vascular disease. Thus, an understanding of the cellular and molecular biology of the endothelial cytoskeleton is essential in our understanding of the pathogenesis of vascular disease, especially atherosclerosis.

Rho and basic fibroblast growth factor involvement in centrosome redistribution and actin microfilament remodeling during early endothelial wound repair.

OBJECTIVE: We have shown that centrosome redistribution to the front of the cell and actin microfilament remodeling occurs during the initiation of early porcine aortic endothelial wound repair even before cell migration. Because Ras homologous protein (Rho) induces actin microfilament polymerization, interacts with microtubules, and is believed to be activated by growth factors, we set forth to study the regulatory roles of basic fibroblast growth factor (bFGF) and Rho signaling on centrosome redistribution and actin microfilament remodeling in endothelial cells at an in vitro wound edge. STUDY DESIGN: With double immunofluorescent confocal microscopy, we studied the distribution of various cytoskeletal proteins in wounded porcine aortic endothelial cells in response to bFGF and exoenzyme C3 treatments. RESULTS: We showed that the addition of 10 ng/mL bFGF for 3 hours after wounding resulted in a significant increase (P <.05) in cells at the wound edge with central microfilaments oriented perpendicular to the wound. Rho inhibition with 2 microg/mL C3 resulted in the reduction of phosphotyrosine, paxillin, and central microfilament staining. Centrosome redistribution and endothelial cell elongation also were significantly inhibited (P <.05) with C3, resulting in decreased wound closure. However, inhibition was reduced with coincubation of bFGF with C3, which also returned the rate of endothelial wound closure toward control values. This Rho-independent bFGF-induced centrosome redistribution was associated with the cells showing a significant increase (P <.05) in acetylated microtubules that extended from the centrosome to the posterior cell border. CONCLUSION: We conclude that Rho regulates centrosome redistribution and central microfilament remodeling during early endothelial wound repair, and bFGF promotes actin remodeling through a downstream Rho-dependent pathway and promotes centrosome redistribution, at least in part, with a Rho-independent pathway.