Chapter 17 The Female Genital Tract and Breasts
They are very common. In the United States, there are approximately 5 million women infected with genital herpes simplex virus (HSV-2), 3 million infected with Chlamydia trachomatis, and 2 million genitally infected with human papillomavirus (HPV).
5 Name the main viral pathogens causing infections of the lower female genital tract (vulva, vagina, and cervix)
Figure 17-1 Cytologic findings in various forms of vaginitis. In all vaginal smears, one may see desquamated epithelial vaginal cells and inflammatory cells (neutrophils). A, Candida albicans vaginitis. The smear contains fungal hyphae. B, Trichomonas vaginalis. The smear contains ciliated protozoa. C, Gardnerella vaginalis. The smear contains “clue cells” (i.e., squamous cells with clumped nuclei, folded cytoplasm, and numerous bacteria attached to their surface).
In clinical practice, the term PID is used for extensive infections involving more than one part of the upper female genital tract. Infections of the fallopian tubes (salpingitis), which are almost invariably present, may be accompanied by endometritis or oophoritis and peritonitis. Pus tends to accumulate in the fallopian tubes (pyosalpinx), but it may penetrate into the pelvis, where it accumulates in the pockets formed by fibrous adhesions with other pelvic organs (e.g., tuboovarian abscess).
PID is most often a complication of sexually transmitted infections caused by Neisseria gonorrhoeae and C. trachomatis. Less often, PID is a complication of puerperal infections (i.e., polymicrobial ascending infection during delivery or abortion). In such cases, PID is caused by staphylococci, streptococci, or enteric bacteria, which usually invade the upper genital tract jointly from the infected uterus.
The vulva is most often involved by infections, especially those that flourish in moist areas (e.g., candidiasis) or involve hair follicles (e.g., staphylococcal boils). Skin of the vulva may be involved with any other skin disease, such as psoriasis or eczema. Vitiligo (i.e., loss of pigmentation of unknown etiology) also may involve vulva.
Koilocytosis is a sign of HPV infection. The nuclei of infected squamous cells show irregular contours and appear crenated or “raisin-like.” The nucleus is hyperchromatic, displaced laterally by clear cytoplasm. Hence the name, which in translation from Greek means “spoonlike cell.” The virus particles can be seen in the nucleus on electron microscopy and are also demonstrable by immunohistochemistry.
VIN, also known as vulvar carcinoma in situ or Bowen disease, is a preinvasive squamous cell carcinoma. It is often multicentric, and like cervical or vaginal carcinoma, it is usually associated with HPV infection.
Most vulvar carcinomas are histologically classified as keratinizing or poorly differentiated (basaloid) squamous cell carcinomas. Other histologic forms, such as extramammary Paget disease or melanoma, are rare.
Most vaginal carcinomas diagnosed in adult women are of the squamous cell type. Clear cell adenocarcinomas are rare vaginal tumors, most of which were found in young women whose mothers took diethyl stilbestrol during pregnancy. Sarcoma botryoides is a rare vaginal tumor of girls younger than 5 years.
Cervicitis occurs in several forms. Mucopurulent acute cervicitis is typically a feature of sexually transmitted infections and is most often caused by Chlamydia and N. gonorrhoeae invading the endocervix. These infections may persist and spread upward to cause endometritis or PID. Chronic persistent or recurrent infection of the squamous epithelium of the exocervix is typically caused by viruses—HPV and HSV-2. Mild, nonspecific chronic inflammation of the endocervix caused by vaginal saprophytic bacteria is found in many women but is of no clinical significance. In some women, it may lead to the formation of endocervical polyps, which cause “spotting.”
Invasive carcinoma of the cervix is the second most common malignant tumor of the female genital tract. Although only 13,000 new cases of invasive cervical carcinoma are diagnosed annually, approximately 1 million others are detected in the preinvasive stages by Pap smear and cured before they become invasive.
Infection with high-risk types of HPV (such as types 16, 18, 31, and 33) is the most important risk factor for cervical cancer. Other risk factors include becoming sexually active at an early age, having multiple sexual partners, and being multiparous. Cigarette smoking has an important cocarcinogenic role.
Tumor cells can be easily scraped from the cervix during routine gynecologic examination; thus Pap smears are the most efficient means for diagnosing preinvasive and invasive cervical carcinoma. Positive exfoliative cytology findings need to be confirmed by a biopsy, which is usually performed under colposcopic guidance. A colposcope, which serves as an intravaginal microscope, provides the gynecologist with a close-up magnified view of the cervix and allows him or her to take the tissue specimens from the pathologically altered portion of the cervix.
CIN represents a spectrum of neoplastic changes of the squamous epithelium of the cervix that have been recognized as precursors of invasive squamous cell carcinoma. CIN is graded on a scale from I to III, which can also be expressed descriptively as mild, moderate, or severe dysplasia, or carcinoma in situ. On Pap smear, these lesions are classified by cytologists as squamous intraepithelial lesions of low or high grade.
CIN I is usually caused by low-risk types of HPV. Koilocytic atypia is typically limited to the lower third of the squamous epithelium. If the atypia becomes more pronounced and extends toward the surface layers of the squamous epithelium, it is classified as moderate (CIN II). If the nuclear atypia can be found in all layers of the epithelium, which in such cases shows no signs of surface maturation, the cancer is classified as CIN III. Lesions classified as CIN II and CIN III are caused by high-risk types of HPV.
Most CINs do not progress to invasive cancer. However, in each case, it is not possible to predict whether the lesion will progress to invasive cancer or regress. Therefore all CINs are treated as potential cancers. The chances that CIN will progress to invasive cancer depend on its grade. More than 85% of all CIN I cancers regress spontaneously, 10% progress to CIN III, and 2% or 3% progress to invasive cancer. Approximately 25% of all untreated cases of CIN III will progress to invasive carcinoma, usually within 10 years of diagnosis.
The treatment of CIN depends on its grade and the extent of cervical involvement. Following initial biopsy, CIN I is followed up with regular Pap smears, colposcopic examinations, or both at regular time intervals. High-grade CIN must be removed surgically by conization (i.e., removal of the involved cone of tissue around the endocervical canal and the transformation zone by laser vaporization or cryosurgery). Women diagnosed with CIN are at risk of developing cancer of the cervix or carcinoma of the vulva and vagina and should be examined at regular time intervals for life.
The age of presentation of CIN I and CIN II peaks at 25 years. The incidence of CIN III reaches its peak between 35 and 40 years, and the peak for invasive cervical carcinoma is approximately 50 years. Assuming that a lesion arose as a CIN II at age 25 years, one can predict that an untreated lesion will progress to carcinoma in situ over 10 to 15 years and from carcinoma in situ to invasive cancer in the next 10 to 15 years.
CIN is being diagnosed earlier. Epidemiologic data show that all forms of cervical neoplasia are being diagnosed in younger women compared with a few decades ago. In part, this is because sexual mores have changed and many women become sexually active at an earlier age. It is also related to the widespread use of Pap smears in most developed countries. However, this does not explain the increased incidence of invasive cervical cancer in women younger than 35 years, which has been recorded worldwide.
Microinvasive carcinoma is diagnosed unexpectedly in approximately 5% of cervical biopsies performed in patients thought to have CIN on colposcopic examination. Such microinvasive carcinomas do not have distinct macroscopic features, and the diagnosis is established only on finding nests of microscopic cancer cells superficially invading the endocervical stroma. Arbitrarily, it was decided to call carcinomas microinvasive if the invasion does not extend more than 5 mm from the nearest basement membrane delimiting the remaining preinvasive CIN.
Approximately 85% of all cervical carcinomas are classified as squamous cell carcinomas. Adenocarcinomas originating from the endocervical glands account for approximately 10% of tumors. The remaining 5% of cancers comprise the less common variants, such as adenosquamous, neuroendocrine (oat cell), and undifferentiated carcinomas.
Cervical carcinoma tends to invade the vagina and parametria locally and also metastasize to the pelvic lymph nodes. Invasion of the rectum, urinary bladder, and distant metastases are found in later stages of cancer spread. Obstruction of the urinary outflow is a common cause of death.
Endometrial hyperplasia, or excessive proliferation of endometrium, is thought to be caused by estrogenic stimulation, even though in most cases the cause of hyperestrinism cannot be identified. Identifiable causes include:
Endometrial hyperplasia is diagnosed microscopically by the pathologist examining the tissue removed by endometrial biopsy or endometrial curettage. Histologically, there are three forms of endometrial hyperplasia, as shown in Fig. 17-2:
Figure 17-2 Endometrial hyperplasia. A, Simple hyperplasia. The endometrium contains an increased number of dilatated glands separated from each other by normal stroma (“Swiss-cheese pattern”). B, Complex hyperplasia without atypia. The endometrium contains an increased number of irregularly shaped glands surrounded by scant stroma. Glandular atypica is not accompanied by cytologic atypia. C, Complex hyperplasia with atypia. There is both histologic and cytologic atypia; the glands are irregular, and the cells forming the glands are hyperchromatic and vary in size and shape.
Simple hyperplasia is a relatively innocuous lesion. Complex hyperplasia, however, can progress to cancer. Only 5% of complex hyperplasias without atypia ultimately progress to cancer. The rate of progression is much higher for complex hyperplasias with atypia; approximately 25% of all patients with these lesions will develop endometrial carcinoma.
Endometrial polyps are solitary fingerlike lesions found in the uterine cavity. Polyps are most likely benign tumors, but some authorities believe that they are nonneoplastic. They are covered by columnar epithelium similar to that covering the surface of the endometrium. Inside the polyp are cystic endometrial glands embedded in rather cellular and fibrotic stroma. Most polyps are diagnosed in perimenopausal women complaining of spotting or irregular bleeding. Polyps are easily removed by curettage.
Endometrial adenocarcinoma does not have a benign equivalent; if it did exist, it would be called endometrial adenoma. Hence, for practical purposes, all endometrial neoplasms should be considered malignant.
Endometrial adenocarcinoma is the most common invasive cancer of the female genital tract. There are approximately 35,000 new cases of endometrial cancer diagnosed annually in the United States. However, most of these cases are diagnosed in early stages when the cancer is curable; thus only 6000 women die every year of this cancer.
Like endometrial hyperplasia, endometrial cancer is thought to be related to hyperestrinism. Endometrial hyperplasia is a common precursor and is the most important warning sign that an invasive carcinoma may develop. Other conditions associated with hyperestrinism, such as estrogen-producing ovarian lesions, are also associated with an increased incidence of endometrial cancer. Exogenous estrogens, especially if unopposed by progesterone, increase the risk of endometrial cancer 3 or 4 times.