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• 30 January 2024

Cervical cancer kills 300,000 people a year — here’s how to speed up its elimination

• Lynette Denny 0 ,
• Ishu Kataria 1 ,
• Lisa Huang 2 &
• Kathleen M. Schmeler 3

Lynette Denny is a professor of special projects in the Department of Obstetrics and Gynaecology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.

You can also search for this author in PubMed   Google Scholar

Ishu Kataria is a senior public-health researcher at the Center for Global Noncommunicable Diseases at RTI International, New Delhi, India.

Lisa Huang is director of the SUCCESS project at Expertise France, Abidjan, Côte d’Ivoire.

Kathleen M. Schmeler is a professor of gynaecological oncology and associate vice-president of the Global Oncology Program, MD Anderson Cancer Center, Houston, Texas.

You have full access to this article via your institution.

Cervical cancer can be prevented through vaccination and be cured if diagnosed early. Yet it still kills more than 300,000 people worldwide each year. Globally, only around 21% of women have had a vaccine against the human papillomaviruses (HPVs) that cause the disease.

Cervical cancer could be eliminated: here’s how

That number needs to rise to 90% by 2030, if cervical cancer is to be eliminated in the next century — as the World Health Organization (WHO) plans . Screening and treatment should also become routine worldwide, with 70% of people with a cervix checked by the age of 35 and again at 45, and 90% of those with signs of cervical cancer treated.

The world is not on track to meet any of these targets. A step change is urgently needed. The tools to vaccinate, screen and treat people are available, and effective. But a lack of funding, staffing and infrastructure — coupled with vaccine hesitancy — are major obstacles. Here, four specialists highlight pockets of good practice that can help to buck the trend.

LYNETTE DENNY: Target schools for vaccination programmes

Oncologist Lynette Denny has spent 29 years working in the field of cervical cancer prevention. Credit: Lynette Denny

Schools are the most effective place to roll out national HPV vaccination programmes. As long as enrolment levels in education are high, it’s easier to reach young people at school than in health-care settings. Political will is crucial, as is collaboration between a government’s health and education departments — and close communication with schools.

I’ve seen the benefits of school-based vaccination at first hand. In 2013, I helped to run a pilot project targeting girls in 31 primary schools in South Africa, in regions where poverty and lack of health-care provision are typically obstacles to high vaccination rates. Our pilot provided 97.8% of eligible girls with what was then the full course of three vaccines 1 . (In December 2022, the WHO advised that a single dose is sufficient to protect against cervical cancer.) Similar results were seen in other pilots, including in Bolivia, Uganda and Vietnam.

Scaling these up to country-wide programmes requires determination. But lessons can be learnt from countries around the world. Take Rwanda. In 2011, it became the first low-income country to implement a national HPV immunization programme for girls in the sixth grade (mostly aged 11–12 years). By 2018, more than one million girls had received a vaccination — 98% of the target population 2 .

Women’s health research lacks funding — these charts show how

To do this, Rwanda had to overcome a lack of resources — a common problem in low- and middle-income countries (LMICs) — and put cervical cancer at the apex of its health agenda. Merck provided free vaccines for three years and helped to prepare for the national roll-out. Later funding came from GAVI, the Vaccine Alliance — an international organization focused on providing vaccines for children in LMICs. Multiple government departments 3 collaborated to set up committees that would oversee all aspects of the programme. Together, these partners organized and delivered school-based vaccinations, rigorously monitored vaccination coverage and ran awareness campaigns 4 . Girls not enrolled in schools, or absent on vaccination days, were tracked by community health workers and vaccinated at health-care facilities instead.

As Rwanda shows, strong, trustworthy and reliable collaboration between all stakeholders is key. We’ve found the same ingredients to be essential in South Africa, where we invested more than six months in regular meetings between health-care workers, education providers, technology specialists and the government to ensure that the roll-out was well coordinated.

High-income countries, which typically have more resources and fewer barriers to introducing vaccination programmes, would do well to learn from Sweden. In 2012, the country rolled out a free, school-based HPV vaccination programme for girls as young as 10 — alongside a successful screening and treatment programme. Here again, planning and stakeholder cooperation was essential. By 2021, 90% of girls in the country had received one vaccine dose by age 15, and 84% had received two.

Going forward, governments around the world must place prevention of cervical cancer high on the health agenda. Health and education departments must cooperate, and must allocate funding to all aspects of HPV vaccination — from vaccine procurement to infrastructure, awareness campaigns to human resources. Without this focus, roll-out will fail.

ISHU KATARIA: Bust myths through communication campaigns

Ishu Kataria surveyed physicians in India to understand their hesitancy around the HPV vaccine. Credit: Ishu Kataria

People in India are generally not hesitant about vaccines, especially for children. Yet, the Indian government has not included the HPV vaccine in its national immunization programme — even though one person dies from cervical cancer every eight minutes here.

In 2019, I interviewed 32 physicians in Kolkata, to try and understand the hesitancy surrounding HPV vaccination 5 . The physicians’ foremost reason was that many parents associate HPV vaccination with promiscuity. Because HPV is transmitted through sexual intercourse, parents often assume that giving a young child the vaccine will be viewed in the community as a sign that they are sexually active.

Physicians were also unclear about the benefits of recommending the HPV vaccine before a child becomes sexually active, and they did not want to risk their reputation by making a recommendation that could be controversial. Similar concerns and misunderstandings are common elsewhere, including in Eastern Mediterranean countries 6 .

Cancer will cost the world $25 trillion over next 30 years

A campaign run by national health departments is needed to instil confidence in the vaccine among physicians. It should make clear that vaccination is most effective between the ages of 9 and 14, because that is when it produces the most robust immune response. The campaign should highlight that the vaccine is extremely safe. It should provide guidance on communicating the benefits to parents in a culturally sensitive way — as a vaccine to prevent cancer, rather than against a sexually transmitted infection.

Raising general awareness — among schoolteachers, parents, children and adolescents — is also crucial.

The campaign run by the health department for the northeastern state of Sikkim when it first rolled out the HPV vaccine in 2018 provides a blueprint for others to follow. Sikkim’s six-month-long campaign educated physicians, community leaders, government officials, the media and the public through workshops, written materials and television and radio broadcasts. It resulted in 97% HPV vaccine uptake among eligible girls 7 .

Indian states cannot afford to roll out the vaccine unless it is part of the national immunization programme (in which case the government covers the cost of the vaccine). The launch of an affordable, cost-effective, India-manufactured vaccine by the Serum Institute in September 2022 has put pressure on the Indian government to fund the HPV vaccine, with a decision expected after this year’s election. States should now lay the groundwork for roll-out, following Sikkim’s lead. Key first steps include communication with physicians and parents, along with logistical planning.

LISA HUANG: Integrate screening into health-care systems

Public-health expert Lisa Huang. Credit: Expertise France

There is no one-size-fits-all approach to rolling out cervical cancer screening programmes. For LMICs, the best strategies focus on maximizing efficiency — and thereby reducing costs — for resource-poor countries.

This can be achieved by integrating screening and treatment programmes into existing health-care systems and facilities. The SUCCESS project, of which I am a director, is trialling such an approach in Burkina Faso, Côte d’Ivoire, Guatemala and the Philippines.

Performing screens in existing health-care settings minimizes the need for extra medical workers, who are scarce in LMICs. Screening programmes can be run in primary health-care settings, gynaecology clinics, family-planning services and — importantly — HIV clinics. The last is essential because the 20 million women living with HIV are six times more likely than other women to develop cervical cancer.

African scientists call for research equity as a cancer crisis looms

Local contexts need to be considered. In many countries, staff members will need to be trained in screening, and supply chains and inventory management systems will need to be set up. Digital health-information systems are crucial, allowing patient information to be passed between departments and between health workers to aid follow-up.

In the SUCCESS project, we’ve seen the benefits of such digital solutions. In Burkina Faso and Côte d’Ivoire we’ve made use of the DHIS2 Tracker, an app available as part of DHIS2 — an open-source health-information management platform widely used in LMICs. Using a tablet, a health-care worker can input patient information into the tracker along with information about any follow-up needed, which the patient can be told of either by instant messaging or when visiting another health centre.

Although it is challenging to collect digital data in LMICs, I am confident that tracking screening will save lives. Governments should aim to implement tracking technologies as soon as possible. People often resist complex changes, so engagement with health-care workers is an essential first step in a move towards digitization, to gain support for the switch. Investment from local and international funders is key, and time must be taken to understand each country’s health-care ecosystem and ensure that new digital solutions are interoperable with those already in use.

KATHLEEN M. SCHMELER: Use international mentors to train doctors

Kathleen Schmeler helps to train medical graduates in Mozambique. Credit: Sarah Berger

LMICs face a shortage of medical providers. Just 4% of the global medical workforce is in Africa, for instance — yet the continent shoulders one-quarter of the global disease burden 8 . Most LMICs have no formal training programmes for cancer specialists, particularly surgeons. In these countries, more specialized nurses and physicians are urgently needed to diagnose and treat cervical cancer.

Global collaboration can help to meet the need for training, as demonstrated by two international projects in which I’ve been involved. Both focused on Mozambique, a country that has no organized screening programme and few trained medical providers. In Mozambique, 39 of every 100,000 women die from cervical cancer, compared with the global average of 7.2.

First, I co-lead a collaboration between the Mozambique Ministry of Health, the MD Anderson Cancer Center in Houston, Texas, and five institutes in Brazil. The collaboration — which was initiated in 2014 at the request of the First Lady of Mozambique — aims to build capacity in Mozambique by teaching the nation’s medical providers to treat ‘pre-cancerous’ cells. Specialists from Texas and Brazil travel to Mozambique three or four times a year to provide lectures, hands-on training and mentoring to trainee doctors and nurses. We train 30–40 participants each time. Ongoing support is provided through monthly video conferences.

Second, I co-chair a global gynaecological oncology fellowship run by the International Society of Gynecologic Cancer (see go.nature.com/4b6edzk ) for institutions in LMICs that lack formal training in cancer care. The fellowship site is paired with a partner institute in a high-income country. Fellows — recently, graduates in obstetrics and gynaecology — spend two years undertaking a comprehensive education and training programme, mainly in their home country, but with a few months at the mentor institution. Maputo Central Hospital in Mozambique was a pilot site when the programme first began in 2017. There are now fellowship sites in 22 countries.

Each of these projects initially required a handful of very motivated international mentors. But training and mentoring is now being performed, at least in part, by programme graduates living in Mozambique.

To scale up these efforts, institutes in high-income countries must coordinate with one another, and enhance collaborations with health ministries and training institutions in LMICs. Funding for our work has come from small grants, philanthropic, institution and foundation budgets, and often from the volunteers themselves. These types of donation can fund individual projects, but investment from governments, United Nations agencies and industry partners is needed to make the approach work on a global scale.

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New ways to prevent and treat cancer of the cervix are being researched. Some of the promising new developments are covered here.

Immunotherapy

Targeted therapy, radiation therapy, chemotherapy, hpv vaccines.

Treatment of cervical cancer includes immunotherapy with drugs called checkpoint inhibitors. These drugs are generally only given to people with metastatic or recurrent disease, with or without chemo. Research is being done to determine if immunotherapy would work better with different combinations of chemo, or if it can be used for people with earlier-stage disease.

Current targeted therapy includes finding cells with changes in the RET and NTRK genes. Scientists are studying how other gene mutations found in cervical cancer cells can be targeted by specific drugs. Genes called oncogenes and tumor suppressor genes, which control cell growth, are of particular interest.

Studies are being done to determine the best ways to use external beam therapy and brachytherapy to treat cervical cancer and still limit damage to normal tissue. Doctors are also looking for ways to use more focused radiation along with other treatments, like immunotherapy, to treat advanced cervical cancers.

Many clinical trials are looking for better chemo drugs to treat cervical cancer. Research is ongoing to understand which specific combinations of chemo drugs allow for the best treatment results.

Vaccines have been developed to prevent infection with some of the high risk HPV types  that are associated with cervical cancer. The current vaccines are intended to produce immunity to HPV types that cause about 90% of cervical cancers.

Other vaccines are meant to help women who already have advanced cervical cancer. These vaccines produce an immune reaction to the parts of the virus (E6 and E7 proteins) that make the cervical cancer cells grow abnormally. It is hoped that this reaction will kill the cancer cells or stop them from growing. It is also being studied in early-stage cervical cancer to see if it can help decrease the chance of the cancer returning.

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Liontos M, Kyriazoglou A, Dimitriadis I, Dimopoulos MA, Bamias A. Systemic therapy in cervical cancer: 30 years in review. Crit Rev Oncol Hematol. 2019 May;137:9-17. doi: 10.1016/j.critrevonc.2019.02.009. Epub 2019 Feb 28. PMID: 31014518.

National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology: Cervical Cancer. Version 3.2024. Accessed at https://www.nccn.org/ on June 8, 2024.

Sharma S, Deep A, Sharma AK. Current Treatment for Cervical Cancer: An Update. Anticancer Agents Med Chem. 2020;20(15):1768-1779. doi: 10.2174/1871520620666200224093301. PMID: 32091347. 

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Role of phytochemicals in treatment of aging and cancer: focus on mechanism of foxo3 activation.

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Park, S.-H. Role of Phytochemicals in Treatment of Aging and Cancer: Focus on Mechanism of FOXO3 Activation. Antioxidants 2024 , 13 , 1099. https://doi.org/10.3390/antiox13091099

Park S-H. Role of Phytochemicals in Treatment of Aging and Cancer: Focus on Mechanism of FOXO3 Activation. Antioxidants . 2024; 13(9):1099. https://doi.org/10.3390/antiox13091099

Park, See-Hyoung. 2024. "Role of Phytochemicals in Treatment of Aging and Cancer: Focus on Mechanism of FOXO3 Activation" Antioxidants 13, no. 9: 1099. https://doi.org/10.3390/antiox13091099

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Recent Advances in Cervical Cancer Management: A Review on Novel Prognostic Factors in Primary and Recurrent Tumors

Angela santoro.

1 Pathology Unit, Department of Woman and Child’s Health and Public Health Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy

Frediano Inzani

2 Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, 27100 Pavia, Italy

Giuseppe Angelico

3 Pathology Unit, Cannizzaro Hospital, 95126 Catania, Italy

Damiano Arciuolo

Emma bragantini.

4 Department of Surgical Pathology, Ospedale S. Chiara, 38122 Trento, Italy

Antonio Travaglino

Michele valente, nicoletta d’alessandris, giulia scaglione, stefania sfregola, alessia piermattei, federica cianfrini, paola roberti, gian franco zannoni.

5 Pathology Institute, Catholic University of Sacred Heart, 00168 Rome, Italy

Simple Summary

The aim of the present review is to analyze the novel and most relevant prognostic factors in primary and recurrent cervical cancer. Based on our findings, tumour budding and cell nest size grading system, depth of stromal invasion, lympho-vascular space invasion, perineural invasion, tumor free distance and tumor infiltrating lymphocytes appeared the most relevant factors which may be included in the pathology report to help future studies to further elucidate cervical cancer prognosis.

Background: Several pathological parameters, including tumor size, depth of stromal invasion, lympho-vascular space invasion and lymph node status, have been proposed as prognostic predictors in cervical cancer. However, given the high mortality and recurrence rate of cervical cancer, novel parameters that are able to provide additional prognostic information are needed in order to allow a better prognostic stratification of cervical cancer patients. Methods: A search was conducted on PubMed to identify relevant literature data regarding prognostic factors in cervical cancer. The key words “cervical cancer”, “prognostic factors”, “pathology”, and “outcome” were used. Results: The novel pathological grading system based on tumor budding and cell nest size appeared the most relevant prognostic factor in primary neoplasms. Moreover, other potentially useful prognostic factors were tumor size, depth of stromal invasion, lympho-vascular space invasion, perineural invasion, tumor-free distance and tumor-infiltrating lymphocytes. Prognostic factors related to advanced-stage cervical cancer, including lymph-nodes status, endometrial and cervical involvement as well as distant metastases, were also taken into consideration. Conclusions: According to our findings, tumor budding and cell nest size grading system, depth of stromal invasion, lympho-vascular space invasion, perineural invasion, tumor-free distance and tumor-infiltrating lymphocytes appeared the most relevant factors included in the pathology report.

1. Introduction

Cervical cancer is one of the most common cancers worldwide, ranking as fourth for both incidence and mortality among all gynecological malignancies [ 1 ]. Squamous cell carcinoma (SCC) is the most frequent histotype, followed by adenocarcinoma (AC), which accounts for approximately 10–25% of cervical tumors [ 1 , 2 ].

Despite the majority of cases, especially in developing countries, being diagnosed at an advanced stage, an increasing percentage of tumors are diagnosed at an early stage [ 1 , 2 ]. For early-stage disease, several pathological parameters, including tumor size, histotype, depth of stromal invasion, lympho-vascular space invasion (LVSI) and lymph node status have been proposed as prognostic predictors, capable of stratifying patients into different risk groups [ 3 , 4 , 5 , 6 ].

However, given the high mortality and recurrence rate of cervical cancer, the abovementioned prognostic factors are still of limited value and provide suboptimal prognostic stratification for recurrence [ 1 , 3 ]. Therefore, novel parameters, able to provide additional prognostic information, are needed in order to allow a better clinical stratification of cervical cancer patients.

Actually, the histopathology report for cervical carcinoma should include all relevant information required for diagnosis, staging, prognosis and patient management. According to the most recent recommendations from College of American Pathologists (CAP) and the International Collaboration on Cancer Reporting (ICCR) [ 4 ], the following essential items should be included in the pathology report:

• - macroscopic tumor site
• - tumor dimensions (measurements of horizontal extent and depth of invasion or tumor thickness)
• - maximum and minimum length of vaginal cuff and parametria in two dimensions
• - histological tumor type and tumor grade
• - coexistent pathology (squamous intraepithelial lesion, adenocarcinoma in situ, stratified mucin-producing intraepithelial lesion)
• - minimum distance of uninvolved cervical stroma
• - extent of invasion (vaginal, uterine corpus, parametrial, adnexal, bladder, rectum involvement)
• - margin status (for invasive tumors and for precursor lesions)
• - lymph node status: sentinel lymph node status, total number of nodes retrieved, number of positive lymph nodes
• - pathologically confirmed distant metastases.

Moreover, the following desired/recommended items should also be included in the pathology report:

• - HPV dependent and independent status
• - Silva pattern of invasion
• - Ancillary studies (p16 immunohistochemistry; in-situ hybridization for HPV).

The aim of our review is to identify and define novel and potentially useful clinicopathological prognostic factors for cervical cancer in order to provide a more accurate prognostic stratification in primary and recurrent tumors.

2. Materials and Methods

In this review we searched for previously published papers regarding pathological prognostic factors in cervical cancer, with a particular focus on those factors not yet codified in the current histological reporting guidelines. A search was conducted on PubMed to identify relevant literature data. The key words “cervical cancer”, “prognostic factors”, “pathology” and “outcome” were used.

3. Prognostic Factors in Primary Neoplasm

The most relevant prognostic factors in primary tumors are summarized in Table 1 and Table 2 .

Prognostic factors related to primary tumors: squamous cell carcinoma.

Prognostic factors related to primary tumors: adenocarcinoma.

3.1. HPV Status

HPV infection represents the main pathogenetic event leading to cervical cancer development. The key step in the pathogenesis of cervical carcinomas is the integration of the HPV genome into the host chromosome, followed by the inactivation of viral E1 and E2 regions and upregulation of oncogenes E6 and E7 [ 7 ]. In detail, E6 oncoprotein degrades p53, inhibiting apoptosis while E7 protein stimulates cell proliferation by suppressing RB1 [ 7 ]. Despite the vast majority of cervical epithelial tumors being related to HPV infection, it is now recognized that a proportion of these tumors, mainly represented by adenocarcinomas, are not associated with HPV infection and carry more aggressive clinical behavior than HPV-related carcinomas [ 2 , 4 ]. In this regard, the 2020 WHO Classification of female genital tumors introduced a novel classification for cervical epithelial tumors based on the presence or absence of HPV infection [ 2 ]. In detail, adenocarcinomas are now categorized into HPV-associated (HPVA) and HPV-independent tumors (HPVI). This latter group includes the following histotypes: gastric-type, clear cell, mesonephric and endometrioid carcinoma [ 2 , 4 ]. On the other hand, the 2020 WHO Classification categorizes squamous epithelial tumors into HPV-associated and HPV-independent categories [ 2 ]. HPV-independent squamous cell carcinoma is exceedingly rare and shows a higher rate of lymph node metastases, with a consequent reduced disease-free and overall survival compared with HPV-associated carcinoma [ 8 ]. However, currently there are not yet differences in treatment strategies between HPV-associated and HPV-independent tumors.

The same distinction (HPV-dependent/HPV-independent) is applied for premalignant precursor lesions, squamous and glandular in type:

• - HPV-dependent SILs (squamous intraepithelial lesions): high grade and low grade, respectively corresponding to CIN1 and CIN2-3 dysplasia
• - HPV-dependent AIS (adenocarcinoma in-situ) and its SMILE variant (stratified mucin producing intraepithelial lesion)
• - HPV-independent AIS: gastric-type AIS and ALEGH (atypical lobular endocervical glandular hyperplasia)

According to ICCR criteria, in the morphological assessment of a cervical cancer, coexisting precursor lesions should always be mentioned; a pathologist should also document the involvement and the distance from the resection margins (ectocervical/vaginal cuff; endocervical; radial/deep stromal) since the presence of a positive margin may influence clinical management and follow-up [ 4 ].

To date, the detection of HPV infection on cervical cancer and precancerous lesions in formalin fixed-paraffin embedded (FFPE) tissues is mainly based on p16 immunohistochemistry, which is widely used as a surrogate marker for high-risk human papillomavirus (hrHPV) infection [ 9 ]. P16 positivity is defined as strong, block-type staining pattern, involving all squamous epithelium layers [ 4 , 9 ].

Direct HPV testing with RNA in-situ hybridization is generally preferred in selected cases such as tumors with morphologic features suggestive of HPV infection but lacking block-type staining for p16 or, alternatively, tumors/premalignant lesions with block-type staining for p16 but lacking the morphological features indicative of viral infection [ 4 ].

3.2. Grading of Cervical Cancer

To date, there is no widespread consensus regarding the prognostic significance of tumor grade, and no validated grading systems are currently available for cervical cancer [ 4 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. Although tumor grading is considered a recommended (not required) pathological feature, in the recent recommendations of the European Society of Gynaecological Oncology (ESGO), the European Society for Radiotherapy and Oncology (ESTRO) and the European Society of Pathology (ESP), it is not taken into account in clinical management of the cervical cancer patients to assess the need for adjuvant therapy following surgery [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. Similarly, the recent ICCR data set for the reporting of cervical cancers and the “Sedlis Criteria” do not take into consideration grading for adjuvant treatment algorithms [ 4 ].

3.2.1. Squamous Cell Carcinoma

Several grading systems are currently applied to grade cervical squamous cell carcinoma [ 12 , 13 , 14 , 15 , 16 , 17 , 18 ]; these include:

• - the Broder’s system, based on the degree of keratinization, cytological atypia and mitotic activity;
• - the grading of invasive tumor front or the pattern-type of invasion (pushing versus infiltrative);
• - the typology of neoplastic cells and the presence/absence of keratinization (large-cell keratinizing, large-cell non-keratinizing, and small-cell non-keratinizing categories);
• - the WHO proposal that considers the degree of keratinization, nuclear pleomorphism, size of nucleoli and mitotic index.

Other authors have described more complex multi-factor grading systems in cervical squamous cell carcinomas, including both conventional grading tumor-related parameters and other factors such as depth of invasion, LVSI and host/stromal inflammatory reaction [ 19 ].

Recently, Jesinghaus et al. demonstrated the prognostic value of a novel pathological grading system in cervical squamous cell carcinoma based on tumor-budding and cell nest size [ 20 ].

The prognostic significance of this novel grading scheme has already been documented in squamous cell carcinomas of the lung, oral cavity, oesophagus and gastrointestinal tract [ 21 , 22 , 23 , 24 ]; whereas only a few but promising articles have been recently published on the prognostic role of tumor-budding and cell nest size in both squamous cell carcinoma and adenocarcinoma of the cervix [ 25 ].

Tumor buds are strictly related to invasiveness, motility and epithelial/mesenchymal transition and are generally defined as isolated cells or clusters of 4 or 5 cells in intratumoral or peritumoral areas ( Figure 1 A) [ 20 , 21 , 22 , 23 , 24 , 25 ]. Cell nest size is another parameter that provides a qualitative measurement of cellular dissociation; its prognostic significance has already been demonstrated for oral, pulmonary and oesophageal tumors [ 20 , 21 , 22 , 23 , 24 , 25 ]. In the article by Jesinghaus et al., two cohorts of cervical squamous cell carcinomas patients were graded using this novel grading system [ 20 ]. Tumor-budding activity was considered as low (1–14 budding foci in 10 high power fields) and high (15 or more budding foci in 10 high power fields). Cell nest size was evaluated as follows: large (cell nests comprising more than 15 cells); intermediate (cell nests comprising 5–15 tumor cells); small (cell nests of 2–4 tumor cells) ( Figure 1 B); single-cell invasion (singular, discohesive tumor cells without nested architecture). In particular, the smallest identifiable cell nests were used in scoring. Finally, a score was attributed to both budding activity (1–3 points) and cell nest size (1–4 points); the sum of both scores results in a 3-tier grading system: G1 (score ranging from 2 to 3); G2 (score ranging from 4 to 5); G3 (score ranging from 6 to 7). By utilizing this novel grading, a significant prognostic impact has been demonstrated on overall survival (OS) and disease-free survival (DFS). Moreover, G2/G3 tumors were significantly associated with higher tumor stage, LVSI, perineural invasion and nodal metastases. Interestingly, data from Jesinghaus et al. have been further validated in a recent paper by Zare et al., which evidenced a significant association of the new grading system with OS, DFS, higher tumor stage and lymph node metastases [ 26 ].

Haematoxylin and eosin (H&E) stained sections (( A ) 10×; ( B ) 20×) illustrating tumor-budding and cell nest size in squamous cell carcinoma of the cervix. ( A ) Cervical squamous cell carcinoma with high tumor-budding activity, characterized by numerous small tumor clusters of <5 cells present at the infiltrating edge of the tumor (×10). ( B ) Small-sized cell nests: cervical cancer showing cell nests consisting of 2–4 tumor cells with nested architecture (×20).

3.2.2. Adenocarcinoma

Several studies suggest a grading system for HPVA adenocarcinomas based on a combination of architectural and nuclear features and similar to the FIGO grading system applied for uterine endometrioid carcinomas [ 27 , 28 ]. The most commonly used cut-offs for solid architecture set at ≤10% (grade 1), 11% to 50% (grade 2), and >50% (grade 3) has been recommended, due to its good prognostic significance. Tumors can be upgraded in the presence of marked nuclear atypia in the majority of cells (>50%) [ 7 ]. Moreover, a clearly defined subset of endocervical adenocarcinomas should be considered intrinsically high-grade regardless of the morphology. Most of these represent HPVI adenocarcinomas (gastric type adenocarcinoma, clear cell carcinoma and mesonephric adenocarcinoma).

Among the cervical HPVA adenocarcinomas, the following variant should be not graded because it is considered automatically high-grade: micropapillary carcinomas, mucinous adenocarcinomas and neuroendocrine carcinomas (also in the mixed forms, irrespective of the percentage of the neuroendocrine component) [ 29 , 30 , 31 ]. A recent paper by Shi et al. demonstrated the reliability of the grading scheme based on tumoral budding and small nest size also in endocervical adenocarcinomas where it seems to outperform the conventional Federation of Gynecology and Obstetrics (FIGO) grading and Silva pattern classification [ 32 ]. Therefore, if further studies on larger cohorts will show similar results, the novel grading system could be included in the pathology reports as an additional tool to guide the therapeutic management of cervical cancer patients.

3.3. Silva Pattern of Invasion for HPV-Associated Adenocarcinomas

Recently, the Silva Pattern Classification has been shown to correlate with the risk of lymph node metastasis and patient survival [ 4 , 33 ]. The Silva classification can only be applied to HPVA cervical adenocarcinoma and sub-classifies tumors into three patterns (A, B, C) based on the presence and degree of destructive stromal invasion, LVSI and grade of cytologic atypia [ 33 ].

In detail, Pattern A tumors are composed of well-formed glands without evidence of destructive stromal invasion, single cells, solid growth, high grade cytology or LVSI. Pattern B tumors show limited destructive invasion with individual cells or clusters of tumor cells not exceeding 5 mm in maximum diameter. Pattern C tumors are characterized by diffuse destructive invasion associated with desmoplastic reaction.

The current literature evidence, mainly based on retrospective studies, suggests that Pattern A tumors do not develop lymph node metastases and carry a very limited risk of recurrence; therefore, they can be suitable for conservative treatment without lymph node dissection [ 2 ]. The risk of lymph node metastases is very low for Pattern B adenocarcinomas, which may benefit from SLN mapping, especially if LVSI is present. Finally, Pattern C tumors have a more significant risk of nodal metastases and tumor recurrences; therefore, standard surgical treatment, including lymph node dissection, is more appropriate for these latter patients [ 2 ].

3.4. Lympho-Vascular Space Invasion (LVSI)

LVSI assessment is a required item in the pathology report of cervical cancer since it is one of the criteria used to select patients suitable for surgical radicality and adjuvant treatment [ 11 ]. Several studies have investigated the prognostic role of LVSI and its association with nodal and distant metastases and patient survival [ 11 , 34 , 35 , 36 , 37 , 38 , 39 ]. However, results are extremely heterogeneous since some studies have shown the negative prognostic role of LVSI while other studies failed to demonstrate statistically significant results [ 11 , 37 , 38 , 39 ]. This discrepancy across studies may be explained by the qualitative method utilized to assess LVSI: present or absent. In this regard, literature data in endometrial cancer patients demonstrated that a semi-quantitative evaluation may better stratify patient prognosis [ 36 , 37 , 38 , 39 ]. In detail, according to the “three-tiered approach” for endometrial cancer, LVSI has been classified as follows: (i) Absent: No LVSI; (ii) Focal: single focus of LVSI around the tumor; (iii) Diffuse: more than 1 focus around the tumor [ 40 , 41 , 42 , 43 ]. With this approach, a diffuse pattern of LVSI has been demonstrated as an independent prognostic factor for nodal metastases, recurrence and decreased survival; on the other hand, endometrial cancer patients with focal LVSI showed a significantly better outcome [ 40 , 41 , 42 , 43 ]. Regarding LVSI in cervical cancer, a recent study by Ronsini et al. demonstrated, for the first time, that a semi-quantitative evaluation of LVSI in early-stage cervical cancer patients could provide a more accurate survival stratification [ 43 ]. In detail, different clinico-pathological features and survival outcomes were observed in patients with absent, focal and diffuse LVSI, respectively. Moreover, diffuse LVSI was associated with increased risk of nodal metastases, parametrial involvement and positive surgical margins [ 43 ]. Literature data also showed that only LVSI outside the tumors border, so called satellite LVSI rather than intratumor LVSI, has a significant prognostic value in cervical cancer [ 44 ].

If future studies on large series will support these findings, a semi-quantitative evaluation of LVSI could be recommended in the pathology reports of cervical cancer patients in order to optimize the diagnostic and therapeutic process.

3.5. Perineural Invasion (PNI)

PNI, according to the Liebig criteria, is defined as the presence of tumor cells along the nerve circumference or invading any of the three layers of the nerve sheath (epineurium, perineurium and endoneurium) ( Figure 2 ) [ 45 ]. PNI is frequently detected in several malignancies, including head and neck squamous cell carcinoma, colorectal adenocarcinoma, prostate cancer, cholangiocarcinoma and pancreatic cancer [ 45 , 46 , 47 , 48 , 49 , 50 ]. In cervical cancer, the reported incidence of PNI ranges from 7.0 to 35.1%; moreover, PNI is frequently detected in combination with other risk factors, such as LVSI, deep cervical invasion, large tumor size, tumor extension to the uterus, positive surgical margins, parametrial invasion and pelvic lymph node metastases [ 50 , 51 , 52 , 53 ]. Therefore, patients with PNI are more likely to receive adjuvant radiotherapy or concurrent chemo-radiation after surgery. However, the real prognostic impact of PNI in cervical cancer is poorly understood and is still a matter of debate. In detail, some studies demonstrated the role of PNI as independent prognostic factor for OS; other studies showed a significant correlation of PNI with DFS and OS at univariate but not at multivariate analysis, whereas other authors failed to demonstrate any prognostic role of PNI [ 50 , 51 , 52 , 53 ]. Despite its limited prognostic role, it is well known that PNI is frequently related to other poor prognostic factors, such as LVSI, deep stromal invasion, large tumor size and parametrium invasion; therefore, its real impact on prognosis needs to be better elucidated [ 50 , 51 , 52 , 53 ]. According to literature data, PNI could be considered as an intermediate-risk factor for cervical cancer patients that may aid in the selection of the more appropriate therapeutic approach [ 50 , 51 , 52 , 53 ].

H&E stained section (10×) illustrating perineural invasion. In this example of squamous cell carcinoma of the uterine cervix with basaloid morphology, a small round nerve structure (center of the field) is surrounded by the neoplastic proliferation (×10).

3.6. Depth of Stromal Invasion (DOI)

Depth of stromal invasion (DOI) represents an essential tool to be included in the pathology report, not only for staging purposes but also for its potential role as prognostic factor in cervical cancer [ 5 ]. According to Sedlis criteria, DOI is expressed as inner third, middle third and outer third of cervical wall thickness infiltration [ 54 ]. Several studies showed that DOI represents an independent prognostic factor for OS and DFS and is strictly related to local recurrences. Moreover, a significant difference of prognosis has been demonstrated between tumors with full-thickness invasion and tumors reaching the cervical–parametrial transition zone [ 54 , 55 ]. According to recent studies, DOI may represent a reliable method to categorize the pathological tumor response in cervical cancer after neoadjuvant therapy [ 5 , 55 ]. In detail, a recent meta-analysis evidenced a statistically significant difference in survival between residual tumor with stromal invasion > and <3 mm. Therefore, a cut-off of 3 mm of residual stromal invasion seems to outperform all other residual tumor scoring systems for prognostic stratification of post-neoadjuvant treatment cervical cancer [ 5 ]. Moreover, the objectivity of the measurement of the depth of stromal invasion makes this system heavily reproducible with limited inter-observer variability.

3.7. Maximum Horizontal Extent of Tumor

The horizontal extent of the tumor represents the longitudinal extent if the tumor is measured in the superior–inferior plane, or the circumferential extent if the tumor is measured perpendicular to the longitudinal axis of the cervix. It is best calculated histologically for smaller neoplasms or grossly for larger tumors [ 4 ].

Despite literature data suggesting its potential role as independent predictor of survival in cervical carcinoma, it is no longer utilized to stage microscopic (Stage IA) disease [ 4 , 56 ]. Therefore, the horizontal extent of the tumor is now considered as an optional element and its inclusion in the pathology report is encouraged to:

• - give a more complete picture of tumor extent (length and width);
• - appreciate tumor volume;
• - help future studies to further clarify its prognostic role.

3.8. Parametrial Involvement

Strictly related to DOI, parametrial involvement is another important histological feature for pathological staging. Parametrial involvement represents an independent predictor of recurrence and shorter DFS for both squamous cell carcinoma and adenocarcinoma [ 57 , 58 , 59 ]. Therefore, infiltration of parametrial structures must be included in the pathology report along with an accurate measurement of the lateral extent of each parametrium [ 4 ].

3.9. Tumor-Free Distance (TFD)

TFD has been proposed as another potentially useful prognostic parameter [ 60 , 61 , 62 , 63 ]. TFD represents the minimum distance of uninvolved stroma between the tumor and peri-cervical stromal ring [ 60 , 61 , 62 , 63 ]. It is well-known that the risk of pelvic lymph node metastases, poor prognosis and poor survival is inversely related to the thickness of the remaining fibromuscular cervical stroma around the tumor [ 61 ]. In a recent study by Cibula et al., TFD, assessed at pre-operative imaging (MRI or US), outperformed other prognostic markers, such as tumor size or depth of stromal invasion, which does not take into account the size of the cervix and tumor location in the cervix [ 63 ]. This study established the best cut-off value of TFD at 3.5 mm and provided further evidence for the independent prognostic role of TFD [ 63 ]. Several studies have also attempted to determine the best threshold for histologically assessed TFD; reported cut-offs range from 2.5 mm to 5 mm, but a consensus has not been established yet [ 60 , 61 , 62 , 63 ]. The prognostic impact of histologically assessed TFD has recently been investigated by Bizarri et al. In this study, patients with TFD <3.0 mm showed a worse DFS and OS compared to patients with TFD >3.0 mm. Therefore, authors concluded that a TFD ≤3.0 mm represents a poor prognostic factor, especially in “low-risk factors” patients, related to increased risk of recurrence and lymph node metastases [ 60 ].

Accordingly, if further studies will validate these findings, TFD could represent a novel prognostic marker for pre-operative assessment of risk factors and for guiding adjuvant treatment decisions.

3.10. Tumor-Infiltrating Lymphocytes (TILs)

TILs are strictly related to the dynamic interaction of the host immune system to tumor antigens and to the tumor microenvironment. Evaluation of TILs, quantification and immunophenotyping can provide useful information for tumor progression and treatment strategies [ 64 ]. So far very few clinical studies have been conducted on the prognostic and predictive role of TILs in cervical cancer [ 65 , 66 , 67 , 68 , 69 ]. In detail, stromal TILs are more useful and have superior predictive value than intraepithelial TILs in terms of prognosis in squamous cell carcinoma [ 65 ]. Moreover, several TIL populations have been described, such as CD4+ and CD8+ T cells, Th17, γδ T cells, natural killer cells, Treg cells, B cells and macrophages [ 63 , 69 ]. Concerning their prognostic value, a higher prevalence of CD4+ and CD8+ seems to correlate with a better outcome; therefore, an accurate definition of TILs may provide useful information for both patient prognosis and therapeutic management [ 69 ]. Moreover, recent studies demonstrated that TILs may represent one of the most effective and specific adaptive cell therapies (ACT) in several tumors including cervical cancer [ 67 , 68 ]. The main goal of TILs therapy is to restore anti-tumor immunity by an in vitro selection of immune cell populations that are tumor specific, such as CD4+ and CD8+ [ 67 , 68 ]. In detail, CD8+ TILs have been shown to directly kill tumor cells when presented with neoantigens and are also capable of activating apoptosis-inducing FAS–FASL pathways; CD4+ T cells play a regulatory role by differentiating into different phenotypes, such as Th1, Th2, Th17 and Treg [ 67 , 68 ]. Clinical application of TIL therapy in cervical cancer is still at its initial stages; however, promising results, especially in HPV-related tumors, have been demonstrated since the selection of viral antigen-specific TILs, such as HPV E6/E7, have been shown to achieve a highly selective tumoricidal effect [ 67 , 68 ]. These preliminary findings are worthy of further studies in order to introduce this novel therapeutic regimen in the clinical practice.

3.11. Margin Status

According to ICCR guidelines, the status (positive/negative and the tumor distance) of all surgical resection margins (ectocervical, endocervical, radial/deep stromal and vaginal cuff) should be recorded [ 4 ]. The prognostic impact of close margins on local and overall recurrence in cervical cancer patients undergoing radical hysterectomy has been assessed by some retrospective studies [ 70 ].

According to Viswanathan et al., the local recurrence rate was 20% in FIGO Stage IB carcinomas with “close” margins (<10 mm) vs. 11% in patients with negative margins (≥10 mm) [ 71 ]. Moreover, McCann et al. suggested that close surgical margins (≤5 mm) were associated with recurrence rates of 24% as compared with recurrence rates of 9% in patients with negative margins [ 72 ].

4. Prognostic Factors in Advanced-Stage

The most relevant prognostic factors in advanced-stage tumors are summarized in Table 3 .

Prognostic factors related to advanced-stage tumors.

4.1. Local Involvement: Endometrial, Adnexal and Vaginal Extension

The revised 2018 FIGO staging does not take into account cervical cancer extension in the endometrium, fallopian tubes, as well as superficial spread to the ovaries [ 4 , 11 , 73 , 74 , 75 ]. However, it is not uncommon for cervical cancer to involve these sites.

The true rate of lower uterine segment involvement is not well-established as this finding is not routinely described in the pathological report. Both adenocarcinomas and squamous cell carcinoma may show diffuse endometrial and myometrial involvement and more rarely an exclusive mucosal colonization of the endometrial glands [ 75 ]. Despite the prognostic significance of these cases remaining uncertain, it is important to take into account the possibility of this phenomenon in order to avoid an erroneous diagnosis of primary endometrial adenocarcinoma with cervical extension [ 76 , 77 , 78 ]. Uterine corpus invasion by cervical cancer is found in approximately 5% of patients, and it has been associated with significantly lower 5-year and 10-year survival rates compared with cervical cancer without uterine corpus invasion [ 76 ]. Other studies have described association with an increased risk of pelvic lymph node metastases and ovarian metastases [ 77 , 78 ]. In their multicenter retrospective study on stage IA2–IIB cervical cancer, Fangjie He et al. demonstrated that myometrial invasion ≥50% within the uterine corpus was associated with worse prognosis, while myometrial invasion <50% had no impact on patient outcomes [ 79 ].

The frequency rate of ovarian metastases ranges from 0.2–4% in cases treated with radical hysterectomy to 17–29% in autopsy series criteria, the latter higher percentages meaning the possible frequency of ovarian involvement in advanced cases [ 80 , 81 ]. However, limited data on the prognostic implications of adnexal involvement are still available in the literature.

Recently, L. Casey and N. Singh described two distinct metastasizing pathways in endocervical cancer: one related to HPVA tumors, pattern A-B sec. Silva and low-stage and one related to HPVI and high-stage tumors [ 82 ]. In detail, the former is characterized by an indolent and slow growth mainly by intraepithelial endometrial and tubal spread and/or transtubal exfoliation [ 82 ]. Differently, HPVI and high-stage tumors show higher incidence of LVSI, multinodular ovarian spread and a more aggressive behavior [ 82 ]. Therefore, the HPVA/low-stage group could be treated conservatively (ovarian sparing surgery), while the HPVI/high-stage group should be treated according to the FIGO stage and the other associated risk factors.

The prognostic impact of vaginal involvement from cervical cancer is well-known and is taken into account in the FIGO classification [ 1 , 4 , 74 ]. Cervical cancer may infiltrate vaginal tissue through contiguity, vessels permeation or both. The higher rates of vaginal invasion are observed in tumors measuring >20 mm and in adenocarcinomas, which frequently spread through vascular permeation [ 83 ]. According to FIGO 2018 classification, when cervical cancer is limited to the upper two-thirds of vagina without parametrial involvement, it is staged as Stage IIA [ 4 , 11 ]. When the disease involves the lower third of the vagina without reaching the pelvic walls, it is staged as Stage IIIA, which accounts for approximately 5% of patients [ 1 , 4 , 74 ]. Different stages mean different treatments. In fact, vaginal involvement by cervical cancer remains crucial for the therapeutic approach. In detail: stage IIA1 (neoplasm < cm 4) is usually treated with type C radical hysterectomy (with removal of upper vagina also); stage IIA2 (neoplasm > cm 4) needs type C radical hysterectomy plus adjuvant chemotherapy; stage IIIA requires concurrent chemo-radiation therapy [ 84 , 85 ].

Vaginal involvement may also be related to the cervical cancer pathogenesis. According to some studies, the vaginal microbiota plays an important role in the natural history of cervical cancer [ 84 ]. Mitra et al. described a possible link between CIN severity and vaginal microbiota: increasing disease severity is associated with the decreasing relative presence of Lactobacillus, suggesting the potential role in regulating Papillomavirus persistence and action [ 86 ].

Finally, four different patterns of recurrence in cervical cancer have been described: (i) endovaginal recurrence; (ii) paravaginal recurrence; (iii) invasion of surrounding organs (bladder, rectum and pelvic wall); (iv) vaginal recurrence associated with distant metastasis [ 87 ]. In a recent work, endovaginal recurrence and being RT naïve were independent factors for improved OS and PFS, in multivariate analyses [ 87 ].

4.2. Lymph Nodes Involvement

The size of pelvic lymph node metastasis is crucial in order to determine the N category according to the TNM staging system. In detail, metastases measuring greater than 2 mm are regarded as macrometastases and staged as pN1 [ 4 ]. Micrometastases measure greater than 0.2 mm but less than 2 mm and are staged as pN1(mi). Isolated tumor cells (ITCs) are single neoplastic cells or small clusters measuring not more than 0.2 mm in greatest dimension. ITCs do not upstage a carcinoma and are staged as pN0 (i+) [ 4 ]. Micrometastases show a negative impact on both the DFS and OS, whereas the real impact of ITCs remains unclear, and it is not known if ITCs can really degenerate in true lymph nodal metastasis [ 88 ].

The number of node metastases has been shown as a powerful prognostic predictor in cervical squamous cell carcinoma patients following radical surgery [ 89 ]. However, the cut-off values of the number of node metastases are slightly different across studies, ranging from 3 to 5 positive lymph nodes [ 89 , 90 , 91 , 92 , 93 , 94 ]. Regarding the total number of removed lymph nodes (RLNs), its prognostic and predictive value has been suggested by some recent studies [ 89 , 90 , 91 , 92 , 93 , 94 ]. However, other studies have failed to demonstrate its real prognostic significance; therefore, the role on RLNs remains controversial [ 89 , 90 , 91 , 92 , 93 , 94 ]. Moreover, excessive resection of negative nodes may increase the risk of postoperative complications. Imaging remains a useful diagnostic tool if pathological examination of lymph nodes cannot be achieved. However, the optimal size related to node positivity on MRI or CT is still debated [ 93 ]. The universally accepted criterion is that a short diameter of the lymph node less than 10 mm carries a good prognosis, while the prognosis significantly decreases in cases of short node diameter larger than 20 mm [ 93 ]. The anatomic location of nodal metastases is crucial for staging purposes since patients with pelvic node metastases are classified as stage IIIC1 and patients with para-aortic node metastases are classified as stage IIIC2; morever, para-aortic node metastases are recognized as an adverse prognostic factor [ 89 , 90 , 91 , 92 , 93 , 94 ].

For patients whose nodal metastases are limited to the pelvic cavity, several studies have demonstrated that multiple metastatic lymph nodes in the pelvic cavity carry a worse prognosis in comparison to a single metastatic node [ 91 ]. In addition, patients with common iliac nodal metastases carry a significantly reduced OS [ 91 ].

Metastatic Lymph Node Ratio (LNR) represents the percentage of metastatic nodes to total nodes retrieved and has recently emerged as a novel prognostic factor in cervical cancer [ 95 ]. According to recent studies, LNR represents a more accurate method to predict the OS of cervical cancer patients since the number and location of lymph nodes vary in each individual [ 95 , 96 , 97 , 98 ]. However, LNR has been demonstrated to not always reflect the real nodal tumor burden [ 95 , 96 , 97 , 98 ]. In this regard, in case of a limited nodal count, LNR may appear relatively high while a low LNR may be observed in more extensive nodal dissections. Therefore, LNR appears to be a reliable prognostic predictor only in cases where an adequate standard of lymphadenectomy is achieved, however, the minimum number of nodes that should be retrieved remains controversial [ 95 , 96 , 97 , 98 ].

Log Odds of Positive Lymph Nodes (LODDs) is a novel parameter that improves the accuracy of lymph node evaluation irrespective of nodal positivity status and has been identified as a powerful prognostic predictor in several malignancies, including cervical cancer, where a nomogram based on LODDS has showed good accuracy in predicting OS [ 99 , 100 ]. LODDs is defined as follows: log [(No. of positive lymph nodes + 0.5)/(No. of harvested lymph nodes–No. of positive lymph nodes + 0.5)] [ 99 , 100 ]. LODDs has the potential to distinguish different prognoses among patients with the same N stage. In this regard, if the number of nodal metastases is zero, the LNR will be zero; however, LODDs will vary according to the number of negative lymph nodes [ 99 , 100 ].

4.3. Distant Metastases

Metastatic cervical cancer carries an extremely poor prognosis and is often difficult to treat [ 101 ]. The reported median survival time of metastatic cervical cancer is 8–13 months, and the 5-year survival rate is 16.5% [ 101 ]. Due to the rarity of metastatic cervical cancer, a large-population based study is still lacking; therefore, the treatment strategies and the prognostic impact of the different metastatic sites are still poorly understood [ 101 , 102 ]. A recent paper by Yin et al. investigated the prognostic impact of metastatic sites in a cohort of 99 cervical cancer patients. His research revealed that liver metastases carried the worst prognosis [ 103 ]. These findings are different from previously published studies, which report similar survival times between different metastatic sites with a median survival of 9 months in lung metastasis, 7 months in liver metastasis, 6 months in brain metastasis and 8 months in bone metastasis [ 101 , 102 , 103 , 104 ]. Moreover, in the paper by Kim et al., patients with lung recurrences after treatment have shown a better prognosis in comparison to patients showing liver recurrences after treatment [ 104 ]. Another large-population-based study, including 1347 metastatic patients from the SEER database, demonstrated that the lung represented the most common metastatic site of cervical cancer; moreover, patients with a single metastatic site showed longer survival times in comparison to multi-site metastatic patients [ 102 ].

5. Molecular Markers and Future Perspectives

All relevant molecular prognostic markers are summarized in Table 4 .

Molecular prognostic markers.

Several genetic alterations are reported in cervical cancer, and some of them are related to HPV-infection [ 105 , 106 , 107 , 108 , 109 , 110 , 111 ]. The progression from stage I to stage IV has been related to the loss of heterozygosity (LOH). Indeed, the loss of tumor suppressor protein caused by LOH is reported in both squamous cell carcinoma and adenocarcinoma of the cervix. The most frequent LOH loci are 3p14-22, 4p16, 5p1, 6p21-22, 11q23, 17p13.3, 18q12-2 and 19q13 [ 99 , 100 ]. Recently, The Cancer Genome Atlas (TCGA) database has expanded the knowledge of the genomic landscape of cervical cancer [ 107 ]. Based on molecular and integrative profiling, the following subgroups defined by different HPVs and molecular features were identified: keratin-low and keratin-high squamous cell carcinomas, adenocarcinoma-rich and endometrial-like cervical cancer. Most of squamous cell carcinomas belong to the keratin-low and keratin-high groups [ 107 ]. The endometrial-like subgroup emerged as HPV-negative tumors and showed a high frequency of KRAS, ARID1A and PTEN mutations. PIK3CA, PTEN and MPK1 were confirmed as significantly mutated genes in cervical cancer [ 101 ]. Several genes were found to be significantly mutated in cervical carcinoma, such as ERBB3, CASP8, HLA-A, SHKBP1 and TGFBR2. Notably, ERBB3 (HER3) may represent a novel therapeutic target. Among several amplifications, in the same study, they found a mutation in BCAR4 that is indirectly targetable by lapatinib and CD274 (PDL1) and PDCD1LG2 (PDL2) genes that may represent novel immunotherapy targets [ 101 ]. Interestingly, deregulated pathways, such as Wnt, PI3K/AKT/mTOR, VEGF, EGFR, Notch Hedgeog, significantly contribute to poor clinical outcome, reduced OS, distance metastasis chemo and radio recurrence [ 107 ]. All these pathways involve molecular inhibitors that could be useful for monitoring therapeutic response and target therapy. Moreover, recent evidence suggests a role of Lynch Syndrome, with MSI-high phenotype, also in cervical cancer [ 108 ]. Another recent study highlighted the role of MSI, PDL1 expression and Tumor Mutation burden in cervical cancer immunotherapy. In this study HPV-associated cervical cancer showed the highest frequency of PD-L1 expressions [ 109 ]. The role of PD-L and MSI as therapeutic biomarkers has also been demonstrated in neuroendocrine cervical cancer [ 110 ].

Finally, PD-L1 immunohistochemical expression with a CPS-score ≥1 is considered an eligibility criterium for pembrolizumab therapy in metastatic and recurrent squamous cell carcinoma [ 111 ].

6. Conclusions

In the present paper we aimed to review novel and potentially underestimated prognostic factors for which preliminary studies have shown promising results. In our opinion, LVSI, PNI, DOI, TFD, a novel grading system and TILs are the most relevant factors that may be included in the pathology report of cervical cancer in order to help future studies in validating and corroborating their suggested prognostic and predictive role.

Funding Statement

This research received no external funding.

Author Contributions

Conceptualization, A.S., G.A. and F.I.; methodology, D.A. and E.B.; software, A.T. and M.V.; validation, N.D., G.S. and S.S.; formal analysis, A.P.; investigation, F.C.; resources, P.R.; data curation, G.F.Z.; writing—original draft preparation, A.S. and G.A.; writing—review and editing, F.I. and E.B.; visualization, D.A.; supervision, M.V., N.D. and G.S.; project administration, G.F.Z.; funding acquisition, G.F.Z. All authors have read and agreed to the published version of the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

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Princess Kate says she's completed 'tough' chemotherapy treatment for cancer

LONDON — Kate, the Princess of Wales , announced Monday that she has completed her chemotherapy treatment and will undertake a light schedule of engagements until the end of the year.

“Doing what I can to stay cancer-free is now my focus,” she said in a video message, some six months after revealing she had an unspecified form of cancer following intense public speculation about her health.

“The last nine months have been incredibly tough for us as a family,” Kate said, adding that the “cancer journey is complex, scary and unpredictable for everyone, especially those closest to you.”

“With humility, it also brings you face to face with your own vulnerabilities in a way you have never considered before, and with that, a new perspective on everything,” Kate said.

Slow music plays as she delivers her message via a voiceover on the video, which was filmed in several locations including a forest, a beach and a field in Norfolk, a county in the east of England. She wears a long white summer dress with patterns throughout.

At times she is featured alone and at other times she is joined by her husband and heir to the British throne, Prince William , and their three children — George, 11; Charlotte, 9; and Louis, 6.

Thanking people for the support she and her family received, she said that “although I have finished chemotherapy, my path to healing and full recovery is long and I must continue to take each day as it comes.”

“I am however looking forward to being back at work and undertaking a few more public engagements in the coming months when I can,” she added.

Calling the video “astonishing,” NBC News royal commentator Daisy McAndrew said it would “come as a huge relief to many royal fans and people who wish Katherine well throughout the world.” 

“It’s incredibly intimate. We really haven’t seen something like this of the family all playing games, holding hands,” she added. “The intimacy between Kate and William is something that we haven’t seen something like this before, real public displays of affection, lots of hand-holding, lots of kissing.”

Kate has made several public appearances since she revealed she had cancer in a video in March where she said she was undergoing “a course of preventative chemotherapy” on the advice of her medical team.

The princess attended the men’s final at Wimbledon with her daughter in July. The pair were joined in the Royal Box by Kate's sister, Pippa Middleton Matthews , 41. 

In June, she attended the Trooping the Colour , a ceremonial parade celebrating the official birthday of the British monarch. Ahead of the parade, she said in a statement that she was “not out of the woods yet” and that she had “good days and bad days.” She said she was “making good progress,” but that her treatment would continue for a few more months.

Kate revealed she had cancer just over a month after Buckingham Palace announced that her father-in-law, King Charles III, had also been diagnosed with the disease when he was hospitalized with an enlarged prostate. The palace has said that he does not have prostate cancer.

The March video was released after months of fervent speculation about Kate's health after Kensington Palace — the Prince and Princess of Wales’ official residence and office — said she would be taking a step back from public duties as she recovered from planned abdominal surgery.

Both Charles and Kate have declined to specify either what type of cancer they have or details about their prognosis.

Like Kate, however, the 75-year-old monarch has attended several engagements since he resumed public duties earlier this year, including D-Day memorial services in France.

He is also set to visit Australia and Samoa next month alongside Queen Camilla, with an itinerary that will span 12 time zones.

While Charlotte attended Wimbledon, the princess and her brothers have largely been out of the public eye since their mother's surgery.

Charles' and Kate's illnesses have highlighted the challenges faced by a slimmed-down royal family as the king pledges to cut costs.

With fewer working royals available to carry out the ribbon cuttings, state events and awards ceremonies that make up the life of a modern royal, the remaining family members have been forced to take on more events.

So Camilla; Princess Anne, the king’s sister; and his youngest brother, Prince Edward, have had to shoulder the load.

Henry Austin is a senior editor for NBC News Digital based in London.

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Screening for cervical cancer: a systematic review and meta-analysis

Affiliation.

• 1 McMaster Evidence Review and Synthesis Centre-MERSC, 1280 Main Street West, DTC-322, Hamilton, ON L8S 4K1, Canada. [email protected]
• PMID: 23706117
• PMCID: PMC3681632
• DOI: 10.1186/2046-4053-2-35

Background: The systematic review on which this paper is based provided evidence for the Canadian Task Force on Preventive Health Care to update their guideline regarding screening for cervical cancer. In this article we highlight three questions covered in the full review that pertain to the effectiveness of screening for reducing cervical cancer mortality and incidence as well as optimal timing and frequency of screening.

Methods: We searched MEDLINE, Embase and Cochrane Central from 1995 to 2012 for relevant randomized controlled trials and observational studies with comparison groups. Eligible studies included women aged 15 to 70 years who were screened using conventional cytology, liquid-based cytology or human papillomavirus DNA tests. Relevance screening, data extraction, risk of bias analyses and quality assessments were performed in duplicate. We conducted a meta-analysis using a random-effects model on the one body of evidence that could be pooled.

Results: From the 15,145 screened citations, 27 papers (24 studies) were included; five older studies located in a United States Preventive Services Task Force review were also included. A randomized controlled trial in India showed even a single lifetime screening test significantly decreased the risk of mortality from and incidence of advanced cervical cancer compared to no screening (mortality: risk ratio 0.65, 95% confidence interval 0.47, 0.90; incidence: relative risk 0.56, 95% confidence interval 0.42, 0.75). Cytology screening was shown to be beneficial in a cohort study that found testing significantly reduced the risk of being diagnosed with invasive cervical cancer compared to no screening (risk ratio 0.38; 95% confidence interval 0.23, 0.63). Pooled evidence from a dozen case-control studies also indicated a significant protective effect of cytology screening (odds ratio 0.35; 95% confidence interval 0.30, 0.41). This review found no conclusive evidence for establishing optimal ages to start and stop cervical screening, or to determine how often to screen; however the available data suggests substantial protective effects for screening women 30 years and older and for intervals of up to five years.

Conclusions: The available evidence supports the conclusion that cervical screening does offer protective benefits and is associated with a reduction in the incidence of invasive cervical cancer and cervical cancer mortality.

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Flow diagram for selection of…

Flow diagram for selection of studies included in the systematic review.

Forest plot of the effect…

Forest plot of the effect of screening on incidence of invasive cervical cancer…

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