I.               THE VULVA

The vulva comprises the external genitalia at the entrance to the vaginal canal. It includes the skin and mucosal folds (labia minora and majora), the clitoris, the skin surrounding the vaginal opening, and the perineum, which is the skin between the vaginal opening and the rectum. Much of the vulva is skin and is therefore susceptible to non-specific dermatological disorders, as well as to diseases specific to the vulva.

The vulva has a high level of exposure to infections due to its function and location. Some sexually transmitted diseases (STDs) commonly affect the vulva.

• Condyloma acuminatum (venereal warts): Venereal warts are very common (1 million cases per year). They are caused by the human papilloma virus (HPV), a DNA virus of which there are over 70 subtypes. These 70 subtypes differ with respect to where they prefer to establish an infection and to their oncogenic (cancer-causing) potential. HPV can infect squamous epithelial cells and cause warts almost anywhere in the body, but some of the subtypes (serotypes 6 and 11, especially) specifically cause venereal warts. About 25 of the subtypes infect the lower genital tract. On the vulva, HPV causes multiple, warty, cauliflower-like (verrucous) lesions. Histologically, HPV causes proliferation and thickening of the squamous epithelium. The epithelium is both hypertrophic and hyperplastic.  Infected epithelial cells that are actively producing virus have a clear halo around the nucleus and are called koilocytes or halo cells. Treatment of choice is removal, e.g., by laser excision; the areas of excision usually heal well.

Important note: Venereal warts of the vulva are benign; there is NO predisposition for them to develop into cancer. Contrast this with HPV infections of the cervix, which are discussed below.

• Herpes simplex virus (HSV): Most cases of genital herpes are caused by HSV type 2, a DNA virus. It is an STD second only to HPV in incidence. This infection can involve the vulva, vagina, and cervix. HSV infects the squamous epithelial cells that cover these sites. Three to seven days after exposure, the primary infection manifests itself as papules (bubbles or vesicles), which then form painful ulcerations. The most severe cases involve a large number of lesions and can include systemic symptoms, such as lymphadenopathy in the inguinal nodes, fever, and malaise. The primary lesions spontaneously heal within 1 to 3 weeks. After the primary infection, the virus persists in a latent state, and reactivation often occurs. The relapses are irregular and unpredictable, with the course of the disease varying greatly from person to person. It was commonly thought that if no active lesion was present, the disease could not be transmitted. However, this is not certain. Medication can ameliorate but not cure the disease. Diagnosis is made from the appearance of the lesions or from a microscopic examination of a scraping of a lesion. Characteristic cell changes include formation of multinucleated giant cells with "ground-glass"-like viral inclusions.
• Candida (yeast infections): is a very common fungal infection of the lower genital tract. It causes pruritis (itching), and white patches may be observed.  Candida may become dominant after antibiotic therapy, which may alter the normal balance of flora in the genital area.  Diabetes, pregnancy, and oral contraceptives can also predispose.  Note that Candida is NOT an STD.  Diagnosis is by microscopic examination of smears, which will show the presence of this filamentous fungus.  Candida infections can be easily treated with topical fungicides.

II.             THE VAGINA

The vagina is a collapsed, hollow, muscular tube. Cancer is relatively uncommon, as are HPV infections.  Any tumors that are seen are usually metastatic (from the cervix, ovary, or endometrium), rather than primary.  This is true even though the vagina is lined with epithelium similar to that of the vulva and cervix.

The most common vaginal problem is infection (vaginitis). Estrogen is required to maintain the vaginal epithelium. These epithelial cells accumulate glycogen. A bacterium called Lactobacillus vaginalis metabolizes this glycogen to lactic acid, maintaining the normally acidic pH of the vagina. This acidic pH helps keep the growth of normal flora in the vagina in check and helps prevent infection by agents that are not usually present. Interference with this pathway can lead to overgrowth of flora or to infection. A decrease in estrogen may be the cause, or antibiotic therapy may kill the needed L. vaginalis. Other disruptions might occur from diabetes, the presence of alkaline secretions (e.g., semen), or oral contraceptives (which have an anti-estrogenic effect). Although menopause might be predicted to upset this pathway, it does not. Apparently, other changes in the vagina at this time of life discourage infection.

Once the stage is set, vaginitis can be caused by a number of agents, including fungi (e.g., Candida), bacteria (Gardnerella), or parasites (Trichomonas). Often, a mixture of organisms is responsible. Vaginitis is characterized by itching and a purulent discharge. Diagnosis is by microscopic examination of a vaginal smear. Trichomonas parasites are single-celled organisms with flagella that look like whiskers.  Infection with Gardnerella is characterized by the presence of so-called "clue cells," which are squamous epithelial cells covered with bacteria, and is also associated with a yellow exudate.  Topical or systemic anti-microbial drugs are used to treat these infections. All organisms that cause vulvar or vaginal infections can also cause cervicitis.

III.           THE CERVIX

If you are unfamiliar with the structure of the uterus and cervix, refer to your text or other diagram. The cervix is the neck of the uterus and has an external os and an internal endocervical canal.

The cervical canal is continuous with the endometrial lining of the uterus, which is continuous with the canal of the fallopian tube. The cervix serves to connect the outer and inner environments. The outer cervix, the vagina, and the vulva are covered with squamous epithelial cells. The endocervical canal is lined with a mucus-producing, columnar epithelium. Between these two types of epithelium, near the opening of the cervix, lies the so-called transformation (also known as the T or transitional) zone. The vast majority of cervical precancers and cancers develop in the transformation zone. The epithelium in this region is turning over at a faster rate than the epithelium on the vulva. It is therefore susceptible to infection by more types of HPV. Types 6 and 11 can infect the cervix and cause benign lesions, but, unfortunately, oncogenic types of HPV may also infect the cervix and lead to cancer (see below). There seems to a particular susceptibility to infection around menarche (the onset of menses).

A.  Cervical dysplasia

Cervical precancers are known by several equivalent terms, including cervical dysplasia, cervical intraepithelial neoplasia (CIN), and squamous intraepithelial lesion (SIL). All of these terms refer to a premalignant condition that may lead to cervical cancer. Nearly all cases of CIN are caused by infection of epithelial cells in the transformation zone with HPV; therefore, CIN is considered an STD. The DNA of HPV is found in >90% of cervical precancers and cancers. Other factors may also be involved, but infection with HPV is required.

In CIN, there are no grossly visible changes in the appearance of the cervix. However, at a microscopic level, formerly normal cells have begun to acquire some features of malignant cells. The nuclei become larger, there is more mitotic activity, and there are more irregularly shaped cells. These changes are generally referred to as cytologic atypia. The dysplasia may involve the thickness of the epithelium to varying degrees; the extent of involvement forms the basis for grading the CIN. Important point: CIN is not a malignancy of the cervix. By definition, the changes of CIN remain confined to the epithelium. There is no invasion through the basement membrane. Therefore, removal of the dysplastic lesion means that there is a complete cure. The tendency of CIN to progress to cancer depends in part on the type of HPV that is present. Types 6 and 11 usually cause mild dysplasia that seldom progresses to malignancy. In contrast, types 16 and 18 tend to cause a more severe dysplasia that is much more likely to progress to cancer. The oncogenic types of HPV integrate into the genomes of the host cells. In the presence of co-factors (e.g., nicotine, oral contraceptives, high parity, immunosuppression), these integrated viruses may cause malignant transformation of the cells, leading to cancer.

It should be noted that not all CIN progresses to cancer, even when caused by the more oncogenic strains of HPV. The course of disease is variable and unpredictable. Sixty percent of women exposed to genital warts of their sexual partners develop vulvar lesions of CIN within 1 to 6 months. Of these, 30% regress, 40% persist, and 30% progress to more severe disease. If untreated, 5% will develop an invasive cancer after a period of 5 to 15 years.  Only 0.4% of women initially infected with HPV will ultimately die from cervical carcinoma.

CIN is a disease of younger, sexually active women (as would be expected for an STD). It is very common, affecting 2 to 3% of the population between the ages of 15 and 40. This amounts to about a million cases a year. Risk factors include a large number of sexual partners and first intercourse at an early age (remember, cells of the transformation zone appear more susceptible to infection with HPV around menarche). Less important risk factors are oral contraceptives (barrier methods may be protective), cigarette smoking (nicotine concentrates in the cervical mucus), and immunodeficiency.

The Pap smear is the best example to date of an effective screening test that has resulted in a marked decrease in invasive cancer. It is simple, inexpensive, and can effectively detect precancers (CIN) before they have progressed to more serious disease. Women must be screened on a regular basis, and in 5-20% of cases, there can be errors, including both false positives and false negatives. However, cervical cancers usually develop so slowly that an abnormality that is missed one year will most likely be picked up the next year, and it will still be in the precancerous stage. Women who develop cervical cancer are usually those who have never had a Pap smear or who have not had one for many years.

In the Pap smear, a scraping of cells from around the transformation zone is taken, and a cytotechnician examines it for the presence of abnormal cells (such as koilocytes). There is some element of subjective judgment involved, so it is possible to miss abnormal cells. The vast majority of women with an abnormal Pap result do not have cervical cancer. There are also many "reactive" changes that occur in cervical epithelial cells that have nothing to do with precancerous changes.

If a woman has a mildly abnormal Pap result, her physician may decide simply to wait six months and repeat the test. Alternatively, or with more severe abnormalities, a colposcopy may be performed to provide a magnified view of the cervix and T zone. Visualization of abnormal areas can be enhanced by applying acetic acid to the cervix, and any such areas can be biopsied for microscopic examination.  Abnormal lesions can be biopsied, either by a punch biopsy or a cone biopsy (see below).

CIN can be treated by ablating the abnormal area using laser vaporization, cryotherapy, or the loop electrocautery excision procedure (LEEP). With LEEP, usually the entire T zone is removed. The defect usually repairs itself with little consequence. The cone biopsy is an older, more radical procedure in which a cone of tissue in the T zone is surgically excised. It may be the preferred treatment in cases where true cancer is suspected. However, it is associated with many more complications (e.g., bleeding, cervical incompetence) than LEEP and so has become a relatively rare procedure.

B. Cervical carcinoma

True cervical carcinomas are tumors that have invaded across the basement membrane of the cervical epithelium. There has been a marked decline in incidence of cervical carcinoma since the advent of the Pap smear, but there are still 15,000 new cases each year in the US (the incidence was three times greater 40 years ago). Worldwide, it is the second most common cancer in women. Because the disease takes a long time to develop, it generally affects women in their 40’s to 50’s. It tends to spread into the bladder or rectum. It may also invade the lateral pelvic sidewall, destroying the ureters and leading to obstruction and renal failure. Renal failure is the most common cause of death from cervical carcinoma. The five year survival rate is ~60%.

In terms of symptoms, the first indication may be spontaneous or post-coital vaginal bleeding, or there may be no symptoms, i.e., the first indication is an abnormal Pap smear. Eighty-five percent of cervical cancers are classified as squamous cell; 10-15% are adenocarcinomas.

Stage I cervical cancers are confined to the cervix.  Stage II is marked by vaginal involvement; Stage III has spread throughout the pelvis.  Stage IV cancers have spread beyond the pelvis; the prognosis is very poor for Stage IV lesions.  Treatment depends on the stage. Stage I lesions smaller than 3 mm in diameter are usually treated by cone excision or a simple hysterectomy, in which only the uterus is removed.  Stage I lesions greater than 3 mm are usually treated with a radical hysterectomy, which includes removal of not only the uterus, but also surrounding tissue and lymph nodes.  Tumors classified as Stage II or greater are treated with radiation therapy.

IV.           THE BODY (CORPUS) OF THE UTERUS

The uterus is a pear-shaped organ with a thick wall (called the myometrium) composed of smooth muscle. The inner cavity of the uterus is lined by the endometrium. In the first half of the menstrual cycle, the ovaries make estrogen, which causes proliferation of the endometrium. After ovulation at day 14, progesterone prepares the endometrium for implantation of an embryo by converting it to a secretory state. If there is no pregnancy, then the endometrium is shed during menstruation.

A.  Abnormal uterine bleeding

Normal uterine bleeding is referred to as menstruation or menses. Abnormally heavy bleeding at the expected time of menses is called menorrhagia, whereas bleeding between the expected times of menses is termed metrorrhagia. These are the two most common types of abnormal uterine bleeding. A combination of these two types of bleeding is called menometrorrhagia. Any bleeding in a post-menopausal woman is abnormal. Abnormal bleeding from the endometrium is common and has many causes including pregnancy, lesions, hormonal imbalance, and systemic diseases.

The endometrium may be surgically scraped away for analysis by the procedure of dilatation and curettage (D & C). The dilatation refers to dilation of the cervical os with plastic dilators to expand it so that a curette can be inserted to scrape the lining. This procedure used to require hospitalization, but use of smaller instruments has allowed D & Cs to be performed in the doctor’s office. Many uterine bleeding problems are benign and can be cured by curettage.

There are two classifications of abnormal uterine bleeding:

1. Dysfunctional uterine bleeding (DUB): is abnormal bleeding that occurs in the absence of a specific, identifiable pathologic lesion (i.e., there is no organic uterine disease). It is caused by upsets in the balance of hormones that regulate the menstrual cycle and may be caused by malfunction of the hypothalamus, pituitary, adrenal gland, thyroid, or ovary. Obesity, malnutrition, and chronic disease may also cause hormonal imbalances.  Diagnosis is usually by exclusion, i.e., no other cause can be found. It is usually related to anovulatory menstrual cycles and is common at menarche and in perimenopausal women.  In anovulatory cycles, there is excessive and prolonged stimulation of the endometrium with estrogen, which, in turn, leads to its excessive proliferation.  DUB is the most common type of uterine bleeding - usually, no specific lesion can be found.  DUB can be treated with hormones.

2. Bleeding due to specific pathological lesions: such as polyps, pregnancy disorders, systemic disease, cancer, endometrial hyperplasia, or myometrial lesions (fibroids). The last three of these will be considered in more detail.

·       Endometrial hyperplasia: is an abnormal proliferation of endometrial glands and usually occurs in response to excessive estrogen or to estrogen whose action is unopposed by progesterone. It can result in bleeding as the endometrial cells outgrow their blood supply. Although it is a benign condition, some specific forms may be precursors to endometrial cancer. Twenty-three percent of women with atypical hyperplasia (in which cells appear abnormal) will develop adenocarcinoma of the endometrium.  Endometrial hyperplasia is most often seen in peri- and post-menopausal women (greater than 45 years old). Histologically, in this condition glands are larger and greater in number than in normal endometrial tissue. It can be treated with progesterone or curettage, although most postmenopausal women end up with a hysterectomy.

§       Endometrial adenocarcinoma (remember, adenocarcinoma refers to cancers that arise from epithelial cells of glands): is the most common invasive carcinoma of the female genital tract. Its overall prognosis is relatively good, with a 10-year survival rate of 80%. The usual type is termed endometrioid and arises in association with hyperplasia. It generally occurs in women in their 50’s to 60’s. These cancers may grow beneath the lining of the myometrium and spread onto the ovary through the Fallopian tubes. They also can spread to the lymph nodes or through the blood to the lung.  Deaths from uterine cancer are relatively rare; it is not usually a highly aggressive cancer.  Ovarian cancer is a much rarer disease, but it causes four times as many deaths.  Uterine cancer is also easier to detect than ovarian cancer.

Since endometrial hyperplasia and adenocarcinoma are related diseases, it is not surprising that they have similar risk factors. These include obesity (androgens are converted into estrogens in fat cells); low parity (low number of pregnancies); oral contraceptives, anovulation (which usually results from unopposed estrogen); early menarche and a late menopause (the greater the number of menstrual cycles, the greater the risk); and a history of breast cancer.  The usual treatment is hysterectomy, including removal of the ovaries to eliminate further stimulation by estrogen.  The prognosis depends on the depth to which the tumor has invaded the myometrial wall.

·      Leiomyomas (popularly but not very precisely referred to as fibroids): are benign tumors of the smooth muscle cell wall of the uterus. They are the most common uterine tumor and occur most frequently in women of reproductive age (30 to 40 years old). They are hormonally driven, since they are not seen prior to menarche and usually shrink after menopause.  They may proliferate rapidly during pregnancy. They can be located beneath the mucosal lining of the uterus (submucosal), within the uterine wall (intramural), or beneath the covering of the uterus (subserosal). They are usually well delimited from the surrounding normal tissue, are firm, and have a "wormy" or fiber-like appearance.  About 80% of uteri harbor leiomyomas, and about 25 to 40% of women of reproductive age have clinically notable leiomyomas.

The majority of women with leiomyomas have no symptoms. The symptoms of the remainder are quite variable, depending on how many leiomyomas there are (they often occur multiply), how big they are, and where they are located. Symptoms can include: bleeding, a feeling of heaviness from the mass of the tumor(s), bladder and/or bowel problems if the tumors press on these structures, pain, and infertility. They may prolapse through the cervix and vagina.  Treatment is by hysterectomy (although this more rarely done than in the past), myomectomy (in which only the tumor is removed), or by anti-estrogen therapy (gonadotropin-releasing hormone analogues). Sometimes, a medical approach is used to first shrink a tumor to a size where it can be more easily excised. Sometimes, a "wait-and-see" approach is used for perimenopausal women, since the tumors tend to diminish naturally after menopause.

V.             THE FALLOPIAN TUBE AND OVARY

The Fallopian tube (FT) is continuous with the uterus. It opens near the ovary, and its function is to catch and transport eggs released from the ovary. Fertilization occurs in the FT. Eight days post-ovulation, the fertilized egg implants in the endometrium. Sometimes the embryo implants within the tube itself, a condition called ectopic pregnancy (ectopic means out of the normal place). Ectopic pregnancies almost always occur within the FT, although other sites are possible. The growing embryo can easily rupture the tube and cause massive bleeding (the placenta and fetus are highly vascularized).

A positive pregnancy test combined with abdominal pain are signs of a possible tubal pregnancy. Women who are most at risk are those with abnormal tubes (e.g., tubes that are scarred due to pelvic inflammatory disease). Sometimes tubal pregnancies resorb spontaneously. Otherwise, treatment is by excision. Alternatively, methotrexate can be given to destroy the placental tissue to try to minimize damage to the tube.

Ovarian cancer is relatively uncommon.  Most lesions of the ovary are benign.  Ovarian follicles grow in the second phase of the menstrual cycle.  Normally, one of these follicles will discharge an ovum each month.  If the ovum is fertilized, then the follicle will develop into a corpus luteum.  Otherwise, it will regress.  Sometimes, however, a follicle will become abnormally cystic and dilated.  It can be felt upon examination and can cause pain.  Cysts can also form from the corpus luteum.  Ovarian cysts of this type are very common and are always benign.  These cysts can be filled with either clear fluid or blood and are called "functional cysts."

VI.           ENDOMETRIOSIS

The term endometriosis refers to endometrial-type tissue located outside of the uterus. It is thought to arise from endometrial tissue that sloughed off through the FTs instead of through the normal route of cervix and vagina. Common sites of implantation are on the ovary or on the surface of the uterus. Such ectopic endometrial tissue undergoes the same changes in response to hormones as normal endometrial tissue. It degenerates at the time of menses, but the sloughed off tissue has no place to go. Endometriosis often causes dysmenorrhea (painful menses). It is also often associated with decreased fertility by impairing ovarian function, causing adhesions to form, and perhaps leading to immunological abnormalities. Endometriosis is common in young women (20 to 35 years old) who have never been pregnant. In the ovary, endometrial tissue can form a cyst filled with degraded blood, which is known as a chocolate cyst. These types of cysts are almost always due to endometriosis. Hormonal treatment (with gonadotropin-releasing hormone) is often effective.

VII.         THE BREAST

The breast, like the endometrium, is a hormonally responsive tissue. Its glands start to develop at puberty and undergo further maturation during pregnancy. Breast tissue undergoes monthly cyclical changes in response to estrogen and progesterone. The breast is composed of multiple lobes of tissue and contains ducts that converge toward the nipple. Most abnormalities of the breast occur in its ducts and glands. Most lumps in the breast are not cancerous:  40% result from fibrocystic disease, 7% from fibroadenomas, 10% from cancers, and 30% are not pathologic.  Common lesions include:

• Fibroadenoma: a benign tumor common in young women (18 to 30 years old). It is well delimited, rubbery, soft, and mobile. It usually occurs as a unilateral, solitary mass that is easy to see by mammography.  It probably develops in response to estrogen. Fibroadenomas may spontaneously regress and can be completely cured by excision.

• Fibrocystic disease (also called fibrocystic change): is very common in women 30 to 50 years old. At least 10% of women have symptoms severe enough to warrant a visit to the doctor. Fibrocystic disease presents as a lumpy, firm, dominant mass, tends to be bilateral, and may cause pain. Fibrocystic disease is thought to arise from an exaggerated response of breast tissue to estrogen and progesterone. As such, it often waxes and wanes during the menstrual cycle. A biopsy is necessary to make an accurate diagnosis. Cysts, either large or small and diffuse, may be present; these form from ducts in the breast.  If cysts are suspected, a needle can be used to attempt to drain them for diagnosis and treatment.  The "fibro" part of fibrocystic disease results from changes in the stroma (connective tissue) of the breast.

There are many variants of fibrocystic disease, but two major categories have been described. Seventy percent of cases are classified as nonproliferative fibrocystic disease. In this form, there is no proliferation of the cells that line glands. In contrast, proliferative fibrocystic disease involves excessive growth of these cells. Much as endometrial hyperplasia predisposes to development of endometrial adenocarcinoma, proliferative fibrocystic disease is associated with an increased risk of developing breast cancer. The increased risk varies from 1.5-fold to 3.5-fold, depending on the particular subtype of the disease. The nonproliferative form is not associated with a greater chance of developing breast cancer.

• Breast cancer: is by far the most common form of cancer in women in the US, with 150,000 new cases a year. In American women, it is the second only to lung cancer in the number of deaths that it causes. It most commonly affects women over the age of 50.

Diagnosis, treatment, and causes of breast cancer are all controversial issues. The risk factors are similar to those for endometrial hyperplasia and carcinoma and include: an early menarche and late menopause, low or nulliparity, first pregnancy at a late age (first pregnancy at less than 20 years old (!) is protective), and a family history of breast cancer in close relatives (although the majority of cases are sporadic). These factors imply that estrogen must be important as a causative factor, although causation is certainly complex. Oral contraceptives may be protective.

There are two major categories of breast cancer. The first is non-invasive, which is confined to the duct and is therefore also called intraductal carcinoma or ductal carcinoma in situ (DCIS). DCIS is analogous to cervical dysplasia. It is not clear if all forms of DCIS progress to invasive cancer, but some types certainly do. DCIS accounts for 2% of all new cancer diagnoses, as mammography is detecting increasing numbers of these non-invasive cancers. Most of these tumors cause no symptoms and are too small to picked up by any means other than mammography.

Invasive breast cancer usually presents as a hard, immobile (because it has invaded adjacent structures), solitary mass. Advanced tumors can lead to dimpling of the skin ("orange-peel skin") and retraction of the nipple. Upon gross examination, excised tumors are stellate, irregular, and have invaded into surrounding tissue. These tumors tend to spread into the axillary lymph nodes, and the extent of spread is often used to determine prognosis and treatment.  Some cancers cause inflammation, resulting in reddened, hot skin; this is usually a sign of advanced disease.  Staging of breast cancer depends on the size of the tumor, the extent of lymph node involvement, and the presence of metastases. Breast cancer often metastasizes to liver, bone, lung, and brain. The overall 10-year survival rate is ~50%. The rate of survival varies with the extent of lymph node involvement.

A word about mammography: mammography is a method of soft tissue radiography that detects tumors by their abnormal density or by the microcalcifications contained within. Although mammography has clearly helped to increase the rate of detection of breast cancers, its benefits in reducing mortality due to breast cancer have not been conclusively shown, particularly in women younger than 50.

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