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25 years ago, it was established that human papillomavirus (HPV) infection, especially high-risk HPV, is the main cause of cervical cancer.
HPV can be found in almost all cervical squamous cell carcinomas and precancerous lesions, including high-grade squamous intraepithelial lesion (HSIL) or grade 2-3 cervical intraepithelial neoplasia (CIN).
Although the sensitivity of HPV testing has increased significantly in recent years, there are still a small number of cervical cancer patients whose tissue specimens have tested negative for HPV.
In the International Federation of Obstetrics and Gynecology (FIGO) staging, HPV-negative cervical cancer is usually at an advanced stage and is associated with a poor prognosis.
An in-depth understanding of the etiology, treatment and prognosis of HPV-negative cervical cancer will help formulate appropriate treatment strategies.
HPV-negative cervical cancer attributable factors 1.
HPV-independent cervical cancer high-risk HPV persistent infection is the main cause of cervical cancer, but it is not the only one.
HPV-independent cervical cancer is considered to be HPV true-negative cervical cancer and has nothing to do with HPV infection.
High-risk HPV infection has been confirmed to be related to the occurrence of most cervical squamous cell carcinomas, and there are no reports of confirmed HPV-independent cervical squamous cell carcinomas.
For cervical adenocarcinoma, the HPV negative rate is about 15-38%.
According to different histological characteristics, the positive rate of HPV in carcinoma in situ is also different.
Although the exact mechanism of cervical cancer that is not related to HPV infection is unclear, most researchers believe that it is related to mutations in tumor-related genes such as TP53, PIK3CA, and CDKN2A.
2.
Misclassified cervical cancer Cervical cancer includes cervical cancer caused by the direct spread of endometrial cancer or distant metastasis of other primary HPV-negative tumors.
Studies have shown that nearly 68% of HPV-negative cervical cancers are misdiagnosed as primary cervical cancer.
A study to detect HPV-negative cervical adenocarcinoma showed that more than 50% of cases cannot be distinguished from endometrial cancer based on histological characteristics alone.
Therefore, in the case of a negative HPV result, it is necessary to immunostain the tumor and stroma to identify the primary tumor site and reduce the false negative rate.
Estrogen receptor (ER), progesterone receptor (PR), waveform antigen and CD10 negative, while carcinoembryonic antigen (CEA), p16 diffuse, CD34 and HPV positive can indicate cervical adenocarcinoma; while ER, PR, Waveform antigen, p16 diffuse, and CD10 positive, while CEA, CD34, and HPV negative indicate uterine adenocarcinoma.
Age is also a factor worth considering.
The classic triad, including advanced age, HPV negative, and non-squamous cell carcinoma, is characteristic of endometrial cancer rather than cervical cancer.
3.
HPV false-negative cervical cancer potential HPV infection HPV natural infection has an incubation period, its virus replication is restricted by the immune system, HPV gene expression is in a silent state, and the viral load is too low to be detected by existing inspection methods.
HPV infection in the incubation period has a lower probability of causing tumors and a higher false-negative rate.
The loss of HPV gene fragments during the integration process.
The integration of HPV DNA and host DNA is considered to be the biggest inducing factor for cervical cancer.
HPV L1 fragments are highly conserved among different HPV genotypes.
Therefore, HPV DNA typing detection technologies based on PCR methods mostly target L1 fragments.
The integration of HPV DNA will result in the loss of L1 gene, so HPV DNA typing test will result in false negatives due to the loss of L1 fragment.
Compared with the first-generation HPV DNA test, the second-generation HPV oncogene E6/E7 mRNA test pays more attention to cervical lesions and indicates the risk of clinical lesions.
Researches on cervical cancer caused by non-high-risk HPV have reported the association between low-risk HPV, such as HPV6, 11, 42, 44, 70 and other genotypes, and cervical cancer.
It is still unknown whether low-risk HPV can cause cervical cancer or accidentally.
Some studies estimate that 1%-2% of primary cervical cancer is related to non-high-risk HPV infection.
Currently, most HPV tests only target high-risk HPV subtypes, and cannot detect non-high-risk HPV infections, resulting in false-negative results for some HPVs.
Deviations caused by HPV testing methods An important reason for false negative HPV testing results is that there are significant differences between HPV testing methods, and testing procedures and sample quality can also lead to HPV false negative results.
Clinical features of HPV-negative cervical cancer.
Age A global study involving 760 cases of cervical adenocarcinoma showed that older patients at first diagnosis are associated with a lower rate of HPV DNA testing.
A similar trend was found in cervical squamous cell carcinoma.
Molecular pathology characteristics Pathology type will affect HPV test results.
Globally, 12.
7% of cervical squamous cell carcinomas and 15%-38% of cervical adenocarcinomas are HPV negative.
Squamous cell carcinoma with hypokeratosis or hyperkeratosis can cause false-negative HPV test results.
In addition, HPV-negative cervical cancer whose histopathology is adenocarcinoma may be missed by HPV testing.
The content of HPV DNA in cervical adenocarcinoma is lower than that in cervical squamous cell carcinoma, which is a challenge for HPV detection.
The common pathological types of HPV-positive adenocarcinoma are intestinal adenocarcinoma, choriocarcinoma, signet ring cell carcinoma and endometrioid adenocarcinoma, accounting for nearly 90% of all cervical adenocarcinomas.
The common pathological types of HPV-negative adenocarcinoma are gastric adenocarcinoma, clear cell carcinoma, serous adenocarcinoma, and mesorenal duct-like adenocarcinoma.
These types are very rare, and their occurrence may not be related to HPV.
The pathological type of cervical adenocarcinoma and its HPV-positive rate FIGO staging HPV-negative cervical cancer patients are usually diagnosed as FIGO advanced stage with lymphatic and vascular space infiltration, leading to a poor prognosis.
A multi-center study showed that 62.
5% of HPV-negative cervical adenocarcinoma was diagnosed as stage II, while 83.
7% of the common type cases were diagnosed as stage I, which is consistent with previous studies. In addition, the HPV-negative cases in this study had larger tumors than the HPV-positive cases.
Research on the FIGO staging and prognosis of HPV-negative cervical cancer Treatment of HPV-negative cervical cancer At present, there is no specific therapy for HPV-negative cervical cancer, so the treatment strategy of HPV-positive cervical cancer can be referred to.
Research on HPV-negative and HPV-positive cervical cancer cell lines shows that the same treatment method is applied to the two types of cervical cancer, but the anti-tumor mechanisms produced are different.
For example, histone deacetylase (HDAC) inhibitors promote apoptosis by inhibiting the E6 activity of HPV-positive cervical cancer cells, but in HPV-negative cervical cancer cells, they cause cancer cell G2 arrest.
The CDK4/6 inhibitor Abemaciclib has achieved excellent efficacy in HPV-negative cancers by inhibiting the CDK4/6-Rb-E2F and mTOR pathways.
Among HPV-positive and HPV-negative patients, the overall survival rate (OS) of patients who underwent surgery combined with other anti-tumor therapies was significantly different; while in patients who only underwent surgery, no difference was seen, which also suggests that adjuvant radiotherapy and chemotherapy may be beneficial.
In HPV-negative cases.
HPV true-negative cervical cancer is related to specific pathological types, so understanding the mechanism of its tumorigenesis will help to choose an appropriate treatment plan.
At present, many explorations focus on the common mutations of cervical adenocarcinoma, such as the TP53, ARID, WNT and PI3K pathways, in order to develop effective targeted therapies.
Recently, lncRNA has become a research hotspot in the treatment of HPV-negative cervical cancer.
The prognosis of HPV-negative cervical cancer As early as 1990, a study using PCR on 106 cases of early invasive cervical cancer showed that there was no difference in the overall risk of recurrence between HPV-positive cervical cancer patients with different HPV genotypes, but HPV-negative patients The overall risk of recurrence is 2.
6 times that of HPV-positive patients, and the risk of distant metastasis is 4.
5 times that of HPV-positive patients.
The 24-month recurrence-free survival rate of HPV-positive cervical cancer patients is higher than that of HPV-negative patients (77% and 40%, respectively).
A meta-analysis of 17 studies involving a total of 2838 cervical cancer patients showed that HPV-positive cervical cancer patients were associated with a better prognosis (OS: HR = 0.
610, p = 0.
001; disease-free survival: HR = 0.
362, p <0.
001).
Three other studies have reached the same conclusion that HPV-negative cervical cancer is related to a poor prognosis.
Nevertheless, a 10-year follow-up study of 204 patients with cervical cancer showed that the 5-year OS rates of HPV-negative and HPV-positive cervical cancer patients were 82% and 58%, respectively (p = 0.
003), indicating that HPV infection is related to patients.
The OS difference is significantly related.
It is necessary to further study to clarify the impact of HPV negative on the prognosis.
Discussion HPV-negative cervical cancer is divided into true negative and false negative.
HPV true-negative cervical cancer has a specific pathological mechanism unrelated to HPV, and HPV vaccination and testing may have little preventive effect on it.
The diagnosis of HPV true-negative cervical cancer mainly depends on cytological screening and histological characteristics, combined with cytological multiple staining.
It is necessary to further study the mechanisms and biomarkers of different pathological types to lay the foundation for precise treatment.
For HPV false-negative cervical cancer, after analyzing the causes of false negatives, other HPV testing methods should be considered for re-testing based on its characteristics.
Cervical adenocarcinoma is the main pathological type of HPV-negative cervical cancer, most likely caused by PI3K-AKT mutation or other ways.
Preclinical studies have shown that the tumorigenesis mechanism of HPV-positive and HPV-negative cervical cancer is different, which provides the possibility for the development of targeted therapy for HPV-negative patients.
Although previous studies have shown that HPV positive is an independent risk factor affecting the prognosis of cervical cancer, studies in the past decade have also suggested that HPV-negative cases are usually diagnosed at a later FIGO stage and are associated with poor prognosis.
Large-scale multi-center studies are needed to further clarify the relationship between HPV negative and cervical cancer.
References: 1.
Xing B, Guo J, Sheng Y, Wu G and Zhao Y (2021) Human Papillomavirus-Negative Cervical Cancer: A Comprehensive Review.
Front.
Oncol.
10:606335.
doi: 10.
3389/fonc.
2020.
606335
HPV can be found in almost all cervical squamous cell carcinomas and precancerous lesions, including high-grade squamous intraepithelial lesion (HSIL) or grade 2-3 cervical intraepithelial neoplasia (CIN).
Although the sensitivity of HPV testing has increased significantly in recent years, there are still a small number of cervical cancer patients whose tissue specimens have tested negative for HPV.
In the International Federation of Obstetrics and Gynecology (FIGO) staging, HPV-negative cervical cancer is usually at an advanced stage and is associated with a poor prognosis.
An in-depth understanding of the etiology, treatment and prognosis of HPV-negative cervical cancer will help formulate appropriate treatment strategies.
HPV-negative cervical cancer attributable factors 1.
HPV-independent cervical cancer high-risk HPV persistent infection is the main cause of cervical cancer, but it is not the only one.
HPV-independent cervical cancer is considered to be HPV true-negative cervical cancer and has nothing to do with HPV infection.
High-risk HPV infection has been confirmed to be related to the occurrence of most cervical squamous cell carcinomas, and there are no reports of confirmed HPV-independent cervical squamous cell carcinomas.
For cervical adenocarcinoma, the HPV negative rate is about 15-38%.
According to different histological characteristics, the positive rate of HPV in carcinoma in situ is also different.
Although the exact mechanism of cervical cancer that is not related to HPV infection is unclear, most researchers believe that it is related to mutations in tumor-related genes such as TP53, PIK3CA, and CDKN2A.
2.
Misclassified cervical cancer Cervical cancer includes cervical cancer caused by the direct spread of endometrial cancer or distant metastasis of other primary HPV-negative tumors.
Studies have shown that nearly 68% of HPV-negative cervical cancers are misdiagnosed as primary cervical cancer.
A study to detect HPV-negative cervical adenocarcinoma showed that more than 50% of cases cannot be distinguished from endometrial cancer based on histological characteristics alone.
Therefore, in the case of a negative HPV result, it is necessary to immunostain the tumor and stroma to identify the primary tumor site and reduce the false negative rate.
Estrogen receptor (ER), progesterone receptor (PR), waveform antigen and CD10 negative, while carcinoembryonic antigen (CEA), p16 diffuse, CD34 and HPV positive can indicate cervical adenocarcinoma; while ER, PR, Waveform antigen, p16 diffuse, and CD10 positive, while CEA, CD34, and HPV negative indicate uterine adenocarcinoma.
Age is also a factor worth considering.
The classic triad, including advanced age, HPV negative, and non-squamous cell carcinoma, is characteristic of endometrial cancer rather than cervical cancer.
3.
HPV false-negative cervical cancer potential HPV infection HPV natural infection has an incubation period, its virus replication is restricted by the immune system, HPV gene expression is in a silent state, and the viral load is too low to be detected by existing inspection methods.
HPV infection in the incubation period has a lower probability of causing tumors and a higher false-negative rate.
The loss of HPV gene fragments during the integration process.
The integration of HPV DNA and host DNA is considered to be the biggest inducing factor for cervical cancer.
HPV L1 fragments are highly conserved among different HPV genotypes.
Therefore, HPV DNA typing detection technologies based on PCR methods mostly target L1 fragments.
The integration of HPV DNA will result in the loss of L1 gene, so HPV DNA typing test will result in false negatives due to the loss of L1 fragment.
Compared with the first-generation HPV DNA test, the second-generation HPV oncogene E6/E7 mRNA test pays more attention to cervical lesions and indicates the risk of clinical lesions.
Researches on cervical cancer caused by non-high-risk HPV have reported the association between low-risk HPV, such as HPV6, 11, 42, 44, 70 and other genotypes, and cervical cancer.
It is still unknown whether low-risk HPV can cause cervical cancer or accidentally.
Some studies estimate that 1%-2% of primary cervical cancer is related to non-high-risk HPV infection.
Currently, most HPV tests only target high-risk HPV subtypes, and cannot detect non-high-risk HPV infections, resulting in false-negative results for some HPVs.
Deviations caused by HPV testing methods An important reason for false negative HPV testing results is that there are significant differences between HPV testing methods, and testing procedures and sample quality can also lead to HPV false negative results.
Clinical features of HPV-negative cervical cancer.
Age A global study involving 760 cases of cervical adenocarcinoma showed that older patients at first diagnosis are associated with a lower rate of HPV DNA testing.
A similar trend was found in cervical squamous cell carcinoma.
Molecular pathology characteristics Pathology type will affect HPV test results.
Globally, 12.
7% of cervical squamous cell carcinomas and 15%-38% of cervical adenocarcinomas are HPV negative.
Squamous cell carcinoma with hypokeratosis or hyperkeratosis can cause false-negative HPV test results.
In addition, HPV-negative cervical cancer whose histopathology is adenocarcinoma may be missed by HPV testing.
The content of HPV DNA in cervical adenocarcinoma is lower than that in cervical squamous cell carcinoma, which is a challenge for HPV detection.
The common pathological types of HPV-positive adenocarcinoma are intestinal adenocarcinoma, choriocarcinoma, signet ring cell carcinoma and endometrioid adenocarcinoma, accounting for nearly 90% of all cervical adenocarcinomas.
The common pathological types of HPV-negative adenocarcinoma are gastric adenocarcinoma, clear cell carcinoma, serous adenocarcinoma, and mesorenal duct-like adenocarcinoma.
These types are very rare, and their occurrence may not be related to HPV.
The pathological type of cervical adenocarcinoma and its HPV-positive rate FIGO staging HPV-negative cervical cancer patients are usually diagnosed as FIGO advanced stage with lymphatic and vascular space infiltration, leading to a poor prognosis.
A multi-center study showed that 62.
5% of HPV-negative cervical adenocarcinoma was diagnosed as stage II, while 83.
7% of the common type cases were diagnosed as stage I, which is consistent with previous studies. In addition, the HPV-negative cases in this study had larger tumors than the HPV-positive cases.
Research on the FIGO staging and prognosis of HPV-negative cervical cancer Treatment of HPV-negative cervical cancer At present, there is no specific therapy for HPV-negative cervical cancer, so the treatment strategy of HPV-positive cervical cancer can be referred to.
Research on HPV-negative and HPV-positive cervical cancer cell lines shows that the same treatment method is applied to the two types of cervical cancer, but the anti-tumor mechanisms produced are different.
For example, histone deacetylase (HDAC) inhibitors promote apoptosis by inhibiting the E6 activity of HPV-positive cervical cancer cells, but in HPV-negative cervical cancer cells, they cause cancer cell G2 arrest.
The CDK4/6 inhibitor Abemaciclib has achieved excellent efficacy in HPV-negative cancers by inhibiting the CDK4/6-Rb-E2F and mTOR pathways.
Among HPV-positive and HPV-negative patients, the overall survival rate (OS) of patients who underwent surgery combined with other anti-tumor therapies was significantly different; while in patients who only underwent surgery, no difference was seen, which also suggests that adjuvant radiotherapy and chemotherapy may be beneficial.
In HPV-negative cases.
HPV true-negative cervical cancer is related to specific pathological types, so understanding the mechanism of its tumorigenesis will help to choose an appropriate treatment plan.
At present, many explorations focus on the common mutations of cervical adenocarcinoma, such as the TP53, ARID, WNT and PI3K pathways, in order to develop effective targeted therapies.
Recently, lncRNA has become a research hotspot in the treatment of HPV-negative cervical cancer.
The prognosis of HPV-negative cervical cancer As early as 1990, a study using PCR on 106 cases of early invasive cervical cancer showed that there was no difference in the overall risk of recurrence between HPV-positive cervical cancer patients with different HPV genotypes, but HPV-negative patients The overall risk of recurrence is 2.
6 times that of HPV-positive patients, and the risk of distant metastasis is 4.
5 times that of HPV-positive patients.
The 24-month recurrence-free survival rate of HPV-positive cervical cancer patients is higher than that of HPV-negative patients (77% and 40%, respectively).
A meta-analysis of 17 studies involving a total of 2838 cervical cancer patients showed that HPV-positive cervical cancer patients were associated with a better prognosis (OS: HR = 0.
610, p = 0.
001; disease-free survival: HR = 0.
362, p <0.
001).
Three other studies have reached the same conclusion that HPV-negative cervical cancer is related to a poor prognosis.
Nevertheless, a 10-year follow-up study of 204 patients with cervical cancer showed that the 5-year OS rates of HPV-negative and HPV-positive cervical cancer patients were 82% and 58%, respectively (p = 0.
003), indicating that HPV infection is related to patients.
The OS difference is significantly related.
It is necessary to further study to clarify the impact of HPV negative on the prognosis.
Discussion HPV-negative cervical cancer is divided into true negative and false negative.
HPV true-negative cervical cancer has a specific pathological mechanism unrelated to HPV, and HPV vaccination and testing may have little preventive effect on it.
The diagnosis of HPV true-negative cervical cancer mainly depends on cytological screening and histological characteristics, combined with cytological multiple staining.
It is necessary to further study the mechanisms and biomarkers of different pathological types to lay the foundation for precise treatment.
For HPV false-negative cervical cancer, after analyzing the causes of false negatives, other HPV testing methods should be considered for re-testing based on its characteristics.
Cervical adenocarcinoma is the main pathological type of HPV-negative cervical cancer, most likely caused by PI3K-AKT mutation or other ways.
Preclinical studies have shown that the tumorigenesis mechanism of HPV-positive and HPV-negative cervical cancer is different, which provides the possibility for the development of targeted therapy for HPV-negative patients.
Although previous studies have shown that HPV positive is an independent risk factor affecting the prognosis of cervical cancer, studies in the past decade have also suggested that HPV-negative cases are usually diagnosed at a later FIGO stage and are associated with poor prognosis.
Large-scale multi-center studies are needed to further clarify the relationship between HPV negative and cervical cancer.
References: 1.
Xing B, Guo J, Sheng Y, Wu G and Zhao Y (2021) Human Papillomavirus-Negative Cervical Cancer: A Comprehensive Review.
Front.
Oncol.
10:606335.
doi: 10.
3389/fonc.
2020.
606335
