The Female Genital Tract

Infections of the Lower Genital Tract

Herpes Simplex Virus

Genital herpes simplex virus (HSV) infection is common and may involve the vulva, vagina, or cervix. HSVs are DNA viruses that include two serotypes, HSV-1 and HSV-2. HSV-1 typically results in perioral infection, whereas HSV-2 usually involves genital mucosa and skin; however, depending on sexual practices, HSV-1 may be detected in the genital region and HSV-2 may cause oral infections as well ( Chapter 8 ). By 40 years of age, approximately 30% of women are seropositive for antibodies against HSV-2.

About one-third of newly infected individuals are symptomatic. Lesions typically develop 3 to 7 days after transmission and are often associated with systemic symptoms such as fever, malaise, and tender inguinal lymph nodes. The earliest lesions usually consist of red papules that progress to vesicles and then to painful coalescent ulcers. The lesions are easily visible on vulvar skin and mucosa, while cervical and vaginal lesions present with purulent discharge and pelvic pain. Lesions around the urethra may cause painful urination and urine retention. The vesicles and ulcers contain numerous viral particles, accounting for the high transmission rate during active infection. The mucosal and cutaneous lesions heal spontaneously in 1 to 3 weeks, but during the acute infection the virus migrates to the regional lumbosacral nerve ganglia and establishes a latent infection. Because of viral latency, HSV infections persist indefinitely, and any decrease in immune function due to stress, trauma, concurrent viral infection, or hormonal changes can trigger reactivation of the virus and recurrence of the skin and mucosal lesions. As expected, recurrences are much more common in immunosuppressed individuals.

Morphology

By the time an HSV lesion is biopsied, it typically has ulcerated. The epithelium is desquamated, and marked acute inflammation is present in the ulcer bed. Smears of the inflammatory exudate from active lesions show characteristic cytopathic changes consisting of multinucleated squamous cells containing eosinophilic to basophilic viral inclusions with a “ground-glass” appearance ( Fig. 22.2 ).

Transmission of HSV takes place mainly during the active phase but occasionally may occur during the latent phase due to subclinical virus shedding. Condoms and antiviral therapies reduce the risk of transmission, but do not prevent it completely. As with other sexually transmitted diseases, the virus is more readily transmitted to women than to men. Previous infection with HSV-1 seems to reduce susceptibility to HSV-2 infection. The gravest consequence of HSV infection is transmission to the neonate during birth. This risk is highest if the infection is active during delivery and particularly if it is a primary (initial) infection in the mother. Cesarean delivery is warranted in such cases to prevent transmission to the neonate. Another important consequence of active genital HSV infection is that it increases the risk of HIV-1 acquisition and transmission.

The diagnosis is based on typical clinical findings and HSV detection. The purulent exudate is aspirated from the lesions and inoculated into a tissue culture. The viral cytopathic effect can be seen after 48 to 72 hours, and the virus can then be serotyped. In addition, some laboratories offer more sensitive polymerase chain reaction tests, enzyme-linked immunosorbent assays, and direct immunofluorescent antibody tests for detection of HSV in the lesional secretions. Individuals with primary, acute HSV infection do not have serum anti-HSV antibodies. Detection of anti-HSV antibodies in the serum is indicative of recurrent/latent infection.

There is no effective treatment for latent HSV; however, antiviral agents like acyclovir or famciclovir shorten the length of the initial and recurrent symptomatic phases. The ultimate solution is an effective vaccine, a tantalizing goal yet to be realized .

Infections Involving the Lower and Upper Genital Tract

Pelvic Inflammatory Disease (PID)

PID is an infection that begins in the vulva or vagina and spreads upward to involve most of the structures in the female genital system, resulting in pelvic pain, adnexal tenderness, fever, and vaginal discharge. Neisseria gonorrhoeae continues to be a common cause of PID, the most serious complication of gonorrhea in women. Chlamydia infection is another well-recognized cause of PID. Infections after spontaneous or induced abortions and normal or abnormal deliveries (called puerperal infections ) are also important causes of PID. In these situations, the infections are typically polymicrobial and may be caused by staphylococci, streptococci, coliforms, and Clostridium perfringens .

With gonococcus, inflammatory changes start to appear approximately 2 to 7 days after inoculation. The initial infection most commonly involves the endocervical mucosa, but it may also begin in the Bartholin gland and other vestibular, or periurethral, glands. From these sites, the organisms may spread upward to involve the fallopian tubes and tubo-ovarian region. The non-gonococcal bacterial infections that follow induced abortion, dilation and curettage of the uterus, and other surgical procedures are thought to spread upward from the uterus through the lymphatics or venous channels rather than on the mucosal surfaces. Therefore, these infections tend to produce more inflammation within the deeper layers of the organs than gonococcal infections.

Morphology

Gonococcal infection is characterized by marked acute inflammation of involved mucosal surfaces. Smears of the inflammatory exudate disclose phagocytosed gram-negative diplococci within neutrophils; however, definitive diagnosis requires culture or detection of gonococcal RNA or DNA. If infection spreads, the endometrium is usually spared (for unclear reasons), but within the fallopian tubes, an acute suppurative salpingitis ensues ( Fig. 22.4A ). The tubal mucosa becomes congested and diffusely infiltrated by neutrophils, plasma cells, and lymphocytes, resulting in epithelial injury and sloughing of the plicae. The tubal lumen fills with purulent exudate that may leak out of the fimbriated end. The infection may then spread to the ovary to create a salpingo-oophoritis. Collections of pus may accumulate within the ovary and tube (tubo-ovarian abscess) or tubal lumen (pyosalpinx) (see Fig. 22.4A ). With time, the infecting organisms may disappear, but the tubal plicae, denuded of epithelium, adhere to one another and slowly fuse in a reparative, scarring process that forms glandlike spaces and blind pouches, referred to as chronic salpingitis (see Fig. 22.4B ). The scarring of the tubal lumen and fimbriae may prevent the uptake and passage of oocytes, leading to infertility or ectopic pregnancy. Hydrosalpinx may also develop as a consequence of the fusion of the fimbriae and the subsequent accumulation of the tubal secretions and tubal distention.

As compared to gonococcal infections, PID caused by staphylococci, streptococci, and the other puerperal invaders tends to show less involvement of the mucosa and the tube lumen, and more inflammation within the deeper tissue layers. These infections often spread throughout the wall to involve the serosa and the broad ligaments, pelvic structures, and peritoneum. Bacteremia is a more frequent complication of streptococcal or staphylococcal PID than of gonococcal infections.

The acute complications of PID include peritonitis and bacteremia, which in turn may result in endocarditis, meningitis, and suppurative arthritis. The chronic sequelae of PID include infertility and tubal obstruction, ectopic pregnancy, pelvic pain, and intestinal obstruction due to adhesions between the bowel and pelvic organs. In the early stages, gonococcal infections are usually readily controlled with antibiotics, although penicillin-resistant strains have emerged. Infections that become walled off in tubo-ovarian abscesses are difficult to eradicate with antibiotics, and it sometimes becomes necessary to remove the organs surgically. Postabortion and postpartum PIDs may also be amenable to treatment with antibiotics, but are far more difficult to control because of the broad spectrum of pathogens that may be involved.

Lichen Sclerosus

Lichen sclerosis presents as smooth, white plaques or macules that in time may enlarge and coalesce, producing a surface that resembles porcelain or parchment. When the entire vulva is affected, the labia become atrophic and agglutinated, and the vaginal orifice constricts. Histologically, the lesion is characterized by marked thinning of the epidermis ( Fig. 22.5A ), degeneration of the basal epithelial cells, excessive keratinization (hyperkeratosis), sclerotic changes of the superficial dermis, and a bandlike lymphocytic infiltrate in the underlying dermis. The disease occurs in all age groups but is most common in postmenopausal women. It may also be encountered elsewhere on the skin. Its pathogenesis is uncertain, but the presence of activated T cells in the subepithelial inflammatory infiltrate and the increased frequency of autoimmune disorders in affected women suggest that an autoimmune reaction is involved. Although lichen sclerosus is not itself a premalignant lesion, women with symptomatic lichen sclerosus have a slightly increased chance of developing squamous cell carcinoma of the vulva.

Squamous Cell Hyperplasia

Previously called hyperplastic dystrophy or lichen simplex chronicus, squamous cell hyperplasia is a nonspecific condition resulting from rubbing or scratching of the skin to relieve pruritus. Clinically it presents as leukoplakia, and histologic examination reveals thickening of the epidermis (acanthosis) and hyperkeratosis (see Fig. 22.5B ). Lymphocytic infiltration of the dermis is sometimes present. The hyperplastic epithelium may show mitotic activity but lacks cellular atypia. While squamous cell hyperplasia is not considered premalignant, it is sometimes present at the margins of vulvar cancers.

Condyloma Acuminatum

Condylomata acuminata are benign genital warts caused by low-risk HPV, mainly types 6 and 11. They may be solitary, but are more frequently multifocal, and they may involve vulvar, perineal, and perianal regions as well as the vagina and, less commonly, the cervix. The lesions are identical to those found on the penis and around the anus in males ( Chapter 21 ). On histologic examination, they consist of papillary, exophytic, treelike cores of stroma covered by thickened squamous epithelium ( Fig. 22.6A ). The surface epithelium shows characteristic viral cytopathic changes referred to as koilocytic atypia (see Fig. 22.6B ), which manifest as nuclear enlargement, hyperchromasia, and a cytoplasmic perinuclear halo (see the Cervix section later in this chapter). Condylomata acuminata are not precancerous lesions. HPV vaccines (described later) provide excellent protection against infection by low-risk HPV and genital warts.

Vulvar Intraepithelial Neoplasia and Vulvar Carcinoma

Carcinoma of the vulva is an uncommon malignant neoplasm (approximately one-eighth as frequent as cervical cancer) representing about 3% of all genital cancers in the female; approximately two-thirds occur in women older than 60 years of age. Squamous cell carcinoma is the most common histologic type of vulvar cancer. In terms of etiology, pathogenesis, and histologic features, vulvar squamous cell carcinomas are divided into two groups:

• Basaloid and warty carcinomas are related to infection with high-risk HPVs, most commonly HPV-16. These are less common (30% of cases) and occur in younger women (average 60 years of age).

• Keratinizing squamous cell carcinomas are unrelated to HPV infection. These are more common (70% of cases) and occur in older women (average 75 years of age).

Basaloid and warty carcinomas develop from an in situ precursor lesion called classic vulvar intraepithelial neoplasia (VIN). This form of VIN occurs mainly in reproductive age women and includes lesions formerly designated as carcinoma in situ or Bowen disease. The risk factors for VIN are the same as those associated with cervical squamous intraepithelial lesions (e.g., young age at first intercourse, multiple sexual partners, male partner with multiple sexual partners), as both are related to HPV infection. VIN is frequently multicentric, and 10% to 30% of patients with VIN also have vaginal or cervical HPV-related lesions. Spontaneous regression of classic VIN has been reported, usually in younger women. The risk of progression to invasive carcinoma is higher in women who are older than 45 years of age or who are immunosuppressed.

Keratinizing squamous cell carcinoma occurs most often in individuals with long-standing lichen sclerosus or squamous cell hyperplasia and is not related to HPV. It arises from a precursor lesion referred to as differentiated vulvar intraepithelial neoplasia (differentiated VIN). It is postulated that chronic epithelial irritation in lichen sclerosus or squamous cell hyperplasia may contribute to a gradual evolution to the malignant phenotype, presumably through acquisition of driver mutations in oncogenes and tumor suppressor genes. In line with this idea, some investigators have reported a high frequency of TP53 mutations in differentiated VIN.

Morphology

The lesions of classic VIN may be discrete and white (hyperkeratotic) or slightly raised and pigmented. Microscopically, it is characterized by epidermal thickening, nuclear atypia, increased mitoses, and lack of cellular maturation ( Fig. 22.7A ), features analogous to those seen in cervical squamous intraepithelial lesions (SIL, see the Cervix section later in this chapter). Invasive carcinomas that arise from classic VIN may be exophytic or indurated with central ulceration. On histologic examination, basaloid carcinoma (see Fig. 22.7B ) consists of nests and cords of small, tightly packed cells that lack maturation and resemble the basal layer of the normal epithelium. The tumor may have foci of central necrosis. By contrast, warty carcinoma is characterized by exophytic, papillary architecture and prominent koilocytic atypia.

Differentiated VIN is characterized by marked atypia of the basal layer of the squamous epithelium and normal-appearing differentiation of the more superficial layers ( Fig. 22.8A ). Invasive keratinizing squamous cell carcinomas that arise in differentiated VIN contain nests and tongues of malignant squamous epithelium with prominent central keratin pearls (see Fig. 22.8B ).

The risk of cancer development in VIN depends on duration and extent of disease, and the immune status of the patient. Invasive carcinomas associated with lichen sclerosus, squamous cell hyperplasia, and differentiated VIN may develop in an insidious fashion and may be misinterpreted as dermatitis or leukoplakia for long periods. Once invasive cancer develops, the risk of metastatic spread is determined by the size of tumor, the depth of invasion, and whether there is lymphatic invasion. The initial spread is to inguinal, pelvic, iliac, and periaortic lymph nodes. Ultimately, hematogenous dissemination to the lungs, liver, and other internal organs may occur. Patients with lesions less than 2 cm in diameter have a 90% 5-year survival rate after treatment with vulvectomy and lymphadenectomy; however, larger lesions with lymph node involvement have a poor prognosis.

Papillary Hidradenoma

Papillary hidradenoma presents as a sharply circumscribed nodule, most commonly on the labia majora or interlabial folds, and may be confused clinically with carcinoma because of its tendency to ulcerate. Its histologic appearance is identical to that of intraductal papilloma of the breast and consists of papillary projections covered by two cell layers, an upper layer of columnar secretory cells and a deeper layer of flattened myoepithelial cells. These myoepithelial elements are characteristic of sweat glands and sweat gland tumors ( Fig. 22.9 ).

Extramammary Paget Disease

This curious and rare lesion of the vulva is similar in its manifestations to Paget disease of the breast ( Chapter 23 ). In the vulva, it presents as a pruritic, red, crusted, maplike area, usually on the labia majora.

Morphology

Paget disease is a distinctive intraepithelial proliferation of malignant cells. Paget cells are larger than surrounding keratinocytes and are seen singly or in small clusters within the epidermis ( Fig. 22.10A ). The cells have pale cytoplasm containing mucopolysaccharide that stains with periodic acid–Schiff (PAS), Alcian blue, or mucicarmine stains. In addition, unlike squamous epithelium, the cells express cytokeratin 7 (see Fig. 22.10B ). Ultrastructurally, Paget cells display apocrine, eccrine, and keratinocyte differentiation and presumably arise from multipotent cells found within the mammary gland–like ducts of the vulvar skin.

In contrast to Paget disease of the nipple, in which 100% of patients have an underlying ductal breast carcinoma, vulvar Paget is typically not associated with underlying cancer and is confined to the vulvar epidermis. Treatment consists of wide local excision, which is necessary because Paget cells spread laterally within the epidermis and may be present beyond the confines of the grossly visible lesion. Intra-epidermal Paget disease may persist for many years or even decades without invasion or metastases. In the rare instances when invasion develops, the prognosis is poor.

Key Concepts

• Approximately 30% of vulvar cancers are caused by infection with high-risk HPVs, principally HPV-16. These cancers develop from an in situ lesion termed classic vulvar intraepithelial neoplasia (classic VIN).

• Most vulvar cancers (70%) are not related to HPV and develop in a background of lichen sclerosus or squamous cell hyperplasia from the premalignant lesion called differentiated vulvar intraepithelial neoplasia (differentiated VIN).

Vaginal Intraepithelial Neoplasia and Squamous Cell Carcinoma

Virtually all primary carcinomas of the vagina are squamous cell carcinomas associated with high-risk HPV infection. Vaginal carcinoma is extremely uncommon (about 0.6 per 100,000 women yearly) and accounts for about 1% of malignant neoplasms in the female genital tract. The greatest risk factor is a previous carcinoma of the cervix or vulva; 1% to 2% of women with an invasive cervical carcinoma eventually develop a vaginal squamous cell carcinoma. Squamous cell carcinoma of the vagina arises from a premalignant lesion, vaginal intraepithelial neoplasia, analogous to cervical squamous intraepithelial lesion (SIL; see the Cervix section later in this chapter). Most often the invasive tumor affects the upper vagina, particularly the posterior wall at the junction with the ectocervix. The lesions in the lower two-thirds of the vagina metastasize to the inguinal nodes, whereas lesions in the upper vagina tend to spread to regional iliac nodes.

Embryonal Rhabdomyosarcoma

Also called sarcoma botryoides, this uncommon vaginal tumor composed of malignant embryonal rhabdomyoblasts is most frequently found in infants and children younger than 5 years of age. These tumors tend to grow as polypoid, rounded, bulky masses that have the appearance and consistency of grapelike clusters (hence the designation botryoides, or grapelike) ( Fig. 22.11 ). The tumor cells are small and have oval nuclei, with small protrusions of cytoplasm from one end, resembling a tennis racket. Rarely, striations (indicative of muscle differentiation) can be seen within the cytoplasm. Beneath the vaginal epithelium, the tumor cells are crowded in a so-called cambium layer, but in the deep regions they lie within a loose edematous fibromyxomatous stroma that may contain many inflammatory cells. Such lesions can be mistaken for benign inflammatory polyps. The tumors tend to invade locally and cause death by penetration into the peritoneal cavity or by obstruction of the urinary tract. Conservative surgery coupled with chemotherapy offer the best hope, particularly in cases diagnosed sufficiently early.

Acute and Chronic Cervicitis

At the onset of menarche, the production of estrogens by the ovary stimulates maturation of the cervical and vaginal squamous mucosa and formation of intracellular glycogen vacuoles in the squamous cells. As these cells are shed, the glycogen provides a substrate for various endogenous vaginal aerobes and anaerobes, but particularly lactobacilli, which are the dominant microbial species in the normal vagina. Lactobacilli produce lactic acid, which maintains the vaginal pH below 4.5, suppressing the growth of other saprophytic and pathogenic organisms. In addition, at low pH, lactobacilli produce bacteriotoxic hydrogen peroxide (H ₂ O ₂ ). If the pH becomes alkaline due to bleeding, sexual intercourse, or vaginal douching, H ₂ O ₂ production by lactobacilli decreases. Antibiotic therapy that suppresses lactobacilli can also cause the pH to rise. In each of these settings, the altered vaginal environment promotes the overgrowth of other microorganisms, which may result in cervicitis or vaginitis. Some degree of cervical inflammation may be found in virtually all women, and it is usually of little clinical consequence. However, infections by gonococci, chlamydiae, mycoplasmas, and HSV may produce significant acute or chronic cervicitis and are important to identify due to their association with upper genital tract disease, complications during pregnancy, and sexual transmission. Marked cervical inflammation produces reparative and reactive changes of the epithelium and shedding of atypical-appearing squamous cells, and therefore may cause an abnormal Pap test result.

Cervical Intraepithelial Neoplasia (Squamous Intraepithelial Lesions)

The classification of cervical precursor lesions has evolved over time, and the terms from the various classification systems are used interchangeably. Hence a brief review of the terminology is warranted. The oldest classification system grouped lesions as having mild dysplasia on one end and severe dysplasia/carcinoma in situ on the other. This was followed by the cervical intraepithelial neoplasia (CIN) classification, with mild dysplasia termed CIN I, moderate dysplasia termed CIN II, and severe dysplasia termed CIN III . Because the decision with regard to patient management is two-tiered (observation vs. surgical treatment), the three-tier classification system has been recently simplified to a two-tiered system, with CIN I renamed low-grade squamous intraepithelial lesion (LSIL) and CIN II and CIN III combined into one category referred to as high-grade squamous intraepithelial lesion (HSIL) ( Table 22.1 ).

LSIL does not progress directly to invasive carcinoma, and, in fact, most cases regress spontaneously; only a small percentage progress to HSIL. LSIL represents a productive HPV infection in which there is a high level of viral replication, but only mild alterations in the growth of host cells. For these reasons, LSIL is not treated like a premalignant lesion. LSIL is approximately ten times more common than HSIL.

By contrast to LSIL, HSIL is considered to be at high risk for progression to carcinoma. In HSIL, there is a progressive deregulation of the cell cycle by HPV, which results in increased cellular proliferation, decreased or arrested epithelial maturation, and a lower rate of viral replication as compared with LSIL. Derangement of the cell cycle in HSIL may become irreversible and lead to a fully transformed malignant phenotype.

Morphology

The diagnosis of SIL is based on identification of nuclear atypia characterized by nuclear enlargement, hyperchromasia (dark staining), coarse chromatin granules, and variation in nuclear size and shape ( Fig. 22.14 ). The nuclear changes are often accompanied by cytoplasmic “halos.” At an ultrastructural level, these “halos” consist of perinuclear vacuoles, a cytopathic change created in part by an HPV-encoded protein E5 that localizes to the membranes of the endoplasmic reticulum. Nuclear alterations associated with perinuclear halos are termed koilocytic atypia. 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 immature squamous cells are confined to the lower one-third of the epithelium, the lesion is called LSIL; if they expand to the upper two-thirds of the epithelial thickness, it is called HSIL.

The histologic features of LSIL correlate with HPV replication and changes in host cell growth and gene expression ( Fig. 22.15 ). The highest viral loads (assessed by in situ hybridization for HPV DNA; see Fig. 22.15B ) are found in maturing keratinocytes in the upper half of the epithelium. HPV E6 and E7 proteins prevent cell cycle arrest. As a result, cells in the upper portion of the epithelium express markers of actively dividing cells, such as Ki-67 (see Fig. 22.15C ), that are normally confined to the basal layer of the epithelium. Disturbed growth regulation also leads to overexpression of p16, a cyclin-dependent kinase inhibitor (see Fig. 22.15D ). Both Ki-67 and p16 staining are highly correlated with HPV infection and are useful for confirmation of the diagnosis in equivocal cases of SIL.

More than 80% of LSILs and 100% of HSILs are associated with high-risk HPVs, with HPV-16 being the most common HPV type in both lesions. Table 22.2 shows rates of regression and progression of SILs within a 2-year follow-up. Although the majority of HSILs develop from LSILs, approximately 20% of cases of HSIL develop de novo, independent of any preexisting LSIL. The rates of progression are by no means uniform, and although HPV type—especially HPV 16—is associated with increased risk, it is difficult to predict the outcome in an individual patient. These findings underscore that the risk of precursor lesions and cancer is conferred only in part by HPV type. Progression to invasive carcinoma, when it occurs, on average takes place over several decades.

Cervical Carcinoma

The average age of patients with invasive cervical carcinoma is between 45 and 50 years. Squamous cell carcinoma is the most common histologic subtype, accounting for approximately 80% of cases. The second most common tumor type is adenocarcinoma, which constitutes about 15% of cervical cancer cases and develops from a precursor lesion called adenocarcinoma in situ. Adenosquamous and neuroendocrine carcinomas are rare cervical tumors that account for the remaining 5% of cases. All of the aforementioned tumor types are caused by high-risk HPVs. The progression time from in situ to invasive adenosquamous and neuroendocrine carcinomas is shorter than in squamous cell carcinoma, and patients with these tumors often present with advanced disease and have a less favorable prognosis.

Morphology

Invasive cervical carcinoma may manifest as fungating (exophytic) or infiltrative masses. Squamous cell carcinoma is composed of nests and tongues of malignant squamous epithelium, either keratinizing or nonkeratinizing, which invade the underlying cervical stroma ( Fig. 22.16A–B ). Adenocarcinoma is characterized by proliferation of glandular epithelium composed of malignant endocervical cells with large, hyperchromatic nuclei and relatively mucin-depleted cytoplasm, resulting in a dark appearance of the glands, as compared with the normal endocervical epithelium ( Fig. 22.17A–B ). Adenosquamous carcinoma is composed of intermixed malignant glandular and squamous epithelium. Neuroendocrine cervical carcinoma has an appearance similar to small cell carcinoma of the lung ( Chapter 15 ) but differs in being positive for high-risk HPVs.

Advanced cervical carcinoma spreads by direct extension to contiguous tissues, including paracervical soft tissue, urinary bladder, ureters (resulting in hydronephrosis), rectum, and vagina. Lymphovascular invasion results in local and distant lymph nodes metastases. Distant metastases may also be found in the liver, lungs, bone marrow, and other organs.

Cervical cancer is staged as follows:

• Stage 0— Carcinoma in situ (CIN III, HSIL)

• Stage I— Carcinoma confined to the cervix

  • Ia—Preclinical carcinoma, that is, diagnosed only by microscopy

  • Ia1—Stromal invasion no deeper than 3 mm and no wider than 7 mm (so-called superficially invasive squamous cell carcinoma)

  • Ia2—Maximum depth of invasion of stroma deeper than 3 mm and no deeper than 5 mm taken from base of epithelium; horizontal invasion no more than 7 mm

  • Ib—Histologically invasive carcinoma confined to the cervix and greater than stage Ia2

• Stage II— Carcinoma extends beyond the cervix but not to the pelvic wall. Carcinoma involves the vagina but not the lower third.

• Stage III— Carcinoma has extended to the pelvic wall. On rectal examination, there is no cancer-free space between the tumor and the pelvic wall. The tumor involves the lower third of the vagina.

• Stage IV— Carcinoma has extended beyond the true pelvis or has involved the mucosa of the bladder or rectum. This stage also includes cancers with metastatic dissemination.

Anovulatory Cycle

The most frequent cause of dysfunctional bleeding is anovulation (failure to ovulate). Anovulatory cycles result from hormonal imbalances and are most common at menarche and in the perimenopausal period. Less commonly, anovulation is the result of the following:

• Endocrine disorders, such as thyroid disease, adrenal disease, or pituitary tumors

• Ovarian lesions, such as a functioning ovarian tumor (granulosa cell tumors) or polycystic ovaries (see the Ovaries section later in this chapter)

• Generalized metabolic disturbances , such as obesity, malnutrition, or other chronic systemic diseases

Failure of ovulation results in excessive endometrial stimulation by estrogens that is unopposed by progesterone. Under these circumstances, the endometrial glands undergo mild architectural changes, including cystic dilation, that usually resolve due to a subsequent ovulatory cycle. However, repeated anovulation may result in bleeding that, in certain clinical situations, may prompt an endometrial biopsy. In this setting, biopsies reveal stromal condensation and eosinophilic epithelial metaplasia, features similar to those seen in menstrual endometrium. However, unlike menstrual endometrium, progesterone-dependent morphologic features (e.g., glandular secretory changes and stromal pre-decidualization) are absent because the source of progesterone, the corpus luteum, does not develop without ovulation. Most commonly, the endometrium is composed of pseudostratified glands and contains scattered mitotic figures (see Fig. 22.20A ). More severe consequences of repeated anovulation are discussed in the Endometrial Hyperplasia section later in this chapter.

Acute Endometritis

Acute endometritis is uncommon and limited to bacterial infections that arise after delivery or miscarriage. Retained products of conception are the usual predisposing factors; the causative agents include group A hemolytic streptococci, staphylococci, and other bacteria. The inflammatory response is chiefly limited to the stroma and is entirely nonspecific. Removal of the retained gestational products by curettage and antibiotic therapy promptly clears these infections.

Chronic Endometritis

Chronic endometritis occurs in association with the following disorders:

• Chronic pelvic inflammatory disease

• Retained gestational tissue, postpartum or postabortion

• Intrauterine contraceptive devices

• Tuberculosis, either from miliary spread or, more often, from drainage of tuberculous salpingitis. Endometrial tuberculosis is rare in high income countries.

The diagnosis of chronic endometritis rests on the identification of plasma cells in the stroma (see Fig. 22.20B ), which are not seen in normal endometrium. In about 15% of cases, no cause is apparent. Some women with this so-called “nonspecific” chronic endometritis have gynecologic complaints such as abnormal bleeding, pain, discharge, and infertility. Chlamydia may be involved and is commonly associated with both acute (e.g., neutrophils) and chronic (e.g., lymphocytes, plasma cells) inflammatory infiltrates. The responsible organisms may not be detected by culture. If infection is suspected on clinical grounds, antibiotic therapy is indicated, even in the face of negative cultures, as it may prevent other sequelae (e.g., salpingitis).