Abstract Cervical cancer is an aggressive type of cancer affecting women worldwide. Many affected individuals rely on smear tests for the diagnosis, surgery, chemotherapy, or radiation for their treatment. However, due to a broad set of undesired results and side-effects associated with the existing protocols, the search for better diagnostic and therapeutic interventions is a never-ending pursuit. In the purview, the bio-concentration of trace elements (copper, selenium, zinc, iron, arsenic, manganese, and cadmium) is seen to fluctuate during the occurrence of cervical cancer and its progression from pre-cancerous to metastatic nature. Thus, during the occurrence of cervical cancer, the detection of trace elements and their supplementation will prove to be highly advantageous in developing diagnostic tools and therapeutics, respectively. This review provides a detailed overview of cervical cancer, its encouragement by human papillomavirus infections, the mechanism of pathology, and resistance. Majorly, the review emphasizes the less explored role of trace elements, their contribution to the growth and inhibition of cervical cancer. Numerous clinical trials have been listed, thereby providing a comprehensive reference to the exploration of trace elements in the management of cervical cancer. 

/pdf/human-papillomavirus-infection-cervical-cancer-and-the-less-12xtztky.pdf

Human papillomavirus infection, cervical cancer and the less explored role of trace elements

Background The decrease in incidence of cervical dysplasia and carcinoma has not been as dramatic as expected with the development of improved research tools and test methods. The human papillomavirus (HPV) test alone has been suggested for screening in some countries. The National Cancer Screening Project in Korea has applied Papanicolaou smears (Pap smears) as the screening method for cervical dysplasia and carcinoma. We evaluated the value of Pap smear and HPV testing as diagnostic screening tools in a single institution. Methods Patients co-tested with HPV test and Pap smear simultaneously or within one month of each other were included in this study. Patients with only punch biopsy results were excluded because of sampling errors. A total of 999 cases were included, and the collected reports encompassed results of smear cytology, HPV subtypes, and histologic examinations. Results Sensitivity and specificity of detecting high-grade squamous intraepithelial lesion (HSIL) and squamous cell carcinoma (SCC) were higher for Pap smears than for HPV tests (sensitivity, 97.14%; specificity, 85.58% for Pap smears; sensitivity, 88.32%; specificity, 54.92% for HPV tests). HPV tests and Pap smears did not differ greatly in detection of low-grade squamous intraepithelial lesion (85.35% for HPV test, 80.31% for Pap smears). When atypical glandular cells were noted on Pap smears, the likelihood for histologic diagnosis of adenocarcinoma following Pap smear was higher than that of high-risk HPV test results (18.8 and 1.53, respectively). Conclusions Pap smears were more useful than HPV tests in the diagnosis of HSIL, SCC, and glandular lesions.

/pdf/comparison-of-papanicolaou-smear-and-human-papillomavirus-2w9mf664lf.pdf

Comparison of papanicolaou smear and human papillomavirus (HPV) test as cervical screening tools: can we rely on HPV test alone as a screening method? An 11-year retrospective experience at a single institution.

False negative (FN) results in cervical cancer (CC) screening pose serious risks to women. We present a comprehensive literature review on the risks and reasons of obtaining the FN results of primary CC screening tests and triage methods and discuss their clinical and public health impact and implications. Misinterpretation or true lack of abnormalities on a slide are the reasons of FN results in cytology and p16/Ki-67 dual-staining. For high-risk human papillomavirus (HPV) molecular tests, those include: truly non-HPV-associated tumors, lesions driven by low-risk HPV types, and clearance of HPV genetic material before sampling. Imprecise disease threshold definition lead to FN results in visual inspection with acetic acid. Lesions with a discrete colposcopic appearance are a source of FN in colposcopic procedures. For FAM19A4 and hsa-miR124-2 genes methylation, those may originate from borderline methylation levels. Histological misinterpretation, sampling, and laboratory errors also play a role in all types of CC screening, as well as reproducibility issue, especially in methods based on human-eye evaluation. Primary HPV-based screening combined with high quality-assured immunocytochemical and molecular triage methods seem to be an optimal approach. Colposcopy with histological evaluation remains the gold standard for diagnosis but requires quality protocols and assurance measures.

/pdf/false-negative-results-in-cervical-cancer-screening-risks-2n5j6kk1.pdf

False Negative Results in Cervical Cancer Screening—Risks, Reasons and Implications for Clinical Practice and Public Health

In 2021, the 2015 German consensus guideline for the diagnosis and treatment of uterine cervical carcinoma was updated. The present article summarises the new recommendations for pathologists: the incorporation of the International Endocervical Adenocarcinoma Classification (IECC), which morphologically separates HPV-associated and non-HPV-associated adenocarcinomas, as well as the reporting of the prognostic relevant growth pattern of the adenocarcinoma of the endocervical subtype (Silva pattern). Histologically, multifocality has been defined as the presence of clearly invasive foci with a minimum distance between each focus of 0.2 cm. Because of its intratumoural heterogeneity, all carcinomas ≤ 2 cm in their largest dimension should be processed completely, and tumours > 2 cm should be processed with one block per centimetre of their greatest dimension. In cases of (radical) trachelectomy/hysterectomy, the distal vaginal resection margin and all parametrial tissue should be processed completely. Sentinel lymph nodes have to be processed completely by lamellation along its long axis in 0.2 cm intervals. Immunohistochemical ultrastaging is mandatory. Staging should be performed using the 2009 FIGO classification and 2017 TNM classification. Reporting the revised 2018 FIGO classification is optional. To date, molecular markers have not been relevant for prognostication and treatment decision making.Im Jahr 2015 wurde die S3-Leitlinie für Diagnostik und Therapie des Zervixkarzinoms erstellt, die 2021 in ihrer revidierten Fassung vorliegt. Neu für die Pathologie sind die Aufnahme der International Endocervical Adenocarcinoma Classification (IECC), die zwischen HPV-assoziierten und non-HPV-assoziierten Karzinomen unterschiedet, sowie des prognostisch relevanten morphologischen Wachstumsmusters bei (HPV-assoziierten) Adenokarzinomen (sog. Silva-Pattern). Die Multifokalität beim mikroinvasiven Zervixkarzinom ist nun definiert als der Nachweis voneinander histologisch klar separierter invasiver Foci mit einem minimalen Abstand von 0,2 cm. Aufgrund einer möglichen intratumoralen Heterogenität sollen Zervixkarzinome ≤ 2 cm vollständig und Tumoren > 2 cm mit einem Block pro Zentimeter größter Ausdehnung eingebettet werden. Bei der (radikalen) Trachelektomie/Hysterektomie sollen der vaginale Resektionsrand und das parametrane Gewebe vollständig eingebettet werden. Neu ist die Empfehlung zur Aufarbeitung von Sentinellymphknoten. Diese sollen entlang ihrer Längsachse in 0,2 cm Abstand lamelliert, vollständig eingebettet und mittels Ultrastaging aufgearbeitet werden. Die FIGO-Klassifikation von 2009 bzw. TNM-Kategorisierung von 2017 wird beibehalten, die Angabe der FIGO-Klassifikation 2018/19 ist optional. Molekulare Marker spielen derzeit noch keine relevante Rolle in der Prognose und zum Therapieentscheid. 

/pdf/revidierte-fassung-der-s3-leitlinie-zervixkarzinom-2021-1jcx8is1.pdf

Revidierte Fassung der S3-Leitlinie Zervixkarzinom 2021 – Anforderungen an die Pathologie

The aim of this study was to evaluate the nuclear expression of histone methyltransferase enhancer of zeste homolog 2 (EZH2) in endocervical neoplastic lesions such as invasive endocervical adenocarcinoma (ECA) and cervical in situ adenocarcinoma (AIS) in comparison with normal endocervix and non-neoplastic counterparts. A total of 54 consecutive neoplastic cases (37 ECA, 17 AIS) and 32 non-neoplastic endocervical lesions (15 reactive atypia, 9 microglandular hyperplasia, 3 tuboendometrioid metaplasia, 3 tunnel cluster, 2 endometriosis) were included in the study with adjacent normal endocervix if present. EZH2 immunoreactivity was evaluated semiquantitatively by three independent experts in lesions and adjacent normal glandular epithelium as well. EZH2 expression was defined robust if at least two of the three experts rated partial or diffuse positivity. Robust EZH2 expression was statistically compared among the neoplastic, non-neoplastic, and normal glandular epithelium samples. Diagnostic test capability of robust EZH2 expression was calculated. Fifty-three out of the 54 neoplastic cases (98%) showed robust EZH2 expression. Robust EZH2 expression was significantly less often (4 out of 32 cases, 12.5%) found in the non-neoplastic endocervical lesions (p < 0.0001) and never (0 out of 66 samples) in the adjacent normal glandular epithelium. Robust EZH2 overexpression had a sensitivity and specificity of over 95% in detecting neoplastic lesions versus non-neoplastic lesions or normal glandular epithelium. EZH2 may play a role in the pathogenesis of endocervical neoplasia, and the detection of robust expression of EZH2 might be a useful differential diagnostic tool in problematic endocervical lesions in histology and cytology as well.

/pdf/robust-expression-of-ezh2-in-endocervical-neoplastic-lesions-57j543vm2z.pdf

Robust expression of EZH2 in endocervical neoplastic lesions.

International Endocervical Adenocarcinoma Criteria and Classification

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International Endocervical Adenocarcinoma Criteria and Classification