Squamous cell hyperplasia

Development

The development of the female genital tract is relevant to both anomalies in this region and the histogenesis of various tumors. The primordial germ cells arise in the wall of the yolk sac by the fourth week of gestation; by the fifth or sixth week they migrate into the urogenital ridge. The mesodermal epithelium of the urogenital ridge then proliferates, to eventually produce the epithelium and stroma of the gonad. The dividing germ cells, which are of endodermal origin, are incorporated into the proliferating mesodermal epithelium to form the ovary.1

A second component of female genital development is the müllerian duct. At about the sixth week, invagination and subsequent fusion of the coelomic lining epithelium forms the lateral müllerian (or paramesonephric) ducts. Müllerian ducts progressively grow caudally to enter the pelvis, where they swing medially to fuse with the urogenital sinus at the müllerian tubercle (Fig. 22-1A). Further caudal growth brings these fused ducts into contact with the urogenital sinus, formed when the cloaca is subdivided by the urorectal septum. The urogenital sinus eventually becomes the vestibule of the external genitalia (Fig. 22-1B). Normally the unfused portions mature into the fallopian tubes, the fused caudal portion develop into the uterus and upper vagina, and the urogenital sinus forms the lower vagina and vestibule. Consequently, the entire lining of the uterus and tubes as well as the ovarian surface is ultimately derived from coelomic epithelium (mesothelium). This close embryologic relationship between the mesothelium and müllerian system may be reflected in adult life in the form of benign (endometriosis) and malignant (endometrioid and serous neoplasia) lesions, which may arise in both the surface of the ovaries and the peritoneal surfaces. In addition, it explains the morphologic overlap of tumors arising in the various parts of the female genital tract (e.g., serous, endometrioid, clear cell).

The epithelium of the vagina, cervix, and urinary tract is formed by induction of basal cells from the underlying stroma, which undergo squamous and urothelial differentiation.2 A portion of these cells remains uncommitted, forming the reserve cells of the cervix. The latter are capable of both squamous and columnar cell differentiation.3

Figure 22-1 Embryology and anatomy of the female genital tract. A, Early in development the mesonephric (blue) and müllerian (red) ducts merge at the urogenital sinus to form the müllerian tubercle. B, By birth the müllerian ducts have fused to form the fallopian tubes, uterus, and endocervix (red), merging with the vaginal squamous mucosa. The mesonephric ducts regress but may be found as a remnant in the ovary, adnexa, and cervix (Gartner duct). (Adapted from Langman J: Medical Embryology. Baltimore, Williams and Wilkins, 1981.)

In males, müllerian inhibitory substance4 from the developing testis causes regression of the müllerian ducts, and the paired wolffian (or mesonephric) ducts form the epididymis and the vas deferens. Normally the mesonephric duct regresses in the female, but remnants may persist into adult life as epithelial inclusions adjacent to the ovaries, tubes, and uterus. In the cervix and vagina these rests may be cystic and are termed Gartner duct cysts. Many of the events in the formation of the internal and external genitalia and their epithelial coverings result from reciprocal epithelial-stromal signaling, leading to mesenchymal remodeling and changes in epithelial cell fate.2,5

Anatomy

During active reproductive life, the ovaries measure about 4 × 2.5 × 1.5 cm in dimension. The ovary is divided into a cortex and a medulla. The cortex consists of a layer of closely packed stromal cells and a thin covering of relatively acellular collagenous connective tissue. Follicles in varying stages of maturation are found within the outer cortex. With each menstrual cycle, one follicle develops into a graafian follicle, which is transformed into a corpus luteum following ovulation. Corpora lutea ranging from recent to senescent (corpora albicans) may be found in the cortex of the adult ovary.

The medulla of the ovary consists of loosely arranged mesenchymal tissue and contains remnants of the mesonephric duct (rete ovarii) and small clusters of round to polygonal, epithelioid cells (hilus cells) around vessels and nerves. These hilus cells are vestigial remains of the gonad from its primitive "ambisexual" phase, are steroid producing, and resemble the interstitial cells of the testis. Rarely, these cells give rise to masculinizing tumors (hilar cell tumors).

The fallopian tube mucosa is composed of numerous delicate papillary folds (plica) consisting of three cell types: ciliated columnar cells; nonciliated, columnar secretory cells; and so-called intercalated cells, which may simply represent inactive secretory cells.

The uterus varies in size depending on the age and parity of the individual. It weighs about 50 gm and measures about 8.0 × 6.0 × 3.0 cm in nulliparous reproductive age women. Following pregnancies, uteri are slightly larger (up to 70 gm in weight), then diminish to half their weight and dimension following menopause.

Figure 22-2 Schematic of the cervical transformation zone where squamous and endocervical columnar epithelia coexist undergoing metaplasia ("transformation") from glandular to squamous differentiation.

The uterus has three distinctive anatomic and functional regions: the cervix, the lower uterine segment, and the corpus. The cervix is further divided into the vaginal portio (ectocervix) and the endocervix. The portio is visible to the naked eye on vaginal examination and is covered by a stratified nonkeratinizing squamous epithelium continuous with the vaginal vault. The squamous epithelium converges centrally at a small opening termed the external os. In the nulliparous woman, this os is virtually closed. Just cephalad from the os is the endocervix, which is lined by columnar, mucus-secreting epithelium that dips down into the underlying stroma to produce endocervical glands. The point at which the squamous and endocervical mucinous columnar epithelium meet is termed the squamocolumnar junction (Fig. 22-2). The position of the junction is variable because of both the cervical anatomy and age-related hormonal influences. The differentiation of basal/reserve cells at the squamocolumnar junction into either squamous or glandular cell type governs the microanatomy of this region and results in a progressive upward migration of the squamocolumnar junction with age. The area of the cervix where the columnar epithelium is ultimately replaced by squamous epithelium is termed the transformation zone (see Fig. 22-2). Metaplasia of glandular epithelium to squamous epithelium at the squamocolumnar junction produces multilayered, initially immature, squamous epithelium known as "squamous metaplasia." These immature squamous cells are susceptible to human papillomavirus (HPV) infection and, as discussed below, it is at the squamocolumnar junction where precancerous lesions and cervical carcinomas develop.6

The corpus consists of the endometrium surrounded by the myometrium. Changes in the endometrium that occur during the menstrual cycle (discussed below) are keyed to the rise and fall in the levels of ovarian hormones, and the reader should be familiar with the complex but fascinating interactions among hypothalamic, pituitary, and ovarian factors underlying maturation of ovarian follicles, ovulation, and the menstrual cycle.

The corpus consists of the endometrium surrounded by the myometrium. Changes in the endometrium that occur during the menstrual cycle (discussed below) are keyed to the rise and fall in the levels of ovarian hormones, and the reader should be familiar with the complex but fascinating interactions among hypothalamic, pituitary, and ovarian factors underlying maturation of ovarian follicles, ovulation, and the menstrual cycle.

Diseases of the female genital tract are extremely common and include complications of pregnancy, infections, tumors, and hormonally induced effects. The following discussion presents the pathology of the major diseases that result in clinical problems. Details can be found in current textbooks of gynecologic pathology and clinical obstetrics and gynecology.7,8 The pathologic conditions peculiar to each segment of the female genital tract are discussed separately, but first we briefly review infections and pelvic inflammatory disease because they can affect many of the various anatomic structures concomitantly.

Infections of the Female Genital Tract

A large variety of organisms can infect the female genital tract. Infections with some microorganisms, such as Candida, Trichomonas, and Gardnerella, are extremely common and may cause significant discomfort with no serious sequelae. Others, such as Neisseria gonorrhoeae and Chlamydia infections, are major causes of female infertility, and others still, such as Ureaplasma urealyticum and Mycoplasma hominis infections, are implicated in preterm deliveries. Viruses, especially herpes simplex viruses (HSVs) and human papillomaviruses (HPVs), also account for considerable morbidity; HSVs cause painful genital ulcerations, whereas HPVs are involved in the pathogenesis of cervical, vaginal, and vulvar cancers.

Many of these infections are sexually transmitted, including trichomoniasis, gonorrhea, chancroid, granuloma inguinale, lymphogranuloma venereum, syphilis, mycoplasma, chlamydia, HSV, and HPV.9 Most of these conditions have been considered in Chapter 8. Here we touch only on selected aspects relevant to the female genital tract, including pathogens confined to the lower genital tract (vulva, vagina, and cervix) and those that involve the entire genital tract and are implicated in pelvic inflamatory disease. Papillomaviruses are also discussed in Chapter 7.

Infections of the Lower Genital Tract

Genital herpes simplex virus infection is common and involves, in the order of frequency, the cervix, vagina, and vulva. HSVs are DNA viruses that include two serotypes, HSV-1 and HSV-2. HSV-1 typically results in oropharyngeal infection, whereas HSV-2 usually involves genital mucosa and skin; however, depending on the sexual practices HSV-1 may be detected in the genital region and HSV-2 may cause oral infections as well (see also Chapter 8). The frequency of genital herpes has increased dramatically in the past decades, particularly in teenagers and young women. By the age of 40, 20% of women are seropositive for antibodies against HSV-2.10

Clinical symptoms are seen in about one third of infected individuals. The initial lesions typically develop 3 to 7 days after sexual transmission and consist of red papules that progress to vesicles and then to painful coalescent ulcers. Such lesions are clinically apparent on vulvar skin and mucosa, while cervical or vaginal lesions present with severe purulent discharge and pelvic pain. Lesions around the urethra may cause painful urination and urine retention. The initial infection typically produces systemic symptoms such as fever, malaise, and tender inguinal lymph nodes. The vesicles and ulcers contain numerous viral particles, accounting for the high transmission rate during active infection. The mucosal and skin lesions heal spontaneously in 1 to 3 weeks, but as with herpetic infections elsewhere, the virus migrates to the regional lumbosacral nerve ganglia establishing a latent infection. Because of viral latency, HSV infections persist indefinitely and any decrease in immune system surveillance, as well as stress, trauma, ultraviolet radiation, and hormonal changes, can trigger reactivation of the virus and recurrence of the skin and mucosal lesions.9 As expected, recurrences are much more common in immunosuppressed individuals. In addition, HSV-2 infections are more likely to recur than HSV-1 infections.

Transmission of HSV may occur during both the active and latent phases (subclinical virus shedding), although it is much less likely in asymptomatic carriers. Condoms offer limited protection against HSV infection, since a large genital area may be affected by the virus. As with other sexually transmitted diseases, women are more susceptible to transmission than 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. Cesarian section is warranted in such cases.

The diagnosis is based on typical clinical findings and HSV detection. For diagnosis the purulent exudate is aspirated from the lesions and inoculated into a tissue culture. After 48 to 72 hours the viral cytopathic effect can be seen, and the virus may then be isolated and serotyped. In addition, some laboratories offer more sensitive polymerase chain reaction, enzyme-linked immunosorbent assays, and direct immunofluorescent antibody tests for detection of HSV in the lesional secretions. Individuals with primary, acute-phase 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 may shorten the length of the initial and recurrent symptomatic phase. Several prophylactic and therapeutic vaccine strategies have been developed using animal models, and several clinical trials are currently underway.11

Molluscum contagiosum is a poxvirus infection of the skin and the mucous membranes. There are four types of molluscum contagiosum viruses (MCVs), MCV-1 to -4, with MCV-1 being the most prevalent and MCV-2 being most often sexually transmitted. The infections are common in young children between 2 and 12 years of age and are transmitted through direct contact or shared articles (e.g., towels). Molluscum may affect any area of the skin but is most common on the trunk, arms, and legs. In adults, molluscum infections are typically sexually transmitted and affect the genitals, lower abdomen, buttocks, and inner thighs. The average incubation period is 6 weeks. Diagnosis is based on the characteristic clinical appearance of pearly, dome-shaped papules with a dimpled center. The papules measure 1 to 5 mm in diameter, and their central waxy core contains cells with intracytoplasmic viral inclusions (Fig. 22-3).

Fungal infections, especially those caused by yeasts (Candida), are extremely common; in fact, yeasts are part of many women's normal vaginal microflora and the development of symptomatic candidiasis is typically a result of a disturbance in the patient's vaginal microbial ecosystem. Diabetes mellitus, antibiotics, pregnancy, and conditions resulting in compromised cell-mediated immunity are permissive to symptomatic infection, which manifests itself by marked vulvovaginal pruritus, erythema, swelling, and curdlike vaginal discharge. Severe infection may result in mucosal ulcerations. The diagnosis is made by finding the pseudospores or filamentous fungal hyphae in wet KOH mounts of the discharge or on Pap smear. Even though sexual transmission of yeast infection has been documented, candidiasis is not considered a sexually transmitted disease.

Trichomonas vaginalis is a large, flagellated ovoid protozoan that can be readily identified in wet mounts of vaginal discharge or Pap smear of infected patients. The infection is usually transmitted by sexual contact and develops within 4 days to 4 weeks. The patients may be asymptomatic or may complain of yellow, frothy vaginal discharge, vulvovaginal discomfort, dysuria (painful urination), and dyspareunia (painful intercourse). The vaginal and cervical mucosa typically has a fiery-red appearance, with marked dilatation of cervical mucosal vessels resulting in characteristic colposcopic appearance of "strawberry cervix."

Gardnerella vaginalis is a gram-negative bacillus that is implicated as the main cause of bacterial vaginosis (vaginitis). Patients typically present with thin, green-gray, malodorous (fishy) vaginal discharge. Pap smears reveal superficial and intermediate squamous cells covered by a shaggy coat of multiple coccobacilli. Bacterial cultures in such cases reveal G. vaginalis and other bacteria including anaerobic peptostreptococci and aerobic α-hemolytic streptococci. In pregnant patients, bacterial vaginosis has been implicated in premature labor.

Ureaplasma urealyticum and Mycoplasma hominis species account for some cases of vaginitis and cervicitis, and have been implicated in chorioamnionitis and premature delivery in pregnant patients.12

Most Chlamydia trachomatis infections take the form of cervicitis. However, in some patients it ascends to the uterus and fallopian tubes, resulting in endometritis and salpingitis, and thus is one of the causes of pelvic inflammatory disease, as discussed below.

For description of genital lesions caused by Treponema pallidium, see Chapter 8. Description of HPV infections is presented in this chapter under "Cervix", and gonorrhea infections are described below.

Infections Involving The Lower and Upper Genital Tract

Pelvic Inflammatory Disease (PID)

PID is an ascending 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. Gonococcus 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. Besides these two organisms, infections after spontaneous or induced abortions and normal or abnormal deliveries (called puerperal infections) are important causes of PID. In these situations the infections are typically polymicrobial and may be caused by staphylococci, streptococci, coliform bacteria, and Clostridium perfringens.

With gonococcus, inflammatory changes start to appear approximately 2 to 7 days after inoculation. Endocervical mucosa is the most common site of initial involvement. Gonococcal inflammation may also begin in the Bartholin gland and other vestibular, or periurethral, glands. From any of 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 of the female genital tract are thought to spread from the uterus upward through the lymphatics or venous channels rather than on the mucosal surfaces. Therefore, these infections tend to produce less mucosal involvement but more reaction within the deeper layers of the organs.

Morphology. Wherever it occurs, gonococcal disease is characterized by marked acute inflammation largely confined to the superficial mucosa. Smears of the inflammatory exudate disclose the intracellular gram-negative diplococcus; however, definitive diagnosis requires culture, or detection of gonoccocal RNA or DNA. If spread occurs, the endometrium is usually spared for unclear reasons. Once the infection reaches the tubes, an acute suppurative salpingitis ensues. The tubal mucosa becomes congested and diffusely infiltrated by neutrophils, plasma cells, and lymphocytes. Gonococcal lipopolysaccharide and inflammatory mediators such as TNF cause 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 further spill over to the ovary to create a salpingo-oophoritis. Collections of pus within the ovary and tube (tubo-ovarian abscesses) or tubal lumen (pyosalpinx) may occur (Fig. 22-4). In the course of time the infecting organisms may disappear, leaving the sequelae of chronic follicular salpingitis and hydrosalpinx (dilated, fluid-filled fallopian tube). 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 follicular salpingitis. The lumen of such tubes may be impenetrable for the oocyte, resulting in infertility or ectopic pregnancy. Hydrosalpinx develops as a consequence of the fusion of the fimbriae and the subsequent accumulation of the tubal secretions and tubal distention. Hydrosalpinx is another cause of post-PID infertility, since lack of flexible tubal fimbriae prevents uptake of the oocyte after ovulation.

PID caused by staphylococci, streptococci, and the other puerperal invaders tends to have less exudation within the lumen of the tube and less involvement of the mucosa, but a greater inflammatory response 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 remote sequelae of PID include infertility and tubal obstruction, increased risk of ectopic pregnancy, pelvic pain, as well as intestinal obstruction due to adhesions between the bowel and pelvic organs.

In the early stages, gonococcal infections are readily controlled with antibiotics, although penicillin-resistant strains have regrettably emerged. When the infection becomes walled off in tubo-ovarian abscesses, it is difficult to achieve sufficient levels of antibiotics within such infectious foci and it sometimes becomes necessary to remove the organs surgically. Postabortion and postpartum PIDs are also amenable to treatment with antibiotics but are far more difficult to control than the gonococcal infections because of the broad spectrum of pathogens that may be involved.

VULVA

Diseases of the vulva in the aggregate constitute only a small fraction of gynecologic practice. Many inflammatory dermatologic diseases that affect skin elsewhere on the body may also occur on the vulva, such as psoriasis, eczema, and allergic dermatitis. The vulva is more prone to skin infections, because it is constantly exposed to secretions and moisture. Nonspecific vulvitis is particularly likely to occur in the setting of immunosuppression. Most skin cysts (epidermal inclusion cysts) and skin tumors can also occur in the vulva. Here we discuss disorders particular to the vulva, including Bartholin cyst, non-neoplastic epithelial disorders, benign exophytic lesions, and tumors of the vulva.

Bartholin Cyst

Infection of the Bartholin gland produces an acute inflammation within the gland (adenitis) and may result in an abscess. Bartholin duct cysts are relatively common, occur at all ages, and result from obstruction of the duct by an inflammatory process. The resulting cysts are lined by the ductal squamous metaplastic and/or epithelium. They may become large, up to 3 to 5 cm in diameter, and produce pain and local discomfort. Bartholin duct cysts are either excised or opened permanently (marsupialization).

Non-Neoplastic Epithelial Disorders

A heterogeneous group of lesions of the vulva presents as opaque, white, plaquelike mucosal thickening that may produce itching (pruritus) and scaling. Because of their appearance, these disorders have traditionally been termed leukoplakia by clinicians. This is a non-specific descriptive term, as white plaques may represent a variety of benign, premalignant, or malignant lesions including (1) inflammatory dermatoses (e.g., psoriasis, chronic dermatitis); (2) vulvar intraepithelial neoplasia, Paget disease, or even invasive carcinoma; and (3) epithelial disorders of unknown etiology. Excluding neoplasms and specific disease entities, non-neoplastic epithelial disorders of unknown etiology are classified into two categories: (1) lichen sclerosus and (2) squamous cell hyperplasia (also known as lichen simplex chronicus). The two disorders may coexist and the lesions are often multiple, making their clinical management particularly difficult.

LICHEN SCLEROSUS

This lesion is characterized by thinning of the epidermis and disappearance of rete pegs, hydropic degeneration of the basal cells, superficial hyperkeratosis, and dermal fibrosis with a scant perivascular, mononuclear inflammatory cell infiltrate (Fig. 22-5). The lesions appear clinically as smooth, white plaques or papules that in time may extend and coalesce. The surface is smoothed out and sometimes resembles parchment. When the entire vulva is affected, the labia become somewhat atrophic and stiffened, and the vaginal orifice is constricted. It occurs in all age groups but is most common in postmenopausal women. It may also be encountered elsewhere on the skin. The pathogenesis is uncertain, but the presence of activated T cells in the subepithelial inflammatory infiltrate and the increased frequency of autoimmune disorders in these women suggests an autoimmune reaction may be involved. Although the lesion in lichen sclerosus is not pre-malignant by itself, women with symptomatic lichen sclerosus have a somewhat increased chance of developing squamous cell carcinoma in their lifetime.13

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. It is marked by epithelial thickening, expansion of the stratum granulosum, and significant surface hyperkeratosis. It appears clinically as an area of leukoplakia. The epithelium may show increased mitotic activity in both the stratum basalis and spinosum. Leukocytic infiltration of the dermis is sometimes pronounced. The hyperplastic epithelial changes show no atypia (see Fig. 22-5B). There is generally no increased predisposition to cancer, but suspiciously, lichen simplex chronicus is often present at the margins of established cancer of the vulva.

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