ABSTRACT
Von Meyenburg complex (VMC) is generally thought to be benign, although its preneoplastic potential for intrahepatic cholangiocarcinoma (iCC) has been a subject of contention. We retrospectively reviewed 86 hepatectomy specimens with a diagnosis of iCC. Morphologically, an association between iCC and VMC was appreciated in 35% of cases that illustrated a gradual neoplastic progression from benign VMC to dysplasia and then to iCC. Among them, 24 cases had VMC lined by epithelial cells with low-grade biliary dysplasia and 13 with high-grade biliary dysplasia. VMC-associated iCCs were smaller in size and well to moderately differentiated, with features of anastomosing glandular architecture, ductal carcinoma in situ-like growth pattern, peritumoral lymphocytic infiltrate, central fibrous scar, and complete pushing border. They often presented as T1 tumors. In contrast, non-VMC-associated iCCs were moderately to poorly differentiated with solid, cribriform or papillary growth patterns. They likely exhibited necrosis, perineural invasion, positive surgical margin, lymphovascular invasion, and high T stage. Additionally, Ki67 and p53 immunostains support the continuing neoplastic evolution from benign VMC to dysplasia and then to iCC. VMC could become neoplastic, serving as an in situ carcinoma lesion to transform to iCC. The underlying molecular alteration and clinical implication of this neoplastic transformation deserves further investigation.
Subject(s)
Bile Duct Diseases/pathology , Bile Duct Neoplasms/pathology , Carcinoma in Situ/pathology , Cell Transformation, Neoplastic/pathology , Cholangiocarcinoma/pathology , Precancerous Conditions/pathology , Aged , Aged, 80 and over , Bile Duct Diseases/surgery , Bile Duct Neoplasms/chemistry , Bile Duct Neoplasms/surgery , Biomarkers, Tumor/analysis , Biopsy , Carcinoma in Situ/chemistry , Carcinoma in Situ/surgery , Cell Differentiation , Cell Proliferation , Cell Transformation, Neoplastic/chemistry , Cholangiocarcinoma/chemistry , Cholangiocarcinoma/surgery , Disease Progression , Female , Hepatectomy , Humans , Immunohistochemistry , Male , Middle Aged , Neoplasm Grading , Neoplasm Staging , Precancerous Conditions/chemistry , Precancerous Conditions/surgery , Retrospective Studies , Tumor BurdenABSTRACT
Objective: To investigate the sorting effect of p16(INK4a)/Ki-67 double immunostaining method in patients with atypical squamous cells of undetermined significance (ASCUS) or low-grade squamous intraepithelial lesion (LSIL) cytology results. Methods: Four-hundred and twenty cases collected during April 2014 to February 2015 of cervical cytology of ASCUS (n=318) and LSIL (n=102) were selected, and residual liquid-based cytology specimens were used for p16(INK4a)/Ki-67 double immunostaining. The sensitivity and specificity of the detection of cervical precancerous lesions and cervical cancer were calculated, and the results were compared with high risk HPV. Taking histological follow-up as the gold standard, the test was considered positive when at least one cell exhibited p16(INK4a)/Ki-67 co-staining, without requirement of adjunct morphologic interpretation of positive cells. Results: Further screening CIN2+ in cytology ASCUS and LSIL group , the sensitivity of p16(INK4a)/Ki-67 double immunostaining was slightly lower than high risk HPV (84.2% vs. 94.7%), while the specificity was higher (84.0% vs. 53.9%). For ASCUS patients, the sensitivity of p16(INK4a)/Ki-67 double immunostaining and high risk HPV was 82.6% and 91.3%, and the specificity was 88.8% and 63.7%, respectively. For LSIL patients, the sensitivity of p16(INK4a)/Ki-67 double immunostaining and high risk HPV was 86.7% and 100.0%, and the specificity was 67.8% and 20.7%, respectively. For patients younger and older than 30 years, specificity of p16(INK4a)/Ki-67 double immunostaining was both higher than that of high risk HPV (80.8% vs. 42.3%; 84.6% vs. 56.9%). Conclusions: p16(INK4a)/Ki-67 double immunostaining can effectively identify the high risk population in ASCUS or LSIL, with higher specificity than high risk HPV test. p16(INK4a)/Ki-67 double immunostaining may benefit patients younger than 30 years of age as a preliminary or potential cytology-combining screening tool.
Subject(s)
Atypical Squamous Cells of the Cervix/chemistry , Cyclin-Dependent Kinase Inhibitor p16/analysis , Ki-67 Antigen/analysis , Uterine Cervical Dysplasia/chemistry , Uterine Cervical Neoplasms/chemistry , Adult , Atypical Squamous Cells of the Cervix/pathology , Female , Humans , Precancerous Conditions/chemistry , Sensitivity and Specificity , Uterine Cervical Neoplasms/pathology , Vaginal Smears , Uterine Cervical Dysplasia/pathologyABSTRACT
Spasmolytic polypeptide-expressing metaplasia (SPEM) and intestinal metaplasia (IM) have been recognized as neoplastic precursors in gastric carcinogenesis. We explored the relationship between SPEM and IM in Epstein-Barr virus-associated (EBVaGC) and Epstein-Barr virus-negative (EBVnGC) gastric cancer. Sixty-four EBVaGC and one hundred and fifty-four EBVnGC patients were included. EBV positivity was identified using Epstein-Barr virus-encoded RNA-1 in situ hybridization. SPEM was subclassified into absent, early, and advanced SPEM. Acute and chronic inflammation was graded as absent, mild, moderate, and marked. Univariate and multivariate logistic regression analyses were conducted to analyze the correlation between SPEM, IM, and inflammation. Our study revealed that SPEM was detected in 87.5% EBVaGC and 85.1% EBVnGC patients. Distribution of patients according to the SPEM classification was significantly different between EBVaGC and EBVnGC groups (P=.038). IM was observed less frequently in EBVaGC when compared with EBVnGC patients (P<.001). No difference was observed between EBVaGC and EBVnGC in the levels of acute and chronic inflammation. A positive correlation between IM and SPEM status was observed in both EBVaGC and EBVnGC patients. Furthermore, advanced SPEM was an independent influential factor to IM in EBVnGC (P=.013). In conclusion, SPEM was associated with both EBVaGC and EBVnGC more frequently than IM. Moreover, advanced SPEM had a stronger association with IM than early SPEM in EBVnGC. These results suggest that identification of SPEM should be used as a high-risk indicator for detecting early gastric carcinoma, and should be brought to the attention of pathologists and clinicians.
Subject(s)
Adenocarcinoma/chemistry , Biomarkers, Tumor/analysis , Epstein-Barr Virus Infections/virology , Herpesvirus 4, Human/isolation & purification , Peptides/analysis , Precancerous Conditions/chemistry , Stomach Neoplasms/chemistry , Stomach/chemistry , Adenocarcinoma/pathology , Adenocarcinoma/surgery , Adenocarcinoma/virology , Biopsy , Chi-Square Distribution , China , Female , Gastritis/metabolism , Gastritis/pathology , Gastritis/virology , Herpesvirus 4, Human/genetics , Humans , Immunohistochemistry , In Situ Hybridization , Intercellular Signaling Peptides and Proteins , Kaplan-Meier Estimate , Logistic Models , Male , Metaplasia , Middle Aged , Multivariate Analysis , Odds Ratio , Precancerous Conditions/pathology , Precancerous Conditions/surgery , Precancerous Conditions/virology , Proportional Hazards Models , RNA, Viral/genetics , Stomach/pathology , Stomach/virology , Stomach Neoplasms/pathology , Stomach Neoplasms/surgery , Stomach Neoplasms/virologyABSTRACT
In normal colonic epithelium, the proliferative zone is limited to the lower half of the colonic crypt. Evaluating the changes in the colonic epithelial proliferation can be useful in understanding pathophysiology of various diseases. Our aim was to investigate the proliferative compartment of serrated polyps (SPs) using MCM2, a protein involved in DNA replication, and assess for changes along the SP spectrum. Immunohistochemistry was performed on serrated polyps (16 microvesicular-type hyperplastic polyps (HP), 58 sessile serrated adenomas (SSA), 7 SSAs with dysplasia) and 6 sections of normal colon using anti-MCM2 antibody. Multiple sections of normal colon showed the following pattern for MCM2 and Ki-67 staining: positive nuclear staining of the lower half of the colonic crypts and/or slightly expanded to the lower two-thirds of the crypt. By MCM2, SPs show expansion of the proliferative compartments; 81.3% of HPs and 100% of SSAs showed some degree of full crypt MCM2 staining. SSAs with dysplasia showed consistent diffuse polyp staining. Aberrant staining in adjacent normal mucosa was also seen in SSAs with dysplasia and in a subset of non-dysplastic SSAs. By using MCM2, we show that serrated polyps exhibit changes in proliferation during progression along the pathway. HPs and SSAs show a similar highly proliferative profile. Aberrant proliferative cell staining patterns in adjacent normal colonic mucosa as seen in SSAs with dysplasia and a subset of SSAs suggest a field effect phenomenon. This indicates that changes in the colonic micro-environment may promote adenoma morphogenesis and predisposition to malignancy.
Subject(s)
Adenomatous Polyps/chemistry , Biomarkers, Tumor/analysis , Cell Proliferation , Colon/chemistry , Colonic Neoplasms/chemistry , Colonic Polyps/chemistry , Epithelial Cells/chemistry , Intestinal Mucosa/chemistry , Minichromosome Maintenance Complex Component 2/analysis , Precancerous Conditions/chemistry , Adenomatous Polyps/pathology , Biopsy , Colon/pathology , Colonic Neoplasms/pathology , Colonic Polyps/pathology , Epithelial Cells/pathology , Humans , Immunohistochemistry , Intestinal Mucosa/pathology , Ki-67 Antigen/analysis , Precancerous Conditions/pathology , Tumor MicroenvironmentABSTRACT
Minichromosomal maintenance (MCM) proteins are participants of DNA replication and may represent more accurate markers in determining the proliferative fraction within a tumor than proliferative marker Ki-67. Our study investigated the correlation between MCM4 and MCM7 expression and Ki-67, Bmi1, and cyclin E expression in esophageal adenocarcinoma, squamous cell carcinoma, and precancerous lesions. MCM4 and MCM7 expression had similar distribution as Ki-67 and Bmi1 expression in esophageal carcinoma and precancerous lesions. The mean percentage of MCM4, MCM7, and Ki-67 expression increased from squamous epithelium (5.5%, 7.3%, and 5.9%, respectively), to columnar cell metaplasia (11.2, 13.5%, and 3.4%), Barrett's esophagus (27.7%, 35.3%, and 8.3%), low-grade dysplasia (42.6%, 52.2%, and 12.9%), high-grade dysplasia (63.2%, 77.7%, and 29.6%), adenocarcinoma (61.3%, 75.5%, and 24.5%), and squamous cell carcinoma (74.1, 85.4%, and 36.3%). The percentages of MCM4 and MCM7 expression were significantly higher than Ki-67 expression. Using univariate analysis we found a high percentage of MCM4 expression (>70%) to be significantly associated with lymph node metastasis and shorter survival in the adenocarcinoma group. We also demonstrated the percentage of MCM4 and MCM7 expression to be significantly correlated with Ki-67, Bmi1, and cyclin E expression in esophageal carcinoma and precancerous lesions. MCM4 and MCM7 may serve as more sensitive proliferative markers for the evaluation of esophageal lesions.
Subject(s)
Adenocarcinoma/chemistry , Barrett Esophagus/metabolism , Carcinoma, Squamous Cell/chemistry , Cell Proliferation , Cyclin E/analysis , Esophageal Neoplasms/chemistry , Ki-67 Antigen/analysis , Minichromosome Maintenance Complex Component 4/analysis , Minichromosome Maintenance Complex Component 7/analysis , Polycomb Repressive Complex 1/analysis , Precancerous Conditions/chemistry , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Barrett Esophagus/mortality , Barrett Esophagus/pathology , Carcinoma, Squamous Cell/mortality , Carcinoma, Squamous Cell/pathology , Chi-Square Distribution , Esophageal Neoplasms/mortality , Esophageal Neoplasms/pathology , Esophageal Squamous Cell Carcinoma , Female , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Lymphatic Metastasis , Male , Multivariate Analysis , Neoplasm Grading , Precancerous Conditions/mortality , Precancerous Conditions/pathology , Predictive Value of Tests , Reproducibility of Results , Risk Factors , Tissue Array AnalysisABSTRACT
An increased rate of second nonmelanoma skin cancers is found in immunocompromised patients. Epidemiological and molecular data implicate ultraviolet radiation as the major risk factor. In addition, there is increasing evidence supporting the role of human papillomavirus (HPV) in the pathogenesis of premalignant and malignant skin lesions in both immunocompetent and immunocompromised patients. In a retrospective cross-sectional study, the authors examined the expression of p16 by immunohistochemistry and the presence of mucosal (α-genus) and cutaneous/epidermodysplasia verruciformis (ß-genus) HPV DNA by polymerase chain reaction in 29 biopsy specimens of extragenital/extraungual Bowen disease (BD) from 24 Eastern European white immunocompromised patients. Furthermore, the author evaluated the association between the expression of p16 protein and the presence of HPV DNA. Among 25 specimens from 21 patients evaluable by polymerase chain reaction, HPV DNA was detected in 10 (40%) BD lesions from 9 patients. Beta-HPV predominated over alpha-HPV types. Among 29 immunohistochemically evaluable BD specimens, 22 lesions (â¼76%) from 20 patients were scored as p16 positive. HPV DNA-positive and HPV DNA-negative lesions displayed the same proportion of p16 positivity (80%) and no correlation was found between the HPV DNA presence and the p16 expression status. Our pilot study demonstrated that ß-HPV infections predominate in BD cases diagnosed among immunocompromised patients, although high- and low-risk mucosal (alpha) HPV genotypes may be detected in a minority of cases. In contrast to anogenital HPV-associated lesions, positive p16 expression is not a reliable marker of high-risk α-HPV infection in BD cases, as it can be also detected in ß-HPV infected and HPV-negative cases.
Subject(s)
Biomarkers, Tumor/analysis , Bowen's Disease/virology , Cyclin-Dependent Kinase Inhibitor p16/analysis , Immunocompromised Host , Papillomaviridae/pathogenicity , Papillomavirus Infections/virology , Precancerous Conditions/virology , Skin Neoplasms/virology , Aged , Aged, 80 and over , Biopsy , Bowen's Disease/chemistry , Bowen's Disease/immunology , Cell Transformation, Viral , Cross-Sectional Studies , Czech Republic , DNA, Viral/genetics , Female , Human Papillomavirus DNA Tests , Humans , Immunohistochemistry , Male , Middle Aged , Papillomaviridae/genetics , Papillomaviridae/immunology , Papillomavirus Infections/immunology , Pilot Projects , Precancerous Conditions/chemistry , Precancerous Conditions/immunology , Predictive Value of Tests , Retrospective Studies , Risk Factors , Skin Neoplasms/chemistry , Skin Neoplasms/immunologyABSTRACT
In the recently published 2015 World Health Organization (WHO) classification of tumors of the lungs, all neuroendocrine tumors of the lungs are presented for the first time in one single chapter. In this classification, high-grade small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) are differentiated from intermediate grade atypical carcinoids (AC) and low-grade typical carcinoids as well as from preinvasive lesion diffuse neuroendocrine hyperplasia DIPNECH. In the 2004 WHO classification, SCLC and carcinoids each had a separate chapter and LCNEC was listed in the chapter on large cell carcinoma of the lungs. The new WHO classification also gives some recommendations for the diagnosis on small biopsies. This review describes morphological, immunohistochemical, and genomic characteristic of these tumors according to the new classification.
Subject(s)
Lung Neoplasms/classification , Neuroendocrine Tumors/classification , Biomarkers, Tumor , Carcinoid Tumor/chemistry , Carcinoid Tumor/classification , Carcinoid Tumor/diagnosis , Carcinoid Tumor/pathology , Cell Differentiation , Diagnosis, Differential , Genes, Neoplasm , Humans , Hyperplasia , Lung Neoplasms/chemistry , Lung Neoplasms/diagnosis , Lung Neoplasms/pathology , Neuroendocrine Cells/pathology , Neuroendocrine Tumors/chemistry , Neuroendocrine Tumors/diagnosis , Neuroendocrine Tumors/pathology , Precancerous Conditions/chemistry , Precancerous Conditions/diagnosis , Precancerous Conditions/pathology , World Health OrganizationABSTRACT
Microglandular adenosis (MGA) is a rare proliferative lesion of the breast composed of small glands lacking myoepithelial cells and lined by S100-positive, oestrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative epithelial cells. There is evidence to suggest that MGA may constitute a non-obligate precursor of triple-negative breast cancer (TNBC). We sought to define the genomic landscape of pure MGA and of MGA, atypical MGA (AMGA) and associated TNBCs, and to determine whether synchronous MGA, AMGA, and TNBCs would be clonally related. Two pure MGAs and eight cases of MGA and/or AMGA associated with in situ or invasive TNBC were collected, microdissected, and subjected to massively parallel sequencing targeting all coding regions of 236 genes recurrently mutated in breast cancer or related to DNA repair. Pure MGAs lacked clonal non-synonymous somatic mutations and displayed limited copy number alterations (CNAs); conversely, all MGAs (n = 7) and AMGAs (n = 3) associated with TNBC harboured at least one somatic non-synonymous mutation (range 3-14 and 1-10, respectively). In all cases where TNBCs were analyzed, identical TP53 mutations and similar patterns of gene CNAs were found in the MGA and/or AMGA and in the associated TNBC. In the MGA/AMGA associated with TNBC lacking TP53 mutations, somatic mutations affecting PI3K pathway-related genes (eg PTEN, PIK3CA, and INPP4B) and tyrosine kinase receptor signalling-related genes (eg ERBB3 and FGFR2) were identified. At diagnosis, MGAs associated with TNBC were found to display subclonal populations, and clonal shifts in the progression from MGA to AMGA and/or to TNBC were observed. Our results demonstrate the heterogeneity of MGAs, and that MGAs associated with TNBC, but not necessarily pure MGAs, are genetically advanced, clonal, and neoplastic lesions harbouring recurrent mutations in TP53 and/or other cancer genes, supporting the notion that a subset of MGAs and AMGAs may constitute non-obligate precursors of TNBCs.
Subject(s)
Biomarkers, Tumor/genetics , Carcinoma/genetics , Fibrocystic Breast Disease/genetics , Mutation , Precancerous Conditions/genetics , Triple Negative Breast Neoplasms/genetics , Tumor Suppressor Protein p53/genetics , Aged , Biomarkers, Tumor/analysis , Carcinoma/chemistry , Carcinoma/pathology , Carcinoma in Situ/genetics , Carcinoma in Situ/pathology , DNA Mutational Analysis , Disease Progression , Female , Fibrocystic Breast Disease/chemistry , Fibrocystic Breast Disease/pathology , Genetic Predisposition to Disease , Humans , Immunohistochemistry , Middle Aged , Phenotype , Precancerous Conditions/chemistry , Precancerous Conditions/pathology , Retrospective Studies , Triple Negative Breast Neoplasms/chemistry , Triple Negative Breast Neoplasms/pathology , Tumor Suppressor Protein p53/analysisABSTRACT
There is a lack of standardized nomenclature for renal cysts lined by multiple cell layers or with short papillary projections but without nests of epithelial cells within the stroma. We retrieved 29 cases (15 nephrectomies, 14 partial nephrectomies) from the surgical pathology files of Johns Hopkins Hospital from 1993 to 2014 and performed immunohistochemistry for CK7, alpha-methylacyl-CoA racemase (AMACR), CAIX, and CD10 and fluorescence in situ hybridization for trisomy 7 and 17 and 3p deletion. The mean age at excision was 58 years (range, 29 to 80 y) with 16 men and 13 women. Mean size was 2.9 cm (range, 0.3 to 10 cm). The cysts were grouped by their morphology into (1) clear cell, (2) eosinophilic stratified, and (3) eosinophilic papillary. By immunohistochemistry, 7/9 (78%) of the clear cell cases were diffusely positive for both CK7 and CAIX resembling the pattern seen in clear cell papillary renal cell carcinoma. The majority of eosinophilic stratified (4/6; 67%) and eosinophilic papillary (12/14; 86%) cases were positive for CK7 and had variable staining for AMACR, CD10, or CAIX, suggesting a differentiation more aligned with papillary renal cell carcinoma. The most common molecular alterations detected were trisomy 17 (n=6) and trisomy 7 (n=4). One case showed deletion of chromosome 3p. Clinical follow-up information was available in 23 patients; 20 were alive with no evidence of disease after a median follow-up of 20 months (range, 3 to 120 mo), 1 patient was dead due to metastatic lung cancer, 1 of sepsis, and 1 of unknown reason. Atypical renal cysts present as complex radiologic lesions, as secondary lesions in patients with a renal mass, or in a background of chronic renal disease. These atypical cysts appear heterogenous, and some follow in their morphology and immunoprofile with well-established renal tumors. The presence of 3p deletion and trisomy 7/17 suggests that in some cases they may be precursors of renal cell carcinoma. Longer follow-up with more cases is needed, but on the basis of our data, these lesions should not be diagnosed as carcinoma.
Subject(s)
Biomarkers, Tumor , Carcinoma, Renal Cell/diagnosis , Immunohistochemistry , In Situ Hybridization, Fluorescence , Kidney Diseases, Cystic/diagnosis , Kidney Neoplasms/diagnosis , Molecular Diagnostic Techniques , Precancerous Conditions/diagnosis , Adult , Aged , Aged, 80 and over , Baltimore , Biomarkers, Tumor/analysis , Biomarkers, Tumor/genetics , Biopsy , Carcinoma, Renal Cell/chemistry , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/surgery , Female , Genetic Predisposition to Disease , Humans , Kidney Diseases, Cystic/genetics , Kidney Diseases, Cystic/metabolism , Kidney Diseases, Cystic/pathology , Kidney Diseases, Cystic/surgery , Kidney Neoplasms/chemistry , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Kidney Neoplasms/surgery , Male , Middle Aged , Nephrectomy , Phenotype , Precancerous Conditions/chemistry , Precancerous Conditions/genetics , Precancerous Conditions/pathology , Precancerous Conditions/surgery , Predictive Value of Tests , Treatment OutcomeABSTRACT
BACKGROUND: The purpose of this study was to evaluate the immunohistochemical expression of NF-κB and IL-6 in oral premalignant and malignant lesions and to investigate their possible correlation with the presence of subepithelial inflammation. MATERIAL AND METHODS: Thirty two oral premalignant lesions, clinically compatible with leukoplakia or erythroplakia, were investigated. Microscopically, 11 of them showed hyperkeratosis and acanthosis (epithelial hyperplasia) and 21 showed dysplasia of varying degrees. Nine cases of OSCC and four control cases of normal oral mucosa were also included in the study. Immunohistochemical staining with NF-κB (p65) and IL-6 was performed. IL-6 and nuclear NF-κB staining were assessed as positive or negative. For cytoplasmic localization of NF-κB, a total score combining intensity and percentage of positive epithelial cells was additionally calculated. The presence of inflammation was also recorded. RESULTS: Intensity and total scores for NF-κΒ cytoplasmic immunostaining showed a statistically significant gradual increase from normal mucosa to OSCC (p=0.012 and p=0.026 respectively). Non-statistically significant increased NF-κΒ nuclear localization was detected in dysplasias and OSCCs. Positive statistical correlation was detected between the presence of inflammation and IL-6 expression (p=0.015). No correlation between NF-κΒ and IL-6 was detected. CONCLUSIONS: NF-κΒ is activated in the early stages of oral carcinogenesis. IL-6 may have an NF-κΒ-independent role, possibly through regulation of the inflammatory response.
Subject(s)
Interleukin-6/biosynthesis , Mouth Neoplasms/metabolism , NF-kappa B/biosynthesis , Precancerous Conditions/metabolism , Adult , Aged , Aged, 80 and over , Female , Humans , Immunohistochemistry , Interleukin-6/analysis , Leukoplakia/chemistry , Leukoplakia/metabolism , Leukoplakia/pathology , Male , Middle Aged , Mouth Neoplasms/chemistry , Mouth Neoplasms/pathology , NF-kappa B/analysis , Precancerous Conditions/chemistry , Precancerous Conditions/pathologyABSTRACT
In a natural history study of anal human papillomavirus (HPV) infection and HPV-related lesions among homosexual men in Sydney, Australia, we identified 15 examples of papillary immature metaplasia (PIM) in anal biopsy samples. PIM has previously been described in the cervix, but not in the anal canal. PIM is a form of exophytic low-grade squamous intraepithelial lesion (eLSIL) also known as condyloma. In contrast to the maturing keratinocytes and koilocytosis seen in conventional eLSIL, the slender papillary structures of PIM have a surface population of immature squamous cells. In our anal samples PIM was characterized by close proximity to conventional eLSIL, was negative for p16 (p16) expression, and revealed the presence of a single low-risk HPV genotype (either 6 or 11) in laser capture microdissected lesions. The clinical significance of recognizing PIM lies in preventing misdiagnosis as high-grade squamous intraepithelial lesion, (the presumed precursor to anal cancer), due to the morphologic immaturity of the cell population. In routine practice, awareness of anal canal PIM and p16 immunostaining will prevent this. Further study of the natural history of anal canal PIM is needed.
Subject(s)
Anal Canal/pathology , Anus Neoplasms/pathology , Condylomata Acuminata/pathology , Precancerous Conditions/pathology , Adult , Anal Canal/virology , Anus Neoplasms/chemistry , Anus Neoplasms/virology , Biomarkers, Tumor/analysis , Biopsy , Condylomata Acuminata/metabolism , Condylomata Acuminata/virology , Cyclin-Dependent Kinase Inhibitor p16/analysis , DNA, Viral/genetics , Diagnosis, Differential , Homosexuality, Male , Human Papillomavirus DNA Tests , Humans , Immunohistochemistry , Male , Metaplasia , Middle Aged , Neoplasm Grading , New South Wales , Papillomaviridae/genetics , Precancerous Conditions/chemistry , Precancerous Conditions/virology , Predictive Value of TestsABSTRACT
We report a case of a 76-year-old female with multiple lung nodules (Fig. 1 Rx). Pathologic evaluation of the lower left video-assisted thoracoscopic surgery (VATS) lobectomy VATS-lobectomy showed four nodules that were described as pulmonary epithelioid hemangio-endothelioma (PEH); the immunohistochemical stains showed that the neoplastic cells expressed CD31, a variable expression for factor VIII and a low expression of CD34. In the remaining parenchyma of the lobe, multiple nests of neuroendocrine cells were observed with immunohistochemical confirmation, and the diagnosis was diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). To our knowledge, the association between PEH and DIPNECH has never been described in the literature.
Subject(s)
Hemangioendothelioma, Epithelioid/pathology , Lung Neoplasms/pathology , Multiple Pulmonary Nodules/pathology , Neuroendocrine Cells/pathology , Precancerous Conditions/pathology , Aged , Biomarkers, Tumor/analysis , Biopsy , Female , Hemangioendothelioma, Epithelioid/chemistry , Hemangioendothelioma, Epithelioid/diagnostic imaging , Hemangioendothelioma, Epithelioid/surgery , Humans , Hyperplasia , Immunohistochemistry , Lung Neoplasms/chemistry , Lung Neoplasms/diagnostic imaging , Lung Neoplasms/surgery , Multiple Pulmonary Nodules/chemistry , Multiple Pulmonary Nodules/diagnostic imaging , Multiple Pulmonary Nodules/surgery , Neuroendocrine Cells/chemistry , Pneumonectomy/methods , Precancerous Conditions/chemistry , Precancerous Conditions/diagnostic imaging , Precancerous Conditions/surgery , Predictive Value of Tests , Thoracic Surgery, Video-Assisted , Tomography, X-Ray Computed , Treatment OutcomeABSTRACT
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with a mortality that is almost identical to incidence. Because early detected PDAC is potentially curable, blood-based biomarkers that could detect currently developing neoplasia would improve patient survival and management. PDAC develops from pancreatic intraepithelial neoplasia (PanIN) lesions, graded from low grade (PanIN1) to high grade (PanIN3). We made the hypothesis that specific proteomic signatures from each precancerous stage exist and are detectable in plasma. METHODS: We explored the peptide profiles of microdissected PanIN cells and of plasma samples corresponding to the different PanIN grade from genetically engineered mouse models of PDAC using capillary electrophoresis coupled to mass spectrometry (CE-MS) and Chip-MS/MS. RESULTS: We successfully characterised differential peptides profiles from PanIN microdissected cells. We found that plasma from tumor-bearing mice and age-matched controls exhibit discriminative peptide signatures. We also determined plasma peptide signatures corresponding to low- and high-grade precancerous step present in the mice pancreas using the two mass spectrometry technologies. Importantly, we identified biomarkers specific of PanIN3. CONCLUSIONS: We demonstrate that benign and advanced PanIN lesions display distinct plasma peptide patterns. This strongly supports the perspectives of developing a non-invasive screening test for prediction and early detection of PDAC.
Subject(s)
Biomarkers, Tumor/blood , Carcinoma in Situ/blood , Carcinoma, Pancreatic Ductal/blood , Neoplasm Proteins/blood , Pancreatic Neoplasms/blood , Peptides/blood , Precancerous Conditions/blood , Animals , Biomarkers, Tumor/analysis , Carcinoma in Situ/chemistry , Carcinoma in Situ/pathology , Carcinoma, Pancreatic Ductal/chemistry , Disease Models, Animal , Mice , Neoplasm Proteins/analysis , Pancreatic Neoplasms/chemistry , Peptides/analysis , Precancerous Conditions/chemistry , Precancerous Conditions/pathology , Protein Array Analysis , Proteome/analysisABSTRACT
DNA methylation is clinically relevant to important tumorigenic mechanisms. This study evaluated the methylation status of candidate genes in cervical neoplasia and determined their diagnostic performance in clinical practice. Cervical cancer and normal cervix tissue was used to select the top 5 discriminating loci among 27 loci in 4 genes (CCNA1, CADM1, DAPK1, JAM3), and one locus of JAM3 (region M4) was identified and confirmed with 267 and 224 cervical scrapings from 2 independent colposcopy referral studies. For patients with atypical squamous cells of unknown significance and those with low-grade squamous intraepithelial lesion, with JAM3-M4 compared to a triage marker of hrHPV testing, the specificity for cervical intraepithelial neoplasia 3 CIN3 and cancer cases (CIN3+) / no neoplasia and CIN1 (CIN1-) was significantly increased, from 21.88 to 81.82 and 15.38 to 85.18, respectively. The corresponding positive predictive value (PPV) was increased from 26.47 to 57.14 and 18.52 to 63.64, respectively. For hrHPV-positive patients, compared to a triage marker of cytology testing, JAM3-M4 showed increased specificity and PPV, from 30.67 to 87.65 and 38.82 to 82.14, respectively. We assessed whether JAM3-M4 could distinguish productive from transforming CIN2; the coincidence rate of JAM3-M4 and P16 was as high as 60.5%.
Subject(s)
Atypical Squamous Cells of the Cervix , Biomarkers, Tumor/genetics , Cell Adhesion Molecules/genetics , DNA Methylation , Papillomavirus Infections/genetics , Precancerous Conditions/genetics , Squamous Intraepithelial Lesions of the Cervix/genetics , Uterine Cervical Dysplasia/genetics , Uterine Cervical Neoplasms/genetics , Adult , Area Under Curve , Atypical Squamous Cells of the Cervix/chemistry , Atypical Squamous Cells of the Cervix/pathology , Atypical Squamous Cells of the Cervix/virology , Biomarkers, Tumor/analysis , Cyclin-Dependent Kinase Inhibitor p16/analysis , Diagnosis, Differential , Female , Humans , Immunohistochemistry , Middle Aged , Papillomaviridae/isolation & purification , Papillomavirus Infections/metabolism , Papillomavirus Infections/pathology , Papillomavirus Infections/virology , Polymerase Chain Reaction , Precancerous Conditions/chemistry , Precancerous Conditions/pathology , Precancerous Conditions/virology , Predictive Value of Tests , ROC Curve , Reproducibility of Results , Squamous Intraepithelial Lesions of the Cervix/metabolism , Squamous Intraepithelial Lesions of the Cervix/pathology , Squamous Intraepithelial Lesions of the Cervix/virology , Uterine Cervical Neoplasms/chemistry , Uterine Cervical Neoplasms/pathology , Uterine Cervical Neoplasms/virology , Vaginal Smears , Uterine Cervical Dysplasia/chemistry , Uterine Cervical Dysplasia/pathology , Uterine Cervical Dysplasia/virologyABSTRACT
OBJECTIVES: Barrett's esophagus (BE) surveillance with white-light endoscopy and quadrantic biopsies (Seattle protocol) is resource intensive and limited by sampling error. Previous work suggests that autofluorescence imaging (AFI) in combination with a molecular panel might reduce the number of biopsies, but this was not sufficiently sensitive for low-grade dysplasia, now a point for endoscopic intervention. Here we used AFI to direct narrow-field imaging tools for real-time optical assessment of dysplasia and biopsies for a biomarker panel. We compared the new diagnostic algorithm with the current standard. METHODS: A total of 55 patients with BE were recruited at a single tertiary referral center. Patients underwent high-resolution endoscopy followed by AFI. AFI-targeted areas (n=194) were examined in turn by narrow-band imaging with magnification (NBIz) and probe-based confocal laser endomicroscopy (pCLE). Biopsies were taken from AFI-targeted areas and tested using an established molecular panel comprising aneuploidy plus cyclin A and p53 immunohistochemistry. RESULTS: In the per-patient analysis the overall sensitivity and specificity of AFI-targeted pCLE were 100% and 53.6% for high-grade dysplasia/intramucosal cancer and 96.4% and 74.1% for any grade of dysplasia, respectively. NBIz had equal specificity for dysplasia detection (74.1%), but significantly lower sensitivity (57.1%) than pCLE. The time required to perform AFI-targeted pCLE was shorter that that taken by the Seattle protocol (P=0.0004). We found enrichment of molecular abnormalities in areas with optical dysplasia by pCLE (P<0.001), regardless of histologic dysplasia. The addition of the 3-biomarker panel reduced the false positive rate of pCLE by 50%, leading to sensitivity and specificity for any grade of dysplasia of 89.2% and 88.9%, respectively. CONCLUSIONS: The combination of pCLE on AFI-targeted areas and a 3-biomarker panel identifies patients with dysplasia.
Subject(s)
Barrett Esophagus/metabolism , Barrett Esophagus/pathology , Optical Imaging , Precancerous Conditions/chemistry , Precancerous Conditions/pathology , Watchful Waiting/methods , Aged , Algorithms , Aneuploidy , Barrett Esophagus/genetics , Biomarkers/analysis , Biopsy , Cyclin A/analysis , Disease Progression , Esophagoscopy , Esophagus/pathology , False Positive Reactions , Female , Humans , Male , Microscopy, Confocal/methods , Middle Aged , Narrow Band Imaging , Precancerous Conditions/genetics , Sensitivity and Specificity , Tumor Suppressor Protein p53/analysisABSTRACT
OBJECTIVE: Problems in pre-cancer diagnosis complicate cancer theragnosis as well as life expectancy. There is uncertainty regarding malignant transformation of oral submucous fibrosis (OSF), an oral pre-cancer with dysplastic (OSFWD) and non-dysplastic (OSFWT) subtypes. Understanding the structural, molecular and physical aspects of epithelial homeostasis may be useful. MATERIALS AND METHODS: Histopathological grading of biopsy sections was performed using H&E staining. Alterations in epithelial surface architecture in different groups was evaluated using scanning electron microscopy (SEM). The expression of crucial epithelial genes (p63, CK-5/6, CK-10, E-cadherin and ß-catenin) was studied by immunohistochemistry, Western blot and RT-PCR analysis. RESULTS: SEM observations revealed that the surface epithelial ridge pattern became thick and dense, and pit pattern gradually decreased in OSFWD and oral squamous cell carcinoma (OSCC). p63, ΔNp63 and CK-5/6 were up-regulated in OSFWD and OSCC but down-regulated in OSFWT. CK-10 was down-regulated in OSFWD compared to OSFWT. Cytoplasmic expression of E-cadherin and ß-catenin was elevated in dysplastic and cancerous conditions. Moreover, statistical correlation between SEM features (ridges and pits) and molecular attributes demonstrated a significant positive relationship between the ridge-to-pit ratio and p63 population density (r=0.85) and the ridge-to-pit ratio and CK-5/6 intensity (r=0.63). CONCLUSIONS: Molecular changes related to epithelial progressive maturation and cellular proliferation are correlated with concomitant alteration of epithelial surface architecture which helps to predict the malignant potentiality of OSF.
Subject(s)
Biomarkers, Tumor/analysis , Cell Transformation, Neoplastic , Epithelial Cells , Mouth Neoplasms/diagnosis , Oral Submucous Fibrosis/diagnosis , Precancerous Conditions/diagnosis , Adult , Biomarkers, Tumor/genetics , Biopsy , Blotting, Western , Cell Transformation, Neoplastic/chemistry , Cell Transformation, Neoplastic/ultrastructure , Disease Progression , Epithelial Cells/chemistry , Epithelial Cells/ultrastructure , Female , Humans , Immunohistochemistry , Male , Microscopy, Electron, Scanning , Mouth Neoplasms/chemistry , Mouth Neoplasms/genetics , Mouth Neoplasms/ultrastructure , Oral Submucous Fibrosis/genetics , Oral Submucous Fibrosis/metabolism , Oral Submucous Fibrosis/pathology , Precancerous Conditions/chemistry , Precancerous Conditions/genetics , Precancerous Conditions/ultrastructure , Predictive Value of Tests , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
BACKGROUND: Hepatocellular carcinoma (HCC) is a multi-factor, multi-step, multi-gene and complicated process resulting from the accumulation of sequential genetic and epigenetic alterations. An important change among them is from precancerous lesions to HCC. However, only few studies have been reported about the sequential genetic changes during hepatocarcinogenesis. METHODS: We observed firstly molecular karyotypes of 10 matched HCC using Affymetrix single-nucleotide polymorphism (SNP) 6.0 arrays, and found chromosomal fragments with high incidence (more than 70%) of loss of heterozygosity (LOH). Then, we selected 28 microsatellite markers at some gene spanning these chromosomal fragments, and examined the frequency of LOH of 128 matched HCC and 43 matched precancerous lesions-dysplastic nodules (DN) by a PCR-based analysis. Finally, we investigated the expression of proteins encoded by these genes in HCC, DN and the surrounding hepatic tissues. RESULTS: The result of Affymetrix SNP6.0 arrays demonstrated that more than 70% (7/10) cases had chromosomal fragment deletion on 4q13.3-35.1, 8p23.2-21.2, 16q11.2-24.3, and 17p13.3-12. Among 28 microsatellite markers selected, LOH frequencies at D8S262 for DN and HCC were found to be the highest, 51.2% and 72.7%, respectively. Immunohistochemically, the positive rate of its adjacent gene CSMD1 in HCC, DN, and the surrounding hepatic tissues were 27.3% (35/128), 75% (33/44), and 82% (105/128), respectively. CONCLUSIONS: LOH at D8S262 may be associated with an early genetic event of hepatocarcinogenesis, and a predictor for the monitor and prevention of HCC. VIRTUAL SLIDES: The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1557074981159099 .
Subject(s)
Biomarkers, Tumor/genetics , Carcinoma, Hepatocellular/genetics , Cell Transformation, Neoplastic/genetics , Liver Neoplasms/genetics , Loss of Heterozygosity , Membrane Proteins/genetics , Microsatellite Repeats , Precancerous Conditions/genetics , Carcinoma, Hepatocellular/chemistry , Carcinoma, Hepatocellular/pathology , Cell Transformation, Neoplastic/chemistry , Cell Transformation, Neoplastic/pathology , Chromosome Deletion , Female , Gene Expression Profiling/methods , Genetic Predisposition to Disease , Hep G2 Cells , Humans , Immunohistochemistry , Karyotyping , Liver Neoplasms/chemistry , Liver Neoplasms/pathology , Male , Membrane Proteins/analysis , Middle Aged , Oligonucleotide Array Sequence Analysis , Phenotype , Polymerase Chain Reaction , Polymorphism, Single Nucleotide , Precancerous Conditions/chemistry , Precancerous Conditions/pathology , Tumor Suppressor ProteinsABSTRACT
Preneoplastic lesions on small bronchial biopsy specimens may cause a diagnostic dilemma. The aim of this study was to estimate karyometric variables and the Ki-67 index of preneoplastic bronchial lesions and squamous cell carcinoma of the lung. The study was performed on endoscopic samples of squamous cell carcinoma (n = 22), normal appearing mucosa surrounding carcinoma (n = 10), bronchial dysplasia of mild (n = 7), moderate (n = 6), and severe grade (n = 6), carcinoma in situ (n = 17), and normal mucosa from patients with chronic bronchitis (n = 26). Karyometric analysis was done using the image analyzer ImageJ 1.47q. Ki-67 activity was also quantified by ImageJ 1.47q with the plugin Cell Counter. The highest values of nuclear area were found in squamous cell carcinoma, and differences were statistically significant compared to normal mucosa, all grades of dysplasia and normal appearing mucosa surrounding carcinoma (p < 0.01). The Ki-67 index was significantly higher in squamous cell lung carcinoma compared to normal mucosa, mild and moderate dysplasia and normal appearing mucosa surrounding carcinoma (p < 0.01). The Ki-67 index was significantly higher in severe dysplasia than in mild and moderate dysplasia (p < 0.01). In conclusion, the Ki-67 index is a useful parameter for more objective grading and can be of prognostic value to determine the biological potential of preneoplastic bronchial lesions.
Subject(s)
Bronchi/chemistry , Carcinoma in Situ/chemistry , Immunohistochemistry , Ki-67 Antigen/analysis , Lung Neoplasms/chemistry , Neoplasms, Squamous Cell/chemistry , Precancerous Conditions/chemistry , Respiratory Mucosa/chemistry , Biopsy , Bronchi/pathology , Bronchitis, Chronic/metabolism , Bronchitis, Chronic/pathology , Carcinoma in Situ/pathology , Case-Control Studies , Diagnosis, Differential , Humans , Karyometry , Lung Neoplasms/pathology , Neoplasm Grading , Neoplasms, Squamous Cell/pathology , Precancerous Conditions/pathology , Predictive Value of Tests , Respiratory Mucosa/pathologyABSTRACT
PURPOSE OF THE STUDY: Aberrant activation of the Akt/mTOR/pS6 signaling pathway has been identified in various types of cancer and is under investigation in cervical cancer. The purpose of this study was to assess the expression of the phosphorylated/activated forms of Akt (upstream molecule), 4E-BP1 and pS6 (downstream molecules) in biopsy samples of cervical low grade squamous intraepithelial lesions (LSIL), high grade squamous intraepithelial lesions (HSIL), and squamous cell carcinoma (Ca) compared to normal cervical epithelium. MATERIAL AND METHODS: The study included 38 cases diagnosed as LSIL, 31 cases as HSIL, 29 cases as Ca, and eight control cases from normal cervix. Immunohistochemistry was used to assess the expression of pAkt, p4E-BP1 and pS6. RESULTS: Statistical analysis revealed significant differences between HSIL and Ca groups compared to controls regarding intensity, positivity, and total scores for all three molecules (p < 0.001). A trend for higher expression with increasing grade of dysplasia was demonstrated. CONCLUSION: These results strongly support the view that the mTOR signaling pathway is involved in cervical carcinogenesis.
Subject(s)
Carcinoma, Squamous Cell/chemistry , Precancerous Conditions/chemistry , Signal Transduction , TOR Serine-Threonine Kinases/metabolism , Uterine Cervical Dysplasia/chemistry , Uterine Cervical Neoplasms/chemistry , Adaptor Proteins, Signal Transducing/analysis , Carcinoma, Squamous Cell/metabolism , Cell Cycle Proteins , Female , Humans , Phosphoproteins/analysis , Phosphorylation , Precancerous Conditions/metabolism , Proto-Oncogene Proteins c-akt/analysis , Ribosomal Protein S6 Kinases/analysis , Uterine Cervical Neoplasms/metabolism , Uterine Cervical Dysplasia/metabolismABSTRACT
OBJECTIVES: Barrett's esophagus (BE) is a common premalignant lesion for which surveillance is recommended. This strategy is limited by considerable variations in clinical practice. We conducted an international, multidisciplinary, systematic search and evidence-based review of BE and provided consensus recommendations for clinical use in patients with nondysplastic, indefinite, and low-grade dysplasia (LGD). METHODS: We defined the scope, proposed statements, and searched electronic databases, yielding 20,558 publications that were screened, selected online, and formed the evidence base. We used a Delphi consensus process, with an 80% agreement threshold, using GRADE (Grading of Recommendations Assessment, Development and Evaluation) to categorize the quality of evidence and strength of recommendations. RESULTS: In total, 80% of respondents agreed with 55 of 127 statements in the final voting rounds. Population endoscopic screening is not recommended and screening should target only very high-risk cases of males aged over 60 years with chronic uncontrolled reflux. A new international definition of BE was agreed upon. For any degree of dysplasia, at least two specialist gastrointestinal (GI) pathologists are required. Risk factors for cancer include male gender, length of BE, and central obesity. Endoscopic resection should be used for visible, nodular areas. Surveillance is not recommended for <5 years of life expectancy. Management strategies for indefinite dysplasia (IND) and LGD were identified, including a de-escalation strategy for lower-risk patients and escalation to intervention with follow-up for higher-risk patients. CONCLUSIONS: In this uniquely large consensus process in gastroenterology, we made key clinical recommendations for the escalation/de-escalation of BE in clinical practice. We made strong recommendations for the prioritization of future research.