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Background: The rising demand for 18F-fluorodeoxyglucose positron emission tomography with computed tomography (18F-FDG PET/CT) has led to an increase of thyroid incidentalomas. Current guidelines are restricted in giving options to tailor diagnostics and to suit the individual patient. Objectives: We aimed at exploring the extent of potential overdiagnostics by performing a systematic review and meta-analysis of the literature on the prevalence, the risk of malignancy (ROM) and the risk of inconclusive FNAC (ROIF) of focal thyroid incidentalomas (FTI) on 18F-FDG PET/CT. Data Sources: A literature search in MEDLINE, Embase and Web of Science was performed to identify relevant studies. Study Selection: Studies providing information on the prevalence and/or ROM of FTI on 18F-FDG PET/CT in patients with no prior history of thyroid disease were selected by two authors independently. Sixty-one studies met the inclusion criteria. Data Analysis: A random effects meta-analysis on prevalence, ROM and ROIF with 95% confidence intervals (CIs) was performed. Heterogeneity and publication bias were tested. Risk of bias was assessed using the quality assessment of diagnostic accuracy studies (QUADAS-2) tool. Data Synthesis: Fifty studies were suitable for prevalence analysis. In total, 12,943 FTI were identified in 640,616 patients. The pooled prevalence was 2.22% (95% CI = 1.90% - 2.54%, I2 = 99%). 5151 FTI had cyto- or histopathology results available. The pooled ROM was 30.8% (95% CI = 28.1% - 33.4%, I2 = 57%). 1308 (83%) of malignant nodules were papillary thyroid carcinoma (PTC). The pooled ROIF was 20.8% (95% CI = 13.7% - 27.9%, I2 = 92%). Limitations: The main limitations were the low to moderate methodological quality of the studies and the moderate to high heterogeneity of the results. Conclusion: FTI are a common finding on 18F-FDG PET/CTs. Nodules are malignant in approximately one third of the cases, with the majority being PTC. Cytology results are non-diagnostic or indeterminate in one fifth of FNACs. These findings reveal the potential risk of overdiagnostics of FTI and emphasize that the workup of FTI should be performed within the context of the patient's disease and that guidelines should adopt this patient tailored approach. [ABSTRACT FROM AUTHOR]

The differential diagnosis of a rapidly enlarging neck mass consists of many different benign ((haemorrhagic) cyst) and malignant (anaplastic thyroid cancer (ATC) and lymphoma) causes. ATC is a rare disease with a median survival of 6 months. As early diagnosis and management are key for fast-growing cancers, in our centre we have implemented a dedicated short-stay in-hospital fast-track diagnostic work-up for patients with a rapid growing mass in the neck. The goal of this track is to have a fast diagnostic and therapeutic plan for this disease. Based on three clinical cases we discuss our experience with this fast-track diagnostic work-up for rapidly growing mass in the neck and illustrate the additional value in this clinical entity.

Background: The rising demand for 18 F-fluorodeoxyglucose positron emission tomography with computed tomography ( 18 F-FDG PET/CT) has led to an increase of thyroid incidentalomas. Current guidelines are restricted in giving options to tailor diagnostics and to suit the individual patient., Objectives: We aimed at exploring the extent of potential overdiagnostics by performing a systematic review and meta-analysis of the literature on the prevalence, the risk of malignancy (ROM) and the risk of inconclusive FNAC (ROIF) of focal thyroid incidentalomas (FTI) on 18 F-FDG PET/CT., Data Sources: A literature search in MEDLINE, Embase and Web of Science was performed to identify relevant studies., Study Selection: Studies providing information on the prevalence and/or ROM of FTI on 18 F-FDG PET/CT in patients with no prior history of thyroid disease were selected by two authors independently. Sixty-one studies met the inclusion criteria., Data Analysis: A random effects meta-analysis on prevalence, ROM and ROIF with 95% confidence intervals (CIs) was performed. Heterogeneity and publication bias were tested. Risk of bias was assessed using the quality assessment of diagnostic accuracy studies (QUADAS-2) tool., Data Synthesis: Fifty studies were suitable for prevalence analysis. In total, 12,943 FTI were identified in 640,616 patients. The pooled prevalence was 2.22% (95% CI = 1.90% - 2.54%, I 2 = 99%). 5151 FTI had cyto- or histopathology results available. The pooled ROM was 30.8% (95% CI = 28.1% - 33.4%, I 2 = 57%). 1308 (83%) of malignant nodules were papillary thyroid carcinoma (PTC). The pooled ROIF was 20.8% (95% CI = 13.7% - 27.9%, I 2 = 92%)., Limitations: The main limitations were the low to moderate methodological quality of the studies and the moderate to high heterogeneity of the results., Conclusion: FTI are a common finding on 18 F-FDG PET/CTs. Nodules are malignant in approximately one third of the cases, with the majority being PTC. Cytology results are non-diagnostic or indeterminate in one fifth of FNACs. These findings reveal the potential risk of overdiagnostics of FTI and emphasize that the workup of FTI should be performed within the context of the patient's disease and that guidelines should adopt this patient tailored approach., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 de Leijer, Metman, van der Hoorn, Brouwers, Kruijff, van Hemel, Links and Westerlaan.)

BRAF mutational testing has become a common practice in the diagnostic process of patients with advanced melanoma. Although time-consuming, DNA sequencing techniques are the current gold standard for mutational testing. However, in certain clinical situations, a rapid test result is required. In this study, the performance of three rapid BRAF mutation tests was compared. Thirty-nine formalin-fixed paraffin-embedded melanoma tissue samples collected between 2007 and 2014 at a single center were included. These samples were analyzed by immunohistochemistry using the anti-BRAF-V600E (VE1) mouse monocolonal antibody (BRAF-VE1 IHC), a V600E-specific Droplet Digital PCR Test, and the Idylla BRAF- Mutation Test (Idylla). Results were compared with the results of conventional BRAF mutation testing, performed using high-resolution melting analysis followed by Sanger sequencing. Next-generation sequencing was performed on samples with discordant results. The Idylla test and Droplet Digital PCR Test correctly identified all mutated and wild-type samples. BRAF-VE1 IHC showed one discordant result. The Idylla test could identify BRAF-V600 mutations other than BRAF-V600E and was the fastest and least laborious test. The Idylla Mutation Test is the most suitable test for rapid BRAF testing in clinical situations on the basis of the broad coverage of treatment-responsive mutations and the fast procedure without the need to perform a DNA isolation step.

Background: The diagnosis of tumors of soft tissue and bone (STB) heavily relies on histological biopsies, whereas cytology is not widely used. Cellient TM cell blocks often contain small tissue fragments. In addition to Hematoxylin and Eosin (H&E) interpretation of histological features, immunohistochemistry (IHC) can be applied after optimization of protocols. The objective of this retrospective study was to see whether this cytological technique allowed us to make a precise diagnosis of STB tumors., Methods: Our study cohort consisted of 20 consecutive STB tumors, 9 fine-needle aspiration (FNAC) samples, and 11 endoscopic ultrasonography (EUS) FNACs and included 8 primary tumors and 12 recurrences or metastases of known STB tumors., Results: In all 20 cases, H&E stained sections revealed that diagnostically relevant histological and cytological features could be examined properly. In the group of 8 primary tumors, IHC performed on Cellient TM material provided clinically important information in all cases. For instance, gastrointestinal stromal tumor (GIST) was positive for CD117 and DOG-1 and a PEComa showed positive IHC for actin, desmin, and HMB-45. In the group of 12 secondary tumors, SATB2 was visualized in metastatic osteosarcoma, whereas expression of S-100 was present in 2 secondary chondrosarcomas. Metastatic chordoma could be confirmed by brachyury expression. Two metastatic alveolar rhabdomyosarcomas were myf4 positive, a metastasis of a gynecologic leiomyosarcoma was positive for actin and estrogen receptor (ER) and a recurrent dermatofibrosarcoma protuberans expressed CD34., Conclusion: In the proper clinical context, including clinical presentation with imaging studies, the Cellient TM cell block technique has great potential for the diagnosis of STB tumors., (© 2018 The Authors. Diagnostic Cytopathology Published by Wiley Periodicals, Inc.)

Background: Medullary thyroid cancer (MTC) comprises only 4% of all thyroid cancers and originates from the parafollicular C-cells. HIF-1α expression has been implied as an indicator of worse prognosis in various solid tumors. However, whether expression of HIF-1α is a prognosticator in MTC remained unclear. Our aim was to evaluate the prognostic value of HIF-1α in patients with MTC., Methods: All patients with MTC who were operated on between 1988 and 2014 in five tertiary referral centers in The Netherlands were included. A tissue microarray was constructed in which 111 primary tumors could be analyzed for expression of HIF-1α, CAIX, Glut-1, VEGF and CD31 and correlated with clinicopathologic variables and survival., Results: The mean age of patients was 46.3 years (SD 15.6), 59 (53.2%) were male. Of the 111 primary tumors, 49 (44.1%) were HIF-1α negative and 62 (55.9%) were HIF-1α positive. Positive HIF-1α expression was an independent negative indicator for progression free survival (PFS) in multivariate cox regression analysis (HR 3.1; 95% CI 1.3 - 7.3). Five-years survival decreased from 94.0% to 65.9% for the HIF-1α positive group (p=0.007). Even within the group of patients with TNM-stage IV disease, HIF-1α positivity was associated with a worse prognosis, shown by a decrease in 5-years survival of 88.0% to 49.3% (p=0.020)., Conclusion: Expression of HIF-1α is strongly correlated with adverse prognosis of MTC. This could open up new ways for targeted systemic therapy of MTC.

Three patients presented some decades after severe traumatic injury with atypical bowel symptoms which were caused by a giant myelolipoma of the adrenal gland. The aetiology of this rare, benign and generally asymptomatic tumour is virtually unknown at present and several hypotheses have been devised. This report describes a possible association between high-energy trauma and the development of giant myelolipomas, further contributing to the hypothesis that severe systemic stress could be an aetiological factor in the development of an adrenal myelolipoma., (2014 BMJ Publishing Group Ltd.)

Objective: To explore the feasibility of DNA methylation analysis for the detection of cervical neoplasia in self-obtained cervico-vaginal lavages., Methods: Lavages collected by a self-sampling device and paired cervical scrapings were obtained from 20 cervical cancer patients and 23 patients referred with an abnormal cervical smear (15 with high-grade cervical intraepithelial neoplasia (CIN2+) and 8 without CIN). All lavages and scrapings were analyzed by liquid based cytology (LBC), Hybrid Capture II (HC-II) for hr-HPV DNA detection and by DNA methylation analysis (JAM3, TERT, EPB41L3 and C13ORF18). Concordance between lavages and scrapings was measured by Cohen's Kappa (k)., Results: In lavages and scrapings from cervical cancer patients (n=20), methylation analysis was positive in 19 (95%) and 19 (95%), HC-II in 16 (80%) and 15 (75%) and LBC in 15 (75%) and 19 (95%), respectively. In lavages and scrapings from CIN2+ patients (n=15), methylation analysis was positive in 10 (67%) and 12 (80%), HC-II in 15 (100%) and 15 (100%) and LBC in 11 (73%) and 12 (80%), respectively. Concordance between cervical scrapings and lavages (n=43) was for LBC k=0.522 (p<0.001), hr-HPV testing k=0.551 (p<0.001) and DNA methylation analysis k=0.653 (p<0.001)., Conclusions: DNA methylation analysis in cervico-vaginal lavages obtained by a self-sampling device is feasible and its diagnostic performance appears to be at least comparable to the detection of cervical neoplasia by cytomorphology and hr-HPV. Our pilot study suggests that detection of cervical neoplasia by DNA methylation analysis in cervico-vaginal lavages warrants exploration of its use in large prospective studies., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background: Fine-needle aspiration (FNA) is the most accurate tool to identify malignancy in solitary thyroid nodules. Although some recommend routinely repeating FNA for nodules that are initially read as benign, there is no consensus. We evaluated clinical relevancy and considered costs of routine follow-up FNA in nodules initially read as benign., Methods: We reviewed the records of all 739 patients who underwent FNA of solitary thyroid nodules at our institution from 1988 to 2004. A total of 815 aspirations were required to obtain satisfactory specimens. According to their physicians practice, some patients had a "follow-up biopsy" after an initially benign FNA reading as a matter of routine (Group I approach) or if their clinical status changed (Group II approach). The outcome information for at least 4 years after the initial FNA in these two groups was compared. In addition, hypothetical costs relating to both methods for deciding whether to do a follow-up FNA were considered., Results: The initial FNA was benign in 576 (78%), suspicious for follicular neoplasms in 106 (14.4%), and malignant in 57 patients (7.7%). Follow-up FNA was performed in 292 patients with initially benign lesions, 235 in Group I approach and 57 in Group II approach. The FNA diagnosis according to Group I approach remained benign on follow-up biopsy in 96.2% (226/235), was altered to follicular neoplasm in 3% (7/235), and was suspicious for malignancy in 0.8% (2/235). When following Group II approach, the follow-up FNA was benign in 93% (53/57), undetermined in 1.7% (1/57), and showed follicular neoplasm in 5.3% (3/57). Combining Groups I and II methods, 5 of 292 patients had a malignant nodule on histological examination, a false-negative rate of 1.7% for the initial FNA, but without a difference in prevalence of thyroid malignancy between the groups. Cost-consequence analysis showed no benefit in routine follow-up FNA after initially benign FNA readings., Conclusions: Routine follow-up FNA in patients whose initial FNA is benign has a low diagnostic upgrading value and is relatively costly. In patients whose initial FNA is benign, we recommend the FNA be repeated only if clinically suspicious signs or complaints develop.

Objective: To assess the compliance of HSIL patients to the national Dutch routine follow-up protocol in the first 2 years after LLETZ and to determine if based on the status of excision margins, follow-up intervals could be modified., Methods: A prospective cohort study was performed in patients, referred because of an abnormal Pap smear between 1996 and 2004 and treated for HSIL with LLETZ. The Dutch national routine follow-up protocol orders a Pap smear after 6, 12 and 24 months, respectively. Follow-up results were completed by using PALGA, the nationwide network and registry of histo- and cytopathology in the Netherlands. To assess compliance to the follow-up protocol, adequate follow-up was defined as three cervical smears taken after 6 (+/-3), 12 (+/-3) and 24 (+/-3) months, respectively., Results: Compliance to the first 2 years follow-up protocol declined from 86.2% to 64.8% to 51.2% for first, second and third follow-up cervical smears, respectively. Patients with involved excision margins had a three times higher overall risk of developing a subsequent HSIL after LLETZ as compared to patients with free excision margins (HR: 3.2, 95% CI=1.3-7.9, p=0.01). Risk for diagnosing HSIL during the first 12 months of follow-up for patients with free excision margins was only 1%., Conclusions: Compliance to the Dutch national routine follow-up protocol in HSIL patients after LLETZ is only moderate. For HSIL patients with free excision margins after LLETZ the first cytological follow-up interval can safely be increased to 12 months.

Fibrinogen is a plasma protein that interacts with integrin alphaIIb beta3 to mediate a variety of platelet responses including adhesion, aggregation, and clot retraction. Three sites on fibrinogen have been hypothesized to be critical for these interactions: the Ala-Gly-Asp-Val (AGDV) sequence at the C-terminus of the gamma chain and two Arg-Gly-Asp (RGD) sequences in the Aalpha chain. Recent data showed that AGDV is critical for platelet adhesion and aggregation, but not retraction, suggesting that either one or both of the RGD sequences are involved in clot retraction. Here we provide evidence, using engineered recombinant fibrinogen, that no one of these sites is critical for clot retraction; fibrinogen lacking all three sites still sustains a relatively normal, albeit delayed, retraction response. Three fibrinogen variants with the following mutations were examined: a substitution of RGE for RGD at position Aalpha 95-97, a substitution of RGE for RGD at position Aalpha 572-574, and a triple substitution of RGE for RGD at both Aalpha positions and deletion of AGDV from the gamma chain. Retraction rates and final clot sizes after a 20-minute incubation were indistinguishable when comparing the Aalpha D97E fibrinogen or Aalpha D574E fibrinogen with normal recombinant fibrinogen. However, with the triple mutant fibrinogen, clot retraction was delayed compared with normal recombinant fibrinogen. Nevertheless, the final clot size measured after 20 minutes was the same size as a clot formed with normal recombinant fibrinogen. Similar results were observed using platelets isolated from an afibrinogenemic patient, eliminating the possibility that the retraction was dependent on secretion of plasma fibrinogen from platelet alpha-granules. These findings indicate that clot retraction is a two-step process, such that one or more of the three putative platelet binding sites are important for an initial step in clot retraction, but not for a subsequent step. With the triple mutant fibrinogen, the second step of clot retraction, possibly the development of clot tension, proceeds with a rate similar to that observed with normal recombinant fibrinogen. These results are consistent with a mechanism where a novel site on fibrin is involved in the second step of clot retraction.