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BACKGROUND: To the authors' knowledge, the impact of the coronavirus disease 2019 (COVID-19) pandemic on cytopathology practices worldwide has not been investigated formally. In the current study, data from 41 respondents from 23 countries were reported. METHODS: Data regarding the activity of each cytopathology laboratory during 4 weeks of COVID-19 lockdown were collected and compared with those obtained during the corresponding period in 2019. The overall number and percentage of exfoliative and fine-needle aspiration cytology samples from each anatomic site were recorded. Differences in the malignancy and suspicious rates between the 2 periods were analyzed using a meta-analytical approach. RESULTS: Overall, the sample volume was lower compared with 2019 (104,319 samples vs 190,225 samples), with an average volume reduction of 45.3% (range, 0.1%-98.0%). The percentage of samples from the cervicovaginal tract, thyroid, and anorectal region was significantly reduced (P < .05). Conversely, the percentage of samples from the urinary tract, serous cavities, breast, lymph nodes, respiratory tract, salivary glands, central nervous system, gastrointestinal tract, pancreas, liver, and biliary tract increased (P < .05). An overall increase of 5.56% (95% CI, 3.77%-7.35%) in the malignancy rate in nongynecological samples during the COVID-19 pandemic was observed. When the suspicious category was included, the overall increase was 6.95% (95% CI, 4.63%-9.27%). CONCLUSIONS: The COVID-19 pandemic resulted in a drastic reduction in the total number of cytology specimens regardless of anatomic site or specimen type. The rate of malignancy increased, reflecting the prioritization of patients with cancer who were considered to be at high risk. Prospective monitoring of the effect of delays in access to health services during the lockdown period is warranted. ispartof: CANCER CYTOPATHOLOGY vol:128 issue:12 pages:885-894 ispartof: location:United States status: published

This brief review discusses legal issues in thyroid cytology and histopathology in England. The principal risks in thyroid cyto/histopathology are either underdiagnosis of a malignant condition as benign, overdiagnosis of a benign condition as malignant, or the failure to recognise or the overdiagnosis as malignant of a benign or inflammatory condition. There are multiple diagnostic pitfalls in both cytology and histopathology and these are reasonably well documented. The interobserver reproducibility as assessed by kappa statistics of some of the major criteria for malignancy, specifically papillary-type nuclei in the diagnosis of papillary thyroid carcinoma, capsular invasion or vascular invasion are comparatively poor hence diagnoses of well differentiated papillary or follicular carcinoma may often be to some extent subjective. This article reviews the current legal situation in England discussing recent legal case precedents with a suggestion for improving communication and the preoperative consent process for patients.

In diagnostic cytology, the known site-specific false positive rates at various anatomical sites for the risk malignancy (ROM) when a confirmed malignant diagnosis is made are comparatively well documented. ROM figures for diagnostic cytology specimens may vary according to the anatomical site of the specimen, the exact nature of the specimen received, the staining method(s) used, and the use of additional laboratory techniques including molecular profiling; furthermore, they often differ to some extent from institution to institution, between differing cytologists within the same institution, and over time. A brief literature review for a selected group of routine diagnostic cytology specimens shows a published ROM for a confirmed malignant diagnosis as follows: bile duct brushings, ~99% (range, 97%-100%); breast fine needle aspiration, 98.5% (range, 92%-100%); serous effusion fluid, 98.9% (range, 90%-100% although lower for squamous cell carcinoma, mesothelioma, and lymphoma), pulmonary endobronchial ultrasound cytology, ~99% (range, 86.6%-100%); thyroid FNA, 98% (range, 97%-99% if NIFTP tumors are excluded), salivary gland FNA, ~90%; (range 57%-100%) and lateral neck cyst FNA, ~99% (range, 95.5%-100%). Because most diagnostic cytology specimens have a small but accepted false-positive rate, this information is vitally important for the clinical management of patients and for shared patient decision making. In our view, the known false-positive rate for a given diagnostic cytology specimen could be included within the cytology report to assist in explaining the limitations of the diagnostic cytology interpretation and help facilitate the clinical decision-making process.

Purpose 18F-FDG thyroid incidentaloma (TI) occurs in ~2% of PET/CT examinations with a cancer prevalence of up to 35–40%. Guidelines recommend fine-needle aspiration cytology (FNA) if a focal 18F-FDG TI corresponds to a sonographic nodule >1 cm. The aim of this systematic review and meta-analysis was to provide evidence-based data on the diagnostic distribution of 18F-FDG TIs in the six Bethesda systems for reporting thyroid cytopathology (BETHESDA) subcategories. Methods Original studies reporting 18F-FDG TIs and cytologically classified according to BETHESDA were included. Six separate meta-analyses were performed to obtain the pooled prevalence (95% confidence interval, 95% CI) of 18F-FDG TIs in the six BETHESDA subcategories. Results Fifteen studies were finally included. Nine studies were from Asian/Eastern and six from Western countries. FNA data according to BETHESDA was available in 2304 cases. The pooled prevalence of 18F-FDG TIs according to BETHESDA was BETHESDA I 10% (6–14), BETHESDA II 45% (37–53), BETHESDA III 8% (3–13), BETHESDA IV 8% (5–12), BETHESDA V 6% (4–9), BETHESDA VI 19% (13–25). A significantly different prevalence was found in the BETHESDA IV between Asian/Eastern (2%) and Western (19%) studies. Conclusion Two-thirds of focal 18F-FDG TIs undergoing FNA have either malignant (BETHESDA VI) or benign (BETHESDA II) cytology while a minority will have indeterminate (BETHESDA III or IV) FNA results. Significant differences between Asian/Eastern and Western studies are also present in the prevalence of indeterminate FNA results.

Background The aims of this study were to compare neoplasia detection rates for nontargeted biopsies (Seattle protocol) versus acetic acid-targeted biopsies (Portsmouth protocol) during Barrett’s surveillance and to explore feasibility, patient/clinician experience, acceptance, and barriers/enablers to study participation and implementation of the acetic acid technique. Methods This was a mixed-methods feasibility study including a pilot multicenter, randomized, crossover trial with qualitative interviews. Patients under Barrett’s surveillance with no history of neoplasia were included. Patients underwent two endoscopies, one with each protocol, 8 weeks apart. Outcomes included recruitment and retention rates, neoplasia yield, and number of biopsies. Results 200 patients were recruited from 6 centers, and 174 (87.0 %) underwent both procedures. Neoplasia prevalence was 4.7 % (9/192). High grade dysplasia and cancer were detected with both protocols. Five low grade dysplasias were detected (two with acetic acid, four with nontargeted biopsies; one lesion was detected with both techniques). A total of 2139 biopsies were taken in the nontargeted arm and 226 in the acetic acid arm. Both patients and clinicians found the acetic acid technique acceptable. Based on these data, a noninferiority, tandem, crossover trial would require an estimated 2828 patients. Conclusions We demonstrated the feasibility of performing a crossover endoscopy trial in Barrett’s surveillance. Low neoplasia yield makes this design necessary and qualitative results demonstrated patient and clinician acceptance. The reduced numbers of biopsies suggest that the acetic acid technique could result in cost savings, providing the lack of missed pathology can be proven in a fully powered definitive trial.

This study assesses the role of [18F] FDG PET/CT, fine needle aspiration (FNA) cytology and ultrasound in the 1&ndash, 2% of patients with focally positive thyroid nodules on FDG PET/CT. All FDG PET/CT scans with focally increased thyroid FDG PET/CT uptake performed over 37 months in one institution were matched to patients undergoing thyroid FNA. Diffuse FDG PET/CT uptake patients were excluded. A total of 47 patients showed focally increased thyroid uptake. Consistent with previous studies, 18 (38.2%) patients had malignancy&mdash, 12 primary thyroid carcinoma, 1 parathyroid carcinoma, 3 metastatic carcinoma to the thyroid and 2 lymphoma. A total of 15 (31.9%) lesions categorized as non-malignant contained H&uuml, rthle cells/oncocytes. A total of 14 lesions (29.8%) had focally increased FDG PET/CT uptake with no specific cytological or histopathological cause identified. No focally PET avid H&uuml, rthle cell/oncocytic lesions were found to be malignant. Exclusion of oncocytic lesions increased the calculated risk of malignancy (ROM) of focally PET avid nodules from 38% to 68%. It may be useful to exclude focally FDG PET/CT avid H&uuml, rthle cell/oncocytic lesions, typically reported as follicular neoplasm or suspicious for a follicular neoplasm, H&uuml, rthle cell type (Oncocytic) type, RCPath Thy 3F: Bethesda IV or sometimes Thy 3a: Bethesda III FNAs) from ROM calculations. Oncocytic focally PET/CT FDG avid lesions appear of comparatively lower risk of malignancy and require investigation or operation but these lesions should be readily identified by FNA cytology on diagnostic work up of focally PET avid thyroid nodules.

Background and study aims Barrett’s esophagus is a potentially pre-cancerous condition, affecting 375,000 people in the UK. Patients receive a 2-yearly endoscopy to detect cancerous changes, as early detection and treatment results in better outcomes. Current treatment requires random mapping biopsies along the length of Barrett’s, in addition to biopsy of visible abnormalities. As only 13 % of pre-cancerous changes appear as visible nodules or abnormalities, areas of dysplasia are often missed. Acetic acid chromoendoscopy (AAC) has been shown to improve detection of pre-cancerous and cancerous tissue in observational studies, but no randomized controlled trials (RCTs) have been performed to date. Patients and methods A “tandem” endoscopy cross-over design. Participants will be randomized to endoscopy using mapping biopsies or AAC, in which dilute acetic acid is sprayed onto the surface of the esophagus, highlighting tissue through an whitening reaction and enhancing visibility of areas with cellular changes for biopsy. After 4 to 10 weeks, participants will undergo a repeat endoscopy, using the second method. Rates of recruitment and retention will be assessed, in addition to the estimated dysplasia detection rate, effectiveness of the endoscopist training program, and rates of adverse events (AEs). Qualitative interviews will explore participant and endoscopist acceptability of study design and delivery, and the acceptability of switching endoscopic techniques for Barrett's surveillance. Results Endoscopists’ ability to diagnose dysplasia in Barrett’s esophagus can be improved. AAC may offer a simple, universally applicable, easily-acquired technique to improve detection, affording patients earlier diagnosis and treatment, reducing endoscopy time and pathology costs. The ABBA study will determine whether a crossover “tandem” endoscopy design is feasible and acceptable to patients and clinicians and gather outcome data to power a definitive trial.

Background - Correlation of cytologic and ultrasound findings is extremely valuable for the cytopathologist in management of thyroid nodules.Methods - Ultrasound scans (US) of all thyroid FNA taken over a 13 month period and reported by a single cytologist were reviewed at the time of reporting, focusing on aspirates that were non-diagnostic/unsatisfactory, equivalent to Bethesda Class I, UK Royal College of Pathologists Class Thy1 or Thy1c.Results - FNA cases [68 (40.7%)] were classified as Thy1, equivalent to Bethesda Class I. US of 3 Thy1 cases were not available for review. On cytologist US review 9 cases were classified as pure cystic, 28 as mixed cystic/solid, 12 as predominantly solid/focally cystic and 16 as purely solid. 27 (41.5%) of cases on cytological assessment were Thy1 and showed no evidence of a cyst on US, 17 (26.1%) were Thy1/Thy1c showing features suggestive of a possible cyst and 21 (32.3%) were Thy1c showing definite features of a cyst. Fifteen of 16 (93.7%) of pure solid cases on US were Thy1, equivalent to Bethesda Class I and all 9 (100%) of cases that were pure cystic on US were reported as Thy1c—equivalent to Bethesda Category I—cyst fluid only (P Conclusion - Cytopathologist review of thyroid US is extremely useful and can be helpful in triaging patients for further management in cases of solid, mixed cystic and/or solid, and pure cystic thyroid lesions with non-diagnostic/unsatisfactory thyroid FNA.

The UK Royal College of Pathologists (RCPath) ‘Thy’ terminology for reporting thyroid FNA cytology is a well-established national and also an international terminology system for cytology reporting which aligns with other international terminology systems: The Bethesda System for Reporting Thyroid FNA Cytopathology and the Italian, Japanese and Australian systems. There are now multiple peer-reviewed publications in the English language literature that utilise the UK RCPath Thyroid FNA terminology, and publications have now confirmed good interobserver reproducibility and its validity for patient management with risk(s) of malignancy and positive predictive value(s) established by audit for all ‘Thy’ categories of FNA, Thy1–Thy5. In the UK RCPath system, multidisciplinary management is emphasised, and the UK RCPath ‘Thy’ terminology is embedded in the multidisciplinary management and treatment recommendations in the 2014 British Thyroid Association Guidelines for the Management of Thyroid Cancer.

Introduction Barrett’s surveillance traditionally requires mapping biopsies to identify neoplasia. Acetic acid (AA) allows only targeted biopsies, potentially reducing the number of biopsies required. This study aims to compare neoplasia detection with AA targeted biopsies and protocol guided non-targeted biopsies during Barrett’s surveillance. Methods Multicentre randomised crossover feasibility study in UK secondary care. Patients under surveillance for Barrett’s metaplasia (>2 cm) with no history of dysplasia or cancer were recruited. All patients underwent two gastroscopies 8 weeks apart, one with AA guided biopsy of abnormal areas only (Portsmouth Protocol) and one with non-targeted mapping biopsies (Seattle Protocol). Neoplasia yield (low grade dysplasia LGD, high grade dysplasia (HGD) and cancer) from each strategy was evaluated and the number of biopsies recorded. Results 200 patients recruited from 6 centres. Mean age 66 years. 145 were male. Mean length C4M6. 175 patients completing both procedures. The prevalence of LGD, HGD and cancer was 11/192 (5.8%). All HGD and cancer was found with both protocols and confirmed with definitive treatment. One LGD was found with Portsmouth protocol not found with Seattle. 5 LGD were found with Seattle protocol not found with Portsmouth. This difference was not significant (p=0.2188), and on follow up gastroscopy no neoplastic changes were found in any of the LGD cases. 2139 biopsies were taken using Seattle protocol at a cost of £1 25 987 (306 biopsies per neoplasia, £18,023). 226 biopsies with Portsmouth Protocol at a cost of £13 311 (75 biopsies per neoplasia, £6,656) a 4 fold difference. In terms of HGD/cancer, 1070 biopsies/neoplasia found using Seattle protocol and 113 biopsies/neoplasia using Portsmouth Protocol, a 9.5 fold difference. Conclusions This is the first RCT comparing these techniques. No HGD or cancer was missed with either technique. There was a 4 fold reduction in biopsies per neoplasia detected with Portsmouth compared to Seattle protocol and a 9.5 fold difference when restricted to high risk neoplasia. If implemented nationally then this could lead to a massive reduction in histopathology work load and costs. LGD remains controversial and we believe inflammation could have resulted in false positive LGD as subsequent OGD and biopsies did not reveal any LGD. This feasibility data would support a definitive trial of AA targeted biopsies in a surveillance population.

Aims: To compare neoplasia detection with AA targeted biopsies and protocol guided non-targeted biopsies during Barrett's surveillance. Methods: Multicentre randomized crossover feasibility study. Patients under surveillance for Barrett's metaplasia with no history of dysplasia/cancer were recruited. All patients underwent two gastroscopies 8 weeks apart, one with AA guided biopsy of abnormal areas only (Portsmouth Protocol) and one with non-targeted mapping biopsies (Seattle Protocol). Neoplasia yield and no. biopsies from each strategy was evaluated. Results: 200 patients recruited from 6 centres. Mean age 66yrs. Mean length C4M6. 175 patients completed both procedures. The prevalence of LGD, HGD and cancer was 11/192 (5.8%). All HGD and cancer was found with both protocols and confirmed with definitive treatment. One LGD was found with Portsmouth protocol and 5 LGD with Seattle protocol. This difference was not significant, and on follow up gastroscopy no neoplastic changes were found in any of the LGD cases. 2139 biopsies were taken using Seattle protocol at a cost of £125,987 (306 biopsies/neoplasia). 226 biopsies with Portsmouth Protocol at a cost of £13,311 (75 biopsies/neoplasia) a 4 fold difference. In terms of HGD/cancer, 1070 biopsies/neoplasia found using Seattle protocol and 113 biopsies/neoplasia using Portsmouth Protocol, a 9.5 fold difference. Conclusions: This is the first RCT comparing these techniques. No HGD or cancer was missed with either technique. There was a 4 fold reduction in biopsies per neoplasia detected with Portsmouth compared to Seattle protocol and a 9.5 fold difference when restricted to high risk neoplasia. If implemented nationally then this could lead to a massive reduction in histopathology work load and costs. LGD remains controversial and we believe inflammation could have resulted in false positive LGD as subsequent OGD and biopsies did not reveal any LGD. This feasibility data would support a definitive trial of AA targeted biopsies in a surveillance population.

Molecular diagnosis of thyroid nodules has moved from a purely research technique to a routine clinical test in laboratories where it is available. The two principal methods currently are the Afirma test which functions as a rule-out test for indeterminate thyroid nodules, and other tests of varying complexity utilising mutational analysis of thyroid nodules e.g. the seven gene test and methods employing next-generation sequencing e.g. ThyroSeq2. This brief chapter discusses the mutational landscape of thyroid nodules and details the application of methods for molecular diagnosis of thyroid nodules in the context of our current knowledge of mutational profiling in benign thyroid nodules and thyroid carcinoma. There is also a brief discussion on prognostic and therapeutic strategies based around mutational profiling of thyroid lesions.

In this paper, we aim to focus on false positive results in the evaluation of thyroid aspirations, covering cystic, inflammatory, follicular and oncocytic lesions, papillary carcinoma, and medullary carcinoma of thyroid. The recently described entity noninvasive follicular thyroid neoplasm with papillary-like nuclear features is also discussed detailing the impact of its introduction on the sensitivity and specificity of thyroid FNA, as well as the use of molecular tests for diagnostics. Medicolegal issues in relation to current practice in English law are also described. This paper review the main causes of false positives in thyroid FNA and give some tips in how to avoid these mistakes.

This review summarises molecular pathological techniques applicable to thyroid FNA. The molecular pathology of thyroid tumours is now fairly well understood. Molecular methods may be used as a rule-in test for diagnosis of malignancy in thyroid nodules, eg BRAF V600E point mutation, use of a seven-gene mutational panel (BRAF V600E, RAS genes, RET/PTC or PAX8/PPARG rearrangement), or as a comprehensive multigene next-generation sequencing panel, eg ThyroSeq v2. Molecular methods can also be applied as rule-out tests for malignancy in thyroid nodules, eg Afirma or ThyroSeq v2 or as markers of prognosis, eg TERT promoter mutation or other gene mutations including BRAF V600E, TP53 and AKT1, and as tests for newly defined tumour entities such as non-invasive follicular thyroid neoplasm with papillary like nuclei, or as a molecular marker(s) for targeted therapies. This review describes practical examples of molecular techniques as applied to thyroid FNA in routine clinical practice and the value of molecular diagnostics in thyroid FNA. It describes the range of molecular abnormalities identified in thyroid nodules and thyroid cancers with some practical applications of molecular methods to diagnosis and prognosis of thyroid nodules and thyroid cancer.

AimsTo ascertain whether BRAF V600 mutational analysis is useful for diagnosis of thyroid cancer in thyroid fine needle aspirate (FNA).MethodsOver 8 months thyroid FNAs reported as Thy 3F (neoplasm possible/suggestive of follicular neoplasm), Thy4 (suspicious of malignancy) and Thy 5 (malignant) were tested for BRAF V600 mutation and managed as malignant if mutations were present.ResultsOf 207 FNAs from 176 patients, 5 were Thy 5, 19 Thy 4, 36 Thy 3f, 13 Thy 3a, 84 Thy 2 and 50 Thy 1. 11 Thy 3f, 15 Thy 4 and 3 Thy 5 FNAs were tested for BRAF V600 mutation. 0 Thy 3F cases, 6 Thy 4 and 1 Thy 5 (24% of the total tested) showed evidence of mutation. Four patients with BRAF V600 mutation underwent surgery to remove all thyroid tissue, two patients received a lobectomy and one patient is awaiting thyroidectomy. All patients with BRAF V600 mutation were found to have malignancy on final histology, with a diagnostic sensitivity for malignancy excluding coincidental microcarcinoma of 43% and specificity of 100%.ConclusionsBRAF V600 mutational analysis can enable single-stage total thyroidectomy for carcinoma if gene mutation is present in preoperative FNA. BRAF V600 co-testing may reduce the need for completion thyroidectomy with implied cost savings and lower patient morbidity associated with completion thyroidectomy when the cytology is inconclusive but where BRAF V600 mutation is identified in preoperative thyroid FNA.

Introduction While fine needle aspiration cytology (FNAC) is the mainstay of diagnosis in thyroid nodules, molecular markers of thyroid cancer have recently been shown to be of value in improving the diagnosis and reducing the rates of unnecessary surgery. Method A technical method is presented for the assessment of the BRAF V600 gene mutation in thyroid cancer using a simple adaptation of a commercially available kit. After standard preparation and reporting of conventionally stained alcohol-fixed Papanicolaou or air-dried Giemsa-stained slides the coverslip is removed from one slide, the DNA is extracted and submitted for PCR analysis. Results Assessment of the BRAF V600 mutational status is feasible in very small quantities of DNA, requiring just greater than 5 ng per case from a single pre-stained FNA slide using this method. From the 14 cases examined thus far, one Thy4/Bethesda Class V case (suspicious of malignancy) has been identified with a BRAF V600 mutation and this patient, after multidisciplinary discussion, received a total thyroidectomy. Conclusion Based on this methodology and other published results for the BRAF mutation, we believe that it is now feasible and cost effective for the UK NHS to BRAF co-test all Thy4/Bethesda Class V thyroid FNAs, as the additional cost of BRAF testing will still be much less than the cost of submitting all Thy4 (Bethesda Class V) patients to a partial and then a later completion thyroidectomy.

The histopathological features of thyroid cancers can be used to risk stratify patients, allowing prognostication and treatment decisions. A detailed accurate histological assessment by experienced pathologists working within a multidisciplinary context is crucial. Experience is also essential for interpretation of preoperative thyroid cytology specimens, which can be challenging. There is now more international harmonisation of numerical reporting systems for thyroid cytology. Understanding of the molecular basis of thyroid cancer has increased dramatically in recent years. Preoperative molecular pathology testing, when available, can refine cytological diagnosis to rule in or out for surgery, as well as assisting prognostication and enabling targeted treatment for thyroid tumours.

The encapsulated and noninvasive follicular variant of papillary thyroid carcinoma has been recently reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). These tumors demonstrate indolent behavior. This change in nomenclature will have great clinical impact by avoiding overtreatment of patients with NIFTP lesions who in the past were diagnosed with thyroid carcinoma and typically received completion thyroidectomy followed by radioactive iodine ablation. The pathologic diagnosis of NIFTP requires surgical removal of the thyroid lesion or the lobe harboring it, and thorough sampling of the complete interface between the tumor capsule and the thyroid parenchyma, to exclude foci of invasion. From a cytologic point of view, the unequivocal differential diagnosis between NIFTP and infiltrative follicular variant of papillary thyroid carcinoma in fine-needle aspiration is close to impossible based on cellular and architectural features. Therefore, use of adjunct molecular testing on fine-needle aspiration specimens may be essential for the preoperative diagnosis of low-risk tumors such as NIFTP for appropriate patient management. This review discusses and summarizes the existing known literature on molecular characteristics of NIFTP tumors, so far reported, including cases retrospectively classified or prospectively diagnosed as NIFTP. Brief reference is also made to new and promising approaches applicable to the diagnosis of this tumor.

Worldwide the rising incidence of cancer is attributed to ageing populations, environmental and lifestyle factors, and increased cancer surveillance. Cancer surveillance leads to increased early detection of indolent cancers, and in some cases to cancer ‘overdiagnosis’.1 In the thyroid, the increased incidence of thyroid cancer and cancer detection is primarily due to widespread use of thyroid ultrasound.2 This excess of newly diagnosed thyroid cancers occurs almost entirely because of greater detection of papillary thyroid cancers, a tumour which under the microscope shows a characteristic papillary growth pattern together with typical nuclear features. Follicular variant of papillary thyroid carcinoma (FVPTC) is one of two major subtypes of papillary thyroid cancer. The encapsulated type of FVPTC (eFVPTC), a tumour that under the microscope shows no invasion of surrounding thyroid, blood vessels or lymphatics, has increased in incidence 2–3 times over the last 20–30 years. eFVPTC is now estimated …

Importance - Although growing evidence points to highly indolent behavior of encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC), most patients with EFVPTC are treated as having conventional thyroid cancer.Objective - To evaluate clinical outcomes, refine diagnostic criteria, and develop a nomenclature that appropriately reflects the biological and clinical characteristics of EFVPTC.Design, Setting, and Participants - International, multidisciplinary, retrospective study of patients with thyroid nodules diagnosed as EFVPTC, including 109 patients with noninvasive EFVPTC observed for 10 to 26 years and 101 patients with invasive EFVPTC observed for 1 to 18 years. Review of digitized histologic slides collected at 13 sites in 5 countries by 24 thyroid pathologists from 7 countries. A series of teleconferences and a face-to-face conference were used to establish consensus diagnostic criteria and develop new nomenclature.Main Outcomes and Measures - Frequency of adverse outcomes, including death from disease, distant or locoregional metastases, and structural or biochemical recurrence, in patients with noninvasive and invasive EFVPTC diagnosed on the basis of a set of reproducible histopathologic criteria.Results - Consensus diagnostic criteria for EFVPTC were developed by 24 thyroid pathologists. All of the 109 patients with noninvasive EFVPTC (67 treated with only lobectomy, none received radioactive iodine ablation) were alive with no evidence of disease at final follow-up (median [range], 13 [10-26] years). An adverse event was seen in 12 of 101 (12%) of the cases of invasive EFVPTC, including 5 patients developing distant metastases, 2 of whom died of disease. Based on the outcome information for noninvasive EFVPTC, the name "noninvasive follicular thyroid neoplasm with papillary-like nuclear features" (NIFTP) was adopted. A simplified diagnostic nuclear scoring scheme was developed and validated, yielding a sensitivity of 98.6% (95% CI, 96.3%-99.4%), specificity of 90.1% (95% CI, 86.0%-93.1%), and overall classification accuracy of 94.3% (95% CI, 92.1%-96.0%) for NIFTP.Conclusions and Relevance - Thyroid tumors currently diagnosed as noninvasive EFVPTC have a very low risk of adverse outcome and should be termed NIFTP. This reclassification will affect a large population of patients worldwide and result in a significant reduction in psychological and clinical consequences associated with the diagnosis of cancer.

The overall interobserver reproducibility of thyroid fine-needle aspiration (FNA) has not been comprehensively assessed. A blinded 6-rater interobserver reproducibility study was conducted of 200 thyroid FNA cases using the UK System, which is similar to The Bethesda System for Reporting Thyroid Cytology: Thy1, nondiagnostic; Thy2, nonneoplastic; Thy3a, atypia, probably benign; Thy3f, follicular lesion; Thy4, suspicious of malignancy; and Thy5, malignant. There was good interobserver agreement for the Thy1 (κ = 0.69) and Thy5 (κ = 0.61), moderate agreement for Thy2 (κ = 0.55) and Thy3f (κ = 0.51), and poor agreement for Thy3a (κ = 0.11) and Thy4 (κ = 0.17) categories. Combining categories implying surgical management (Thy3f, Thy4, and Thy5) achieved good agreement (κ = 0.72), as did combining categories implying medical management (Thy1, Thy2, and Thy3a; κ = 0.72). The UK thyroid FNA terminology is a reproducible and clinically relevant system for thyroid FNA reporting. This study demonstrates that international efforts to harmonize and refine thyroid cytology classification systems can improve consistency in the clinical management of thyroid nodules.

A 47-year-old white man was admitted to the hos ith dysuria, generalized weakness, and volume depleti hree days before admission, he was treated with amox in for a urinary tract infection caused by Escherichia coli, hich was believed to be the precipitating cause of his llness. He reported a 2-year history of polyuria and pol ia. There was no history of problems with blood pressu ther medical conditions. He had 8 siblings with no si ant medical history, in addition to twins who were still e had attended a special-needs school as a child. On physical examination, he was clinically volume leted with a pulse rate of 120 beats/min and supine sy lood pressure of 70 mm Hg. He was in acute renal ith a urea level of 84 mg/dL (30.1 mmol/L) and crea evel of 3.3 mg/dL (293 mol/L). He had severe hypokal ic alkalosis with a potassium level of 1.4 mE 1.4 mmol/L) and bicarbonate level of 41.1 mEq/L ( mol/L). He was also hyponatremic, with a sodium lev 25 mEq/L (125 mmol/L), and hypomagnesemic, with m esium level of 1.1 mg/dL (0.47 mmol/L), but serum ium level was normal. Urine dipstick results showed protein of and a trac f blood. A 24-hour urine sample showed nephrotic-ra

Extracapsular nodal spread is a major prognostic indicator in head and neck cancer. Nitric oxide (NO), primarily produced by the enzyme inducible NO synthase (iNOS), has a large number of actions in cancer biology, but no studies have investigated its possible role in extracapsular spread or tumor invasion.Immunochemistry was used to study iNOS expression in 48 patients with either extracapsular or encapsulated metastasis. In vitro invasion assays were performed using H357 (an oral squamous cell carcinoma cell line) using the iNOS inhibitor drug, 1400 W.iNOS expression was significantly associated with extracapsular spread, with 22/27 cases showing positive iNOS expression compared with 8/21 cases in the encapsulated group (p = .01). Invasion of H357 cells was inhibited by 1400 W at concentrations of 100 microM and 1 mM (p = .002, p = .003).iNOS protein seems to be associated with extracapsular spread and invasion in head and neck cancer. Further studies are required to understand this role more fully.

Background: The demand for screening for coeliac disease has grown rapidly over the last few years. Laboratories depending on immunofluorescence assays are faced with an increasing workload using a labour-intensive test, and an alternative to this test has been sought. This study compares tissue transglutaminase (TTG) and endomysium antibodies (EMA) in a routine clinical laboratory situation. Methods: An immunofluorescence IgA EMA test was compared with a guinea pig TTG antibody ELISA for 816 unselected requests for gut antibody screening. Discrepant results were investigated more fully using a variety of human source TTG antigen kits. Results: Guinea pig TTG ELISA and EMA assays showed agreement for 93·6% of samples. Four samples were misclassified and 48 samples gave false positive TTG results. Study of 46 EMA samples (this group included 39 of the 'discrepant' negative EMA/positive guinea pig TTG group) using three different human purified and/or recombinant TTG sources showed that 42 patients had no TTG antibodies using human sources, three were misclassified and one patient had negative EMA and positive TTG results that could not be readily explained. Further study of 32 EMA positive samples showed almost complete agreement between the human source TTG kits. Conclusions: We can recommend the replacement of EMA with ELISA for TTG antibodies for the routine screening for coeliac disease, but all positive TTG antibodies should still be followed up with IgA EMA and samples should be screened for IgA deficiency.

There have been many recent developments in thyroid fine-needle aspiration (FNA). Thyroid fine-needle aspiration was traditionally practised freehand although in recent years the majority of thyroid fine-needle aspirations are now taken under ultrasound guidance.1 While thyroid fine-needle aspiration practice has changed relatively little, new molecular technologies have developed apace. The principal new technology is the application of molecular markers to thyroid fine-needle aspirates.2 The prototypical marker is BRAF V600E. Mutations of the BRAF V600 gene in thyroid cancer were described over 10 years ago and are quite common in thyroid cancer, melanoma and adenocarcinomas, such as lung and colorectal tumours.3 Mutation of the BRAF V600E within primary tumours of the …

BACKGROUND Although fine-needle aspiration (FNA) of the thyroid is the key preoperative investigation of thyroid lesions, there are overlaps in the criteria for diagnosis of certain lesions, particularly important among which are those for follicular neoplasms. A proposal for a 5-category working system for thyroid FNA diagnosis is presented, devised using clearly defined diagnostic guidelines with a prospective 2-year evaluation in 1 center. METHODS The results of FNA of 156 patients with nodular thyroid lesions are presented. All patients were observed over a 2-year period in a multidisciplinary thyroid clinic. In some cases, the aspirates were repeated before excision of the lesion. The results of the FNA are classified by worst category for each patient, according to a 5-category scheme: THY1: inadequate; THY2: benign; THY3: indeterminate; THY4: suspicious lesion; THY5: malignant. RESULTS Seventy-five of the 156 patients (48.1%) proceeded to excision, of these 50 (67%) showed multinodular goiter or adenomatoid nodule within a goiter, 7 (9.3%) showed evidence of Hashimoto thyroiditis or lymphocytic thyroiditis alone, 1 (1.3%) showed evidence of Reidel thyroiditis, and 1 (1.3%) showed evidence of a parathyroid cyst. Eight patients (11%) showed evidence of follicular adenoma, and 5 patients (6.6%) showed papillary carcinoma; 1 (1.3%) showed follicular carcinoma, and 2 (2.7%) showed lymphoproliferative disease. There was a significant difference in the number of benign as compared with neoplastic thyroid lesions excised in the indeterminate (THY3) (2 of 13 [15%]) as compared with the suspicious categories (THY4) (10 of 24 [42%]), (P = 0.05). Although no false-negative FNAs were identified in this series, there was 1 false-positive (THY5) FNA. CONCLUSIONS The use of an indeterminate (THY3) category is helpful because it improves the diagnostic efficacy of thyroid FNA. The indeterminate (THY3) category is clinically useful and may markedly reduce or eliminate false-negative FNA in many patients with thyroid nodules. Cancer (Cancer Cytopathol) 2000;90:239–44. © 2000 American Cancer Society.

Aim The purpose of this survey was to ascertain reporting habits of pathologists towards sessile serrated adenomas/polyps (SSA/P). Methods A questionnaire designed to highlight diagnostic criteria, approach and clinical implications of SSA/P was circulated electronically to 45 pathologists in the UK and North America. Results Forty-three of 45 pathologists agreed to participate. The vast majority (88%) had a special interest in gastrointestinal (GI) pathology, had great exposure to GI polyps in general with 40% diagnosing SSA/P at least once a week if not more, abnormal architecture was thought by all participants to be histologically diagnostic, and 11% would make the diagnosis if a single diagnostic histological feature was present in one crypt only, while a further 19% would diagnose SSA/P in one crypt if more than one diagnostic feature was present. The vast majority agreed that deeper sections were useful and 88% did not feel proliferation markers were useful. More than one-third did not know whether, or did not feel that, their clinicians were aware of the implications of SSA/P. Conclusions 98% of pathologists surveyed are aware that SSA/P is a precursor lesion to colorectal cancer, the majority agree on diagnostic criteria, and a significant number feel that there needs to be greater communication and awareness among pathologists and gastroenterologists about SSA/P.

ObjectiveFew studies have modelled the economics of thyroid FNA.MethodsA simple spreadsheet economic model for delivery of thyroid fine needle aspiration (FNA) cytology is described using the UK Royal College of Pathologists’ Classification for thyroid FNA which is based on The Bethesda System for Reporting Thyroid Cytopathology.ResultsWe show an estimated 27.8% cost treatment reduction per patient if low rates of non-diagnostic for cytological diagnosis (Thy 1) and neoplasm possible atypia/non-diagnostic (Thy 3a) are achieved, which require rapid onsite FNA adequacy assessment of aspiration samples. If we assume that the number of thyroid FNAs performed in the UK annually is around 500 per million, and the UK population is 62 million, this could save the UK National Health Service significant sums, as the additional cost per patient treated in this model varies from £781 for a scenario with ultrasound guided FNA and inclinic cell adequacy assessment to £998 where aspirates are taken in conventional fashion without any inclinic adequacy assessment.ConclusionsThis model makes a strong economic case for the introduction of rapid onsite assessment of thyroid FNA across cancer networks, to improve the diagnostic efficacy of thyroid FNA.

A series of 346 patients with primary operable breast cancer and a series of 145 patients with advanced breast cancer were investigated for c-erbB-3 protein expression using the monoclonal antibody RTJ1. Formalin-fixed, paraffin-embedded tumour samples were stained using a standard immunochemical method and staining was assessed on a four-point scale. The study aimed to observe the expression of the c-erbB-3 protein and investigate any relationship between expression and established prognostic indicators and prognosis. In both the primary and advanced series breast tumour tissue was found to stain heterogeneously for c-erbB-3. The staining was observed to be predominantly cytoplasmic and the majority of tumours exhibited moderate positivity. However, 15% and 35% of cases in the primary operable and advanced series respectively displayed strong positive staining. No significant difference was found between the staining in the primary and advanced series. In the primary operable breast cancers, no significant associations were demonstrated with overall survival, disease-free interval, regional recurrence, the presence of distant metastases, age, menopausal status, oestrogen receptor status, histological grade, lymph node stage, vascular invasion and c-erbB-2 protein expression. However, a significant association was seen between the degree of c-erbB-3 immunoreactivity and both tumour size (P < 0.01) and tumour type prognostic group (P = 0.05). No overall association with local recurrence was seen when the four groups of c-erbB-3 expression were analysed (P = 0.12), but when those tumours showing no or weak staining were compared with those showing moderate and strong immunoreactivity it was seen that the latter were significantly more likely to develop local recurrence (P = 0.03). In the series of patients with advanced disease, no significant associations were demonstrated with survival, UICC criteria, age, menopausal status, oestrogen receptor status, histological grade, c-erbB-2 status or the presence of vascular invasion. In conclusion this study found variable expression of c-erbB-3 protein in human breast carcinoma and an association with some recognised prognostic factors in those patients with primary operable breast carcinoma. It seems, however, unlikely that c-erbB-3 protein expression will emerge as a powerful enough prognostic factor to be of value in clinical practice. Images Figure 1 Figure 2

BACKGROUND There is controversy and confusion regarding therapy for patients with ductal carcinoma in situ (DCIS) of the breast. The Van Nuys Prognostic Index (VNPI) was developed to aid in the complex treatment selection process. METHODS The VNPI combines three significant predictors of local recurrence: tumor size, margin width, and pathologic classification. Scores of 1 (best) to 3 (worst) were assigned for each of the 3 predictors and then totaled to give an overall VNPI score ranging from 3 to 9. Three hundred thirty-three patients with pure DCIS treated with breast preservation (195 by excision only and 138 by excision plus radiation therapy) were studied with detection of local recurrence as the end point. RESULTS There was no statistical difference in the 8 year local recurrence free survival in patients with VNPI scores of 3 or 4, regardless of whether or not radiation therapy was used (100% vs. 97%; P = not significant). Patients with VNPI scores of 5, 6, or 7 received a statistically significant 17% local recurrence free survival benefit when treated with radiation therapy (85% vs. 68%; P = 0.017). Patients with scores of 8 or 9, although showing the greatest relative benefit from radiation therapy, experienced local recurrence rates in excess of 60% at 8 years. CONCLUSIONS DCIS patients with VNPI scores of 3 or 4 can be considered for treatment with excision only. Patients with intermediate scores (5, 6, or 7) show a 17% decrease in local recurrence rates with radiation therapy. Patients with VNPI scores of 8 or 9 exhibit extremely high local recurrence rates, regardless of irradiation, and should be considered for mastectomy. Cancer 1996;77:2267-74.

We present a new prognostic classification designated the Van Nuys classification for ductal carcinoma-in-situ (DCIS). The classification combines high nuclear grade and comedo-type necrosis to predict clinical recurrence. Three groups of DCIS patients were defined by the presence or absence of high nuclear grade and comedo-type necrosis: 1--non-high-grade DCIS without comedo-type necrosis, 2--non-high-grade DCIS with comedo-type necrosis, 3--high-grade DCIS with or without comedo-type necrosis. There were 31 local recurrences in 238 patients after breast-conservation surgery 3.8% (3/80) in group 1, 11.1% (10/90) in group 2, and 26.5% (18/68) in group 3. The 8-year actuarial disease-free survivals were 93%, 84%, and 61%, respectively (all p < or = 0.05). The Van Nuys classification defines three distinct and easily recognisable groups, each of which has a different likelihood of local recurrence if treated with breast conservation.

The immunohistochemical expression of the aspartyl protease enzyme cathepsin D was examined in a consecutive series of 103 primary operable breast carcinomas with the polyclonal antibody NCL-CDp. Expression of cathepsin D was identified within the epithelial and stromal components of all tumours examined. No significant associations of increased cathepsin D expression in the epithelial tumour component with conventional prognostic indices such as tumour size, grade, lymph node stage, or patient survival were identified. However, significant associations of increased stromal cathepsin D expression and high tumour grade, chi 2 = 11.40 (df = 2), p = 0.003; increased tendency to local recurrence, chi 2 = 6.87 (df = 1), p = 0.009; regional recurrence, chi 2 = 7.44 (df = 1), p = 0.006; poorer disease free survival, chi 2 = 14.9 (df = 1), p = 0.0001; and poorer overall patient survival, chi 2 = 6.90 (df = 1), p = 0.0086, were identified. Cathepsin D expression is present in all breast tumours. Stromal cathepsin D expression is a neglected immunohistochemical prognostic parameter which could explain some of the previous apparently conflicting reports concerning the effect on patient prognosis of biochemical (i.e. total) and immunohistochemical estimations of cathepsin D in breast cancers.

Aims (1) To compare the use of scanned virtual slide images (virtual microscopy) with glass slides (conventional microscopy) in the assessment of morphological characteristics of breast cancers within the setting of the Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH), involving a cohort of women under 40 years of age, presenting with breast cancer. (2) To assess the acceptability to histopathologists of the use of virtual slide images. Methods 13 histopathologists from the UK and Australia participated in the POSH pathology review. The observers were asked to assess multiple morphological features such as tumour grade and type. Comparisons were made for a single observer using both virtual images and glass slides. Intra- and inter-observer variability was calculated using the k statistic and a comparison was made between the use of each image modality. Results Diagnostic performance with virtual slides was comparable to conventional microscopic assessment, with the measurement of agreement best for vascular invasion, necrosis and the presence of a central scar (k¼0.37e0.78), and poor for more subjective parameters such as pleomorphism, stroma, the nature of the tumour border and the degree of lymphocytic infiltrate (k¼0.1). Conclusion Virtual slides represent an acceptable methodology for central review of breast cancer histopathology and can circumvent the need for either travel to view material, or the potential problems of sending it by post.

Background & Aims Esophageal adenocarcinoma (EA) is increasingly common among patients with Barrett's esophagus (BE). We aimed to provide consensus recommendations based on the medical literature that clinicians could use to manage patients with BE and low-grade dysplasia, high-grade dysplasia (HGD), or early-stage EA. Methods We performed an international, multidisciplinary, systematic, evidence-based review of different management strategies for patients with BE and dysplasia or early-stage EA. We used a Delphi process to develop consensus statements. The results of literature searches were screened using a unique, interactive, Web-based data-sifting platform; we used 11,904 papers to inform the choice of statements selected. An a priori threshold of 80% agreement was used to establish consensus for each statement. Results Eighty-one of the 91 statements achieved consensus despite generally low quality of evidence, including 8 clinical statements: (1) specimens from endoscopic resection are better than biopsies for staging lesions, (2) it is important to carefully map the size of the dysplastic areas, (3) patients that receive ablative or surgical therapy require endoscopic follow-up, (4) high-resolution endoscopy is necessary for accurate diagnosis, (5) endoscopic therapy for HGD is preferred to surveillance, (6) endoscopic therapy for HGD is preferred to surgery, (7) the combination of endoscopic resection and radiofrequency ablation is the most effective therapy, and (8) after endoscopic removal of lesions from patients with HGD, all areas of BE should be ablated. Conclusions We developed a data-sifting platform and used the Delphi process to create evidence-based consensus statements for the management of patients with BE and early-stage EA. This approach identified important clinical features of the diseases and areas for future studies.

Purpose : C-erbB-2 oncogene expression is found in 60% of DCIS cases. C-erbB-2 expression in DCIS has been shown to correlate with comedo subtype, large cell size, lymphoid infiltrate, nuclear pleomorphism, multinucleation and high mitotic rate. These findings have led to the suggestion that the subgroup of DCIS that expresses c-erbB-2 may be a biologically definable category with prognostic significance. The purpose of this study was to identify any differences in the mammographic appearances between DCIS which expresses c-erbB-2 and DCIS that does not express this oncogene. Materials and Methods : C-erbB-2 staining characteristics and preoperative mammograms were available for review in 126 patients with pure DCIS. All the mammograms were reviewed by a radiologist knowing the patient had DCIS but without any further pathological or immunohistochemical information. Results : C-erbB-2 positive DCIS showed the following features more commonly than c-erbB-2 negative disease: calcification (65 of 71 (92%) vs 28 of 39 (72%), P P P P P Conclusion : We have demonstrated significant differences in the mammographic features of c-erbB-2 positive and negative disease. As c-erbB-2 expression has been shown to correlate with aggressive histological features, the differences in the mammographic appearances between c-erbB-2 positive and c-erbB-2 negative DCIS may be of practical value.

Ductal carcinoma in situ shows heterogeneous clinical behavior and response to treatment depending on its pathologic features. The aim of this study was to correlate the radiologic and pathologic features of ductal carcinoma in situ of the breast. Differences, if present, may allow refinement of diagnosis and selection of treatment options.The mammograms of 128 patients with ductal carcinoma in situ of the breast were analyzed by a radiologist who knew that the patients had ductal carcinoma in situ but had no other pathologic information. The radiologic and pathologic features of subgroups characterized according to cell size and presence of necrosis were then compared. Statistical comparisons were made by using the chi 2- and Fisher's exact tests.Patients with small-cell ductal carcinoma in situ more commonly have a normal mammogram (28% vs 6%, respectively, p.001) or an abnormal mammogram without calcification (42% vs 5%, respectively, p.001) than do patients with large-cell ductal carcinoma in situ. Among patients with abnormal mammographic findings, calcification is present in 58% of those with small-cell ductal carcinoma in situ, compared with 95% of those with large-cell ductal carcinoma in situ (p.001). No significant differences were found in the calcification morphology of small- and large-cell ductal carcinoma in situ. These features were seen more commonly in ductal carcinoma in situ with necrosis than in ductal carcinoma in situ without necrosis, respectively: abnormal mammographic findings (95% vs 73%, p.001), calcification (96% vs 61%, p.001), calcification with a ductal distribution (80% vs 45%, p.005), and rod-shaped calcification (83% vs 45%, p.001). An abnormal mammogram without calcification (39% vs 4%, p.001) or predominantly punctate calcification (36% vs 13%, p.05) was seen more commonly in ductal carcinoma in situ without necrosis than in ductal carcinoma in situ with necrosis, respectively.We have shown that the radiologic features of ductal carcinoma in situ vary according to cell size and the presence of necrosis in particular. Necrosis has been found to be a feature of more biologically aggressive in situ breast cancer, so these findings may be of practical value in deciding the management of indeterminate calcification clusters and whether to offer breast conservation.

To compare the mammographic and pathologic features of screening-detected and symptomatic ductal carcinoma in situ (DCIS).The mammographic and pathologic features of 54 screening-detected and 77 symptomatic cases of DCIS were compared. Patients were aged 30-76 years (mean, 58 years).Diffuse involvement was seen in 10 patients (13%) with symptoms but in none of the screening-detected group (P.05). The disease was radiologically more extensive in the symptomatic group. Calcifications in the symptomatic group (n = 48) were less likely to have a ductal distribution than those in the screening-detected group (n = 48) (30 [63%] vs 40 [83%], respectively; P.05). At histologic examination in some cases, the symptomatic group (n = 76) included eight (11%) patients with cribriform-micropapillary, large-cell tumors (P.05) and less comedocarcinoma (20 [26%] vs 23 [45%], respectively; P.05) compared with the screening-detected group (n = 51).The results show differences in the radiologic and pathologic features of screening-detected and symptomatic DCIS.

Fibromatosis of the breast is uncommon. The histopathology of this condition is well documented but the mammographic appearances are less well described. Three distinct mammographic appearances of this condition are presented — a stellate mass, an area of asymmetrical density with architectural distortion and a rapidly growing well-circumscribed mass. The latter two have not been previously described. All three of these mammographic appearances may be misinterpreted as representing primary breast carcinoma. The diagnosis and treatment implications of this condition are described.

The expression of oestrogen receptor protein (ER) was examined in 151 cases of symptomatic or screening detected pure ductal carcinoma in situ (DCIS) of the breast by immunocytochemical assay (ERICA), in formalin-fixed paraffin-embedded tissue, with the monoclonal antibody H 222 (Abbott). Forty-eight tumours (31.8%) of cases were ER positive. Twenty-seven (17.9%) of cases showed high level ER expression and 21 (13.9%) of cases showed low level ER immunoreactivity. Significant associations of positive tumour ER immunoreactivity and non-comedo architecture chi 2 = 6.76; (d.f. = 1): P < 0.001, small cell size chi 2 = 4.49; (d.f. = 1): P = 0.034, higher S-phase fraction chi 2 = 4.71; (d.f. = 1): P = 0.03 and lack of c-erbB-2 protein overexpression chi 2 = 7.96; (d.f. = 1): P < 0.01 were identified. No significant associations of ER expression and patient age, histological grade of necrosis in DCIS, or DNA ploidy were found. ER expression is detectable in less than one third of symptomatic and screening detected cases of DCIS, implying that endocrine therapy of DCIS may be a more appropriate form of management for morphological subtypes of DCIS which show higher rates of oestrogen receptor expression, particularly those of non-comedo and small cell type. Images Figure 1

We describe the case of a patient with Rett syndrome, a syndrome characterized by progressive infant encephalopathy, developmental delay, dementia, autism, ataxia, microcephaly, spastic paraparesis, and autonomic neuropathy with constipation. At colonoscopy, multiple foci of tiny white, sessile, polypoid lesions were seen throughout the colon and rectum, mimicking the appearances of small hyperplastic or adenomatous polyps, associated with generalized melanosis coli. This is the first case to our knowledge describing melanosis coli in a patient with Rett syndrome. As melanosis pigment deposition is characteristically not seen in lymphoid tissue, the lymphoid tissue was identifiable at endoscopy as multiple white nodules mimicking generalized colonic polyposis throughout the colon. We discuss the likely mechanisms of lymphoid hyperplasia and coexistent melanosis coli in Rett syndrome.

Background & Aims Diagnosis of Barrett's neoplasia requires collection of large numbers of random biopsy samples; the process is time consuming and can miss early-stage cancers. We evaluated the role of acetic acid chromoendoscopy in identifying Barrett's neoplasia. Methods Data were collected from patients with Barrett's esophagus examined at a tertiary referral center, between July 2005 and November 2008 using Fujinon gastroscopes and EPX 4400 processor (n = 190). All procedures were performed by a single experienced endoscopist. Patients were examined with white light gastroscopy and visible abnormalities were identified. Acetic acid (2.5%) dye spray was used to identify potentially neoplastic areas and biopsy samples were collected from these, followed by quadrantic biopsies at 2 cm intervals of the remaining Barrett's mucosa. The chromoendoscopic diagnosis was compared with the ultimate histological diagnosis to evaluate the sensitivity of acetic acid chromoendoscopy. Results Acetic acid chromoendoscopy had a sensitivity of 95.5% and specificity of 80% for the detection of neoplasia. There was a correlation between lesions predicted to be neoplasias by acetic acid and those diagnosed by histological analysis (r = 0.98). There was a significant improvement in the detection of neoplasia using acetic acid compared with white light endoscopy (P = .001). Conclusions Analysis of this large series showed that acetic acid-assisted evaluation of Barrett's esophagus detects neoplasia better than white light endoscopy, with sensitivity and specificity equal to that of histological analysis.

The expression of p53 protein, oestrogen receptor protein, epidermal growth factor receptor (EGFR) and overexpression of the c-erbB-2 oncoprotein was examined in a series of 149 primary symptomatic breast carcinomas. Expression of p53 was present in 62 of 146 cases (42.5%) of the invasive carcinoma and one of three cases (33.3%) of ductal carcinoma in situ (DCIS) examined. Statistical associations of tumour oestrogen receptor positivity and lack of p53 protein expression, chi 2 = 19.78 (d.f. = 1), P less than 0.001, positive tumour p53 status and poor tumour grade; chi 2 = 14.1 (d.f. = 2), P less than 0.001, EGFR expression chi 2 = 7.07, (d.f. = 1), P less than 0.01 and tumour c-erbB-2 protein overexpression; chi 2 = 4.61 (d.f. = 1), P = 0.032 were identified. Expression of p53 is rare in invasive lobular carcinoma of classical type (8.3% of cases examined) in contrast to other common types of mammary carcinoma. Non-significant trends of p53 protein expression and increased regional tumour recurrence; chi 2 = 3.20 (d.f. = 1), P = 0.074 and also poorer patient survival; chi 2 = 3.76 (d.f. = 1), P = 0.053 were identified. p53 protein expression is a common event in human breast cancer and is present in both DCIS and invasive mammary carcinoma. Abnormal expression of p53 protein is a feature of both in situ and invasive breast carcinoma, implying that the abnormal p53 protein expression may be implicated in the early stages of mammary carcinoma progression. Images Figure 1

Aim —To determine the frequency of skip lesions in an unselected series of temporal artery biopsies and compare the results with other series. Methods —The study was a retrospective review of 102 consecutive temporal artery biopsies taken in a five year period (1992–1997) in one large hospital. Results —35 cases (34.3%) showed evidence of active cranial vasculitis with pathological evidence of inflammation of the intima or media, with or without giant cells. Three of these cases (8.5%) showed apparent skip lesions: normal intima, media, and adventitia in one segment while in other segments there was clear evidence of active vasculitis. Immunocytochemical stains for leucocyte common antigen (LCA) and CD15 were helpful in identifying the absence of intimal or medial inflammatory cell infiltrates within skip lesions. Skip lesions have been described in up to 28.3% of cases in some series, while others have not found evidence of skip lesions or have identified them in a much smaller percentage of cases. Conclusions —In this series skip lesions were relatively rare, accounting for 8.5% of cases of active vasculitis. The degree of inflammation in temporal arteritis is discontinuous. Immunostaining for inflammatory cells, for example LCA and CD15, may be helpful in identifying the presence of an inflammatory cell infiltrate in skip lesion segments of the temporal artery.

The overexpression of the c-erbB-2 oncoprotein is now thought by most authors to be associated with adverse prognosis in breast carcinoma. In this study, we investigate the relationship between overexpression of the c-erbB-2 oncoprotein and nuclear size by morphometry in a series of 150 human breast carcinomas, comprising 65 cases of ductal carcinoma in situ (DCIS) and 85 cases of invasive adenocarcinoma. The mean nuclear size for c-erbB-2 positive cases of DCIS was 54.8 micron 2 and invasive carcinoma was 52.1 micron 2 respectively, in contrast with 41.6 micron 2 and 42.5 micron 2 for c-erbB-2 negative cases of DCIS and invasive carcinoma respectively. Flow cytometric examination of DNA in a subset of 91 of these tumours showed no association between tumour cell aneuploidy and c-erbB-2 overexpression. S-phase fraction could be calculated on 20 cases of DCIS and 48 invasive carcinomas. There was a strong association between c-erbB-2 overexpression, S-phase fraction (p less than 0.001) and proliferative index (p less than 0.001) in 20 cases of DCIS. A weak association of S-phase fraction and c-erbB-2 overexpression was seen in 48 invasive carcinomas (p = 0.047). This study confirms the subjective impression that there is a relationship between large tumour cell nuclear size and an overexpression of the c-erbB-2 oncoprotein, and also shows an association with increased tumour cell proliferation.

Introduction Fine needle aspiration cytology (FNAC) for salivary gland tumours requires expertise in interpretation. When a diagnosis is not clear (despite a cellular aspirate), published work is lacking on the value of repeating the test. Methods A retrospective study of 135 patients who had FNAC followed by definitive excision for a suspected salivary gland tumour. Accuracy was compared among those requiring repeat FNAC on one more occasion because of a non-diagnostic initial cytology report. Results 33 patients (24% of study group) had repeat FNAC. A definite cytological diagnosis was subsequently made in 27/33 patients (82%). The sensitivity (84%) and specificity (93%) of repeat FNAC in distinguishing benign from malignant tumours was similar to initial FNAC (70% and 95%, respectively). Conclusions Repeat FNAC may provide a cytological diagnosis in cases where the initial diagnosis is not clear, although cytology should be used in conjunction with other investigations of salivary tumours, including image-guided biopsy examination where appropriate. Ideally salivary gland FNAC should be interpreted by a specialist pathologist.

Objectives: Current models of clonal expansion in human Barrett’s oesophagus are based upon heterogenous, flow-purified biopsy analysis taken at multiple segment levels. Detection of identical mutation fingerprints from these biopsy samples led to the proposal that a mutated clone with a selective advantage can clonally expand to fill an entire Barrett’s segment at the expense of competing clones (selective sweep to fixation model). We aimed to assess clonality at a much higher resolution by microdissecting and genetically analysing individual crypts. The histogenesis of Barrett’s metaplasia and neo-squamous islands has never been demonstrated. We investigated the oesophageal gland squamous ducts as the source of both epithelial sub-types.\ud \ud Methods: Individual crypts across Barrett’s biopsy and oesophagectomy blocks were dissected. Determination of tumour suppressor gene loss of heterozygosity patterns, p16 and p53 point mutations were carried out on a crypt-by-crypt basis. Cases of contiguous neo-squamous islands and columnar metaplasia with oesophageal squamous ducts were identified. Tissues were isolated by laser capture microdissection and genetically analysed.\ud \ud Results: Individual crypt dissection revealed mutation patterns that were masked in whole biopsy analysis. Dissection across oesophagectomy specimens demonstrated marked clonal heterogeneity, with multiple independent clones present. We identified a p16 point mutation arising in the squamous epithelium of the oesophageal gland duct, which was also present in a contiguous metaplastic crypt, whereas neo-squamous islands arising from squamous ducts were wild-type with respect to surrounding Barrett’s dysplasia.\ud \ud Conclusions: By studying clonality at the crypt level we demonstrate that Barrett’s heterogeneity arises from multiple independent clones, in contrast to the selective sweep to fixation model of clonal expansion previously described. We suggest that the squamous gland ducts situated throughout the oesophagus are the source of a progenitor cell that may be susceptible to gene mutation resulting in conversion to Barrett’s metaplastic epithelium. Additionally, these data suggest that wild-type ducts may be the source of neo-squamous islands.

Introduction Endoscopic therapy of Barrett9s Oesophagus (BE) with high grade dysplasia (HGD) and/or intramucosal cancer (IMC) by endoscopic mucosal resection (EMR) or radiofrequency ablation (RFA) is a recognised alternative to surgical resection. The aim of this study is to compare the outcomes of two radically different endotherapy approaches of focal EMR of neoplastic foci followed by RFA versus focal EMR followed by more radical EMR as necessary. Methods Patients referred with Barrett9s HGD and/or IMC where treated with either focal EMR to visibly elevated lesions with subsequent intensive RFA of residual BE (Group A) or by a protocol of focal EMR to eradicate neoplasia (Group B). There were 37 patients (83% males) in Group A with a mean age of 66 years and a mean Barrett9s segment length was 6.9 cms (1–14). In Group B we had 44 patients (90% males) with a mean age of 68 years and mean segment length of 5.0 cms (2–15). All patients were followed up in a rigorous endoscopic programme. The mean duration of follow-up was 23 months in Group A and 32 months in Group B. Results In Group A total of 23 EMR procedures were performed with a mean of 0.6 sessions per patient. Treatment then proceeded with a RFA-intensive protocol such that a total of 79 ablations were administered with a mean of 2 sessions per patient. Thereafter, Nd:YAG laser was applied to residual islands less than 0.5 cm in length. In Group B a total of 72 EMR procedures were performed with a mean of 1.6 sessions per patient. In this group RFA was employed in 6 patients only. No significant post-procedural complications were identified in these patients. Eradication of neoplasia (HGD and IMC) was achieved in 35/37 patients (95%) in Group A and 41/41 (100%) in Group B. Furthermore, during this relatively short follow-up period eradication of Barrett9s oesophagus was achieved in 31/37 of patients (84%) in Group A. Conclusion This is the largest reported series demonstrating similarly excellent outcomes for two radically different endoscopic approaches for the ablation of Barrett9s neoplasia. In addition, the RFA-intensive strategy has proved effective in eradicating residual Barrett9s oesophagus. These observations call for a randomised controlled trial comparing these two strategies in order to identify the most cost-effective option.