References of "Herfs, Michael"
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See detailOrigins of cervical disease and biomarker selection
Herfs, Michael ULg

Conference (2013)

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See detailPredictive Value of Squamo-Columnar Junction Markers and p16ink4 in Multi-Observer Classification of Cervical Precursor Lesions
Jimenez, C; Howitt, BE; Nucci, MR et al

Poster (2013)

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See detailIntestinal-type endocervical adenocarcinoma in situ: an immunophenotypically distinct subset of AIS affecting older women.
Howitt, Brooke E.; Herfs, Michael ULg; Brister, Kathriel et al

in The American journal of surgical pathology (2013), 37(5), 625-33

Conventional endocervical adenocarcinoma in situ (cAIS) is typically strongly and diffusely positive for p16 with a high Ki67 index consistent with its frequent association with high-risk human ... [more ▼]

Conventional endocervical adenocarcinoma in situ (cAIS) is typically strongly and diffusely positive for p16 with a high Ki67 index consistent with its frequent association with high-risk human papillomavirus (HPV) infection. The intestinal variant (iAIS) is less common, and its relationship to HPV infection has not been thoroughly examined. This study compares the clinicopathologic features, frequency of HPV infection, and expression of CDX2 and surrogate biomarkers of HPV infection (p16, Ki67) in cAIS with those of iAIS. A total of 86 cases with a diagnosis of AIS (49 iAIS, 37 cAIS) were identified from our multi-institutional files. Of these, 13 iAIS and 20 cAIS cases had slides and tissue available for histopathologic review, immunohistochemical analysis, and molecular tests. All 86 cases were used to evaluate clinical parameters; however, HPV DNA analysis and immunohistochemical analysis for p16, MIB-1, CDX2, and p53 were performed only on those cases with available slides or paraffin blocks. The average age at diagnosis was significantly higher in iAIS compared with that in cAIS (44.5 vs. 32.6 y) (P=0.0001). All 20 cAIS cases showed moderate to strong and diffuse p16 staining; however, only 9/13 iAIS cases showed this degree of p16 staining, whereas 4/13 (31%) iAIS cases showed weak and patchy distribution (P<0.02). Only 6/9 (67%) iAIS cases were positive for either HPV type 18 (5) or 33 (1), in contrast to 11/11 conventional cAIS (P=0.04). Similarly, 12/14 cAIS, but only 5/13 iAIS, cases showed a high Ki67 proliferative index. CDX2 was positive in all iAIS cases, whereas p53 was negative. Most iAIS cases are positive for high-risk HPV and show moderate to strong and diffuse p16 staining; however, a subset of iAIS shows variable staining with p16 and Ki67, is not associated with HPV, and occurs in a distinctly older age group suggesting an alternative pathogenesis. Awareness that iAIS can show variable staining for p16 and Ki67 is important when resolving problematic endocervical lesions, particularly in small biopsies with unusual p16 staining patterns. [less ▲]

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See detailCervical squamocolumnar junction-specific markers define distinct, clinically relevant subsets of low-grade squamous intraepithelial lesions.
Herfs, Michael ULg; Parra-Herran, Carlos; Howitt, Brooke E. et al

in The American journal of surgical pathology (2013), 37(9), 1311-8

Low-grade cervical squamous abnormalities (low-grade squamous intraepithelial lesions [LSIL, CIN1]) can be confused with or followed by high-grade (HSIL, CIN2/3) lesions, expending considerable resources ... [more ▼]

Low-grade cervical squamous abnormalities (low-grade squamous intraepithelial lesions [LSIL, CIN1]) can be confused with or followed by high-grade (HSIL, CIN2/3) lesions, expending considerable resources. Recently, a cell of origin for cervical neoplasia was proposed in the squamocolumnar junction (SCJ); HSILs are almost always SCJ, but LSILs include SCJ and SCJ subsets. Abnormal cervical biopsies from 214 patients were classified by 2 experienced pathologists (panel) as LSIL or HSIL using published criteria. SILs were scored SCJ and SCJ using SCJ-specific antibodies (keratin7, AGR2, MMP7, and GDA). Assessments of interobserver agreement, p16 staining pattern, proliferative index, and outcome were compared. The original diagnostician agreed with the panel diagnosis of HSIL and SCJ LSIL in all cases (100%). However, for SCJ LSIL, panelists disagreed with each other by 15% and with the original diagnostician by 46.2%. Comparing SCJ and SCJ LSILs, 60.2% and 94.9% were p16 positive, 23% and 74.4% showed strong (full-thickness) p16 staining, and 0/54 (0%) and 8/33 (24.2%) with follow-up had an HSIL outcome, respectively. Some SCJ LSILs are more likely to both generate diagnostic disagreement and be associated with HSIL. Conversely, SCJ LSILs generate little observer disagreement and, when followed, have a very low risk of HSIL outcome. Thus, SCJ biomarkers in conjunction with histology may segregate LSILs with very low risk of HSIL outcome and conceivably could be used as a management tool to reduce excess allocation of resources to the follow-up of these lesions. [less ▲]

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See detailGiant Condyloma of the Cervix: An Uncommon Entity Associated With Low-risk Human Papilloma Virus Infection.
Parra-Herran, Carlos; Herfs, Michael ULg; Doria, Manuel et al

in American Journal of Surgical Pathology (2013), 37(2), 300-4

"Giant Condylomas" of the cervix are very uncommon, and have not been fully characterized in the English literature. We report 4 cases of cervical giant condyloma seen in our practice. Patients were ... [more ▼]

"Giant Condylomas" of the cervix are very uncommon, and have not been fully characterized in the English literature. We report 4 cases of cervical giant condyloma seen in our practice. Patients were predominantly young and presented with a cervical lesion producing bleeding or a mass effect. Biopsy/excision revealed a uniformly bland, exophytic squamous epithelial proliferation with viral cytopathic changes and absence of stromal invasion. Human papilloma virus types 6 and 11 were detected in all cases. Follow-up was uneventful without recurrence or spread. Giant condylomas of the cervix as defined in this report signify a benign albeit extensive variant of low-risk human papilloma virus infection. This term is proposed as a specific descriptor for such lesions and should be considered in the setting of any large well-differentiated exophytic cervical squamous lesion in young or immunosuppressed women. The term "giant condyloma of Buschke and Loewenstein" should be discontinued given the lack of specificity. [less ▲]

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See detailA novel blueprint for "top down" differentiation defines the cervical squamocolumnar junction during development, reproductive life and neoplasia.
Herfs, Michael ULg; Vargas, Sara O.; Yamamoto, Yusuke et al

in Journal of Pathology (The) (2013), 229(3), 460-8

The cervical squamocolumnar (SC) junction is the site of a recently discovered "embryonic" cell population that was proposed as the cell of origin for cervical cancer and its precursors. How this ... [more ▼]

The cervical squamocolumnar (SC) junction is the site of a recently discovered "embryonic" cell population that was proposed as the cell of origin for cervical cancer and its precursors. How this population participates in cervical remodeling and neoplasia is unclear. In the present study, we analyzed the SC junction immunophenotype during pre and postnatal human and mouse development and in the adult, processes of metaplastic evolution of SC junction, microglandular change and early cervical neoplasia. Early in life, embryonic cervical epithelial cells were seen throughout the cervix and subsequently diminished in number to become concentrated at the SC junction in the adult. In all settings, there was a repetitive scenario in which cuboidal embryonic/SC junction cells gave rise to subjacent metaplastic basal/reserve cells with a switch from the SC junction positive to negative immunophenotype. This downward or basal (rather than upward or apical) evolution from progenitor cell to metaplastic progeny was termed reverse or "top down" differentiation. A similar pattern was noted in high grade squamous intraepithelial lesions (HSIL), suggesting HPV infection of the cuboidal SC junction cells initiated outgrowth of basally-oriented neoplastic progeny. The progressive loss of the embryonic/SC junction markers occurred with top-down differentiation during development, remodeling and early neoplasia. Interestingly, most low grade SILs were SC junction negative, implying infection of metaplastic progeny rather than the original SC junction cells. This proposed model of "top down" differentiation resolves the mystery of how SC junction cells both remodel the cervix and participate in neoplasia and provides for a second population of metaplastic progeny (including basal and reserve cells), the infection of which is paradoxically less likely to produce a biologically aggressive precursor. It also provides new targets in animal models to determine why the SC junction is uniquely susceptible to carcinogenic HPV infection. Copyright (c) 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [less ▲]

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See detailA discrete population of squamocolumnar junction cells implicated in the pathogenesis of cervical cancer.
Herfs, Michael ULg; Yamamoto, Yusuke; Laury, Anna et al

in Proceedings of the National Academy of Sciences of the United States of America (2012), 109(26), 10516-21

Infection by carcinogenic human papillomaviruses (HPV) results in precancers [cervical intraepithelial neoplasia (CIN)] and cancers near the ectoendocervical squamocolumnar (SC) junction of the cervix ... [more ▼]

Infection by carcinogenic human papillomaviruses (HPV) results in precancers [cervical intraepithelial neoplasia (CIN)] and cancers near the ectoendocervical squamocolumnar (SC) junction of the cervix. However, the specific cells targeted by HPV have not been identified and the cellular origin of cervical cancer remains elusive. In this study, we uncovered a discrete population of SC junctional cells with unique morphology and gene-expression profile. We also demonstrated that the selected junctional biomarkers were expressed by a high percentage of high-grade CIN and cervical cancers associated with carcinogenic HPVs but rarely in ectocervical/transformation zone CINs or those associated with noncarcinogenic HPVs. That the original SC junction immunophenotype was not regenerated at new SC junctions following excision, not induced by expression of viral oncoproteins in foreskin keratinocytes, and not seen in HPV-related precursors of the vagina, vulva, and penis further support the notion that junctional cells are the source of cervical cancer. Taken together, our findings suggest that carcinogenic HPV-related CINs and cervical cancers are linked to a small, discrete cell population that localizes to the SC junction of the cervix, expresses a unique gene expression signature, and is not regenerated after excision. The findings in this study uncover a potential target for cervical cancer prevention, provide insight into the risk assessment of cervical lesions, and establish a model for elucidating the pathway to cervical cancer following carcinogenic HPV infection. [less ▲]

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See detailBarrett's metaplasia, dysplasia and esophageal ademnocarcinoma: an inadequate antitumour immunity?
Somja, Joan ULg; Demoulin, Stéphanie ULg; Herman, Ludivine et al

Conference (2012, February 09)

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See detailA candidate cell of origin for cervical cancer
Herfs, Michael ULg; Yamamoto; Laury et al

in Modern Pathology : An Official Journal of the United States & Canadian Academy of Pathology, Inc (2012, February), 25(2), 4-552

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See detailImmature Metaplastic CIN1: A Variant with Intense P16 Staining and Low Proliferative Index
Parra-Herran, Christopher P.; Lane, Bruno; Hirsch, MS et al

Poster (2012)

Background: Epithelial maturation traditionally is used to grade CIN in histologic sections. However, in some an immature epithelium displays atypia that is low in proportion to the level of epithelial ... [more ▼]

Background: Epithelial maturation traditionally is used to grade CIN in histologic sections. However, in some an immature epithelium displays atypia that is low in proportion to the level of epithelial maturity. Although MIB1 and p16ink4 are helpul in establishing the diagnosis of CIN in this setting, classifying such lesions can be problematic. We analyzed a subset of these atypias, and this study summarizes a correlation between morphology and p16 and MIB1 immunostaining. Design: Immature metaplastic atypias were divided into those with putative low (uniform nuclear spacing, minimal nuclear variation, absent or mild nuclear hyperchromasia) and high-grade (irregular nuclear spacing, heterogeneous nuclear morphology, increased nuclear chromasia) features. Immunohistochemical staining for p16 was classifi ed as patchy or diffuse (horizontally) and MIB-1 proliferation index was recorded as percentage of positive cells and location of elevated proliferative index as a function of basal, middle and superfi cial third of the epithelium. Staining patterns and histologic grade were correlated. Results: Forty-three cases were classified without knowledge of the immunohistochemistry. Immature metaplastic low grade CINs exhibited strong and diffuse staining for p16 and but unlike High grade CINs, the proliferating (MIB1+) cells were concentrated in the more basal 1-2 thirds of the epithelium and the proliferative index was less than 30%. Variable columnar differentiation was observed in some, with strong staining of both the columnar and squamous cells by p16. Conclusions: A distinct subset of immature CINs displays a uniform cell population and based on both cytology and proliferative index, warrants classifi cation as low grade CIN (CIN1). p16 immunohistochemistry, although helpful in the recognition of these lesions, will not distinguish them from higher grade CIN (CIN2/3). Attention to regularity in nuclear morphology with absence of noticeable differences in cell size and shape, combined with MIB1 staining, is helpful,. The presence of columnar differentiation, which also stains positive for p16 is consistent with bidirectional differentiation in the transformation zone epithelium. Further studies of this entity are warranted to precisely determine its biologic behavior. [less ▲]

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See detailA candidate cell of origin for cervical cancer
Herfs, Michael ULg

Conference (2012)

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