Marc Pusztaszeri

Impact of reclassifying noninvasive follicular variant of papillary thyroid carcinoma on the risk of malignancy in The Bethesda System for Reporting Thyroid Cytopathology.

Recent discussions have focused on redefining noninvasive follicular variant of papillary thyroid carcinoma (NI‐FVPTC) as a neoplasm rather than a carcinoma. This study assesses the potential impact of such a reclassification on the implied risk of malignancy (ROM) for the diagnostic categories of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC).

Update on the Cytologic and Molecular Features of Medullary Thyroid Carcinoma

Medullary thyroid carcinoma (MTC) accounts for only 5% to 10% of all thyroid carcinomas, but it is the most aggressive form of well-differentiated thyroid carcinoma, being responsible for 8% to 15% of all thyroid cancer-related deaths. MTC is frequently diagnosed at a locally advanced or metastatic stage, and 10-year survival rates in these cases are <20%. Fine-needle aspiration biopsy of the thyroid gland is an accurate method to diagnose MTC, having a high sensitivity and specificity. The cytologic features of MTC are characteristic and the cytologic diagnosis of classic MTC is often straightforward, especially when combined with immunocytochemistry. However, because of its morphologic heterogeneity and overlap with other tumors, the differential diagnosis of MTC on cytology and on histology is broad with several potential pitfalls. Significant advances have been made over the last decade in understanding MTC. This concerns mainly the early detection of MTC, especially in familial forms (eg, multiple endocrine neoplasia type 2), and the identification of key molecular pathways and alterations which now offer promising targets for specific therapies in progressive MTC cases. Genetic testing (eg, RET mutation) has allowed for early detection in asymptomatic carriers and high-risk patients, with prophylactic thyroidectomy often being curative. Targeted therapies with multityrosine-kinase inhibitors (eg, vandetanib or cabozantinib) have emerged as promising new treatments for recurrent or metastatic MTC. In this review article, we discuss the cytologic features of MTC and its variants, its differential diagnosis, the role of ancillary studies, and the salient molecular features of MTC.

Ultrasound Measurement of the Fibrous Cap in Symptomatic and Asymptomatic Atheromatous Carotid Plaques

Background—Fibrous cap thickness (FCT) is an important determinant of atheroma stability. We evaluated the feasibility and potential clinical implications of measuring the FCT of internal carotid artery plaques with a new ultrasound system based on boundary detection by dynamic programming. Methods and Results—We assessed agreement between ultrasound-obtained FCT values and those measured histologically in 20 patients (symptomatic [S]=9, asymptomatic [AS]=11) who underwent carotid endarterectomy for stenosing (>70%) carotid atheromas. We subsequently measured in vivo the FCT of 58 stenosing internal carotid artery plaques (S=22, AS=36) in 54 patients. The accuracy in discriminating symptomatic from asymptomatic plaques was assessed by receiver operating characteristic curves for the minimal, mean, and maximal FCT. Decision FCT thresholds that provided the best correct classification rates were identified. Agreement between ultrasound and histology was excellent, and interobserver variability was small. Ultrasound showed that symptomatic atheromas had thinner fibrous caps (S versus AS, median [95% CI]: minimal FCT=0.42 [0.34 to 0.48] versus 0.50 [0.44 to 0.53] mm, P=0.024; mean FCT=0.58 [0.52 to 0.63] versus 0.79 [0.69 to 0.85] mm, P<0.0001; maximal FCT=0.73 [0.66 to 0.92] versus 1.04 [0.94 to 1.20] mm, P<0.0001). Mean FCT measurement demonstrated the best discriminatory accuracy (area under the curve [95% CI]: minimal 0.74 [0.61 to 0.87]; mean 0.88 [0.79 to 0.97]; maximal 0.82 [0.71 to 0.93]). The decision threshold of 0.65 mm (mean FTC) demonstrated the best correct classification rate (82.8%; positive predictive value 75%, negative predictive value 88.2%). Conclusions—FCT measurement of carotid atheroma with ultrasound is feasible. Discrimination of symptomatic from asymptomatic plaques with mean FCT values is good. Prospective studies should determine whether this ultrasound marker is reliable.

Circadian Clock Characteristics Are Altered in Human Thyroid Malignant Nodules

CONTEXT The circadian clock represents the bodys molecular time-keeping system. Recent findings revealed strong changes of clock gene expression in various types of human cancers. OBJECTIVE Due to emerging evidence on the connection between the circadian oscillator, cell cycle, and oncogenic transformation, we aimed to characterize the circadian clockwork in human benign and malignant thyroid nodules. DESIGN Clock transcript levels were assessed by quantitative RT-PCR in thyroid tissues. To provide molecular characteristics of human thyroid clockwork, primary thyrocytes established from normal or nodular thyroid tissue biopsies were subjected to in vitro synchronization with subsequent clock gene expression analysis by circadian bioluminescence reporter assay and by quantitative RT-PCR. RESULTS The expression levels of the Bmal1 were up-regulated in tissue samples of follicular thyroid carcinoma (FTC), and in papillary thyroid carcinoma (PTC), as compared with normal thyroid and benign nodules, whereas Cry2 was down-regulated in FTC and PTC. Human thyrocytes derived from normal thyroid tissue exhibited high-amplitude circadian oscillations of Bmal1-luciferase reporter expression and endogenous clock transcripts. Thyrocytes established from FTC and PTC exhibited clock transcript oscillations similar to those of normal thyroid tissue and benign nodules (except for Per2 altered in PTC), whereas cells derived from poorly differentiated thyroid carcinoma exhibited altered circadian oscillations. CONCLUSIONS This is the first study demonstrating a molecular makeup of the human thyroid circadian clock. Characterization of the thyroid clock machinery alterations upon thyroid nodule malignant transformation contributes to understanding the connections between circadian clocks and oncogenic transformation. Moreover, it might help in improving the thyroid nodule preoperative diagnostics.

Riedel's thyroiditis with increased IgG4 plasma cells: evidence for an underlying IgG4-related sclerosing disease?

BACKGROUND Riedels thyroiditis (RT) is a very rare chronic fibrosing disorder of unknown etiology that is often associated with multifocal fibrosclerosis (MFS). Immunoglobulin (Ig) G4-related sclerosing disease (IgG4-RSD), a new clinico-pathological entity also associated with MFS, is characterized by IgG4+ plasma cell infiltration and fibrosis in one or more organs. Although the association of RT and IgG4-RSD has been suggested, it has seldom been studied or reported. We report a classical case of RT with serological (IgG4 levels) and immunohistochemical (IgG and IgG4) assessment, in search of an underlying IgG4-RSD. PATIENT The patient was a 57-year-old woman who underwent a subtotal thyroidectomy for a long-standing goiter with a rapidly enlarging isthmic nodule. RESULTS Histopathological examination of the surgical specimen revealed all of the morphological features of RT and IgG4-RSD, including partial fibrosis of the thyroid gland with destruction of the thyroid follicular architecture; obliterative phlebitis; and a mixed infiltrate composed of lymphocytes, eosinophils, and plasma cells. The fibro-inflammatory process extended beyond the thyroid capsule into the surrounding tissues. Immunohistochemical examination revealed approximately 70 IgG4+ plasma cells per high power field (HPF) with an IgG4/IgG ratio of 35%. Although serum levels of IgG4 were normal (20 mg/dL), total IgG levels were slightly elevated (1370 mg/dL). There was no evidence of involvement of other organs at the time of RT diagnosis. CONCLUSIONS The morphological similarities between RT and IgG4-RSD suggest that these entities are closely related. Therefore, RT with increased IgG4+ plasma cells, with or without elevated IgG4 serum levels, may represent the first clinical manifestation of an underlying IgG4-RSD. However, due to the rarity of both conditions and the limited specificity and sensitivity of both IgG4 serum levels and IgG/IgG4 immunohistochemistry in the diagnosis of IgG4-RSD, further studies are needed to verify this hypothesis.

Update in salivary gland cytopathology: Recent molecular advances and diagnostic applications

Salivary gland tumors (SGT) are notorious for their extraordinary diversity and for the morphological overlap that exists between many of these entities. Fine-needle aspiration biopsy (FNAB) has a well-established role in the evaluation of patients with a salivary gland lesion, helping to guide clinical management. However, salivary gland FNAB has several limitations and does not allow for a specific diagnosis in some cases. For these reasons, salivary gland FNAB is considered one of the most challenging areas in cytopathology. Over the last decade, new salivary gland entities have been recognized, enlarging SGT diversity and complexity even more. In addition, a subset of SGT, including common entities such as pleomorphic adenoma and uncommon new entities such as mammary analog secretory carcinoma, have been characterized cytogenetically by the presence of specific translocations. The molecular consequences of these translocations and their potential prognostic and therapeutic values are not yet well characterized. However, these translocations and their resulting fusion oncogenes and oncoproteins can be used as diagnostic clues in salivary gland FNAB material in order to overcome the limitations of cytomorphological evaluation alone. In this review, we focus on SGTs currently known to harbor translocations and fusion genes, including uncommon and recently recognized entities, and discuss their potential application to salivary gland FNAB.

MYB immunostaining is a useful ancillary test for distinguishing adenoid cystic carcinoma from pleomorphic adenoma in fine‐needle aspiration biopsy specimens

The distinction between adenoid cystic carcinoma (ACC) and pleomorphic adenoma (PA) on fine‐needle aspiration biopsy (FNAB) can be challenging. Recently, a specific translocation t(6;9) involving the v‐myb avian myeloblastosis viral oncogene homolog (MYB) and nuclear factor I/B (NFIB) genes was identified in ACCs, in which it contributes to MYB overexpression. The authors investigated the use of MYB immunocytochemistry in FNAB specimens as an ancillary test for the cytologic diagnosis of ACC.

Fine-needle aspiration biopsy of secondary neoplasms of the thyroid gland: a multi-institutional study of 62 cases.

Secondary neoplasms of the thyroid gland (SNTGs) are uncommon, and it is important to recognize them in thyroid fine‐needle aspiration biopsy (FNAB).

The bethesda system for reporting thyroid cytopathology: Proposed modifications and updates for the second edition from an international panel

The Bethesda System for Reporting Thyroid Cytology (TBSRTC) was proposed in 2007 at the National Cancer Institute Thyroid Fine Needle Aspiration State of the Art and Science » Conference held in Bethesda, Maryland. The aim was to address the inconsistent and sometimes confusing reporting terminologies used for thyroid FNA throughout the world. The TBSRTC consists of 6 diagnostic categories, each associated with an implied risk of malignancy that translates directly into a clinical management algorithm. Since the publication of the TBSRTC cytology Atlas in January 2010, considerable experience has been gained regarding its application in cytology practice, clinical impact, and limitations. In conjunction with the International Academy of Cytology (IAC), an international panel composed of sixteen cytopathologists and an endocrinologist with special interest in thyroid cytology, including several co-authors of the 2010 TBSRTC Atlas, was created to: 1) analyze the current worldwide impact of TBSRTC, 2) report on the current state of TBSRTC based upon a review of the published literature, and 3) provide possible recommendations for a future update of TBSRTC. Herein, we summarize the panels deliberations and key recommendations that our panel hopes will be useful during the preparation of the second edition of TBSRTC.

Clitoral neuroma after female genital mutilation/cutting: a rare but possible event

INTRODUCTION Female genital mutilation/cutting (FGM/C), in particular, type III, also called infibulation, can cause various long-term complications. However, posttraumatic neuroma of the clitoris is extremely rare; only one case was previously reported in the literature. AIM The aim of this study was to describe the case of a patient presenting a clitoral neuroma post-FGM/C in detail and her successful multidisciplinary treatment. METHODS We report the case of a 24-year-old woman originating from Somalia presenting a type III a-b FGM/C who attended our outpatient clinic at the Geneva University Hospitals complaining of primary dysmenorrhea and a post-mutilation painful clitoral mass. The mass was clinically diagnosed as a cyst and surgically removed. Histopathological analysis revealed that it was a posttraumatic neuroma and a foreign body granuloma around the ancient surgical thread. Our patient was also offered a multidisciplinary counseling by a specialized gynecologist on FGM/C, a sexologist, and a reproductive and sexual health counselor. RESULTS One month after surgical treatment, the vulvar pain was over. CONCLUSIONS This is the second case of clitoral neuroma after FGM/C reported and the first with complete clinical, as well as histopathological documentation and multidisciplinary care. Considering the high frequency of clitoral cysts in case of infibulation, clitoral neuroma should be considered in the differential diagnosis. In this case, if symptomatic, the treatment should be surgery, clinical follow-up, and counseling. If necessary, appropriate sexual therapy should be offered too.