Evaluation of human papillomavirus (HPV) prediction using the International Endocervical Adenocarcinoma Criteria and Classification system, compared to p16 immunohistochemistry and HPV RNA in-situ hybridization

Ren, Hezhen; Pors, Jennifer; Chow, Christine; Ta, Monica; Stolnicu, Simona; Soslow, Robert A.; Huntsman, David G.; Hoang, Lynn

doi:10.4132/jptm.2020.07.18

Cited by 10 publications

(8 citation statements)

References 32 publications

(34 reference statements)

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“…Cases where neoadjuvant chemoradiation affected proper histologic assessment, repeat cases, and adenosquamous carcinomas were excluded. Slides of all ECAs were reviewed and reclassified as previously established under the IECC criteria, using a combination of histology, p16 immunohistochemistry, and HPV RNA in situ hybridization as previously described (12). In brief, ECAs were assigned as HPVA based on the presence of classic HPVA histomorphologic features including apical mitotic features and apoptotic bodies present at scanning magnification.…”

Section: Case Selection and Tumor Classificationmentioning

confidence: 99%

International Endocervical Adenocarcinoma Criteria and Classification (IECC): An Independent Cohort With Clinical and Molecular Findings

Ren

Almadani

Pors

et al. 2021

International Journal of Gynecological Pathology

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and Classification (IECC) has reorganized the classification of endocervical adenocarcinomas (ECAs), separating them into human papilloma virus (HPV)-associated (HPVA) and HPVA independent (HPVI) categories. In this study, we sought to revalidate the IECC clinical findings in an independent cohort and assess the mutational differences between HPVA and HPVI ECAs using next generation sequencing. Consecutive cases of ECAs were reclassified under the IECC. Clinicopathologic information was collected and tissue was sent for targeted next-generation sequencing in 33 genes. Associations between HPV status, clinicopathologic parameters and mutation status, with survival were evaluated. The series comprised of 85/100 HPVA (63 HPVA-usual type, 4 villoglandular, 3 mucinous intestinal, 15 mucinous not otherwise specified) and 15/100 HPVI (9 gastric, 4 mesonephric, 1 clear cell, 1 not otherwise specified). HPVA ECAs presented at a lower age (P = 0.001), smaller tumor sizes (P = 0.011), less margin positivity (P = 0.027), less Silva pattern C (P = 0.002), and lower FIGO stages (P = 0.020). HPVA had superior survival compared with HPVI ECA [overall survival (P = 0.0026), disease-specific survival (P = 0.0092), and progression-free survival (P = 0.0041)]. Factors that correlated with worse prognosis irrespective of HPV status were FIGO stage, positive margins and lymphovascular invasion (Po0.05). TP53 mutations were detected in a significantly higher proportion of HPVIs than HPVAs (Poo0.001). The study revalidates the IECC system by reaffirming the clinical and prognostic differences between HPVA and HPVI ECAs in an independent dataset.

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Section: Case Selection and Tumor Classificationmentioning

confidence: 99%

International Endocervical Adenocarcinoma Criteria and Classification (IECC): An Independent Cohort With Clinical and Molecular Findings

Ren

Almadani

Pors

et al. 2021

International Journal of Gynecological Pathology

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“…32 study, where they also reported a higher interobserver agreement in mesonephric carcinoma and clear cell carcinomas. Ren et al 15 also reported that WHO 2020 can predict the HPV status in most of the cases.…”

Section: Discussionmentioning

confidence: 98%

“…Briefly, M/A criteria and cytoplasmic features were not enough for correct classification in some cases and ancillary tests are needed. Ren et al (15) also reported challenges on their initial histologic assessment of 5 HPVA; mucinous ECAs. They were reclassified as HPVI-gastric type, HPVI-mucinous-NOS, and unclassifiable.…”

Section: Discussionmentioning

confidence: 99%

“…HR-HPV testing is crucial for ECA diagnosis. Several direct methods for HPV detection are currently available such as HPV DNA in situ hybridization (HPV DNA ISH), HPV real time-polymerase chain reaction (RT-PCR), HPV RNA ISH, and in addition to those, p16 immunohistochemistry (IHC) can be thought as an indirect method for the presence of HR-HPV (15,16). However, there is no clear consensus yet on the most optimal method(s) for detecting HR-HPV.…”

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confidence: 99%

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Reproducibility of Morphologic Parameters of the International Endocervical Adenocarcinoma Criteria and Classification System and Correlation With Clinicopathologic Parameters: A Multi-Institutional Study

Bulutay

Haberal

Özen

et al. 2021

International Journal of Gynecological Pathology

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Endocervical adenocarcinomas (ECAs) have been recently reclassified according to their morphologic features linked to etiology by the International Endocervical Adenocarcinoma Criteria and Classification (IECC) and this system is adopted by WHO 2020. This classification separates the ECAs as human papillomavirus (HPV)-associated (HPVA) and HPV-independent (HPVI) subtypes. According to WHO 2020, high risk (HR)-HPV association can be histologically recognized by the presence of luminal mitoses and apoptosis. Therefore, investigating the reproducibility of the morphologic criteria of this new classification will be important in observing the recognizability of tumor types. Full slide sets of 94 ECAs were collected from 4 institutions in Turkey and reclassified on the basis of IECC/WHO 2020 criteria and the presence or absence of HR-HPV. HR-HPV presence was confirmed by HPV DNA in situ hybridization, p16 immunohistochemistry and in conflicted cases with real time-polymerase chain reaction. The final diagnoses were given based on the combination of the histologic evaluation and ancillary test results. Our cohort consisted of 73.4% HPVA and 26.6% HPVI cases. According to the WHO 2020 criteria 92.7% of HPVAs and 88% of HPVIs were easily classified. HPV DNA in situ hybridization was positive in 91.3% of the HPVAs and p16 was positive in all HPVAs, and also positive in 8% of the HPVIs. In conclusion, most of the ECAs can be diagnosed by their characteristic morphologic features by the WHO 2020 criteria. However, we want to emphasize that mitosis/apoptosis criteria may not be helpful especially in mucinous ECAs and ancillary tests for HR-HPV should be used in challenging cases.

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“…Appropriate RNA and HPV controls were included. The system contains probes targeting E6 and E7 mRNA for the following 18 high risk types: 16,18,26,31,33,35,39,45,51,52,53,56,58,59, 66, 68, 73, and 82. ISH stained TMAs were scanned and digitized using Aperio, and the tissue spots were independently reviewed by 3 pathologists who scored HPV RNA-ISH expression as positive per the manufacturers specifications of any nuclear or cytoplasmic signal occurring in a tumor cell.…”

Section: Methodsmentioning

confidence: 99%

Testing Algorithms for the Diagnosis of Malignant Glandular Tumors of the Uterine Cervix Histotyped per the International Endocervical Adenocarcinoma Criteria and Classification (IECC) System

Duggan

Duan

Pfeiffer

et al. 2021

Applied Immunohistochemistry &Amp; Molecular Morphology

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The International Endocervical adenocarcinoma Criteria and Classification (IECC) categorizes tumors into human papilloma virus (HPV) associated (HPVA), not associated (NHPV), and invasive adenocarcinoma not otherwise specified (IA NOS). HPVA and NHPV encompass 11 histotypes and an algorithm of mucin content, HPV ribonucleic acid (RNA), estrogen receptor and GA-TA3 is proposed for the diagnosis of most. In this study, the IECC algorithm's diagnoses were compared with hematoxylin and eosin (H&E) based IECC histotyping. Kappa statistics measured performance agreement. With additional markers, hierarchical clustering by random forest (RF) classification identified the most discriminating between tumor types, and investigated other algorithms. Three pathologists independently reviewed digitized H&E images of n = 152 primary cervical adenocarcinomas for IECC histotype and mucin content, and tissue microarrays for expression of HPV RNA by in situ hybridization and 16 antibodies by immunohistochemistry. Results were finalized by consensus. There were n = 113 HPVA, n = 22 NHPV, and n = 17 IA NOS. Mucin was obvious in n = 36 and limited in n = 116. Among n = 124 with satisfactory test results, HPV RNA was positive in n = 96, estrogen receptor in n = 72, and GA-TA3 in n = 15. The IECC algorithm diagnosed n = 99 which agreed with H&E histotyping in n = 64 for a fair κ of 0.36 (95% confidence interval, 0.21-0.50): n = 12 were undiagnosed and n = 13 were IA NOS. Small sample sizes restricted RF to HPVA versus NHPV which were discriminated by p16, HPV RNA, and MUC6 with an area under the curve of 0.74 (95% confidence interval, 0.58-0.90). The IECC algorithm for histotyping under-performed. The RF algorithmin for categorization was favorable, but validation in larger studies and investigation of additional algorithms to discriminate between all IECC histotypes are needed.

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Evaluation of human papillomavirus (HPV) prediction using the International Endocervical Adenocarcinoma Criteria and Classification system, compared to p16 immunohistochemistry and HPV RNA in-situ hybridization

Cited by 10 publications

References 32 publications

International Endocervical Adenocarcinoma Criteria and Classification (IECC): An Independent Cohort With Clinical and Molecular Findings

International Endocervical Adenocarcinoma Criteria and Classification (IECC): An Independent Cohort With Clinical and Molecular Findings

Reproducibility of Morphologic Parameters of the International Endocervical Adenocarcinoma Criteria and Classification System and Correlation With Clinicopathologic Parameters: A Multi-Institutional Study

Testing Algorithms for the Diagnosis of Malignant Glandular Tumors of the Uterine Cervix Histotyped per the International Endocervical Adenocarcinoma Criteria and Classification (IECC) System

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