Cervical cancer is a cancer of the female reproductive system that originates in the cervix. It’s one of the most common cancers in women and it’s usually the result of an infection by the human papillomavirus, or HPV. It has also played a huge role in scientific research thanks to cervical cancer cells from a woman called Henrietta Lacks, which were the first human cells to be grown in a laboratory and which continue to be used to this day in labs around the world.
The cervix is also called the neck of the uterus, and it protrudes into the vagina. The interior cavity of the cervix is called the cervical canal and it can be divided into two sections. The endocervix is closer to the uterus, not visible to the naked eye, and it’s lined by columnar epithelial cells that produce mucus. The ectocervix is continuous with the vaginaand it’s lined by mature squamous epithelial cells. Where the squamous epithelium of the ectocervix and the columnar epithelium of the endocervix meet, there’s a line called the squamocolumnar junction.
And right where the two types of cells meet, there’s the transformation zone – which is where sub-columnar reserve cells multiply and transform into immature squamous epithelium through a process called metaplasia. Normally, mature cells are stuck in the G1, or Growth 1, phase of the cell cycle, which is when cells grow and take care of regular cellular business, like synthesizing proteins and producing energy. Eventually, whenever new cells are needed, they’ll exit G1 and keep going through the rest of the cell cycle to eventually divide into two new identical daughter cells.
Sometimes though, cells can be pushed out of G1 and go through the cell reproduction cycle faster than the body needs new cells. This uncontrolled growth and multiplication are called dysplasia and it’s exactly how cervical cancer develops from precancerous cells. Dysplasia in the epithelial layer of the cervix, also called cervical intraepithelial neoplasia or squamous epithelial lesion, usually starts in the basal layer of the transformation zone, typically in the immature squamous epithelium there. In most cases, cervical intraepithelial neoplasia caused by an HPV infection.
There are over 100 different types of HPV, but only about 15 of them have been linked with cervical cancer. Specifically, HPV-16 is responsible for more than half of all cervical cancers. The virus is like a house guest that overstays their welcome and starts using the kitchen to make all their favorite foods: it inserts itself into the immature squamous cells of the transformation zone and then integrates its DNA into the host DNA. Using the host DNA, HPV makes huge amounts of two of its proteins, E6 and E7.
These proteins are responsible for pushing mature squamous cells through the cell replication cycle by blocking the action of tumor suppressor genes, like p53. The end result is uncontrolled replication of cervical epithelial cells which are resistant to apoptosis, or normal programmed cell death. Now, you might see a couple of different ways of describing the stages of cervical intraepithelial neoplasia, but the most common is based on how much of the epithelium is involved.
Grade 1 cervical intraepithelial neoplasia affects the lower one-third of the epithelium, thickness-wise. Grade 2 affects two-thirds, Grade 3 affects almost all of the epithelium, and finally, carcinoma in situ affects the entire thickness of the epithelium. The higher the grade, the more likely the dysplasia will evolve into cancer. Eventually, carcinoma in situ can progress to invasive cervical cancer, which is when cancerous cells break through the epithelial basement membrane and into the cervical stroma.
Then, it can spread to neighboring tissues, like epithelial layers of the uterus and of the vagina. Finally, it can pass through the pelvic wall and affect the bladder and rectum. Lastly, it can also spread via the lymphatic and circulatory systems to other areas of the body like the liver and lungs. Because HPV tends to invade squamous cells first, the majority of cervical cancer cases are squamous cell carcinomas. The second most common type, also associated with HPV, is cervical adenocarcinoma, which involves the epithelial gland cells of the cervix.
But either way, the progression from HPV infection to cervical intraepithelial neoplasia to cancer is generally slow and it can take between10 and 20 years before invasive cervical cancer develops. Ok, now, since HPV is a sexually transmitted infection, the risk of developing cervical cancer is highest in females who do not use condoms and have multiple sexual partners. Not every HPV infection results in cervical cancer, though. In fact, the immune system fights off most HPV infections. So it’s believed that there are other factors involved.
For example, the risk increases depending on the type of HPV, how long the infection lasts, and if the person is immunocompromised. Environmental factors like smoking also increase the risk. But the good news is that vaccination against HPV immunizes against several HPV types linked with cervical cancer, including HPV-16. The first symptom of cervical cancer is often abnormal vaginal bleeding, especially after sexual intercourse. Other symptoms include vaginal discomfort, vaginal discharge with an unpleasant smell, and pain when urinating.
If cancer has spread beyond the pelvic wall, it can cause symptoms like constipation and bloody urine. Screening for cervical intraepithelial neoplasia and cervical cancer is done with a Pap smear with high-risk HPV testing. Pap tests are so good at detecting precancerous cells that screening recommends a pap smear every 3 years for females between 21 and 65years of age. Together with the HPV vaccine, this has contributed significantly to the drop in cases of cervical cancer worldwide.
Now, during a Pap test, some cells from the transformation zone are collected with a brush, and then they’re examined under a microscope for dysplasia. If the Pap test comes back positive for dysplasia, it may be followed up with a colposcopy, which is when a magnifying device called a colposcope is used to get a zoomed-in view of the cervix, and then obtain biopsies. Treatment options for cervical intraepithelial neoplasia include cryosurgery.
Where liquid nitrous oxide is used to freeze and kill abnormal cells, and conization, where the transformation zone and some or all of the endocervix is removed surgically. Conization can be done with a scalpel, called cold-knife conization, laser, or by heating a loop of thin wire with electricity, called loop electrosurgical excision procedure, or large loop excision of the transformation zone. Treatment of early cervical cancer is to surgicallyremove either just the tumor or also the uterus and associated lymph nodes.