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Understanding HPV-Negative Cervical Cancer

A recent study explains more about this rare type of the disease.
Allison Flynn Becker
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Allison Flynn Becker

Most cases of cervical cancer, up to 95 percent, are caused by the human papillomavirus (HPV) infection, but in some cases, HPV is not associated with cervical cancer at all. This is the case with HPV-negative cervical cancer.

HPV-negative cervical cancer means the test results for HPV infection are truly negative or falsely negative. A 2021 study in Frontiers in Oncology explained that most cases of HPV-negative cervical cancer come from cervical adenocarcinomas of an unclear cause. The prognosis for HPV-negative cancer is typically poor, therefore, management requires greater attention.

What causes HPV-negative cervical cancer?

Out of all cases of cervical cancer, rates of HPV-negative cervical cancer are relatively low.

"Five to 11 percent of cervical cancers are reported to be HPV-negative," said John Diaz, M.D., chief of gynecologic oncology at Miami Cancer Institute.

Little is known about what causes this type of cervical cancer. Stephanie Blank, director of gynecologic oncology for the Mount Sinai Health System in New York, explained that genetics may play a role.

"There are some rare genetic syndromes associated with rare cervical cancers and some mutations that may be the reason," Blank said.

Diaz explained that the prevalence of HPV-negative cervical cancer depends on the specific anatomy of the malignant lesion.

The 2021 study states that most researchers consider this type of cancer to be caused by mutations in tumor-associated genes, such as TP53, PIK3CA and CDKN2A. In other cases, HPV-negative cervical cancers could not be distinguished from endometrial carcinomas or distant metastases of other HPV-negative tumors.

HPV-negative vs. HPV-positive cervical cancer

For the most part, HPV-negative and HPV-positive cervical cancer present similarly and are treated in much the same way.

"To date, there is no difference in the presentation of HPV-negative versus HPV-positive cervical cancers," Diaz said.

Treatment depends on the clinical stage of cancer and often consists of surgery, chemotherapy, radiation or a combination of these treatment modalities.

However, the diagnosis of these two cancer types often differs.

"If a cervical cancer is truly HPV-negative, it would not be picked up by screening or prevented with HPV vaccine, therefore, these cancers are often picked up when they are larger and more advanced," Blank explained.

Usually, the first warning of cervical cancer associated with HPV is seen on a Pap smear. But in HPV-negative cervical cancer, that's not the case.

The study also explained how the type of pathology differs among HPV-negative and HPV-positive cervical cancers. Additionally, the different cancer types may be associated with different mutations in the genome. However, there are still no therapies specific to HPV-negative cervical cancer, therefore, both types use the same treatment strategies.

Mortality rate for HPV-negative vs. HPV-positive cervical cancer

Mortality rates for HPV-negative cervical cancer tend to be worse than for HPV-positive cervical cancer. Part of the reason, Blank explained, is that it is often picked up at a more advanced stage and associated with more aggressive cell types. It's also rarer than HPV-positive cervical cancer, so less is known about treating it.

The response to treatment also differs among the two types of cancer.

"HPV-positive tumors appear to have a better response to chemotherapy and radiation therapy than their HPV-negative counterparts," Diaz explained.

Additionally, the HPV vaccine can offer protection against HPV-positive cervical cancer, but not with HPV-negative cancer.

The study suggested that the risk of overall relapse is higher in HPV-negative cervical cancer. Because of this, the relapse-free survival rate is higher in women with HPV-positive cervical cancer compared with those who have HPV-negative cervical cancer. Still, more research is needed to uncover the effects of negative HPV testing on prognosis.