Cervical cancer: Pathology review

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Case Study0:00–0:48

At the gynecology clinic, 28-year-old Luciana comes in because she was told that her Pap smear showed abnormal cervical cells.
She is totally asymptomatic and her previous pap smear from 3 years ago was normal. Next, there is 36-year-old Cassie who presents to the office after noticing vaginal bleeding after sexual intercourse.
There’s no associated pain with urinating, bloody urine, constipation or pelvic pain. She admits she has never done a pap test in her life.
Pelvic exam shows a friable mass growing on the cervix.In further history, both have been sexually active with multiple sexual partners and use oral contraceptive pills as their method of contraception.
Both Luciana and Cassie have different types of cervical pathologies.So, first let’s talk physiology real quick!. The cervical canal can be divided into two sections.

Physiology0:48–2:12

The endocervix is closer to the uterus, and is lined by columnar epithelial cells. The ectocervix is continuous with the vagina and 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.
For your exams, it’s necessary to remember that, right where the two types of cells meet, there’s the transformation zone, which is where cells multiply and transform into immature squamous epithelium through a process called metaplasia.Now, metaplasia is when a stimulus, usually a stressor, causes the stem cells in a region to differentiate into another type of cell that replaces the typical cell type in that region.
For example with Barrett’s esophagus, chronic stomach acid irritation causes the normal stratified squamous cells that line the esophagus to get replaced by simple columnar cells.
This is different from dysplasia where fully differentiated cells turn into immature cells that have varying shape and nuclear morphology.
Metaplasia is usually reversible if the stressor is removed while only mild or moderate dysplasia is reversible. So, in the cervix, right at the basal layer of the transformation zone is where dysplasia might start.

HPV Infection2:12–4:24

This is also known as cervical intraepithelial neoplasia or squamous epithelial lesion.In most cases, cervical intraepithelial neoplasia is linked to HPV infection, particularly high-risk strains, like HPV 16, 18, 31 and 33.
Don’t confuse these with low-risk strains, like HPV 6 and 11, which are responsible for warts. HPV viruses are DNA viruses that invade stratified squamous epithelial cells.
They especially prefer immature squamous cells, so areas under constant friction or irritation with high cell turnover, like the vocal cords or the anus, are especially vulnerable.
In the cervix, the virus inserts itself into the immature squamous cells of the transformation zone and then integrates its DNA into the host DNA.
An important fact to know is what sets low- and high-risk HPV strains apart. And that is the ability of the high-risk ones to make huge amounts of two proteins, E6 and E7, using the host DNA.These proteins are responsible for pushing mature squamous cells through the cell replication cycle by blocking the action of tumor suppressor genes.
Specifically, remember that E6 inhibits p53, while E7 inhibits retinoblastoma tumor suppressor gene product, or pRB for short.
The end result is uncontrolled replication of cervical epithelial cells which are resistant to apoptosis, or normal programmed cell death.
Since HPV is a sexually transmitted infection, a high yield fact to remember is that the number one risk factor for it: is having multiple sexual partners and not using condoms.
Other factors also increase the risk, like early age at first sexual intercourse, smoking, immunosuppression, like in HIV infected individuals or transplant recipients, and low socioeconomic status.Now, in cervical intraepithelial neoplasia, dysplastic, HPV-infected epithelial cells are often described as “koilocytes”.

Cervical Intraepithelial Neoplasia (CIN)4:24–7:23

These are immature squamous cells with dense irregularly staining cytoplasm and perinuclear clearing, resembling a halo.
And these cells pile up in the cervical epithelium, starting from the basal layer and moving upwards.So, depending on how much of the epithelium is involved, thickness-wise, cervical epithelial neoplasia is divided into grades.Grade 1 or CIN I affects the lower one-third of the epithelium, grade 2 or CIN II affects two-thirds, grade 3 or CIN III affects almost all of the epithelium, and finally carcinoma in situ or CIS affects the entire thickness of the epithelium.
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.
These are mostly 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, what you need to remember is that CIN classically progresses in a stepwise fashion, meaning from CIN I to CIN II to CIN III to CIS and, eventually, to invasive carcinoma.
However, progression doesn’t always occur, especially in low grades. In other words, the higher the grade, the more likely it is to progress to carcinoma and the less likely it is to regress to normal.
And this progression from HPV infection to cervical intraepithelial neoplasia to cancer is generally slow, meaning that it can take between 10 and 20 or even 30 years before invasive cervical cancer develops.
So, given that an HPV infection most commonly occurs in the early years of sexual activity, so, let’s say between the age of 20 and 30, an invasive cervical cancer typically presents in a middle-aged individual, between the age of 40 and 50.Now, in advanced cases, invasive cervical carcinoma can spread to neighboring tissues, like the uterus and the vagina.
And that is why you need to remember that the majority of vaginal cancer is metastatic from the cervix. It can also pass through the pelvic wall and affect the bladder and rectum.
A high-yield fact to know is that if it invades and blocks the ureters, it can cause hydronephrosis and eventually, renal failure.
That’s because the kidney will continue to produce urine, but this urine cannot drain into the bladder. As a result, it builds up within the ureter and calyceal system, resulting in distention of the renal pelvis and kidney.Lastly, the cancer may also spread via the lymphatic and circulatory systems to other areas of the body like the liver and lungs.
Cervical intraepithelial neoplasia as well as cervical cancer, if not caught early, can progress without any symptoms for a long period of time.

Clinical Presentation7:23–8:12

When symptoms appear, they typically include abnormal vaginal bleeding, especially after sexual intercourse, also known as postcoital bleeding.
Vaginal discomfort and a foul- smelling vaginal discharge might also be present. In later stages, when the cancer has spread to the bladder, there may also be symptoms like urinary frequency, dysuria and hematuria.
If the cancer has spread to the rectum, there may be constipation. Flank pain that radiates to the groin can be also present and, in your test, it is a clue to hydronephrosis.
And if there is metastasis to the lymph nodes, the individual might also experience pelvic pain.Diagnosis of an asymptomatic individual, or in other words, screening for cervical intraepithelial neoplasia and cervical cancer is done with a Pap smear, along with high-risk HPV DNA testing.

Diagnosis8:12–9:35

Remember that cervical cancer is the most common gynecological cancer worldwide due to the lack of screening and availability of vaccines, but in high socioeconomic countries like the US, it’s less common- so endometrial cancer takes the highest spot.
Now, during a Pap smear, 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.
In a symptomatic individual, diagnosis begins with a pelvic examination, where a lesion suggestive of cervical cancer, which may look like an ulceration or mass, might be identified.
In some cases, the cervix might be enlarged and indurated with a smooth surface. A key word examiners like to use for that is "barrel shaped cervix".
Diagnosis will be confirmed with a biopsy.Afterwards, a CT or MRI can be done to look for evidence of metastasis. Treatment of cervical intraepithelial neoplasia usually consists of local excision of the lesion, with cryosurgery, where liquid nitrous oxide is used to freeze and kill abnormal cells, or conization, where the transformation zone and some or all of the endocervix is removed surgically.

Treatment9:35–10:33

In contrast, treatment for cervical cancer is to surgically remove either just the tumor, or also the uterus and associated lymph nodes.
If the cancer is more advanced, radiation and chemotherapy may be done. To end on a bright note, remember that anti-HPV vaccination is available.
In the United States, there’s a vaccine which targets 9 HPV strains; the 7 high risk strains, 16, 18, 31, 33, 45, 52 and 58, as well as 2 low-risk strains, 6 and 11.All right, as a quick recap… Cervical cancer starts as cervical intraepithelial neoplasia and develops very slowly.

Review10:33–11:09

It can be classified in squamous cell carcinomas, which are the most common ones, and adenocarcinomas. Both are most often caused by a high-risk human papillomavirus infection.
Many cases of cervical cancer can now be caught very early on by screening for precancerous lesions with a Pap test. Precancerous lesions can be managed with cryosurgery or conization, whereas treatment for cervical cancer is surgical.Okay, back to our cases.
Both Luciana and Cassie have risk factors for cervical carcinogenesis, including multiple sexual partners and no use of condoms.

Summary11:09–11:52

Luciana was asymptomatic and came in with an abnormal pap test result, after which she was referred for a colposcopy and biopsy.
The biopsy showed CIN II, which was removed with cryosurgery.In contrast, Cassie neglected her screening with pap tests and had postcoital vaginal bleeding, as well as a vaginal mass found on pelvic exam, both of which point us towards invasive cervical cancer.
This was confirmed with a biopsy of the mass. Imaging tests showed no metastasis and she was referred for surgical removal of the uterus and associated lymph nodes.
Cervical cancer: Pathology Review: Video, Causes | Osmosis