Intraepithelial Neoplasm Research Articles

Sporadic foveolar-type gastric adenoma with a raspberry-like appearance in Helicobacter pylori-naïve patients.

Sporadic foveolar-type gastric adenoma (FGA) has been described as an extremely rare polyp that is whitish and flatly elevated. However, we recently found that sporadic FGA with a raspberry-like appearance (FGA-RA) is not rare in Helicobacter pylori (H. pylori)-naïve gastric mucosa. We endoscopically or surgically treated 647 patients with gastric epithelial neoplasms in the last 5 years, with 7.7% (50/647) being H. pylori-naïve. Among these, 43 FGA-RAs were diagnosed based on histologic and endoscopic features in 34 patients, who were all enrolled in this retrospective study. All lesions were observed by white-light endoscopy (WLE) and narrow-band imaging with magnification endoscopy (NBIME). We subsequently analyzed their endoscopic and microscopic features and patient characteristics. The patients were 22 males and 12 females aged 57±23 years (mean±2SD). WLE showed raspberry-like small polyps mimicking gastric hyperplastic polyps in the oxyntic gastric compartment (body/fundus). Multiple growths were confirmed in 20.6% (7/34) of the patients. NBIME revealed irregularly shaped papillary/gyrus-like microstructures with abnormal capillaries. Histologically, all lesions were intraepithelial neoplasms, and most of lesions (62.8%, 27/43) exhibited low-grade dysplasia. Immunohistochemically, neoplastic cells featured strong and diffuse MUC5AC expression, negative or very low MUC6 expression, and negative MUC2/CD10 expression. They also showed Ki-67 hyperexpression with a mean labeling index of 59.4±48.7%. The coexistence of fundic gland polyps in the background mucosa was significantly higher in multiple FGA-RA cases than in solitary cases (100% vs. 55.5%, P< 0.05). FGA-RA is a newly suggested histologic variant of sporadic FGA whose occurrence is not rare in daily endoscopic practice.

Prevalence and genotype distribution of high-risk human papillomavirus in 34 420 cases in Yangzhou city, Jiangsu province, China.

We aimed to study the infection status and distribution of human papillomavirus (HPV) in Yangzhou City to provide precise guidance for the prevention and treatment of cervical cancer in this area.Reproductive tract secretions were collected from patients admitted at Subei People's Hospital over the past 3 years. Fifteen high-risk HPV (HR-HPV) genotypes were analyzed by fluorescent polymerase chain reaction.The positive rate of HR-HPV in 34 420 subjects was 23.56%. There was no significant difference in the rate of overall infection between males and females (χ 2 = 0.04; p = 0.952 > 0.05). The five genotypes with high infection rates in the population were HPV52, HPV58, HPV16, HPV51, and HPV39. Single infection was found to be dominant, primarily with the HPV52 genotype. The infection rate was higher in patients less than 20 years old and more than 60 years old. Most patients with cervical intraepithelial neoplasms 2/3 and cervical cancer were infected by HPV16, followed by those infected by HPV52 and HPV58. There was a significant difference in the infection rate of HPV16 among patients with different cervical lesions (χ 2 = 31.660; p < 0.01), and the infection rate of HPV16 was higher in patients with cervical cancer than in healthy individuals.Single infection was dominant among the study patients with HPV infection in Yangzhou city. There was no significant difference in infection rate and genotype distribution between males and females. The infection rate in young and old women was higher, and the rate increased with age (>20 years).

648 Dermoscopic findings and HPV genotypes of genital keratotic lesions: Bowenoid papulosis, seborrheic keratosis, and condyloma acuminatum

Dermatologists often encounter keratotic lesions in the genital area. Although making a clear diagnosis can be difficult, it is important for the treatment and prognosis closely related to the patient's quality of life. Dermoscopy has proven to be a useful, non-invasive tool. However, there is still a lack of dermoscopic data comparing bowenoid papulosis (BP), seborrheic keratosis (SK), and condyloma acuminatum (CA). More than 40 human papillomaviruses (HPV) genotypes infect the genital area and manifest as various intraepithelial neoplasms. This study is conducted to find distinctive dermoscopic features and HPV genotype distribution of BP, genital SK, and CA. Dermoscopically, glomerular vessels were predominant in BP that appeared in 7 cases (70.0%). Hairpin vessels were the most common vascular structures that accounted for 12 cases of CA (66.7%). SK was the least vascular-patterned disease as no vessel was observed in eight cases of SK (66.7%). Mucosal pigmentation was observed in 6 cases (60.0%) of BP. Seven cases of BP (70.0%) were classified into 'flat'. SK showed cerebriform appearance in seven cases (58.3%). Most CA cases had knob-like or finger-like appearance and whitish halo. All of BP ad CA presented positive results in HPV DNA detection, while seven cases (58.3%) of SK had positive results. For the high-risk genotype, principally HPV 16, BP showed the highest detection rate with 90.0%. SK and CA showed 58.3% and 44.4%, respectively. For the low-risk genotype, principally HPV 6 followed by HPV 11, CA presented the highest detection rate, with 88.9%. BP and SK showed 40.0% and 8.3% detection rate, respectively. The coexistence of the high-risk and the low-risk HPV was seen in three cases (30.0%) of BP, one case (8.3%) of SK, and six cases (33.3%) of CA. Dermoscopy can be useful for differentiating the entity of genital keratotic lesions ahead of an invasive method and a physician should consider the morphologic plasticity of HPV-related keratosis in the genital area or the genital wart in the expanded concept.

Vulvar Paget's disease and stromal invasion: Clinico-pathological features and survival outcomes

PURPOSETo evaluate clinico-pathological features, treatments and survival outcomes of vulvar Paget's disease (VPD). MethodsWe retrospectively reviewed VPD diagnosed between 1983 and 2018 at the Department of Surgical Sciences, Sant’Anna Hospital, Turin. Clinico-pathological characteristics and surgical treatment outcomes were investigated according to the depth of invasion. ResultsA total of 122 patients were identified. Eighty-seven patients were diagnosed with intraepithelial VPD, 22 with microinvasive (<=1 mm) VPD and 16 with invasive VPD. The median follow-up was 94.6 months (interquartile range 25th-75th, 26–120). Most of patients 95/122 (77%) were treated by surgery. Local recurrence was observed in 69/95 (73%) patients without significant difference between the 3 groups (p = 0.33), however, total vulvectomy showed better local control in microinvasive and invasive VPD than in intraepithelial tumors. At 120 months the cancer-specific survival was 100% for intraepithelial and microinvasive VPD versus 31% for invasive VPD (log-rank p = <0.0001) Age ≥65 years (OR: 4.17 CI 1.12–15.5, p = 0.03) and VPD's area ≥15 cm2 (OR: 5.83 CI 1.75–19.3, p = 0.004) were associated with risk of invasiveness. ConclusionMicroinvasive VPD has an identical prognosis to intraepithelial VPD, suggesting the omission of lymphadenectomy or adjuvant treatments are safe in this subset of patients. We recommend caution to propose medical treatment in patients who are ≥65 years old and with wide tumor area, as they are at the greatest risk of invasiveness.

Aberrant Melan-A Expression in Extramammary Paget Disease

To the Editor: A 50-year-old White man was diagnosed with invasive extramammary Paget disease (EMPD) on the left inguinal fold. Excisional biopsy revealed an intraepithelial (in situ) and subjacent intradermal/subcutaneous neoplasm composed of single, nests and cords of cells containing pale staining/vacuolated/foamy cytoplasm and large vesicular nuclei (Figs. 1A–C). Focal glandular/pseudoglandular differentiation was noted. There was intracellular cytoplasmic/interstitial positivity for PAS and Alcian blue (Fig. 1D). By immunohistochemistry, tumor cells were strongly reactive for AE1/AE3, Cam 5.2, CK7, CEA, and GATA-3, with focal nuclear reactivity for estrogen receptor and strong (3+) membranous expression for Her-2/neu. Tumor cells were negative for p63, D2-40, CK20, villin, CDX2, TTF-1, prostate-specific antigen, and progesterone receptor, in addition to S-100, HMB-45, SOX10, and MITF. The tumor showed diffuse intracytoplasmic grainy positivity for melan-A (A103 clone) (Figs. 2A–F).FIGURE 1.: In situ and invasive components of EMPD (A–C). Tumor cells show cytoplasmic positivity for Alcian blue (A, B, original magnification ×40; (C) original magnification ×100; and (D) original magnification ×200).FIGURE 2.: By immunohistochemistry, tumor cells are positive for CK7 (A) and negative for p63 (B) and S-100 (C). There is diffuse intracytoplasmic grainy immunoreactivity for melan-A (A103 clone) (D–F) (A–D, original magnification ×40; (E) original magnification ×100; and (F) original magnification ×200).Melan-A (A103 clone) and MART-1 (melanoma antigen recognized by T cells) (M2-7C10 clone) antibodies recognize the same gene product, a melanosome-associated protein that is involved in melanosome biogenesis by ensuring the stability of GPR143.1 This protein plays a vital role in the expression, stability, trafficking, and processing of melanocyte protein PMEL, which is critical to the formation of stage II melanosomes.1 Both antibodies are widely used in dermatopathology and expressed by normal melanocytes, nevi, and melanoma.2 Melan-A and MART-1 staining are also well-known observations in clear cell sarcoma and other nonmelanocytic tumors that contain premelanosomes, including perivascular epithelioid cell tumor (PEComa), angiomyolipoma, lymphangioleiomyomatosis, and sugar tumor of the lung.1,2 Furthermore, melan-A but not MART-1 expression has been documented in steroid-synthesizing normal cells and their respective benign and malignant tumors of the adrenal cortex and gonads (which lack premelanosomes).1 These findings suggest a lower specificity for premelanosomes of the melan-A antibody as compared to MART-1. Melan-A positivity [in addition to expression of other melanogenic markers (ie, HMB45)] has been reported in melanotic Xp11-associated tumor of the gastrointestinal and genitourinary tracts.3 With reference to cutaneous pathology, reactivity for both melan-A and MART-1 antibodies has been reported in pigmented (melanotic) and nonpigmented variants of diffuse neurofibroma, in addition to melanotic schwannomas.4,5 Melan-A and MART-1 expression was identified in 2 cases of atypical fibroxanthoma and one case of undifferentiated pleomorphic sarcoma of the skin.1 Staining was reported as multifocal rather than diffuse and almost exclusively within large multinucleated tumor cells, although one case showed immunoreactivity within mononucleated epithelioid cells.1 Smith-Zagone et al6 also identified melan-A expression (in addition to HMB-45) limited to large, multinucleated cells with vacuolated cytoplasm in atypical fibroxanthoma. More recently, immunohistochemical expression of melanocytic markers (melan-A, HMB45, and S-100) has been reported in cases of mammary Paget disease and EMPD.7,8 Eftimie et al7 highlighted aberrant melan-A expression in the pagetoid (in situ) cells in EMPD. Our case of EMPD demonstrated diffuse reactivity for melan-A in both intraepithelial and invasive tumor cells. Cross-reactivity of melan-A antibody with an unrecognized epitope within tumor cells has been proposed as the underlying pathogenetic mechanism in nonmelanocytic skin neoplasms in previous reports.1,4–8 Of note, melan-A antibody cross-reactivity has also been identified in molluscum contagiosum bodies.9 This phenomenon likely accounts for the finding of melan-A reactivity in our case of EMPD. Another possibility is that immunoreactive melanosomes/melanin granules produced by stimulated melanocytes in the epidermis might be transported into the cytoplasm of adjacent in situ EMPD cells, although this is unlikely to explain the diffuse melan-A positivity noted throughout the invasive component of our tumor. “False-positive” melan-A expression in EMPD demonstrates the need for caution in microscopic interpretation and for using multiple immunohistochemical stains (including other markers of melanocytic differentiation) to corroborate clinical and histopathological features and ensure accurate diagnosis. This report adds to the growing literature of aberrant melan-A expression in cutaneous nonmelanocytic tumors.

Could Extension Into the Lacrimal Gland and Sac Thwart Topical Chemotherapy for Intraepithelial Sebaceous Carcinoma?

To identify the frequency of intraepithelial (Pagetoid) spread beyond the ocular surface-namely beyond conjunctiva and cornea-in patients undergoing orbital exenteration for advanced periocular Sebaceous carcinoma (SC). A retrospective, noncomparative observational case series. Patients undergoing orbital exenteration for biopsy-proven SC, at Moorfields Eye Hospital between 1997 and 2013. Review of clinical records and histological specimens, with particularly reference to involvement of conjunctiva and the extent of Pagetoid infiltration beyond the examinable ocular surface-here termed "hidden" disease. Histological evidence of intraepithelial SC within the lacrimal sac or lacrimal gland. Twenty-nine patients had clinical data and histological specimens adequate for review. Seventeen (59%) did not have a discrete mass (clinically or histologically) and, on clinical examination, were thought to only have extensive intraepithelial carcinoma; foci of microscopic invasion were, however, detected histologically in 11/17 (65%) of these specimens. Moreover, the in situ carcinoma was found to have invaded far in lacrimal gland ductules in 1/17 patients, in the lacrimal sac (in 2 patients; 12%) or in both the gland and sac (in 2 patients); these 5/17 (29%) cases all showed extensive poorly differentiated intraepithelial SC. Of the 12 other patients who had both Pagetoid spread and a clinically evident nodule, 3 had histological evidence of "hidden" disease. Although-due to their being operated in the era prior to the accepted usage of topical therapy for this condition-some of these exenterations might have had particularly advanced in situ SC, over a quarter of patients with periocular SC warranting orbital exenteration show "hidden" intraepithelial tumor within the lacrimal gland and sac. This important finding might significantly reduce the efficacy (particularly in the lacrimal gland) of the various topical therapies used for in situ SC of the ocular surface, and it also emphasizes the importance of excising both the lacrimal gland and sac in all orbital exenterations for this particular tumor.

Abstract PS16-01: Intra-epithelial tumor immune landscapes are associated with clinical outcomes in early-stage triple-negative breast cancer

Abstract Introduction: Stromal tumor-infiltrating lymphocytes (sTILs) have established prognostic and predictive significance in triple-negative breast cancer (TNBC). However, the roles of other immune cells in TNBC are less well-established. We performed high-plex quantitative spatial profiling in a cohort of early-stage TNBC to 1) apply spatial context to tumoral immune landscapes and 2) identify immune proteins associated with clinical outcomes, independently of TILs and other established prognostic clinicopathologic variables, in patients (pts) treated with or without adjuvant chemotherapy (CTX). Methods: The Mayo TNBC cohort comprises pts with centrally-verified, CTX-naive tumors resected from 1985-2012. Using a cohort-based TMA, with Nanostring GeoMX DSP, we quantitated 58 proteins within spatially-distinct intra-epithelial, cytokeratin-positive tumor segments and adjacent cytokeratin-negative/nuclei-positive stromal segments. Differentially-expressed (DE) proteins were identified using a negative binomial generalized linear model (SNR&amp;gt;2, p&amp;lt; 0.05) and a target DE protein set was dichotomized (80th percentile). After adjusting for prognostic clinicopathologic variables, proteins associated with recurrence-free survival (RFS, defined as time from surgery to either local, regional, and distant recurrence, or death by any cause) were identified by performing variable selection using the Akaike Information Criterion (AIC) obtained from fitting all possible Cox proportional hazards regression models (performed separately for intra-epithelial/stromal segments, and in groups +/- adjuvant CTX. Results: From the TNBC TMA, DSP data (N=250 tumors) included 169 pts who received adjuvant CTX+ and 81 who did not (CTX-). Overall, 85/250 developed recurrent disease. In the CTX+ group, intra-epithelial tumor segments from pts without recurrent disease were enriched in 10 immune proteins, including CD8, markers involved in antigen presentation/dendritic cells (CD11c, CD40, HLA-DR) or NK cells (CD56) (FC: 1.4-2.1, p&amp;lt;0.05); CD14 was increased in stroma (FC: 1.5, p&amp;lt;0.05). In contrast, in the CTX- group, both the intra-epithelial tumor and stromal segments from pts without recurrences were enriched in immune proteins (N= 12 and 15 respectively; FC 1.6-5.5, p&amp;lt; 0.05) most markedly CD40, IDO1 and HLA-DR (FC: 3.2-5.5, p&amp;lt; 0.05). Overall, CD3, CD4, CD27, CD44, and ICOS among others were enriched only in the CTX- group; CD14 and CD56 were enriched only in the CTX+ group. Based on these spatial data, biologic function and DSP data from another set of TNBC (FinXX trial), CD11c, CD14, CD27, CD40, CD56, and IDO1 were selected for RFS analysis. After applying our model selection criterion and adjusting for pt age at surgery, tumor size, lymph node status, and sTILs, intra-epithelial CD56 was independently associated with improved RFS in the CTX+ group (HR: 0.31[0.12, 0.81]). In the CTX- group, intra-epithelial CD11c was independently associated with improved RFS (0.10 [0.01, 0.81]). Conclusion: In this early-stage TNBC cohort, spatially-distinct tumor immune landscapes were associated with RFS but differed according to receipt of CTX after surgical resection. In the patients who received CTX, the intra-epithelial compartment, rather than stromal compartment, was immune-enriched in pts without recurrences. Among a targeted protein set, intra-epithelial CD56 remained associated with improved outcomes, independent of sTILs and other clinicopathologic features. In the CTX- group, spatial landscapes were more balanced, and intra-epithelial CD11c was independently associated with improved outcomes. These data provide insight into the spatial context of intrinsic immune landscapes in TNBC, and identify candidate prognostic immune biomarkers which may inform therapeutic strategies. Citation Format: Jodi M Carter, Saranya Chumsri, David W Hillman, David M Zahrieh, Yaohua Ma, Xue Wang, Jennifer M Kachergus, Judy C Boughey, Minetta C Liu, Krishna R Kalari, JC Villasboas, Roberto A Leon Ferre, Fergus J Couch, Matthew P Goetz, E. Aubrey Thompson. Intra-epithelial tumor immune landscapes are associated with clinical outcomes in early-stage triple-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS16-01.

Abstract PD7-05: Neoadjuvant chemotherapy selectively alters spatially-defined immune landscapes in clinical luminal B HR+/HER2- breast cancers: Analysis of the breast cancer genome guided therapy study (BEAUTY)

Abstract Introduction: The immune microenvironment of high-risk HR+ breast cancer (BC) is poorly understood. BEAUTY is a prospective neoadjuvant chemotherapy (NAC) study of stage I-III BC patients treated with neoadjuvant weekly taxane followed by anthracycline-based chemotherapy. Among clinical luminal B BC (St. Gallen criteria) from BEAUTY, we used high-plex digital spatial profiling (DSP) to characterize the intra-epithelial tumor and stromal immune landscapes to 1) assess the impact of NAC on these landscapes and 2) identify immune biomarkers predictive of response to NAC. Methods: The tissue set included FFPE sections of resected tumors from 35 patients (median 51y; range: 21-71y) with clinically-defined luminal B BC (ER &amp;gt; 10%/grade 2/Ki67 ≥ 15% or ER &amp;gt; 10%/grade 3), and 16 paired pre-NAC biopsies. Nanostring GeoMX DSP was used to quantitate 58 immune and BC biomarker proteins in intra-epithelial, cytokeratin-positive tumor segments and adjacent stromal (cytokeratin-negative/SYTO13 (nuclear stain)-positive) segments. Data were normalized using the geometric mean of two negative controls (RbIgG and MsIgG1). A general linear model with negative binomial identified differentially-expressed (DE) proteins in pre/post-NAC tumors. Based on DE protein data and biologic function, a targeted protein subset (N=19) was evaluated in pre-NAC biopsies for associations between protein abundance and residual cancer burden (RCB) class (0-II vs. III) (Wilcoxon-rank sum test: p-value &amp;lt; 0.025 considered significant) or RCB ‘breast only’ index (Spearman correlation). Results: Comparing tumor segments in pre-NAC specimens, intra-epithelial segments were predictably enriched in cytokeratin, ER, PR and Ki-67, but also CD127 and NY-ESO-1; whereas stromal segments were enriched in proteins associated with T cell subsets (e.g. CD3, CD4, CD8), macrophages (CD68 and CD163), antigen presentation/dendritic cells (CD11c, HLA-DR) and immune checkpoint proteins (PD-L1, PD-L2, B7-H3, TIM-3, VISTA) among others. While NAC did not alter the spatial distribution of proteins (intra-epithelial vs. stromal segments), it markedly attenuated the immune landscape, with decreased abundance of functionally-diverse immune proteins (e.g. CD45, CD3, CD4, CD127, granzyme B, CTLA4; STING, B7-H3, CD11c, and CD68, log2FC: 0.27-1.52 p &amp;lt; 0.05), including low abundance proteins PD-1, PD-L1, PD-L2, CD20, and OX40L (log 2FC: 0.15-1.16, p &amp;lt; 0.05). Both PR and Ki-67 decreased in post-NAC tumors whereas ER was not significantly altered (p &amp;lt; 0.05). CD8, CD14, CD163, HLA-DR, IDO-1 and TIM-3 were not significantly altered by NAC. In the pre-NAC biopsies (which had subsequent residual tumor burdens of RCB class 0 or I (n=1 each), II (n=6), and III (n=8), and median RCB ‘breast only’ index of 3.39 (range: 0.00-38.02), 19 proteins were used for RCB analysis (CD3, CD4, CD8, CD14, CD34, CD44, CD45, CD68, CD127, CD163, CTLA4, granzyme B, STING, B7-H3, fibronectin, Ki-67, HLA-DR, SMA and TIM3). Among them, stromal CD127 was significantly higher in RCB class III than RCB class 0-II (p=0.021) and RCB ‘breast only’ index was positively correlated with intra-epithelial granzyme B (rho = 0.61; p=0.012), and negatively correlated with intra-epithelial Ki-67 (rho= -0.71; p=0.0022). Conclusion: In this series of clinical luminal B BC, NAC markedly attenuated the tumoral immune landscapes with a small set of “NAC-resistant” immune proteins. Among a targeted set, stromal CD127 was significantly higher in RCB III, and RCB breast-only index was positively correlated with intra-epithelial granzyme B. These data provide insight into the impact of NAC on HR+ BC, and identify potential immune biomarkers to predict response to neoadjuvant chemotherapy. Citation Format: Jodi M Carter, Judy C Boughey, Jun He, Vera J Suman, Xue Wang, Jennifer M Kachergus, Krishna R Kalari, Liewei Wang, Richard Weinshilboum, Ann M Moyer, Sarah A McLaughlin, Alvaro Moreno-Aspitia, Donald W Northfelt, Richard J Gray, James N Ingle, E. Aubrey Thompson, Matthew P Goetz. Neoadjuvant chemotherapy selectively alters spatially-defined immune landscapes in clinical luminal B HR+/HER2- breast cancers: Analysis of the breast cancer genome guided therapy study (BEAUTY) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD7-05.

ZNF471 modulates EMT and functions as methylation regulated tumor suppressor with diagnostic and prognostic significance in cervical cancer

Cervical cancer (CC) is a leading cause of cancer-related death among women in developing countries. However, the underlying mechanisms and molecular targets for therapy remain to be fully understood. We investigated the epigenetic regulation, biological functions, and clinical utility of zinc-finger protein 471 (ZNF471) in CC. Analysis of cervical tissues and five independent public datasets of CC showed significant hypermethylation of the ZNF471 gene promoter. In CC cell lines, promoter DNA methylation was inversely correlated with ZNF471 expression. The sensitivity and specificity of the ZNF471 hypermethylation for squamous intraepithelial lesion (SIL) vs tumor and normal vs tumor was above 85% with AUC of 0.937. High methylation and low ZNF471 expression predicted poor overall and recurrence-free survival. We identified −686 to +114 bp as ZNF471 promoter, regulated by methylation using transient transfection and luciferase assays. The promoter CpG site methylation of ZNF471 was significantly different among cancer types and tumor grades. Gal4-based heterologous luciferase reporter gene assays revealed that ZNF471 acts as a transcriptional repressor. The retroviral mediated overexpression of ZNF471 in SiHa and CaSki cells inhibited growth, proliferation, cell migration, invasion; delayed cell cycle progression in vitro by increasing cell doubling time; and reduced tumor growth in vivo in nude mice. ZNF471 overexpression inhibited key members of epithelial-mesenchymal transition (EMT), Wnt, and PI3K-AKT signaling pathways. ZNF471 inhibited EMT by directly targeting vimentin as analyzed by bioinformatic analysis, ChIP-PCR, and western blotting. Thus, ZNF471 CpG specific promoter methylation may determine the prognosis of CC and could function as a potential tumor suppressor by targeting EMT signaling.

Incidental Prostatic Adenocarcinoma in Open Prostatectomy Specimens: An Institutional Experience.

Prostatic diseases cause significant morbidity and mortality in African men. Most Nigerian patients presenting with huge prostate enlargement are availed open prostatectomy to relieve symptoms of prostatism. Some prostates removed for benign enlargement have indolent cancers that are only discovered after histopathological examination. The incidence of these incidental adenocarcinomas of the prostate varies widely. We carried out a 10-year retrospective review of open prostatectomy specimens received in the Department of Pathology, from January 2009 to December 2018. At grossing, a minimum of 6 cassettes were used depending on size, and tissue was taken from representative areas for microscopic examination. The data was analysed for the presence of, and the relationship between, incidental adenocarcinoma of the prostate and clinicopathological parameters in each case using relevant statistical tools in the SPSS version 23. Incidental adenocarcinoma of the prostate was found in 5.7% of 158 open prostatectomy specimens seen during the study period. High-grade prostatic intraepithelial neoplasm (HGPIN) was present in 1.9% of cases. Patients in the 7th and 8th decade accounted for 88.8% of all incidental adenocarcinomas. The mean weight of the excised glands was 89.8g (range10-500g). The weight of the prostate did not predict diagnosis of incidental adenocarcinoma. In-hospital consultation accounted for 66.9% of open prostatectomy samples received in the department but the majority (72.7%) of incidental adenocarcinomas were seen in specimens form external consultations. The tumours were mostly ISUP grade group one tumours. The rate of diagnosis of occult prostate cancer is low with majority of the tumours being well differentiated. Organ weight had no relationship with histological diagnosis. Cases managed outside the teaching hospital were more likely to have incidental prostate cancer.

Immune response in cervical intraepithelial neoplasms

Immune response in cervical intraepithelial neoplasms

ASSESSING THE UTILITY OF A CYTOKINE IN THE DIAGNOSIS OF CERVICAL INTRAEPITHELIAL NEOPLASM AMONG WOMEN IN BENIN CITY, NIGERIA

Cervical cancer has been recognized as the fourth commonest cancer worldwide with 70 % of deaths from cases occurring from developing countries. The mortality rate among women in Nigeria can be drastically reduced by early specific diagnosis of premalignant lesions. Although Cytokines are not routinely used as diagnostic markers for cervical cancer, this study investigated the strength of Granulocyte Monocyte Colony Stimulating growth Factor (GM-CSF) as an indicator in the prediction of Cervical Intraepithelial Neoplasm (CIN). The study was carried out at the Department of Obstetrics and Gynaecology, University of Benin Teaching Hospital Benin City and Department of Chemical Pathology, Edo University Iyamho, Edo state Nigeria, between August, 2017 and January 2019. It was a cross-sectional prospective study. A total of 197 female participants were recruited for this study. Based on histological diagnosis they were grouped as; Negative, CIN 1, CIN 2 and CIN 3. Venous blood was obtained from participants and serum GM-CSF levels were determined using standardized laboratory methods. The results showed a statistically significant elevation of serum GM-CSF in participants with CIN lesions (56.27±1.21ng/ml) compared to those without (33.43±3.03ng/ml). The study also suggests a 56.3% sensitivity and a 95.3% specificity of GM-CSF marker to CIN with an Area under the Curve (AUC) of 0 .907, p&lt;0.001 from the Receivers Operator Curve (ROC). This research suggests the use of GM-CSF as a good marker for screening of those at risk of cervical cancer because of its high prospect to reduce the incidence of false positives. However, because of the low sensitivity, it is recommended that GM-CSF be used as a CIN diagnostic tool in combination with the standard Pap smear test.

エラスターゼ1高値を契機に発見され腫瘤形成を認めた高異型度膵上皮性腫瘍性病変の1例

エラスターゼ1高値を契機に発見され腫瘤形成を認めた高異型度膵上皮性腫瘍性病変の1例

An unusual presentation of corneal intraepithelial neoplasia

Introduction: Conjunctival/corneal intraepithelial neoplasms are premalignant lesions usually showing conjunctival or limbal involvement. We report the rare case of an isolated corneal intraepithelial lesion.Clinical case: An 80-year-old woman with an elevated, avascular, well-demarcated grey corneal plaque. After epitheliectomy and alcohol, the excised lesion was identified as a high-grade epithelial neoplasia. Treatment was topical interferon α-2b for 1 month without recurrences.Conclusions: A well-defined greyish corneal opacity should always raise suspicion of an intraepithelial neoplasia. In the present case, epitheliectomy and topical recombinant interferon proved successful.

ANÁLISE DA FREQUÊNCIA DOS DIAGNÓSTICOS HISTOPATOLÓGICOS DAS NEOPLASIAS INTRAEPITELIAS CERVICAIS CONFORME A FAIXA ETÁRIA EM HOSPITAL DE REFERÊNCIA REGIONAL.

O câncer de colo uterino representa um grande problema de saúde pública. Em geral, a evolução do câncer do colo do útero é lenta, passando por fases pré-clínicas detectáveis e curáveis. Os programas de rastreamento para as lesões precursoras (neoplasias intraepiteliais cervicais) se baseiam na utilização do exame citopatológico (preventivo), também conhecido como exame de Papanicolau. O objetivo deste estudo foi verificar a frequência dos diagnósticos histopatológicos de neoplasias intraepiteilais cervicais de baixo risco (NIC 1) e de alto risco (NIC 2 e 3), conforme as faixas etárias, em hospital de referência regional do norte fluminense no período de 2014 a 2016, verificando se as recomendações do ministério da saúde refletem nos dados epidemiológicos encontrados na nossa região. Trata-se de uma pesquisa de abordagem quali-quantitativa envolvendo 352 amostras. Os dados foram analisados estatisticamente por meio do Software EPIDATA versão 3.0. Os resultados demonstram que os maiores percentuais de diagnósticos obtidos de lesões precursoras, tanto da lesão de baixo risco quanto de alto risco, ocorreram na faixa etária de 25 a 35 anos, com declínio progressivo destes diagnósticos à medida em que as faixas etárias aumentaram.

Correlation of serum PSA level with histomorphologic study in prostatic diseases

Correlation of serum PSA level with histomorphologic study in prostatic diseases - IJPO- Print ISSN No: - 2394-6784 Online ISSN No:- 2394-6792 Article DOI No:- 10.18231/2394-6792.2018.0117, Indian Journal of Pathology and Oncology-Indian J Pathol Oncol

Clinical treatment of intra-epithelia cervical neoplasia with photodynamic therapy

Objectives This clinical study was developed to primarily evaluate the Complete Cytopathological Response Rate of Cervical Intraepithelial Neoplasms to PDT using chitosan nanocapsules containing Chlorocyan-aluminum phthalocyanine as a photoactive agent. Analyses of the Free Recurrence Interval, toxicity profile (immediate and late), and complications (immediate and late), were secondarily analyzed. Methods This study was previously approved by the National Council of Ethics in Research of Brazil (CONEP), on May 28, 2014, under case number 19182113.4.0000.5009. On the surface of the cervix of each selected patient was applied one mL of the formulated gel, and after 30 min, the light was applied. Reports or the identification of adverse effects and/or complications were observed in follow-up visits, in addition to the collection of cervical oncotic cytology. Results Out of the total group, 11 (91.7%) primarily treated patients evolved with negative cervical oncotic cytology as soon as in the first evaluation following treatment, and one did not achieve any therapeutic benefit, even after reapplication. Two patients with initially positive response presented cytological recurrence determined by histopathology. A new round of PDT was developed, and both evolved with cytological remission three weeks later, remaining negative until the last follow-up. No important side effects were observed in all the patients. Conclusions Our trial demonstrates that treatment of CIN 1 and 2 lesions using our PDT formulation is feasible and safe. Large randomized clinical trials are required to establish efficacy.

ZNF671 Methylation as a Potential Biomarker to Identify Women with Cervical Intraepithelial Neoplasms Type 3 and Worse

Background: Cervical screening aims to identify women with cervical intraepithelial neoplasia 3 (CIN3) and squamous cell carcinoma (SCC), termed as CIN3+. Identification of women with CIN3+ ensure that they can receive optimal treatment and prevent overtreatment. Studies have suggested that the higher degree of cervical lesions, the more accumulation of DNA methylation (SCC > CIN3 > CIN2 > CIN1). DNA methylation analysis as a triage for women in cervical scrapings is feasible, but finding novel biomarkers with high sensitivity and high specificity is still a challenge. Zinc finger protein 671 (ZNF671), a member of the KRAB-ZFP family of mammalian transcriptional repressors, was hypermethylation of its promoter and downregulated in SCC. Methods: We investigated methylation of PAX1 or ZNF671 and genotyping of high-risk human papillomavirus (hrHPV) for detection of CIN3+ in 1006 women underwent Thinprep Cytologic test (TCT) and biopsy under colposcopy. Real-time methylation-specific PCR (qMSP) was used to detect the level of PAX1m and ZNF671m. Bisulfite pyrosequencing, the gold standard for detecting DNA methylation, was also used to measure the level of ZNF671m in 532 subjects. Findings: Sensitivities and specificities for CIN3+ were respectively, 75.69% and 77.54% for PAX1m, 79.52% and 85.76% for ZNF671m. High sensitivity (89.39%) but low specificity (60.63%) was observed for hrHPV. The sensitivities and specificities of PAX1m or hrHPV were 90.28% and 59.09%, of ZNF671m or hrHPV were 93.13% and 63.19%, of PAX1m or ZNF671m were 77.44% and 75.93%, respectively. The sensitivities and specificities of PAX1m(Algorithm 1) or ZNF671m (Algorithm 2) combined with hrHPV for CIN3+ were 98.61% and 51.57%, 76.77% and 88.42%, respectively. Interpretation: Compared with PAX1m, the level of ZNF671m could separate women more accurately into high risk groups either combined hrHPV genotyping or analysis alone. ZNF671mmay serve as a potential biomarker to identify women with CIN3+. And we propose that ZNF671m might be applied as a triage test alone or combined hrHPV genotyping and contribute to the globalization of cervical cancer screening. Funding Statement: This research was supported by Chinese National Major Project for New Drug Innovation (2019ZX09201-002-006), the National Natural Science Foundation (NNSF) of China (81973401) and the Natural Science Foundation for Young Scientist of Hunan Province, China (2018JJ3829). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: This study was undertaken in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethical Committee of Xiangya Hospital of Central South University, China. All patients gave written informed consent before participation in this study.

Loss of Jag1 cooperates with oncogenic Kras to induce pancreatic cystic neoplasms.

Notch signaling exerts both oncogenic and tumor-suppressive functions in the pancreas. In this study, deletion of Jag1 in conjunction with oncogenic Kras G12D expression in the mouse pancreas induced rapid development of acinar-to-ductal metaplasia and early stage pancreatic intraepithelial neoplasm; however, culminating in cystic neoplasms rather than ductal adenocarcinoma. Most cystic lesions in these mice were reminiscent of serous cystic neoplasm, and the rest resembled intraductal papillary mucinous neoplasm. Jag1 expression was lost or decreased in cystic lesions but retained in adenocarcinoma in these mice, so was the expression of Sox9. In pancreatic cancer patients, JAG1 expression is higher in cancerous tissue, and high JAG1 is associated with poor overall survival. Expression of SOX9 is correlated with JAG1, and high SOX9 is also associated with poor survival. Mechanistically, Jag1 regulates expression of Lkb1, a tumor suppressor involved in the development of pancreatic cystic neoplasm. Collectively, Jag1 can act as a tumor suppressor in the pancreas by delaying precursor lesions, whereas loss of Jag1 promoted a phenotypic switch from malignant carcinoma to benign cystic lesions.

Precancerous Lesions and Liver Atrophy as Risk Factors for Hepatolithiasis-Related Death after Liver Resection for Hepatolithiasis.

Background:Cholangiocarcinoma and secondary biliary cirrhosis can develop after liver resection for hepatolithiasis and are causes of hepatolithiasis-related death. We determined potential risk factors for hepatolithiasis-related death and subsequent cholangiocarcinoma, including precancerous lesions such as biliary intraepithelial neoplasia (BilIN) and intraductal papillary neoplasm of the bile duct, in patients undergoing liver resection for hepatolithiasis. Methods:The study cohort included 62 patients who underwent liver resection for hepatolithiasis without concomitant cholangiocarcinoma and had surgical specimens available for pathological examination. Univariate and multivariate analyses were conducted to examine risk factors associated with subsequent cholangiocarcinoma after hepatolithiasis and hepatolithiasis-related death. In 28 patients with BilIN lesions, the specimens were immunohistochemically stained for γ-H2AX and S100P. Results:In the study cohort, the causes of death were subsequent cholangiocarcinoma, biliary cirrhosis, and other diseases in 5, 3, and 7 patients, respectively. Liver atrophy, precancerous lesions, postoperative repeated cholangitis, and jaundice for ≥1 week during the follow-up period were risk factors for hepatolithiasis-related death. Multivariate analysis showed that liver atrophy and precancerous lesions were independent risk factors for hepatolithiasis-related death. Liver atrophy or precancerous lesions were also risk factors for subsequent cholangiocarcinoma by univariate analysis. The positive expression of γ-H2AX and S100P was observed in 18 and 14 of the 28 BilIN lesions, respectively. Conclusions:Liver atrophy and precancerous lesions with malignant transformation were risk factors not only for subsequent cholangiocarcinoma but also hepatolithiasis-related death after liver resection for hepatolithiasis, indicating that long-term follow-up is necessary even after liver resection in patients harboring these risk factors.