Atypical Grade Research Articles

A CASE OF EARLY GASTRIC CANCER IN WHICH THE DEGREE OF HISTOLOGICAL ATYPIA WAS CORRECTLY PREDICTED BY MAGNIFYING ENDOSCOPY COMBINED WITH NARROW BAND IMAGING

We herein report a case of early gastric cancer with mixed components having different grades of atypia, which was correctly predicted by magnifying endoscopy combined with narrow band imaging. A 67-year-old man had a flat elevated lesion (0-IIa) in the anterior wall of the gastric antrum. With narrow band imaging, a flat lateral extension (0-IIb), not recognized with white light imaging was seen in the anal side of the main tumor. Magnifying endoscopy combined with narrow band imaging saw a relatively regular fine network pattern of micro-vessels in the surface of the 0-IIa area. However, in the surface of the 0-IIb area, a villous structure with villi of various size and heterogeneity, micro-vessels showing tortuousity were observed. We judged the grade of atypia to be higher in the 0-IIb area than in the 0-IIa area. Histological examination of the resected specimen verified the 0-IIa area and 0-IIb area as adenoma and adenocarcinoma, respectively.

Abstract 3157: Expression of progesterone receptor and p4EBP1 as molecular predictors of response to progestin treatment in endometrial adenocarcinoma and complex atypical hyperplasia

Abstract Objective: Progestin therapy is a fertility-sparing treatment option for women with complex atypical hyperplasia (CAH) or low grade endometrial adenocarcinoma (Grade 1 EA). However, no biological markers have yet been identified that reliably predict response to treatment. Expression of progesterone receptor and activation of the PI3K/Akt/mTOR pathway have been hypothesized to impact the effectiveness of progestin treatment. We investigated whether the expression of progesterone receptor isoforms PR-A and PR-B, and of pAkt and p4EBP1 as indicators of PI3K/Akt/mTOR pathway signaling in pretreatment biopsy specimens predict the response of patients with CAH and Grade 1 EA to progestin treatment. Methods: Premenopausal women with CAH or Grade 1 EA who underwent progestin therapy for a minimum of 8 weeks were identified. Pre-treatment endometrial biopsy specimens and matched second specimens obtained while on progestin treatment were stained by immunohistochemistry for expression of PR-A, PR-B, pAkt and p4EBP1. The H-score (staining intensity × % of cells) was determined for tumor cells and stroma. T tests were used to compare mean H-scores. Standardized resolution ratios (SRR) were calculated to assess relationship with resolution. Results: 38 subjects were identified with a median age of 36 years (range 23-48). On initial sampling, pathology showed G1EAC in 35% and CAH in 65% of subjects. 50% of subjects had documented resolution to normal histopathology with a median time to resolution of 7 months. Staining for PR-A, PR-B, pAkt and p4EBP1 was found to be positive in 84%, 87%, 84%, and 24% of all patients. The H-score was significantly higher in tumor tissue compared to stromal tissue (p<.0003) for all four markers. PR-A and PR-B expression was significantly decreased in the second specimen under progestin treatment for subjects both with and without resolution (p<.00001). In contrast, pAkt expression decreased significantly after treatment only in subjects with resolution (p = .02). Expression of p4EBP1 did not change significantly with treatment (p = .24). Strong positive PR-A or PR-B staining in tumor tissue of pretreatment biopsies showed a positive correlation with resolution (SRR=1.95, CI 1.15-3.18; SRR = 2.37, CI 1.25-4.13, respectively). In addition, p4EBP1 positivity was associated with resolution (SRR = 2.3, CI 1.48-3.52). Expression of pAkt did not correlate significantly with resolution (SRR = 1.5, CI 0.66-3.29). Conclusions: Our data suggest that the response of premenopausal women with CAH or Grade 1 EA to progestin treatment is significantly correlated with expression of PR-A, PR-B or p4EBP1 in pre-treatment tumor tissue. We propose that the expression of PR-A, PR-B and p4EBP1 may serve as valuable molecular predictors of response to progestin therapy in CAH and Grade 1 EA. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3157. doi:10.1158/1538-7445.AM2011-3157

Immunohistochemical and morphologic findings in columnar cell lesions of the breast

Columnar cell lesions (CCLs) with or without atypia frequently coexist with invasive or in situ breast carcinomas. In this study, 39 mastectomy specimens containing CCLs coexisting with invasive carcinomas were retrospectively analyzed for cellular characteristics and structural pattern of CCL neighboring the tumor. The expression of estrogen receptor (ER), progesterone receptor (PR), and p53 antibodies in CCL and coexisting invasive tumors, type of invasive tumor, histopathologic grade, and presence of atypia in CCL have been studied. Sixteen (41%) of all CCLs were with atypia, whereas 23 (59%) of them were without atypia. No correlations were found between the presence of CCLs with atypia and either the morphologic type of carcinoma or histopathologic grade of the tumors. Presence of atypia in the CCL was not correlated with the expression of p53 in the invasive tumors. CCLs without atypia dominated in Grade III tumors. The percentages of CCLs without atypia were also higher in both ER (-) and PR (-) tumors. CCL with atypia is generally considered to be a precursor of invasive carcinoma; however, in our study, CCLs without atypia more frequently coexisted with breast carcinoma.

Minichromosome Maintenance Protein Expression According to the Grade of Atypism in Actinic Keratosis

The minichromosome maintenance (MCM) family is a group of proteins that are key initiation factors for DNA replication and are expressed only in cycling cells. Recent studies on various cancerous conditions have shown that MCM proteins are better markers for malignant cells compared to other proliferative markers. It has been also proven that MCM proteins are independent prognostic factors. The aim of this study was to characterize the pattern and frequency of MCM 2 protein expression in actinic keratosis (AK) and determine whether the expression is correlated with the degree of histological atypism. Biopsy samples of 34 patients who had been diagnosed as AK were used in this study. Samples were divided into three groups (grade I, grade II, and grade III) according to the degree of atypism. Immunohistochemical staining for MCM 2 protein, Ki-67, and proliferating cell nuclear antigen was performed, and the number of positively staining cells per unit area (10⁻⁴ μm²) was calculated for evaluation of immunoreactivity. MCM 2 protein was expressed in atypical keratinocytes in AK. Mean numbers of immunoreactive cells positive for MCM 2 were 165.1 in grade I, 304.5 in grade II, and 513.3 in grade III. Moreover, the correlation between the immunoreactivity for MCM 2 protein and AK grade was significantly more positive than that for other markers. Thus, we suggest that MCM 2 protein is a reliable marker for diagnosing and grading AK and further could be hypothesized as an important prognostic factor.

Multifocal High Grade Prostatic Intraepithelial Neoplasia is a Risk Factor for Subsequent Prostate Cancer

The risk of under diagnosed or development of subsequent prostate cancer and the treatment of patients diagnosed with high grade prostatic intraepithelial neoplasia remain controversial. We evaluated the relationship between high grade prostatic intraepithelial neoplasia on initial biopsy and the future presence of prostate cancer. From December 1997 to February 2008 a total of 328 men underwent a second prostate biopsy after being initially diagnosed with high grade prostatic intraepithelial neoplasia. Men with prostate cancer or atypia on initial biopsy were excluded from study. Another 335 men without high grade prostatic intraepithelial neoplasia, prostate cancer or atypia underwent a second prostate biopsy based on clinical suspicion alone. A Cox proportional hazards model was used to estimate the effect of high grade prostatic intraepithelial neoplasia on the subsequent diagnosis of prostate cancer after adjustment for prostate specific antigen, age, presence of inflammation, abnormal digital rectal examination and number of cores obtained at biopsy. High grade prostatic intraepithelial neoplasia was also stratified into multifocal disease and laterality. Adjusted Kaplan-Meier plots were generated to estimate the rates of prostate cancer. High grade prostatic intraepithelial neoplasia alone on initial prostate biopsy had a significant effect on the subsequent diagnosis of prostate cancer (HR 1.89; 95% CI 1.39, 2.55; p <0.0001). Stratifying high grade prostatic intraepithelial neoplasia into multifocal and bilateral disease significantly increased the hazard ratios to 2.56 (95% CI 1.83, 3.60) and 2.20 (95% CI 1.51, 3.21), respectively, resulting in estimated 3-year cancer rates of 29.0% and 37.0% compared to 12.5% and 18.9%, respectively, following benign biopsy. Multifocal and bilateral disease are adverse features of high grade prostatic intraepithelial neoplasia that significantly increase the risk of prostate cancer despite adjusting for other clinical indicators such as prostate specific antigen and abnormal digital rectal examination.

The evolution of cancer of the colon and rectum

The malignant potential of adenomas of the colon and rectum varies with size, histological type and grade of epithelial atypia. The adenomatous polyp is usually small and has a low malignant potential, whereas tumors with a villous structure are usually larger and have a much higher cancer rate. Severe atypia is more common in villous adenomas than in adenomatous polyps. Evidence is presented which suggests that most cancers of the colon and rectum have evolved through the polyp-cancer sequence although the majority of adenomas do not become cancerous during a normal adult life span. The slow evolution of the polyp-cancer sequence is stressed. The implications of the polyp-cancer sequence for the design of cancer prevention programmes and the study of the aetiology of large bowel cancer are discussed.

Severe architectural disorder is a potential pitfall in the diagnosis of small melanocytic lesions

Little is known about the significance of severe architectural disorder in small melanocytic lesions with features of dysplastic nevi (DN). Using previously reported criteria, 355 consecutive DN were scored for architectural disorder and cytologic atypia. The DN were classified according to their size as small (equal or less than 3 mm) or large (greater than 3 mm). Of these 136 (38.3%) DN were classified as small. Grades of architectural disorder and cytologic atypia were equally distributed in small and large DN. Forty lesions were diagnosed as dysplastic nevi with severe architectural disorder (DNSAD). Thirteen DNSAD were small; of these, 84.6% were junctional. DN showing only mild to moderate architectural disorder were found to be predominantly compound. DN with severe cytologic atypia were mainly large (8/10 cases) with no particular type (junctional or compound) predominance. Seven cases displayed both severe architectural disorder and severe cytologic atypia; only one of these cases (a junctional lesion) measured less than 3 mm. Small melanocytic lesions displaying severe architectural disorder are mainly junctional and tend to show only mild cytologic atypia. Caution is needed when interpreting the degree of architectural disorder in these small melanocytic lesions, in order to avoid overdiagnosis of melanoma.

Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Application of MRI in severity grading and activity staging in thyroid associated ophthalmopathy

The influence of MRI on severity grading and activity staging in thyroid associated ophthalmopathy (TAO) was evaluated.The results showed that MRI had a higher detection rate in abnormalextraocular muscle than NOSPECS scores(χ~2 = 19.37,P = 0.000).MRI had higher sensitivity,specificity,and accuracy in detection of active TAO than clinical activity score (100% vs 95.7%,88.2% vs 35.3%,96.9% vs 79.7%,respectively).Therefore,MRI improves early detection of atypical grade 4 cases.Signal intensity elevation in adipose suppressed T2WI is helpful to define active stage. Key words: Thyroid associated ophthalmopathy; NOSPECS scores; Clinical activity; Magnetic resonance imaging

CD44v6 Expression in Intraductal Papillary Mucinous Neoplasms of the Pancreas

The purpose of this study was to examine CD44v6 expression in intraductal papillary mucinous neoplasms (IPMNs) and clarify the role of CD44v6 in progression, invasion, metastasis, and morphogenesis of IPMNs. One hundred fifty-one samples of IPMNs and 30 normal controls were subjected to immunohistochemical analysis for CD44v6. The IPMNs were divided into 4 groups according to the grade of atypia (adenoma, borderline IPMN, noninvasive carcinoma, and invasive carcinoma) and 5 subtypes according to histological phenotype (gastric, intestinal, pancreatobiliary, oncocytic, and unclassified). Correlations were investigated between CD44v6 expression and clinicopathological characteristics including grade of atypia, subtype, lymph node metastasis, and invasion pattern. Whereas normal ductal epithelium did not express CD44v6, CD44v6 expression was observed from the early stage of IPMNs and up-regulated in the progression of IPMNs to invasive carcinoma. CD44v6 expression in intestinal-type IPMNs was significantly lower compared with that in other subtypes. Whereas no correlation was observed between lymph node metastasis and CD44v6 expression in invasive IPM carcinomas, the invasion pattern was significantly correlated to CD44v6 expression. The present data indicate that CD44v6 expression determines the morphology and aggressiveness of IPMNs and is involved in development and invasion of IPMNs.

Expression of dipeptidyl peptidase-IV activity and/or structure homologs in human meningiomas

Meningiomas are tumors derived from arachnoid cap cells that represent approximately 30% of all intracranial tumors. In this study, we investigated 22 human meningiomas for the expression of dipeptidyl peptidase (DPP)-IV activity and/or structure homologs (DASH), including canonical DPP-IV/CD26, fibroblast activation protein-alpha (FAPalpha), DPP8 and DPP9. DPP-IV-like enzymatic activity, including all enzymatically-active DASH molecules, was found in all 18 benign meningiomas WHO grade I and IV atypical meningiomas WHO grade II by continuous rate fluorimetric assay in tissue homogenates and catalytic enzyme histochemistry in situ. In atypical meningiomas, this activity was significantly higher and was associated with higher cell proliferation as detected by Ki67 antigen immunohistochemistry. The expression of DPP-IV/CD26 and FAPalpha demonstrated by real-time RT-PCR and immunohistochemistry was low. As shown histochemically, it occurred most often on the surface of fibrous bundles and whorls rich in extracellular matrix. Compared to DPP-IV/CD26 and FAPalpha, the expression of DPP8 and DPP9 was higher and, in addition, it was present also in the cells inside these structures. Expression of CXCR4, the receptor of pro-proliferative chemokine stromal cell-derived factor-1alpha (SDF-1alpha), DPP-IV substrate, was found in all tumors, suggesting higher values in atypical grade II samples. This is the first report on the expression status of dipeptidyl peptidase-IV and related molecules in meningiomas. It shows that DPP8 and DPP9 prevail over canonical DPP-IV/CD26 and FAPalpha in all examined patients. In addition, the study suggests an increase of DPP-IV-like enzymatic activity in these tumors of WHO grade II.

Up-regulated Proteins in the Fluid Bathing the Tumour Cell Microenvironment as Potential Serological Markers for Early Detection of Cancer of the Breast

Breast cancer is by far the most common diagnosed form of cancer and the leading cause of cancer death in women today. Clinically useful biomarkers for early detection of breast cancer could lead to a significant reduction in mortality. Here we describe a detailed analysis using gel-based proteomics in combination with mass spectrometry and immunohistochemistry (IHC) of the tumour interstitial fluids (TIF) and normal interstitial fluids (NIF) collected from 69 prospective breast cancer patients. The goal of this study was to identify abundant cancer up-regulated proteins that are externalised by cells in the tumour microenvironment of most if not all these lesions. To this end, we applied a phased biomarker discovery research strategy to the analysis of these samples rather than comparing all samples among each other, with inherent inter and intra-sample variability problems. To this end, we chose to use samples derived from a single tumour/benign tissue pair (patient 46, triple negative tumour), for which we had well-matched samples in terms of epithelial cell numbers, to generate the initial dataset. In this first phase we found 110 proteins that were up-regulated by a factor of 2 or more in the TIF, some of which were confirmed by IHC. In the second phase, we carried out a systematic computer assisted analysis of the 2D gels of the remaining 68 TIF samples in order to identify TIF 46 up-regulated proteins that were deregulated in 90% or more of all the available TIFs, thus representing common breast cancer markers. This second phase singled out a set of 26 breast cancer markers, most of which were also identified by a complementary analysis using LC-MS/MS. The expression of calreticulin, cellular retinoic acid-binding protein II, chloride intracellular channel protein 1, EF-1-beta, galectin 1, peroxiredoxin-2, platelet-derived endothelial cell growth factor, protein disulfide isomerase and ubiquitin carboxyl-terminal hydrolase 5 were further validated using a tissue microarray containing 70 malignant breast carcinomas of various grades of atypia. A significant number of these proteins have already been detected in the blood/plasma/secretome by others. The next steps, which include biomarker prioritization based on the hierarchal evaluation of these markers, antibody and antigen development, assay development, analytical validation, and preliminary testing in the blood of healthy and breast cancer patients, are discussed.

Chronic Pancreatitis and Pancreatic Cancer: Prediction and Mechanism

We investigated the SPINK 1 mutations in 156 sporadic pancreatic cancer (PCa), and 8 pancreatic cancer with chronic pancreatitis (CPPCa) patients, and in 527 healthy subjects. The results demonstrated that 3 of 8 patients with CPPCa (37.5%) had the SPINK 1 gene N34S mutation. In addition, 3 of 156 sporadic PCa patients (1.9%) and 1 of them (0.6%) had the N34S and IVS3+2T>C mutation, respectively. The combined frequency of 2.5% was significantly higher than that of healthy subjects (0.38%), suggesting that the SPINK 1 mutation is an important risk factor for the development of pancreatic cancer. To investigate the genetic difference between sporadic PCa and CPPCa, we investigated several factors involved in the pathogenesis of PCa in 6 CPPCa and 15 sporadic PCa patients. The factors examined were genes including K-ras, p53, smad 4, p-smad 1, CXCL 14, NF-kB subunit p65 and Wnt 5a. No significant difference was found in the comparative examination of these factors, suggesting that the molecular disorders appeared to occur similarly in CPPCa as well as sporadic PCa. To assess the role of fibrosis in pancreatic carcinogenesis, we investigated the effects of pancreatic stellate cells (PSCs), which are largely responsible for pancreatic fibrogenesis, on duct cells, in vitro and in vivo. Activated PSCs were found surrounding precancerous duct cells in the tissues of a dimethylbenzanthracene mouse model and those of human PCa. Consistently, human pancreatic epithelial duct cells cultured with PSC conditioned media showed increased cell proliferation and colony formation, suggesting that PSCs may promote pancreatic ductal tumorigenesis.

Management of conjunctival melanoma

Invasive conjunctival melanoma can arise de novo, from nevus or from melanoma in situ. The literature reports that after treatment of invasive conjunctival melanoma more than 50% of patients develop local tumor recurrence, with 20% eventually requiring orbital exenteration and 20–30% developing fatal metastasis. Our results have improved since we replaced adjuvant cryotherapy with radiotherapy and topical chemotherapy. There is scope for multicenter clinical trials and translational research, but these require consistent staging and grading of disease. We propose that the term ‘primary acquired melanosis’ should only be used clinically, when the histology is not known. We have devised a clinical system for mapping conjunctival melanocytic lesions and a system for scoring the histological grade of atypia of conjunctival melanocytic intra-epithelial neoplasia/melanoma in situ. We anticipate that these measures will improve outcomes after treatment of conjunctival melanoma in situ and invasive melanoma.

Biliary intraepithelial neoplasia in patients without chronic biliary disease

Biliary intraepithelial neoplasia (BilIN) represents a spectrum of proliferative and/or cytologically atypical lesions of the large intrahepatic bile ducts. BilIN is believed to be a major pathway leading to the development of intrahepatic cholangiocarcinoma (CCA) through a dysplasia-carcinoma sequence. Recently, a large interobserver agreement study in patients with hepatolithiasis, choledochal cysts, and primary sclerosing cholangitis proposed diagnostic criteria for 3 categories of BilIN based on increasing grades of nuclear atypia and loss of nuclear polarity: BilIN-1, BilIN-2, and BilIN-3. BilIN has not been systematically studied as a potential precursor lesion in patients with nonbiliary liver disease, despite the epidemiologic association between intrahepatic CCA, hepatitis C infection (HCV), and alcohol (EtOH) consumption. We submitted 12 paraffin blocks targeted to the large intrahepatic and hilar ducts in each of 244 explanted livers with EtOH cirrhosis (n = 94), HCV cirrhosis (n = 44), EtOH + HCV (n = 26), and noncirrhotic controls (eg, livers removed for metabolic disorders, massive hepatic necrosis) (n = 80), and classified all bile duct profiles as normal/reactive, metaplastic, or BilIN-1, -2, or -3 (flat or papillary). Livers transplanted for EtOH and EtOH + HCV cirrhosis had the highest prevalence of BilIN, greater numbers of ducts with BilIN, and a shift toward higher grades of BilIN as compared with HCV alone and with noncirrhotics. In EtOH, the highest grades of BilIN were 0 = 3%, BilIN-1 = 35%, BilIN-2 = 57%, BilIN-3 = 4%; in EtOH + HCV: 4%, 38%, 54%, 4%; in HCV: 18%, 55%, 20%, 7%; and in noncirrhotics: 45%, 39%, 16%, 0%, respectively. In both univariate and multivariate analysis, EtOH (P < .001), EtOH + HCV (P < .001), and HCV cirrhosis (P < .001) were all significant predictors of BilIN grade. Multifocal BilIN (>/=10 ducts) was present in 91% of EtOH, 92% of EtOH + HCV, and 61% of HCV cirrhosis, as compared with only 34% of noncirrhotics (P values of <.0001, <.001, and .002, respectively, in both univariate and multivariate analysis). Papillary or micropapillary architecture of BilIN was also more common in EtOH (47%) than in EtOH + HCV (19%), HCV (23%), or noncirrhotics (17%) (P < .001 in both univariate and multivariate analysis). BilIN-3 occurred only in the setting of cirrhosis (8 of 164 cirrhotic livers, 5%) and was associated with CCA (2 cases) or mixed hepatocellular/CCA (1 case) elsewhere in the liver. In aggregate, these findings provide morphologic support for the epidemiologic role of alcohol and HCV in the development of CCA.

Clear cell meningioma presenting as rapidly deteriorating visual field and acuity during pregnancy

Clear cell meningioma is a rare histological phenotype of meningioma. It has an atypical grade II World Health Organization classification due to a high recurrence rate. This report documents the rapid deterioration of visual field and acuity in a pregnant 32-year-old woman and the successful post-operative resolution of symptoms. We review the literature about this rare disease and identify clinical and pathological features unique to this patient.

Genomic profiling distinguishes familial multiple and sporadic multiple meningiomas

BackgroundMeningiomas may occur either as familial tumors in two distinct disorders, familial multiple meningioma and neurofibromatosis 2 (NF2), or sporadically, as either single or multiple tumors in individuals with no family history. Meningiomas in NF2 and approximately 60% of sporadic meningiomas involve inactivation of the NF2 locus, encoding the tumor suppressor merlin on chromosome 22q. This study was undertaken to establish whether genomic profiling could distinguish familial multiple meningiomas from sporadic solitary and sporadic multiple meningiomas.MethodsWe compared 73 meningiomas presenting as sporadic solitary (64), sporadic multiple (5) and familial multiple (4) tumors using genomic profiling by array comparative genomic hybridization (array CGH).ResultsSporadic solitary meningiomas revealed genomic rearrangements consistent with at least two mechanisms of tumor initiation, as unsupervised cluster analysis readily distinguished tumors with chromosome 22 deletion (associated with loss of the NF2 tumor suppressor) from those without chromosome 22 deletion. Whereas sporadic meningiomas without chromosome 22 loss exhibited fewer chromosomal imbalance events overall, tumors with chromosome 22 deletion further clustered into two major groups that largely, though not perfectly, matched with their benign (WHO Grade I) or advanced (WHO Grades II and III) histological grade, with the latter exhibiting a significantly greater degree of genomic imbalance (P < 0.001). Sporadic multiple meningiomas showed a frequency of genomic imbalance events comparable to the atypical grade solitary tumors. By contrast, familial multiple meningiomas displayed no imbalances, supporting a distinct mechanism for the origin for these tumors.ConclusionGenomic profiling can provide an unbiased adjunct to traditional meningioma classification and provides a basis for exploring the different genetic underpinnings of tumor initiation and progression. Most importantly, the striking difference observed between sporadic and familial multiple meningiomas indicates that genomic profiling can provide valuable information for differential diagnosis of subjects with multiple meningiomas and for considering the risk for tumor occurrence in their family members.

Endoscopic retrograde cholangiopancreatography-guided brush cytology diagnosis of pancreatobiliary tumors

To study the cytologic features of pancreatobiliary tumors in endoscopic retrograde cholangiopancreatography (ERCP)-guided brushing preparations and to evaluate the usefulness of cytology in the diagnosis of pancreatobiliary malignancy. A retrospective analysis of 212 cases of ERCP-guided brush cytology smears performed during the period from January, 2004 to December, 2006. The cytologic diagnosis was confirmed either by the histologic diagnosis or the strict clinical criteria. Two of the cases studied were unsatisfactory for diagnosis, with no epithelial cells identified. One hundred and thirty-seven smears were diagnosed as "negative", 45 of which subsequently confirmed to be malignant (negative predictive value = 60.2%). Six of the 11 cases with "low-grade atypia" were proven to be malignant (positive predictive value = 54.5%), as compared to 19 of 23 cases of "high-grade atypia" (positive predictive value = 86.4%). All of the 41 cases with cytologic diagnosis of "malignancy" were confirmed to be malignant (positive predictive value = 100%). The cytologic features of malignancy in ERCP-guided brushing preparations included overlapping nuclei, anisonucleosis, coarse chromatin pattern, poor cellular cohesion, tumor diathesis, prominent nucleoli and atypical mitotic figures. The accuracy of ERCP-guided brush cytology relies on good specimen preparation and application of morphologic criteria. Grading of cytologic atypia is of clinical significance. A "negative" or "low-grade atypia" cytologic diagnosis requires further diagnostic workup to rule out the possibility of underlying malignancy, while a "high-grade atypia" or "malignant" diagnosis is relatively specific in guiding subsequent management of suspected pancreatobiliary malignancy.

Evaluation of women presenting with postcoital bleeding by cytology and colposcopy

Objective To evaluate women with postcoital bleeding (PCB) by clinical examination, cytology, colposcopy, and histopathology. Methods A cross-sectional study of 123 women with PCB, who were referred to the Colposcopy Clinic of Arash Hospital, Tehran, over a 2-year period. Results Clinical examinations revealed cervical polyps in 18 women and ectropion in 14. Cervical cytology identified 13 patients with atypical squamous cells of undetermined significance, 2 with atypical glandular cells, 4 with low-grade squamous intraepithelial lesions, and 3 with high-grade squamous intraepithelial lesions. Colposcopy indicated invasive cancer in 1 patient. Transitional zones appeared normal in 39.8% of the cohort, were atypical grade 1 in 33.3%, and atypical grade 2 in 4.9%. Fourteen abnormalities were detected at histology, including 1 squamous cell carcinoma, 1 low-grade glandular neoplasm, 9 cervical intraepithelial neoplasia (CIN) grade 1, 2 CIN grade 2, and 1 CIN grade 3. The sensitivity and specificity of cytology were 50% and 86.5%, respectively. A total of 21.4% of abnormal pathologies were missed using colposcopy, which had a sensitivity of 79%. Conclusion Because of its higher sensitivity, colposcopy can be recommended for the investigation of persistent PCB, even in the presence of normal cytology.

A new histological classification for intra‐operative histological examination of the ductal resection margin in cholangiocarcinoma

The purpose of this study was to establish a standard histological classification for intra-operative histological examination of ductal resection margins in cholangiocarcinoma to distinguish between epithelial and intramural lesions and to clarify correlations between the new classification and clinical outcomes. Intra-operative diagnosis of ductal margins was performed for 357 stumps from 216 patients undergoing surgical resection of cholangiocarcinoma at the National Cancer Center, Japan. Three expert pathologists reviewed the materials and established a histological classification defined by grade of atypia. The new classification comprised four categories: 'insufficient', insufficient for diagnosis due to distortion of specimen; 'negative for malignancy', no atypia suggestive of neoplasia; 'undetermined lesion', specimen showing either cellular or structural atypia; and 'positive for malignancy', specimen showing both cellular and structural atypia. Each category was defined to distinguish between epithelial and intramural lesions. Validity and reproducibility of the proposed classification were found to be moderate to substantial. Multivariate analyses using the clinicopathological factors identified to be associated with overall survival by univariate analyses indicated that patients diagnosed with 'positive for malignancy' in intramural lesions of the proximal margin displayed significant poor prognosis. Meanwhile, in patients diagnosed with 'positive for malignancy' or 'undetermined lesion' in epithelial lesions of the proximal margin, no difference in overall survival was apparent compared to patients diagnosed with 'negative for malignancy'. We propose new histological classification for intra-operative histological examination of ductal resection margins in cholangiocarcinoma that shows a correlation with patients' prognosis and should facilitate the determination of ductal resection margin status for cholangiocarcinoma.