Had an Abnormal Pap smear?

For anyone that has ever freaked out because they had an abnormal pap smear with HPV present, here is some useful information. These are clips from a pathophysiology case study that I got 100% on. References available upon request. Enjoy.

Cervical Dysplasia

The cervix is a round, internal structure that presents as the opening of the uterus. The interior lining adjacent to the uterus consists of mucous-secreting ciliated epithelium, and the distal, or “vaginal end” is composed of stratified squamous epithelium (Schuiling & Likis, 2006). Estrogen production in the proliferative phase of the menstrual cycle stimulates cervical cell changes to promote thinning of the cervical wall and mucous secretions to better enable potential sperm passage. As the cycle progresses, hormone levels fluctuate in preparation for embryo implantation. Towards the end of the cycle, increases in progesterone production causessubsequent thickening of the cervical wall and increased mucous production (Marieb, 1998). With each new menstrual cycle, there is a sloughing and shedding of endometrial and cervical tissue that is then replaced with new, immature cells. It is during this time of epithelial shedding and replacement of immature squamous cells that the cervix is most vulnerable to HPV infection (Kumar et al., 2010). When there is a dysfunction in the cell cycle, such as with viral replication and koilocytosis, some of the infected cells are shed regularly, and can be detected with a Pap smear (Schuiling & Likis, 2006). The abnormalities can be seen primarily as koilocytosis, characterized by perinuclear halos and nuclear alterations. Furthermore, there may be expansion of basal cell layer with varied immature squamous cells, depending on the extent of the severity of the dysplasia (Kumar et al., 2010).

Although most cervical cell abnormalities are due to changes caused by HPV infections, the cervix consists of cells that are regularly changing and proliferating in response to hormonal fluctuations of the menstrual cycle. This makes the cervix susceptible to a variety of carcinogens and oncogenic factors that can alter and dysregulate the cell cycle (Kumar et al., 2010).

Etiology.

The most common causes of cervical dysplasia and neoplasms have been closely associated with infections by the human papilloma virus (Kumar, Abbas, Fausto, & Aster, 2010). There are several different types of HPV, however only a handful being linked to malignant cervical cell changes, usually type 16 and type 18. HPV is typically transmitted by sexual intercourse, classifying it as a sexually transmitted disease (Center for Disease Control and Prevention [CDC], 2009). Although there has been a significant decrease in mortality rates of cervical cancer due to early detection and prevention, there are a number of factors that have been shown to cause a marked increase in risk for cancer development from HPV precursor lesions. These include tobacco smoking, which doubles an individual’s risk due to the consumption of carcinogens, genetic predisposition by inherited gene mutations that impair tumor suppression, poor nutritional status, such as diets low in folate and vitamins E and C, and most recently, data has suggested oral contraceptives may have an impact on cervical cancer development (Schuiling & Likis, 2006).

Pathogenesis.

The cellular components of the cervix have an abundance of immature squamous metaplastic epithelium. Since HPVs generally infect areas containing these kinds of cells, or in instances where there are epithelial breaks in the squamous basal epithelium, such as by intercourse or reproductive cycle factors, it is an area of the body that is significantly more vulnerable to HPV infection (Kumar et al., 2010).

Low risk types of HPV’s typically affect the superficial epithelium, and maturation of the epithelial tissue is generally preserved (Mitchell, Kumar, Abbas & Fausto, 2006), and the resulting process that is seen is koilocytosis. This is a pathognomic feature of HPV infection, in which there is vacuolation of the epithelial cytoplasm, and the cells develop a “perinuclear halo” (Lawson, 2009), and a subsequent development of benign condylomas, observed as endocervical polyps, or warts (Mitchell et al., 2006). This alteration in the structure with the HPV oncoproteins contributes to stimulation of cell proliferation, and impaires cell cycle regulation by inhibiting tumor suppressor genes, resulting in uncontrolled replication of virus-infected cells (Lawson, 2009).

The majority of women that have abnormal cervical cell changes identified by their pap smear are affected by these low risk HPV’s, and the koilocytosis that takes place in these women is generally insignificant, and will be cleared by the immune system within 8 months to 2 years without further complications (Kumar et al., 2010).

Some of the higher risk HPV’s on the other hand, are often associated with a persistent infection that is not as readily cleared from the body. Because the infection is present longer, the increased exposure of the cells to the virus sustains greater damage than that of the lower risk types. In addition, koilocytosis and viral replication are more potent in the high-risk types, as they readily affect all of the cell layers, and significantly reduce the cellular maturation by interfering with the mitotic cell cycle (Mitchell et al., 2006). The virus integrates its DNA into the host cell’s genome, and produces viral oncoproteins that inactivate and mutate the host’s primary tumor suppressor genes inhibiting repair of damaged DNA and apoptosis (Schuiling & Likis, 2006).  This interference results in genomic instability by altering the regulation of the cell cycle and promoting uncontrolled cell growth resulting in neoplasms (Mitchell et al., 2006).

Morphologic changes.

Diagnosis of cervical dysplasia is dependant of the progression of cellular atypia, and the degree of maturation of the involved epithelial cells (Mitchell et al., 2006). A classification system has been developed to determine the severity of the dysplasia or carcinoma, and is know as the cervical intraepithelial neoplasia (CIN) system. This system was based on the progression of mild, moderate, and severe dysplasia, termed CIN I, CIN II, and CIN III,  respectively. Because of recent regards to observation and surgical treatment in patient management, the system was reduced to a two level system, known as the Bethesda System in which mild dysplasia, or CIN I, was classified as low-grade squamous intraepithelial lesion (LSIL), and moderate and severe dysplasia (CIN II and III) were both combined and classified as high-grade squamous intraepithelial lesion (HSIL). As defined per Kumar et al. (2010),

The grading of SIL into low or high grade is based on expansion of the immature cell layer from its normal, basal location. If the atypical, immature squamous cells are confined to the lower one third of the epithelium, the lesion is graded as LSIL; if they expand to two thirds of the epithelial thickness, it is graded as HSIL. (p.1020)

Investigation of the morphology is typically preceded by a colposcopy and/or a biopsy of the areas of cervical abnormality after one or more abnormal Pap smear results (American College of Obstetricians and Gynecologists [ACOG], 2009). Abnormal diagnostic findings on the colposcopy may include a smooth surface that, when doused with acetic acid, is interrupted by whitish areas with dense, sharp or irregular outer borders in a mosaic pattern (Zheng, 2009).

Functional derangements.

Generally, there are usually no physical symptoms that are associated with HPV infections or cervical dysplasia. Some individuals infected with certain strains of HPV may experience benign polyps or “genital warts,” but many times the body is capable of fighting off the virus before changes are noticed (CDC, 2009). Similarly, cervical changes that are caused by HPV infections are also usually asymptomatic, and any abnormalities are only detected with a Pap smear, or further testing via colposcopy or cervical biopsy. Occasionally, women may experience mild symptoms such as a scant, watery discharge, lower back pain, abnormal heavy menses, or pain and spotting after intercourse (Schuiling & Likis, 2006).  More often than not, these symptoms may be associated with other problems, and typically are not indicative of HPV or cervical abnormalities, and detection through screening tests are the best way to achieve a definitive conclusion (CDC, 2009).

Epidemiological studies have seen increased incidences of cervical dysplasia in women with HPV infections. Because HPV is becoming a significantly more common STD, it is estimated that most women infected with HPV will experience some degree of cervical dysplasia at some point in their lives (CDC, 2004). Because there are only a handful of cancer linked types of HPV, only a very small fraction of these infected individuals will progress to cervical cancer development. However, the presence of associated risk factors make some individuals more susceptible than others. This is especially true in immunosuppressed patients, those with genetic predispositions, high parity, and tobacco use (Schuiling & Likis, 2006). Furthermore, Smith et al. (2003) suggest increased incidences of HPV infections and cervical changes in women that use oral contraceptives. This finding is believed to be due to the theory that women using oral contraceptives (OC) are less likely to use condoms during sex than women that do not use OC’s, thus predisposing them to more STI’s and increased exposure to a variety of HPV types (Smith et al., 2003).

Laboratory and Diagnostic Tests

Cervical Dysplasia

The most significant diagnostic finding is the presence of abnormal cervical cells due to koilocytosis on the Papanicolaou test. As the cervix undergoes cellular changes in response to the menstrual cycle, abnormal cells from a cervical lesion are sloughed off, and can be scrapped from the cervical surface during a pelvic exam, and viewed for abnormalities under a microscope (Schuiling & Likis, 2006). Furthermore, a colposcopy and cervical biopsy can be performed on any lesions, as identified by acetic acid. Findings conclusive of dysplasia are associated with the presence of nuclear atypia by enlargement, and cytoskeletal disruption, as indicated by perinuclear halos on microscopic examination (Kumar et al., 2010). Recently, an alternative test, known as Thin Prep, has been developed to replace conventional Pap smears, using liquid-based methods of cytology (Shuiling & Likis, 2006). This new test offers an improved system for detection of abnormal cells through computer imaging that readily identifies abnormal cellular characteristics in a more accurate representation of the specimen. The liquid-based system also allows for improved specimen preservation that enhances the ability to detect koilocytosis and nuclear atypia (Hologic, 2010).

Additionally, an HPV assay may be performed using the specimen collected from the Pap test or biopsy, which looks for HPV DNA, known as the Hybrid Capture 2 assay. This test can be used to identify the HPV typing to in order to determine the level of risk present for progression to cervical malignancy (Schuiling & Likis, 2006). The Food and Drug Administration ([FDA], 2003) recommends that the HC2 test should be used in conjunction with Pap smears in early detection and screening for cervical dysplasia and cancers.

Management of these findings is through consistent follow-up cervical cancer screening recommendations, as proposed by the American Cancer Society. It is recommended that women over the age of 21 receive a pap test at least every 2 years if results are normal, and for women over the age of 30, they may get them every 3 years if they have had at least 3 consistent normal pap smears in a row (ACOG, 2010).

Health Assessment Findings

The patient’s past medical history of HPV infection and abnormal pap smears indicate the need for additional testing and observation. Based on physical findings on the pelvic exam, the areas highlighted by acetic acid that consist of pale pink and white tissue are suggestive of tissue abnormalities or lesions, as would be expected in cases of dysplasia. Further physical examination revealing tenderness upon palpation is also a consistent finding indicating the possibility of inflamed lesions or infection, especially in the presence of HPV infections. Furthermore, the patient reports a history of pain with sexual intercourse, with subsequent vaginal bleeding and spotting, which may be due to irritation of the lesions and areas of inflammation. Additionally, mild lymphadenopathy was noted in her inguinal nodes. These nodes may be affected from the cervical inflammation, but in the presence of a possible malignancy in the cervical tissue, these lymph nodes may be involved.

Current Research

HPV Vaccination and Cervical Cancer

Although cervical cancer can arise from a variety of etiologies, infection by human papilloma virus has been seen to be the most prevalent cause associated with cervical cancer development, found in at least 70% of cancer cases. While there are many different HPV types, and infection at some point in one’s life is not uncommon, infections by type 16 have been strongly associated with cervical cancer development, and these are the most commonly found HPV infections worldwide (Smith et al., 2007). Due to the severe implications of HPV and cervical cancer, a vaccine has been developed to protect against many of the subtypes of HPV associated with cancer. Jenkins (2008) performed a study that examined the efficacy and impact of the cross-protective effects of the HPV vaccine. This was a longitudinal study to explore the long-term effects of the vaccine in cervical cancer prevention. In Jenkins’s study, he not only confirmed the efficacy of the vaccine in preventing infection by high risk HPV types, but he also found that they played a protective role in preventing cervical abnormalities by other HPV oncogenes not originally intended for vaccination. This finding contributes to significant reduction in precancerous cervical lesions and subsequent cervical cancers. Due to the increased health benefits established by the HPV vaccine, the World Health Organization ([WHO], 2006) has recommended vaccinations for adolescent and young adult females to further decrease HPV infections and cervical cancer.


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Everything you ever wanted to know about…the MENSTRUAL CYCLE!!

Happy New Year! It has been a while since my last post, and since today was my first day of OB/GYN bootcamp….I’m going to share some of the things I learned today about…The Menstrual Cycle.

The menstrual cycle is the monthly reproductive lifespan experienced by females that involves the fluctuation of numerous hormones that stimulate a variety of responses and changes within the body, all for one common goal…ovulation. Although no two cycles are the same, most women experience a cycle lasting about 28 days, but can vary between 21-35 days. As a woman, it is important to have an idea of how many days your cycle is, and what is typical for you. Not only can this help to identify any deviations from the norm, but the length of the cycle is a crucial factor in determining the different phases of ovulation. Although every woman has a different cycle, ovulation (release of the female reproductive egg) is invariably always 14 days before the onset of menstruation (the first day of your period). This can be important when trying prevent or get pregnant. If it is assumed that ovulation occurs in the middle of a 35 day cycle, timing sexual intercourse can be off, resulting in less than desired outcomes, such as unplanned pregnancy, or during times of infertility.

Now for the technical stuff….the menstrual cycle is initiated by the release of a chemical called Gonadotropin Releasing Hormone (GnRH) by the hypothalamus (the control center of the brain). This hormone is usually secreted in pulses, about every 90 minutes, and fluctuating throughout the cycle. Increases in GnRH act on the pituitary gland in the brain in response to low circulating estrogen levels in the body, and stimulates the secretion of two more very important hormones, Lutenizing Hormone (LH) and Follicle Stimulating Hormone (FSH). FSH acts on the ovaries to promote follicle stimulation (hence the name), in order to basically “grow” a new egg each month. With the rise in FSH, the ovaries begin to secrete estrogen, which increases the circulating levels, and at first, in order to regulate production, signals to the pituitary gland to decrease the amount of hormones being produced, with a system known as the negative feedback mechanism. When estrogen levels increase to reach a certain point, however, this mechanism in the brain is reversed, and LH is rapidly secreted in what is called an LH surge. When this surge occurs, the follicle sac with the egg ruptures, releasing the egg (ovulation), and can be expected to occur in approximately 10-12 hours. Soon after release, the ruptured follicle becomes enlarged and firm (which is why it is not uncommon to experience tender, physiologic ovarian cysts during ovulation) and it becomes the corpus luteum (CL). This transition is a key contributor to the final phase of the cycle, so called the Luteal Phase. The CL secretes progesterone and estrogen to restart the negative feedback loop on the hypothalamus, and prevent further ovulation. ***Rises in progesterone levels promote the production of endometrial (uterine) lining in preparation for potential egg fertilization and implantation. This lasts from about Day 15-Day 28, and is important because this will not occur if there is no ovulation***.Within a couple days, the CL begins to degrade, decreasing progesterone and estrogen levels, which degrades the inner uterine lining, causing disruption of the uterine vessels and subsequent bleeding into the uterine cavity. The tissue disruption stimulates the inflammatory response in the uterus, by which chemicals are secreted that cause the notorious symptoms of menstruation: swelling (bloating), contractions of the uterine muscles (cramping), and sloughing of the degraded endometrial tissue (bleeding), thus indicating the start of a new cycle.

How do hormonal contraceptives and birth control pills play a role in this? Well, contrary to popular belief, taking the pill does not “fool” your body into thinking it is pregnant. Come on, you think its THAT simple?! Actually, most contraceptives work by providing a steady dose of estrogen (amongst other things), that keeps the LH levels low, preventing the monthly release of an egg. Similarly, many forms of the pill provide steady, low doses of progesterone, which limits endometrial proliferation, and often contributes to the lighter periods women experience when they are on the pill. When the steady doses of these hormones are stopped, such as at the end of the pack of pills, or when a pill is missed, the rapid decline in estrogen and progesterone stimulate the endometrial degradation and bleeding that occurs. Furthermore, the decline in estrogen levels may cause an LH surge. If this occurs midcycle, release of an egg may occur. If unprotected sex occurs at this time….oopsies.

So now you may be asking, “well if all this is occurring internally, how do I KNOW when I am at risk for being fertile?!” The answer….? Know yourself, be in tune with your body. OK so that sounds super tree-hugger I know, but it really is that simple. For one, just knowing how often and when to expect your period each month can provide you plenty of information on what is going to happen, and when (remember ovulation always occurs 14 days BEFORE you get your period!). Additionally, being aware of changes in your body helps too. First of all, estrogen plays a huge role in the female sex drive. When estrogen spikes just before ovulation, many women feel very sexually stimulated (naturally a response to the innate reproductive instinct). Any sudden sexual desires midway between periods might give you a clue as to what ovulatory phase you are in. You may have heard of checking your basal body temperature when trying to get pregnant. This is very accurate, HOWEVER, the increase in temp is VERY slight, so temperature must be by a precise thermometer, by the same route (if taken orally it must be done orally every day) at the same time every day, and must be recorded. It can be a tedious task, and will take some practice. Finally, there is one of the easiest ways, which is where I encourage the “know your body” saying. Just like the cells that make up mucus secreting cells in the gastrointestinal tract, mouth/nose, and respiratory tract, and any opening to your body, the female genitalia are also composed of similar cells that secrete mucus (preventing infections), particularly, in the cervix. At the beginning of the month, during the infertile phase, the cervical mucous is often thick, dry and sticky. Remember that the cervix is the opening into uterus, the only route accessible to sperm for fertilization. When the cervix secretes this thick mucous, its matrix like properties form a plug that prevent sperm from entering the uterus. During this time, little to no mucous can be identified in the vagina. As ovulation approaches, the cervix becomes soft and vascular, and it begins producing increased amounts of mucous. These secretions, however, are not only copious in amount, but they have the consistency of egg whites (or snot), and are often clear, thin, and stretchy (known as Spinnbarkeit) and it has vertical microscopic properties that allow sperm to enter the uterus in search of an egg. When ovulation is over and progesterone levels increase, the cervical mucous returns to being “thick and hostile” once again. In order to determine which stage your cervical mucous is in, you may need to…explore your true self a little. Today’s society doesn’t always encourage this method, but screw it. Nature knows whats up, so should you.

After all that, my final words of advice for today are as follows…

1. Know your own unique cycle. Know whats normal for you, and be smart about.

2. Don’t miss your pills. If you do, use protection.

3. Understand that the cycles ALWAYS start on the FIRST day of your period. People often seem confused when asked the date of their last period, and give the last day. This messes up everyone’s calculations.

4. Don’t be afraid of know and be comfortable with yourself and the changes your body is constantly going through, whether it be on the course of puberty to menopause, or the monthly changes of the menstrual cycle.

5. Love your nurse-midwife.

Oh and most importantly, go Gators. ❤