Cervical Squamous Intraepithelial Lesions

Mills, Anne M.; Stoler, Mark H.

doi:10.1007/978-3-319-51257-0_6

Cited by 2 publications

(4 citation statements)

References 54 publications

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“…17 All lesions in this study arose within the metaplastic squamous epithelium of the transformation zone with an abrupt transition between precursor lesion and squamous epithelium of the exocervix. The majority resembled thick and thin HPV-induced HSIL as defined by the WHO, 18 but some cervical precursor lesions were highly keratinized proliferations akin to differentiated vulvar intraepithelial neoplasia. Some preinvasive HPV-negative lesions featured diffuse block staining/overexpression of p16 ink4a , reminiscent of transforming HPV-infection after HPV-E7 oncogeneinduced inactivation of the retinoblastoma (Rb) protein pathways.…”

Section: Discussionmentioning

confidence: 94%

“…Pretreatment liquid-based cytology specimens (Roche HPV assay; Roche Molecular Systems, Pleasanton, CA) were subjected to the Aptima HPV Assay (which detects E6/E7 mRNA; Hologic) and the Cobas HPV test (Roche HPV assay, which detects HPV-DNA; Roche Molecular Systems). These tests detect 14 high-risk HPV types (HPV 16,18,31,33,35,39,45,51,52,56,58,59, 66, and 68). After surgical treatment, HPV genotyping was performed on microdissected formalin-fixed and paraffin-embedded lesional tissue.…”

Section: Hpv Testingmentioning

confidence: 99%

“…The CHIPRON HPV3.5LCD-array (CHIPRON GmbH, Berlin, Germany) detects DNA of 32 HPV subtypes. These include HPV high-risk subtypes 16,18,31,33,35,39,45 . The CHIPRON system includes internal hybridization controls and additional beta-globin spots to ascertain amplificability of extracted DNA as well as absence of polymerase chain reaction inhibitors.…”

Section: Hpv Testingmentioning

confidence: 99%

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HPV-negative Squamous Cell Carcinomas of the Cervix With Special Focus on Intraepithelial Precursor Lesions

Regauer

Reich

Kashofer

2021

American Journal of Surgical Pathology

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Recently, the World Health Organization (WHO) recognized human papilloma virus (HPV)-independent invasive cervical squamous cell carcinoma (SCC) without recognizing the existence of precursor lesions. This is a detailed characterization of 3 preinvasive lesions and 6 invasive SCC negative for HPV-DNA (32 genotypes), HPV-mRNA (14 genotypes) and genomic HPV sequencing. We evaluated histologic features, expression of p16ink4a, p53, CK7, and CK17, aberrations in 50 cancer genes and chromosomal copy number variations. HPV-negative preinvasive lesions were extensive basaloid or highly differentiated keratinizing intraepithelial proliferations of 3 to 20 cell layers thickness, partly with prominent cervical gland involvement. Overall, 2/3 intraepithelial lesions and the in situ component of 1/6 SCC showed p16ink4a block staining, while 1/6 in situ component revealed heterogenous p16ink4a staining. All invasive components of keratinizing SCC were p16ink4a-negative. Preinvasive and invasive SCC showed inconsistent CK7 and CK17 staining. Nuclear p53 overexpression was restricted to the TP53 gene mutated SCC. The highly vascularized peritumoral stroma showed a dense inflammatory infiltrate including plasma cells and intratumoral and peritumoral eosinophilic granulocytes. Inconsistent somatic gene mutations (PIK3CA, STK11, TP53, SMARC2B, and GNAS) occurred predominantly in nonhotspot locations at low mutational frequency in 3/6 SCC. Consistent aberrations included the pathogenic (angiogenic) germline polymorphism Q472H in the KDR gene (7/9 patients), and chromosome 3q gains (4/9 patients). In conclusion, HPV-negative intraepithelial cervical precancerous lesions exist, either as highly differentiated keratinized intraepithelial proliferations reminiscent of differentiated vulvar intraepithelial neoplasia, or undifferentiated basaloid intraepithelial lesions with occasional p16ink4a block staining resembling high-grade squamous intraepithelial lesion. Gains of chromosome 3q, angiogenic germline variants the inflammatory infiltrate may contribute to progression of HPV-negative cervical carcinogenesis.

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Section: Discussionmentioning

confidence: 94%

Section: Hpv Testingmentioning

confidence: 99%

Section: Hpv Testingmentioning

confidence: 99%

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HPV-negative Squamous Cell Carcinomas of the Cervix With Special Focus on Intraepithelial Precursor Lesions

Regauer

Reich

Kashofer

2021

American Journal of Surgical Pathology

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“…1,2 Precursor lesions are termed high-grade squamous intraepithelial lesions (HSILs), synonymously high-grade cervical intraepithelial neoplasia (CIN III). 3 The World Health Organization classification Female Genital Tumours defines several histologic subtypes of precursor lesions 4 with an important subclassification based on epithelial thickness. The common classic HSIL was defined as ≥ 10 cell layers thick and full-thickness proliferation ≤ 9 cell layers as thin HSIL.…”

mentioning

confidence: 99%

Cervical Precancers Originate From Infected Proliferating Reserve Cells

Regauer

Reich

Kashofer

2021

American Journal of Surgical Pathology

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Human papillomavirus (HPV)-induced invasive cervical squamous cell cancer (SCC) develop via high-grade squamous intraepithelial lesion (HSIL). In contrast to classic thick HSIL, thin HSIL (≤9 cell layers) are poorly documented. This study compares histology, HPV genotypes, and aberrations in 50 cancer genes of 45 thin HSIL to 45 thick HSIL, 20 pT1a SCC, and 40 ≥pT1b SCC. Thin HSIL arose from proliferating reserve cells within endocervical epithelium or immature metaplasia throughout the transformation zone after infection with high-risk HPV genotypes (36/45; 80%), and 20% non–high-risk HPV genotypes compared with 2.5% thick HSIL, pT1a SCC, and ≥pT1b SCC. Thin HSIL were multifocal proliferations with varying epithelial thickness between 1 and 2 to 9 cell layers, with occasional transitions to thick HSIL or concomitant lesions of thick HSIL. Overall, 40% thin HSIL were located distant to and most thick HSIL occurred near or at the squamocolumnar junction. Only 20% thick HSIL showed koilocytosis. All HSIL lacked somatic gene mutations, compared with 30% pT1a and 55%≥pT1b SCC. Overrepresented rare germline variants in the MET, JAK3, and FGFR3 genes occurred in all patient groups. In summary, thin and thick HSIL arose independently of somatic gene mutations. The maturation level of the squamous epithelium at the time of transforming infection determines if a thick HSIL develops directly from HPV-infected proliferating reserve cells via thin HSIL or in stratified glycogenated squamous epithelium via low-grade squamous intraepithelial lesion. These observations raise doubts about the biological relevance of separation into thin and thick HSIL. The oncogenic potential of HPV genotypes but also germline variants may influence the natural history.

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Cervical Squamous Intraepithelial Lesions

Cited by 2 publications

References 54 publications

HPV-negative Squamous Cell Carcinomas of the Cervix With Special Focus on Intraepithelial Precursor Lesions

HPV-negative Squamous Cell Carcinomas of the Cervix With Special Focus on Intraepithelial Precursor Lesions

Cervical Precancers Originate From Infected Proliferating Reserve Cells

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