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Current Opinion in Virology Dec 2021Most research models of HPV-associated squamous cervical carcinogenesis focus on stratified glycogenated squamous epithelium, a permissive environment for HPV-life-cycle... (Review)
Review
Most research models of HPV-associated squamous cervical carcinogenesis focus on stratified glycogenated squamous epithelium, a permissive environment for HPV-life-cycle completion, while immature squamous metaplastic epithelium and reserve cells as targets of HPV-infection have received less attention. Subcolumnar reserve cells of urogenital sinus origin with a CK17/p63-phenotype serve as the primary stem cell for squamous metaplasia. The area of manifest or potential squamous metaplasia, referred to as transformation zone, is the site where most squamous cancers occur after a transforming HPV infection of proliferating reserve cells and/or metaplastic epithelium. Improper use of terminology, in particular confusion of transformation zone with transition zone (synonymous: squamous-columnar junction or SCJ), as well as poorly substantiated postulates of a stem cell niche at the squamous-columnar junction with 'embryonic stem cell markers' have complicated understanding of HPV-related squamous carcinogenesis. Reserve cells as target cells and reservoirs of HPV should move into future research focus.
Topics: Alphapapillomavirus; Carcinogenesis; Carcinoma, Squamous Cell; Female; Humans; Metaplasia; Papillomavirus Infections; Uterine Cervical Neoplasms
PubMed: 34655910
DOI: 10.1016/j.coviro.2021.09.012 -
The American Journal of Surgical... Sep 2021Immunotherapy for the treatment of programmed death-ligand 1 (PD-L1) positive locally advanced or metastatic triple negative breast cancer may benefit patients with...
Immunotherapy for the treatment of programmed death-ligand 1 (PD-L1) positive locally advanced or metastatic triple negative breast cancer may benefit patients with metaplastic breast cancer (MpBC). Previous study of PD-L1 in MpBC scored tumor cells (TCs), different from Food and Drug Administration-approved scoring methods. We sought to define PD-L1 expression in MpBCs and to evaluate concordance of 3 PD-L1 assays. Primary, treatment naive MpBC treated at our Center from 1998 to 2019 were identified. PD-L1 expression was assessed using SP142, E1L3n, and 73-10. We evaluated PD-L1 expression on tumor infiltrating immune cells (IC) and also in TCs. For each assay, we scored PD-L1 expression using ≥1% IC expression according to the IMpassion130 trial criteria and using combined positive score (CPS) ≥10 according to the KEYNOTE-355 trial cutoff. A total of 42 MpBCs were identified. Most MpBC had PD-L1 positivity in ≥1% IC with all 3 assays (95%, 95%, 86%) in contrast to a maximum 71% with a CPS ≥10. PD-L1 IC expression was comparable between the SP142 and 73-10 assays and was lowest with E1L3n. PD-L1 TC expression was lowest using SP142. The overall concordance for IC scoring was 88% while 62% had concordant CPS. For each assay, the results of the 2 scoring algorithms were not interchangeable. The SP142 assay showed distinct expression patterns between IC (granular, dot-like) and TC (membranous) while 73-10 and E1L3n showed membranous and/or cytoplasmic expression in both IC and TC. Most MpBC in our cohort were positive for PD-L1 indicating eligibility for anti-PD-L1/programmed death-1 immunotherapy.
Topics: Adult; Aged; Aged, 80 and over; B7-H1 Antigen; Biomarkers, Tumor; Breast Neoplasms; Carcinoma; Female; Humans; Immunohistochemistry; Middle Aged; Reproducibility of Results
PubMed: 34115674
DOI: 10.1097/PAS.0000000000001760 -
Turk Patoloji Dergisi 2020To evaluate the pathological and radiological features, hormone profiles, surgery and treatment methods of metaplastic breast carcinoma cases diagnosed at our center in...
OBJECTIVE
To evaluate the pathological and radiological features, hormone profiles, surgery and treatment methods of metaplastic breast carcinoma cases diagnosed at our center in the light of current literature.
MATERIAL AND METHOD
A total of 38 metaplastic breast cancer cases diagnosed between 2006-2018 at our center were included in the study. The patients were evaluated in terms of age, tumor size, localization, histological grade, hormone profiles (ER, PR, Her2-neu), American Joint Committee on Cancer (AJCC) Tumor, Lymph node status, Metastases (TNM) stage, progression, survival, radiological features, types of surgery and therapy modalities (chemotherapy and / or radiotherapy).
RESULTS
The age of the patients ranged between 32 and 95 years. Pathological evaluation of cases showed that 14 were pure epithelial (IC-NST + squamous cell carcinoma) and 24 were metaplastic carcinomas with mesenchymal differentiation. Ductal carcinoma in situ (DCIS) was accompanying an invasive component in twenty cases. Seventeen patients had lymph node metastasis. Twelve patients developed distant metastasis. Thirty patients were triple negative for hormone receptors. The mean follow-up period of the patients was 34 months. The estimated life expectancy was 116 months. All of the patients received chemotherapy and 28 patients received adjuvant radiotherapy. There was no correlation between tumor size and lymph node or distant metastasis in our series. Our findings are consistent with the literature.
CONCLUSION
Metaplastic breast carcinoma is a rare entity among breast carcinomas. Metaplastic carcinomas of the breast draw attention with the differences in their clinical course and the radiological and pathological heterogeneity.
Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Breast Neoplasms; Carcinoma; Female; Humans; Lymphatic Metastasis; Metaplasia; Middle Aged; Neoplasm Staging; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Treatment Outcome; Tumor Burden; Turkey
PubMed: 31769499
DOI: 10.5146/tjpath.2019.01472 -
Breast Cancer Research : BCR Aug 2020Metaplastic breast carcinoma (MBC) is a rare histological type of breast cancer, which commonly shows resistance to standard therapies and is associated with poor...
BACKGROUND
Metaplastic breast carcinoma (MBC) is a rare histological type of breast cancer, which commonly shows resistance to standard therapies and is associated with poor prognosis. The immune microenvironment in MBC and its significance has not been well established due to its low incurrence rate and complex components. We aimed to investigate the diversity of immune parameters including subsets of TILs and PDL1/PD1 expression in MBC, as well as its correlation with prognosis.
METHODS
A total of 60 patients diagnosed with MBC from January 2006 to December 2017 were included in our study. The percentage (%) and quantification (per mm) of TILs and presence of tertiary lymphoid structures (TLS) were evaluated by hematoxylin and eosin staining (HE). The quantification of CD4+, CD8+ TILs (per mm), and PD-1/PDL1 expression were evaluated through immunohistochemistry and analyzed in relation to clinicopathological characteristics. A ≥ 1% membranous or cytoplasmatic expression of PD1 and PDL1 was considered a positive expression.
RESULTS
We found squamous cell carcinoma MBC (33/60, 55%) exhibiting most TILs of all the MBC subtypes (p = 0.043). Thirty-three of 60 (50%) of the patients had coexisting invasive ductal carcinoma of no special type (IDC-NST), and the average percentage of TILs in MBC components was lower compared with NST components (p < 0.001). Thirty (50%) patients exhibited positive (≥ 1%) PDL1 expression in their tumor cells, while 36 (60%) had positive (≥ 1%) PDL1 expression in their TILs. Twenty-seven (45%) of all the patients had positive (≥ 1%) PD1 expression in their tumor cells and 33 (55%) had PD1-positive (≥ 1%) stromal TILs. More CD8+ TILs were associated with positive PDL1 expression of tumor cells as well as positive PD1 expression in stromal cells. Greater number of stromal TILS (> 300/mm, 20%), CD4+ TILs (> 250/mm), and CD8+ TILs (> 70/mm) in MBC were found associated with longer disease-free survival. Positive expression of PDL1 in tumor cells (≥ 1%) and PD1 in stromal cells (≥ 1%) were also associated with longer survival.
CONCLUSIONS
The immune characteristics differ in various subtypes as well as components of MBC. Immune parameters are key predictive factors of MBC and provide the clinical significance of applying immune checkpoint therapies in patients with MBC.
Topics: Adult; Aged; Aged, 80 and over; B7-H1 Antigen; Biomarkers, Tumor; Breast Neoplasms; CD8-Positive T-Lymphocytes; Carcinoma, Squamous Cell; Female; Humans; Lymphocytes, Tumor-Infiltrating; Middle Aged; Neoplasm Metastasis; Prognosis; Programmed Cell Death 1 Receptor; Survival Rate; Tumor Microenvironment
PubMed: 32811533
DOI: 10.1186/s13058-020-01330-6 -
The American Journal of Surgical... Aug 2022The literature indicates that mesonephric carcinoma (MC) and mesonephric-like adenocarcinoma (MLA) typically lack mucinous and squamous features/differentiation. We...
The literature indicates that mesonephric carcinoma (MC) and mesonephric-like adenocarcinoma (MLA) typically lack mucinous and squamous features/differentiation. We report 4 cases of ovarian mucinous tumors (1 mucinous cystadenofibroma and 3 mucinous borderline tumors/atypical proliferative mucinous tumors [MBT/APMT]) co-existing with mesonephric-like lesions which were highlighted by Gata3 and Pax8 expression. All cases contained benign mesonephric-like proliferations (MLP) which focally displayed gastrointestinal-type mucinous metaplasia/differentiation and some were intimately admixed with mucinous glands associated with the mucinous tumor. Metaplastic mucinous epithelium retained expression of Gata3 and Pax8 in some areas while 1 mucinous cystadenofibroma and 1 MBT/APMT were focally positive for Pax8. Along with these mesonephric components, case 1 exhibited features of mesonephric hyperplasia and in 2 cases, 3 and 4, MLA was identified. In case 4, a KRAS c.35G>T (p.Gly12Val) somatic mutation was detected in both the MBT/APMT and the MLA, indicating a clonal origin. This same mutation was also detected in the benign MLP, indicating that it was likely an early genetic event. A CTNNB1 c.98C>T (p.Ser33Phe) somatic mutation, FGFR2 amplification, and CDKN2A/p16 deletion were only detected in the MLA but not in the MBT/APMT. Our result provides evidence to demonstrate the clonal relationship between these morphologically distinct components. Although speculative, we postulate that benign MLPs may give rise to lineage-specific mucinous and mesonephric-like lesions and propose that the MLPs are a new possible origin of some ovarian mucinous tumors. Whether these MLPs arise through transdifferentiation of Müllerian tissue or represent true mesonephric remnants, however, remains largely unknown.
Topics: Adenocarcinoma; Biomarkers, Tumor; Cell Proliferation; Cystadenofibroma; Female; Humans; Ovarian Neoplasms
PubMed: 35405716
DOI: 10.1097/PAS.0000000000001903 -
Clinical Cancer Research : An Official... Aug 2017Although most human cancers display a single histology, there are unusual cases where two or more distinct tissue types present within a primary tumor. One such example...
Although most human cancers display a single histology, there are unusual cases where two or more distinct tissue types present within a primary tumor. One such example is metaplastic breast carcinoma, a rare but aggressive cancer with a heterogeneous histology, including squamous, chondroid, and spindle cells. Metaplastic carcinomas often contain an admixed conventional ductal invasive or mammary carcinoma component, and are typically triple-negative for estrogen receptor, progesterone receptor, and HER-2 amplification/overexpression. An unanswered question is the origin of metaplastic breast cancers. While they may arise independently from their ductal components, their close juxtaposition favors a model that postulates a shared origin, either as two derivatives from the same primary cancer or one histology as an outgrowth of the other. Understanding the mechanism of development of these tumors may inform clinical decisions. We performed exome sequencing for paired metaplastic and adjacent conventional invasive ductal carcinomas in 8 patients and created a pipeline to identify somatic variants and predict their functional impact, without having normal tissue. We then determined the genetic relationships between the histologically distinct compartments. In each case, the tumor components have nearly identical landscapes of somatic mutation, implying that the differing histologies do not derive from genetic clonal divergence. A shared origin for tumors with differing histologies suggests that epigenetic or noncoding changes may mediate the metaplastic phenotype and that alternative therapeutic approaches, including epigenetic therapies, may be required for metaplastic breast cancers. .
Topics: Adult; Aged; Aged, 80 and over; Breast; Breast Neoplasms; Carcinoma, Ductal, Breast; Clone Cells; DNA Copy Number Variations; Female; Humans; Metaplasia; Middle Aged; Mutation; Triple Negative Breast Neoplasms; Exome Sequencing
PubMed: 28424200
DOI: 10.1158/1078-0432.CCR-17-0108 -
Scientific Reports Nov 2023Studies have suggested that cancerous tissue has a lower N/N ratio than benign tissue. However, human data have been inconclusive, possibly due to constraints on...
Studies have suggested that cancerous tissue has a lower N/N ratio than benign tissue. However, human data have been inconclusive, possibly due to constraints on experimental design. Here, we used high-sensitivity nitrogen isotope methods to assess the N/N ratio of human breast, lung, and kidney cancer tissue at unprecedented spatial resolution. In lung, breast, and urothelial carcinoma, N/N was negatively correlated with tumor cell density. The magnitude of N depletion for a given tumor cell density was consistent across different types of lung cancer, ductal in situ and invasive breast carcinoma, and urothelial carcinoma, suggesting similar elevations in the anabolism-to-catabolism ratio. However, tumor N depletion was higher in a more aggressive metaplastic breast carcinoma. These findings may indicate the ability of certain cancers to more effectively channel N towards growth. Our results support N/N analysis as a potential tool for screening biopsies and assessing N metabolism in tumor cells.
Topics: Humans; Female; Carcinoma, Ductal, Breast; Carcinoma, Transitional Cell; Urinary Bladder Neoplasms; Breast Neoplasms; Nitrogen
PubMed: 37957187
DOI: 10.1038/s41598-023-45597-z -
Breast Cancer (Tokyo, Japan) Mar 2021Metaplastic carcinoma is an aggressive, triple-negative breast cancer (TNBC) with differentiation towards squamous, spindle, or mesenchymal cell types. The molecular...
BACKGROUND
Metaplastic carcinoma is an aggressive, triple-negative breast cancer (TNBC) with differentiation towards squamous, spindle, or mesenchymal cell types. The molecular underpinnings of the histological subtypes are unclear. Our lab discovered a cytoplasmic function of EZH2, a transcriptional repressor, whereby pEZH2 T367 binds to cytoplasmic proteins in TNBC cells and enhances invasion and metastasis. Here, we investigated the expression and subcellular localization of pEZH2 T367 protein in metaplastic carcinomas.
METHODS
Thirty-five metaplastic carcinomas (17 squamous, 10 mesenchymal, and 8 spindle) were evaluated and immunostained with anti-pEZH2 T367. We analyzed staining intensity (score 1-4), subcellular localization (nuclear/cytoplasmic), and localization within the tumor (center/invasive edge). Protein expression of pEZH2 T367-binding partners was measured from a quantitative multiplex proteomics analysis performed in our lab.
RESULTS
Cytoplasmic pEZH2 T367 was significantly upregulated in squamous (14 of 17, 82%) compared to mesenchymal (4 of 10, 40%) and spindle (2 of 6, 33%) subtypes (p = 0.011). Twenty-five of 34 (73%) tumors with available tumor-normal interface showed accentuated cytoplasmic pEZH2 T367 at the infiltrative edge. Cytoplasmic pEZH2 T367 was upregulated in 9 of 10 (90%) tumors with lymph node metastasis (p = 0.05). Bioinformatics analyses identified an EZH2 protein network in metaplastic carcinomas (p value: < 1.0e-16). Using quantitative proteomics, we found significantly increased expression of cytoplasmic EZH2-binding partners in squamous compared to spindle and mesenchymal subtypes.
CONCLUSIONS
pEZH2 T367 expression and subcellular localization may be useful to distinguish metaplastic carcinoma subtypes. pEZH2 T367 may play a role in the histological diversity and behavior of these tumors.
Topics: Carcinoma, Squamous Cell; Cohort Studies; Computational Biology; Cytoplasm; Enhancer of Zeste Homolog 2 Protein; Female; Humans; Immunohistochemistry; Lymphatic Metastasis; Middle Aged; Phosphorylation; Prognosis; Proteome; Proteomics; Triple Negative Breast Neoplasms; Up-Regulation
PubMed: 33247371
DOI: 10.1007/s12282-020-01189-7 -
Archives of Pathology & Laboratory... Oct 2011Barrett esophagus is a metaplastic, premalignant lesion associated with approximately 0.5% annual incidence of progression to esophageal adenocarcinoma. Diagnosis and... (Review)
Review
CONTEXT
Barrett esophagus is a metaplastic, premalignant lesion associated with approximately 0.5% annual incidence of progression to esophageal adenocarcinoma. Diagnosis and screening of Barrett esophagus and Barrett-related dysplasia relies on histologic evaluation of endoscopic mucosal biopsies, a process that is burdened with interobserver variability.
OBJECTIVES
To review the histologic features and classification of Barrett esophagus and Barrett-related dysplasia, to discuss the underlying difficulties in diagnosis and pitfalls, and to provide a brief review of new developments related to therapeutic modalities for patients diagnosed with dysplasia.
DATA SOURCES
Sources include a review of relevant literature indexed in PubMed (US National Library of Medicine).
CONCLUSIONS
In spite of interobserver variability, histologic assessment of dysplasia is currently the accepted method of surveillance, and subsequent patient management is dictated by this evaluation. Although not universal, endoscopic therapy is increasingly important in replacing esophagectomy for patients with high-grade dysplasia or early carcinoma.
Topics: Adenocarcinoma; Barrett Esophagus; Disease Progression; Esophageal Neoplasms; Esophagoscopy; Gastroesophageal Reflux; Humans; Immunohistochemistry; Metaplasia; Precancerous Conditions; Risk Factors
PubMed: 21970480
DOI: 10.5858/arpa.2011-0019-RA -
Diagnostic Pathology Jul 2014Metaplastic breast carcinoma is a rare entity of breast cancer expressing epithelial and/or mesenchymal tissue within the same tumor. The aim of this study is to...
BACKGROUND
Metaplastic breast carcinoma is a rare entity of breast cancer expressing epithelial and/or mesenchymal tissue within the same tumor. The aim of this study is to evaluate the clinicopathological features of metaplastic breast carcinoma and to confirm the triple negative, basal-like and/or luminal phenotype of this type of tumor by using immunohistochemical staining.
METHODS
Seven cases of MBC were evaluated for clinico-pathological features including follow up data. Cases were studied immunohistochemically by CK-Pan, Vimentin, ER, PR, HER2, basal markers (CK5/6, p63, EGFR, SMA and S-100), luminal cytokeratins (CK8, CK18 and CK19), markers for syncytial cells (β-HCG and PLAP), as well as prognostic markers (p53, ki-67 and calretinin).
RESULTS
The mean age of the patients was 36 years. Three cases showed choriocarcinomatous features. All of our cases were negative for ER, PR and HER2. Six out of the 7 cases showed basal-like differentiation by demonstrating positivity with at least one of the basal/myoepithelial markers. Also 6 out of the 7 cases expressed luminal type cytokeratins (CK8, CK18 and/or CK19). P53 was positive in 3 cases, ki-67 was strongly expressed in only one case, while calretinin was expressed in 6 cases.
CONCLUSION
Metaplastic breast carcinoma presents in our population at a younger age group than other international studies. All cases are categorized immunohistochemically under the triple negative group of breast cancer and 86% of them exhibited basal-like and luminal phenotype. Majority of cases developed local recurrence and distant metastasis in a relatively short period of time.
VIRTUAL SLIDES
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1101289295115804.
Topics: Adult; Aged; Biomarkers, Tumor; Breast Neoplasms; Carcinoma; Female; Humans; Immunohistochemistry; Middle Aged; Young Adult
PubMed: 25030022
DOI: 10.1186/1746-1596-9-139