Diseases of the Vagina
The vagina, like other orifices that interface between the external environment and the interior milieu, acts as a barrier to many potentially invasive microorganisms. It is, thus, not surprising that the vagina is the site of a variety of infections, both sexually and nonsexually transmitted, and this, in fact, represents the predominant type of pathology of this organ. In contrast, neoplasms are relatively unusual in this site, which is somewhat unexpected in view of the relationship between infection (e.g., human papillomavirus infection) and the development of carcinoma of the vulva and cervix.
The vagina, like other orifices that interface between the external environment and the interior milieu, acts as a barrier to many potentially invasive microorganisms. It is, thus, not surprising that the vagina is the site of a variety of infections, both sexually and nonsexually transmitted, and this, in fact, represents the predominant type of pathology of this organ. In contrast, neoplasms are relatively unusual in this site, which is somewhat unexpected in view of the relationship between infection (e.g., human papilloma virus infection) and the development of carcinoma of the vulva and cervix.
Because of its profound effects on the development of the vagina, the pathology of in utero diethylstilbestrol (DES) exposure has been integrated into the Developmental Disorders and Malignant Neoplasms sections of this chapter. This well-intended therapy for women with a history of early pregnancy loss had serious and wholly unexpected consequences that prompted research that elucidated many interrelationships among embryology, anatomy, physiology, and neoplasia of the vagina. The astute reader will note, however, that the failure to identify many aspects relating to the pathogenesis of numerous other diseases of the vagina reflects our current state of ignorance.
The müllerian ducts first appear as funnel-shaped openings of the coelomic epithelium in the mesonephric ridge at about postconception day 37 (Cunha 1975). They grow caudally as paired tubes, extending to meet the posterior wall of the urogenital sinus. At about day 54, the caudal portions of the müllerian ducts fuse, forming a straight uterovaginal canal that is lined by simple columnar epithelium. The uterovaginal canal continues to elongate caudally until about day 66. Shortly thereafter, the epithelium from the caudal tip of the canal to the external cervical os changes to a stratified squamous type; this results from a migration of squamous cells from the urogenital sinus, rather than from squamous metaplasia of the native müllerian columnar epithelium (Robboy et al. 1982a). Continued stratification of the squamous epithelial lining progressively occludes the more caudal portion of the canal, leading to the development of a solid vaginal plate. In the 16th week, the squamous epithelium of the vagina and ectocervix begins to mature, becoming glycogenated and thickened. Desquamation subsequently results in the canalization of the vaginal plate. Vaginal development is essentially complete by the 18th–20th week. A band of subepithelial stroma extending from the endocervix to the vulva has been described, but the role of the vaginal stroma in induction of mucosal changes remains unclear (Cunha 1975, Roberts et al. 1988).
In the past, our knowledge of vaginal embryology was derived from classic dissections of the fetus. Several experiments of nature in humans (in utero exposure to DES, transverse vaginal septation, and partial vaginal agenesis) and in mice (testicular feminization syndrome and agenesis of the lower vagina (Cunha 1975) as well as studies using human fetal grafts transplanted into the nude mouse (Cunha et al. 1987) have provided the opportunity for elegant studies of altered development. Such studies reaffirm that the vagina is of dual origin, with a native lining of müllerian columnar cells that are retained unless there is a contribution of squamous cells from the urogenital sinus.
Blood is supplied to the vagina primarily by branches of the internal iliac artery, including the uterine, vaginal, middle rectal, and internal pudendal arteries. Extensive anastomoses provide alternate routes of flow, which minimize the possibility of ischemic damage. A complex network of veins surrounds the vagina, forming a plexus with the uterine, pudendal, and rectal veins, which drain into the interior iliac vein.
The lymphatic drainage of the vagina is complex and variable. The lymphatics of the proximal anterior vagina and vaginal vault join those of the cervix and drain primarily into the external iliac lymph nodes. The posterior portion of the vagina drains into the inferior gluteal, sacral, and anorectal lymph nodes, whereas the distal part of the vagina, like the vulva, drains into the femoral lymph nodes. It is important to note that, as a consequence of extensive anastomotic channels, any pelvic, anorectal, or femoral node may be involved in the lymphatic drainage of any part of the vagina.
The innervation of the vagina is principally from the superior hypogastric plexus of the autonomic nervous system. This plexus bifurcates and is joined by branches of the second through fifth sacral nerves, forming the pelvic plexuses.
Histology and Physiology
Variable quantities of glycogen may be present in the intermediate and superficial cell layers. The glycogen accumulates initially in a perinuclear location within intermediate cells, resulting in a clear zone around the nucleus. This appearance may cause confusion with the perinuclear clearing of koilocytes. However, the presence of nuclear membrane irregularity in koilocytes and the characteristic location of these normal cells in the middle rather than superficial third of the epithelium are helpful distinguishing features. Melanocytes have been identified as a normal constituent of the basal layer in about 3% of women.
There are few data concerning vaginal function during coitus or parturition (Masters 1960). Distension and lengthening of the proximal two thirds of the vagina occurs during the early phases of sexual response, followed by constriction of the distal third. The anterior portion of the levator ani, the pubococcygeus muscle, appears to be involved in orgasmic function, but the mechanism is speculative (Masters 1960; Senekjian et al. 1986). Functional MRI has provided evidence that the vagus nerve may be either a primary or secondary pathway for nerve impulse conduction during vaginal orgasm (Komisaruk et al. 2005). Even the source of vaginal fluids that are present during arousal has been disputed. Glands are not normally present in the vagina, and candidate sources include secretions from sebaceous, sweat, Bartholin, and Skene glands or the endocervix. Fine droplets appear scattered throughout the rugal folds of the vaginal wall during arousal, followed by a rapid coalescence (Masters 1960). The fluid is believed to represent a transudate resulting from associated vasoconstriction within the venous plexus (Masters 1960). The fluid is usually acidic, with a pH around 4.6, but the pH rises during the sexual response. This fluid contains a variety of enzymes, enzyme inhibitors, and immunoglobulins, which may play a role in the liquefaction of coagulated semen and capacitation of spermatocytes or have antimicrobial activity. The immunoglobulin A levels are highest during the late proliferative phase (Hill 1984), but the significance of this observation is unclear. During pregnancy and immediately postpartum, edema, vascular congestion, and loss of collagen have been noted in the lamina propria, which may serve to increase elasticity of vaginal tissues during delivery.
Lesions Related to In Utero Exposure to DES
Diethylstilbestrol and the chemically related drugs hexestrol and dienestrol are synthetic, nonsteroidal estrogens that were administered frequently to gravid women who were thought to be at high risk for early pregnancy loss during the 1940s through the 1960s. An estimated five to ten million Americans received DES during pregnancy or were exposed to the drug in utero (Giusti et al. 1995). In 1971, the rare development of clear cell adenocarcinoma of the vagina in young women was linked to their in utero exposure to these drugs (Herbst et al. 1971). Subsequently, a number of nonneoplastic changes were identified in the genital tract of daughters of women exposed to DES, such as adenosis, cervical ectropion, various types of cervicovaginal ridges, and structural abnormalities of the uterine corpus and fallopian tube. DES was soon thereafter withdrawn from the market for use during pregnancy.
Gross Structural Changes of the Vagina and Cervix
Vaginal Epithelial Changes: Adenosis and Squamous Metaplasia
Vaginal adenosis and metaplastic squamous epithelium – vaginal epithelial changes (VECs) – are common in DES-exposed females. In the pre-DES era, vaginal adenosis was a clinical rarity, detected only occasionally in women, usually in their 30s or 40s, who often complained of an excessive mucous discharge from the vagina. The demographics are again changing. Adenosis caused by DES exposure has become rare, although acquired adenosis in adult women with vaginal dysplasia treated with topical 5-fluorouracil occasionally has been reported (Dungar and Wilkinson 1995; Goodman et al. 1991). Clinically, adenosis should be suspected when the vaginal mucosa contains red granular spots or patches (Fig. 9) and does not stain with an iodine solution. On colposcopy, adenosis appears as glandular or metaplastic epithelium replacing the native squamous epithelium of the vaginal mucosa.
The Embryologic Basis of Vaginal Adenosis and Cervical Ectropion
The DES experience and the experimental studies it has fostered have provided insights into the development of the normal lower genital tract and the effects caused by prenatal DES exposure (Robboy 1983). In brief, the embryonic squamous epithelium of the urogenital sinus normally extends up the vagina and exocervix to the squamocolumnar junction, replacing the original columnar (müllerian) epithelium lining these organs (Fritsch et al. 2013). Experimental work has suggested that inhibition of p63 by DES may alter the urogenital sinus and müllerian duct epithelial differentiation and result in adenosis (Kurita et al. 2005; Laronda et al. 2012). Further, the stroma of the vaginal wall (like the uterine corpus and fallopian tube) induces the growth of a tuboendometrial-type epithelium, while the stroma of the superficial endocervix favors mucinous columnar epithelium. In DES-exposed fetal organs, the stromal components of the uterine wall fail to segregate normally into an outer layer of smooth muscle and an inner layer of endometrial stroma (Robboy et al. 1982a). Recently, work suggests that DES induces vaginal adenosis by inhibiting the BMP4/activin A-regulated vaginal cell fate decision (Laronda et al. 2013).
Vaginal adenosis is not limited exclusively to women exposed to DES in utero but has also been reported in 2–10% of non-exposed females who have no known risk factors (Chattopadhyay et al. 2001; Ragnarsson-Olding et al. 1993). Adenosis may occur following topical treatment of squamous dysplasia with 5-fluorouracil (Georgiev et al. 2006), but the mechanism by which it induces glandular metaplasia remains unclear.
Imperforate hymen probably represents the most common significant congenital anomaly of the vagina. Its frequency is reported to be about 1 in 2000 female patients. The presence of a thick mucoid secretion that distends the vagina may provide a clue to the diagnosis in the neonate, but often an imperforate hymen is not recognized until puberty, when there is abdominal pain and retention of menstrual detritus (Polasek et al. 1995). If it is not corrected promptly, infertility may result from endometriosis and pelvic adhesions associated with retrograde menstruation (Wheelock et al. 1985). The treatment is surgical, with either a central incision or local excision (Acar et al. 2007). No detailed pathologic description of this condition has been reported.
Complete vaginal agenesis is relatively rare, occurring in about 1 in 5000 female births (Droegemueller et al. 1987; Fujimoto et al. 1997; Van Lingen et al. 1998). Patients typically are identified when being evaluated for primary amenorrhea. As an isolated defect, it results from incomplete caudal development and fusion of the lower part of the müllerian ducts (müllerian dysgenesis). The external genitalia usually appear normal, except for the introitus, where a short blind pouch may be present (Wheelock et al. 1985). Therapy usually involves construction of an artificial vagina. Although this rarely results in a specimen for pathologic examination, the defect often is associated with the absence of the uterus and fallopian tubes (müllerian agenesis or Mayer–Rokitansky–Kuster–Hauser syndrome, the latter being the second most common cause of primary amenorrhea) (Fliegner 1987; Patnaik et al. 2015) and with anomalies of the urinary tract (Opitz 1987). The latter syndrome provides insight into embryologic development and demonstrates that an intact mesonephric duct is required for the growth and caudal lengthening of the müllerian duct during fetal life (Ludwig 1998a, b). Because the gonads are not of müllerian origin, they usually are normal. About 25% of women with vaginal agenesis have a uterus, and they may have complications from retrograde menstruation.
Transverse Vaginal Septum
A transverse vaginal septum is uncommon, with an estimated prevalence of about 1 in 50,000 women (Polasek et al. 1995), and may occur anywhere within the vagina but most frequently at the junction of the cranial and middle third. It presumably results from incomplete migration or excavation of the vaginal plate. A complete vaginal septum results in obstructive symptoms similar to an imperforate hymen, whereas a partial septum may allow passage of menstrual flow but cause dyspareunia or lacerate during childbirth. Patients are typically treated by resection, either vaginally or laparoscopically, with low complication rates and good long-term outcome (Willams et al. 2014). The microscopic appearance of the septum is typically that of a fibrovascular stroma covered on two surfaces by the epithelium. Although the caudal surface is covered by a stratified nonkeratinizing squamous epithelium, the cranial aspect is covered typically by glandular epithelium, as might be predicted from the embryologic development.
Miscellaneous Congenital Disorders
Complete duplication of the vagina with a septum including muscularis extending to the introitus is rare and typically is accompanied by cervical and uterine duplication (Bartlett et al. 1977). Longitudinal septa that lack a muscular layer are more common; they often are clinically asymptomatic. Congenital rectovaginal fistulas often are associated with an imperforate anus. Typically, the anus opens into the posterior caudal portion of the vagina, near the fourchette.
Infectious Inflammatory Disorders
The normal vaginal flora is varied and changes from birth through menarche to menopause. Although it has long been evident that lactobacilli split glycogen to form lactic acid, thus reducing the pH of the vagina, this does not provide a complete explanation for the regulation of the vaginal flora. The ecosystem reflects a delicate balance that includes the interplay of steroid hormones, vascularity, vaginal acidity, and glycogen. It can be upset easily by mechanical, chemical, or hormonal manipulation. Approximately 109 obligate anaerobic and 108 facultative bacteria are present in a gram of vaginal secretion, of which lactobacilli probably are the most common (Mårdh 1991). Three hundred and forty-five organisms were represented in 52 specimens collected from healthy adults, including the following anaerobes, Peptococcus, Bacteroides, Peptostreptococcus, Lactobacillus, and Eubacterium spp., and aerobes, Staphylococcus epidermidis, Corynebacterium spp., and Lactobacillus sp. (Bartlett et al. 1977). The proportion of aerobic organisms decreases about 100-fold during the week before menses. During pregnancy, more lactobacilli and yeast, but fewer anaerobic bacteria, are present (Lindner et al. 1978). On the third day after parturition, there is a dramatic increase in the number of anaerobic bacteria. Postmenopausal women also have a relatively larger proportion of anaerobes, with more lactobacilli recovered from those treated with estrogen (Larsen and Galask 1980). Organisms that at times are associated with vaginitis may colonize the vagina of healthy, asymptomatic women.
Sexually transmitted pathogens
Group B Streptococcus
Herpes simplex virus
Hepatitis B virus
Molluscum contagiosum virus
The clinical diagnosis of vaginitis is frequently based on the presence of a vaginal discharge. Reliance on this finding alone may lead to overdiagnosis, as the production of vaginal fluid is a physiologic event caused by transudation of fluid through the vaginal wall, with additional contributions by cervical and uterine secretions, exfoliated epithelial cells, bacteria, and bacterial products. This event is particularly noticeable at mid-cycle when cervical mucus becomes watery and profuse and often is interpreted erroneously as a “discharge.” Other relatively nonspecific criteria of vaginitis include subjective assessment of the color, odor, quantity, or quality of the discharge. In contrast to the discharge caused by vaginitis, normal vaginal secretions are floccular rather than homogeneous and neither malodorous nor associated with pruritus. Although accurate diagnosis of vaginitis does not require a biopsy, some infectious agents cause highly specific tissue reactions, with which the pathologist should be familiar.
Candida probably is the most common potential or active pathogen in the female genital tract. It can be isolated from the vagina of about 20% of asymptomatic healthy women, and about 70% of women will have a symptomatic candidal infection at some time during their lives (Sobel et al. 1995). C. albicans is found frequently in the colon of healthy individuals, and spread from the contaminated perineum probably is the usual method of introduction of the organism into the vagina (Sobel et al. 1995). Interestingly, fomites from bathtubs or toilet seats do not appear to be a common mechanism for transmission (Andrew et al. 1975). Sexual transmission plays a role in some patients, resulting from either oral–genital or less likely penile–genital transmission (Chapman et al. 1984). Factors associated with an increased risk of developing symptomatic infection include pregnancy, oral contraceptive use, antibiotic therapy, diabetes mellitus, and antibiotic use. Changes in the vaginal flora likely play a role in the development of candidiasis.
Vulvar pruritus is the typical presenting symptom, often accompanied by a white, granular vaginal discharge. The vagina appears reddened, and superficial erosion of the mucosa may be evident after the removal of a pseudomembrane of adherent granular debris.
Saline or potassium hydroxide suspensions of a discharge containing blastospores and pseudohyphae permit a presumptive microscopic diagnosis to be made immediately. Unfortunately, the sensitivity of the wet prep exam is only about 65% (Merkus et al. 1985), and the morphologic appearance is not entirely specific. In one study, Papanicolaou-stained smears demonstrated the organism in 46% of infected patients, compared with 85% for the wet prep and 94% for culture (McLennan et al. 1972). In daily practice, it is the experience of the examiner that seems to be the most critical determinant for accurate recognition of the organism. Definitive identification of the fungus is generally made by culture or polymerase chain reaction (Mardh et al. 2003).
Candidal species other than C. albicans are responsible for about 10–20% of cases of fungal vaginitis (Richart 1986; Sobel et al. 1995), and infection with C. tropicalis or C. glabrata is associated with a high rate of recurrence (Richart 1986). C. glabrata typically produces milder symptoms than C. albicans (Boquet-Jiménez and Alvarez San Cristóbal 1978), but C. glabrata has been reported to cause a severe ulcerative vaginitis-simulating malignancy (Clark et al. 1978). The microscopic appearances of most Candida species are similar, but C. glabrata produces only yeasts (blastospores), which are slightly smaller than those of C. albicans (Boquet-Jiménez and Alvarez San Cristóbal 1978).
Efforts to restore the local environment by topical administration of acetic acid, estrogen, or fermented milk products have been ineffective. In contrast, antimicrobial therapy with metronidazole or intravaginal clindamycin produces clinical cure in most women, further supporting the concept that anaerobes acting with Gardnerella produce bacterial vaginosis (Spiegel et al. 1980). The initiating cause remains unknown, but sexual transmission occurs in many instances (Larsson et al. 1991; Nilsson et al. 1997). Although bacterial vaginosis was previously thought to carry no appreciable morbidity, it recently has been associated with a 3- to 15-fold increased risk of upper genital tract infection, including salpingitis and endometritis (Hillier et al. 1996; Korn et al. 1995; Peipert et al. 1997; Sweet 1995). In addition, the anaerobic bacteria cultured from the endometrium and fallopian tubes of women with asymptomatic endometritis or symptomatic salpingitis were those associated with bacterial vaginosis (Korn et al. 1995; Soper et al. 1994). During pregnancy, bacterial vaginosis significantly increases the likelihood of premature onset of labor and chorioamnionitis (Holst et al. 1994; McGregor et al. 1994; Newton et al. 1997; Soper et al. 1994). A recent study in mice has shown that colonization of the cervicovaginal space by Gardnerella vaginalis induces an immune response, alters the epithelial barrier, and induces cervical remodelling suggesting the bacterium may play a pathobiologic role in premature cervical remodelling leading to preterm birth (Sierra et al. 2018).
Trichomoniasis is responsible for more than 2.5 million infections per year in the United States and about 180 million infections worldwide (Thomason and Gelbart 1989). It is found in about 10% of asymptomatic women and almost 50% of those attending STD clinics (Sweet and Gibbs 1985a). The prevalence among reproductive-aged women in the United States is 3.1% with a significant racial disparity; the prevalence among non-Hispanic black women is approximately ten times higher than among non-Hispanic and Hispanic white women (Sutton et al. 2007). The organism is almost always sexually transmitted (Zhang 1996), although trichomonads reportedly may survive in tap water, soapy water, and chlorinated swimming pools. The mechanism by which Trichomonas causes disease is unknown, but the organisms are found both in the vaginal lumen and adherent to squamous, but not columnar, epithelial cells (Rein and Müller 1990). Invasion of the squamous mucosa does not occur. Trichomonas is a strict anaerobe, and there is frequently an alteration in the associated vaginal flora, with increased anaerobic bacteria (van der Meijden et al. 1988). Although the role of sex steroids is unclear, infection is generally lower in women taking oral contraceptives (Bramley and Kinghorn 1979).
Symptoms of infection include vaginal discharge, intense pruritus, and dyspareunia, with exacerbations often temporally related to menses. However, in one study, only 17% of culture-positive women noted pruritus, and more than one third did not even complain of a vaginal discharge (McLellan et al. 1982). When present, the vaginal discharge usually is copious, homogeneous, yellow-green to gray, and malodorous. Typically, the vaginal mucosa is erythematous, and punctate hemorrhages may be present, particularly on the cervical mucosa, leading to what is unfortunately described as a “strawberry cervix.”
Acquired Immunodeficiency Syndrome
Slightly more than one million persons in the United States are living with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS). Women account for about one quarter of newly reported cases, and heterosexual contact represents the mode of transmission in about 28% of all cases in the United States. It is the fifth leading cause of death among American women 25–44 years of age. There are no gross or histopathologic changes of AIDS specific to the vagina.
Most HIV infections resulting from heterosexual contact have occurred in women who reported only vaginal intercourse (Peterman et al. 1988). The virus has been identified in both semen and cell-free seminal fluid (Lifson 1992). Certain STDs are considered risk factors for sexual transmission of HIV, particularly those that cause ulceration of the vaginal mucosa, facilitating HIV exposure to vascular channels, as well as providing a large number of CD4 lymphocytes and macrophages that contain or could bind HIV at the site of injury (Clemetson et al. 1993). It is estimated that a fivefold to tenfold increase in the risk of heterosexual transmission of HIV is present in those with genital ulcers (de Virgiliis et al. 1985). A twofold to fivefold increase in risk is associated with the presence of an inflammatory or exudative STD, presumably reflecting the presence of microscopic ulcerations or increased concentrations of CD4 lymphocytes in the discharge (Levine et al. 1998; de Virgiliis et al. 1985). Localization of simian immunodeficiency virus (SIV) in dendritic cells of the monkey vagina has been demonstrated in an experimental model, suggesting that heterosexual transmission of HIV may occur across an intact mucosa (Miller et al. 1992). Nevertheless, the precise mechanism by which heterosexual transmission of HIV occurs remains to be defined.
Group B Streptococcus
Group B streptococci (Streptococcus agalactiae) can be found in 5–35% of normal females (Hoogkamp-Korstanje et al. 1982; Yow et al. 1980) and thus are considered to be part of the normal vaginal flora. These bacteria frequently are sexually transmitted (Hill 1984), although they also can ascend from the lower intestinal tract, which may serve as a reservoir (Newton et al. 1996). Although group B streptococcal colonization of the vagina or urethra usually causes little morbidity to the adult female, vaginitis at times may occur (Hill 1984). Histopathologic changes resulting from vaginal infection by group B streptococci have not been well described. More significantly, this organism is a frequent cause of abortion, chorioamnionitis, premature rupture of membranes, perinatal death, and intrapartum and postpartum bacteremia (Regan et al. 1996; Sweet 1995). For reasons that currently are unknown, only a small proportion of colonized mothers or infants develop symptomatic infection (Sweet 1995).
Malacoplakia and Xanthogranulomatous Pseudotumor
Malacoplakia and xanthogranulomatous pseudotumor of the vagina are closely related entities resulting from infection by gram-negative bacilli, usually Escherichia coli (Lin et al. 1979; Strate et al. 1983). Typically, yellow polypoid nodules arise from the vaginal mucosa, at times accompanied by a discharge. The microscopic findings are identical to those described in other body sites and include the presence of large collections of histiocytes with abundant granular to pale foamy cytoplasms (von Hansemann cells), with interspersed plasma cells and lymphocytes. Both intracellular and extracellular, concentrically laminated basophilic masses (Michaelis – Gutmann bodies) are present in variable numbers. The clinical suspicion of tumor may lead the pathologist to the misdiagnosis of a rare neoplasm such as a granular cell tumor, unless care is taken to consider this lesion. The correct diagnosis may be confirmed by the finding of numerous gram-negative rodlike bacteria on tissue Gram stain, on silver stain, or by electron microscopy.
Genital tract tuberculosis is no longer frequent in the United States but remains a significant problem in Third World nations. The vagina is involved in about only 1% of these women, and patients present with localized ulceration (Nogales-Ortiz et al. 1979). Characteristic microscopic features include necrotizing granulomata containing Langhans giant cells underlying an ulcerated epithelium (Coetzee 1972).
Emphysematous vaginitis is a rare entity (about 200 reported cases), characterized by multiple, discrete, gas-filled cystic cavities in the vaginal mucosa. Most patients present with symptoms of vaginal discharge, although some are aware of popping sounds associated with the rupture of the cysts during intercourse. The dramatic presentation and physical findings have prompted an interest disproportionate to the frequency or significance of the disease. There is evidence that it is an unusual manifestation of a common infection in an immunocompromised host (Josey and Campbell 1990; Tjugum et al. 1986). No single organism has been identified as the causative agent, although both Trichomonas vaginalis and Gardnerella vaginalis have been implicated (Gardner and Fernet 1964). Chemical analyses of the lesions have disclosed a wide variety of gases, including ammonia, hydrogen sulfide, nitrogen, oxygen, carbonic acid, and trimethylamine. The microscopic findings are variable, with cysts in the stroma lined by either multinucleated giant cells, squamous cells, or both. A scattering of chronic inflammatory cells accompanies the cysts (Gardner and Fernet 1964; Kramer and Tobin 1987). Bacterial or protozoan production of gas with transmucosal passage into the stroma has been suggested, but the pathogenesis remains obscure (Gardner and Fernet 1964).
Unusual Types of Bacterial Vaginitis
Occasionally, vaginitis may be caused by bacteria that are commonly pathogenic in other sites. Shigella vulvovaginitis has been identified primarily as a cause of a chronic, sanguinous, and purulent vaginal discharge in children, unassociated with intestinal infection (Davis 1975; Rajkumar et al. 1979). Haemophilus influenzae, Corynebacterium diphtheria, and Neisseria meningitidis also rarely cause vaginitis in children (Charles and Charles 1978; Fallon and Robinson 1974; Farrand 1971; Sunderland et al. 1972), but the histologic changes have not been documented. Staphylococcal infection of the vagina after systemic antibiotic therapy was reported more than 30 years ago and thought to result from a disturbed indigenous flora (Lang et al. 1958) (see section “Toxic Shock Syndrome”).
Parasitic infection of the vagina, although currently rare in the United States, may be encountered more commonly because of more frequent global travel.
Vaginal amebiasis caused by Entamoeba histolytica has been reported in Mexico, South Africa, and India, where the infection is endemic (Heinz 1973; Hingorani and Mahapatra 1964; Munguia et al. 1966; van den Broek et al. 1996). Most patients present with a bloody vaginal discharge. The gross appearance mimics carcinoma, with one or more ulcerated, necrotic growths typically involving the vagina and cervix. Microscopically, the lesions are characterized by ulceration of the epithelium with replacement by a fibrinopurulent exudate containing trophozoites 15–60 μm in diameter. In cytologic preparations they appear somewhat larger than histiocytes and approximate the size of parabasal cells. Positive staining with periodic acid–Schiff (PAS) stain or acid phosphatase provides further support for the diagnosis.
Eggs of Enterobius vermicularis or Trichuris trichiura usually are found after incidental contamination of the vagina associated with intestinal infestation by these worms (de Mundi et al. 1978). Eggs and worms of Schistosoma mansoni and haematobium have been identified in pelvic tissues including the vagina, presumably reflecting anastomoses between hemorrhoidal and hypogastric veins (Gelfand et al. 1972). They elicit a striking host inflammatory response, ultimately resulting in dense fibrosis.
Toxic Shock Syndrome
In 1978, Todd et al. described an acute, potentially life-threatening disease characterized by fever, hypotension, headache, confusion, rash, vomiting, diarrhea, and oliguria. The disease was termed toxic shock syndrome (TSS) because it was associated with infection with strains of Staphylococcus that produced a unique epidermal toxin (Todd et al. 1978). By 1980, more than 98% of cases had been related to the use of tampons during menses (Friedell and Mercer 1986). The incidence is about 6 cases per 100,000 menstruating women per year. Although S. aureus rarely inhabits the vagina normally, it has been isolated from about 75% of women with TSS (Davis et al. 1980; McKenna et al. 1980; Sweet and Gibbs 1985c). More recently it has become evident that children or adults with any focal staphylococcal infection are also at risk for TSS, and about 11% of all reported cases are nonmenstrual (Resnick 1990; Gaensbauer et al. 2018).
There is a strong relationship between localized infection with S. aureus and the development of TSS. Studies of patients with TSS as well as experimental systems have revealed that some staphylococci elaborate a protein of about 22 kDa termed toxic shock syndrome toxin 1 (TSST-1), which produces essentially all the systemic biologic effects (Bergdoll et al. 1981). TSS can also occur in the absence of this toxin, and other staphylococcal enterotoxins (such as staphylococcal exotoxin B), streptococcal exotoxins, and endotoxins from gram-negative bacteria have been implicated in some cases of TSS (Resnick 1990; The Working Group on Severe Streptococcal Infections 1993). The mechanism by which tampon use during menses predisposes to TSS remains somewhat unclear, but it is believed that microulcerations of the vaginal mucosa caused by tampons (see below, Tampon Ulcer) permit the growth of toxin-producing staphylococci. A diminished host immune response to the toxin, access of toxin through a denuded endometrial mucosa, and the normal menstrual phase decrease in lactobacilli that are inhibitory to the growth of staphylococci may facilitate the process (Friedell and Mercer 1986; Sanders et al. 1982). A multifactorial sequence is supported by the observation that about 10% of healthy women are colonized vaginally by Staphylococcus aureus, and 85% of women have antibodies to TSST-1 (Paris et al. 1982), whereas other women have recurrent episodes of the illness. A dramatic reduction in the incidence of TTS occurred when Rely superabsorbent tampons were withdrawn from the market in 1980 (Krause 1992).
The diagnosis of TSS is based on a constellation of clinical features, as follows: fever, hypotension, palmar or diffuse erythroderma followed by desquamation, hyperemia of conjunctivae or mucous membranes of the vagina or pharynx, and multisystem dysfunction including vomiting; diarrhea; impaired renal, cerebral, or hepatic function; cardiopulmonary dysfunction; thrombocytopenia; elevated creatine phosphokinase; and decreased serum calcium and phosphate (Davis et al. 1980). Vaginal erythema, erosions, and vaginitis, sometimes accompanied by a purulent exudate, typically are present (Wager 1983). Abdominal or bilateral adnexal tenderness is present in about half of cases (Helms et al. 1981).
Gross and Microscopic Findings
The disease is systemic, with pathologic abnormalities described in the lung, liver, and kidney, as well as genital tract (Abdul-Karim et al. 1981; Paris et al. 1982). Ulceration and discoloration of the vaginal and cervical mucosa are present focally. Microscopically, there is extensive desquamation of the epithelium, with underlying subacute vasculitis, perivascular inflammatory cell infiltrates, and platelet thrombi (Abdul-Karim et al. 1981; Paris et al. 1982). Rare gram-positive cocci have been found in the fibrinopurulent exudate associated with ulcers. Deep tissue invasion by the organisms has not been described (Paris et al. 1982).
Clinical Behavior and Treatment
The spectrum of severity of TSS varies from a relatively mild to a rapidly fatal illness, with a mortality rate of about 4% (Sweet and Gibbs 1985b). The treatment includes beta-lactamase-resistant anti-staphylococcal antibiotics and aggressive, supportive measures for systemic manifestations related to shock (Resnick 1990). Intravenous immunoglobulin therapy also has been effective, supporting the concept that the symptoms of TSS result from a toxin that may be neutralized by infused antibodies (Barry et al. 1992).
Noninfectious Inflammatory Diseases
The vagina is occasionally the site of involvement by a systemic disease, a generalized disease of squamous mucosa, or by extension a disease elsewhere in the pelvis. In one study of chronic vaginitis, the most common diagnoses were as follows: contact dermatitis (21%), recurrent vulvovaginal candidiasis (21%), atrophic vaginitis (15%), and vulvar vestibulitis syndrome (13%) (Nyirjesy et al. 2006).
Desquamative Inflammatory Vaginitis
Idiopathic desquamative inflammatory vaginitis is the term that has been applied to an unusual process in which bright red, well-delineated areas replace portions of the normal mucosa of the cranial half of the vagina. A pseudomembrane at times replaces the ulcerated mucosa. It must be distinguished from other disorders causing erosion such as pemphigus vulgaris and pemphigoid (Murphy 2004). It typically affects premenopausal Caucasian women, and serum estrogen levels are normal. A copious purulent to hemorrhagic vaginal discharge is present, smears of which display numerous neutrophils and a high proportion of parabasal cells. Vaginal pH is always elevated above 4.5 (Reichman and Sobel 2014). In rare cases in which biopsies have been performed, a nonspecific mixed inflammatory cell infiltrate has been reported (Murphy and Edwards 2008). The etiology is unknown, and no single bacterial or viral agent has been identified by culture. Nevertheless, the replacement of long gram-positive bacilli by gram-positive cocci in the vaginal discharge of some affected women suggests an infectious etiology. It has also been postulated to be a form of erosive lichen planus as it can coexist with gingival mucositis. Treatment with clindamycin and topical steroids results in clinical improvement in more than 95% of patients (Sobel 1994).
Allergic Reactions to Seminal Fluid
A few women display allergic reactions after exposure to seminal fluid (Levine et al. 1973). The severity of the response varies from localized vulvovaginal urticarial reactions to generalized urticaria and bronchospasm. The onset of symptoms immediately follows contact with seminal fluid, and the duration of the reaction is between 2 and 72 h.
About 20% of females with Crohn disease have vaginal symptoms (Graham et al. 2008). Rectovaginal fistulas occur in some patients with Crohn disease (Faulconer and Muldoon 1975), and they represent the site of about 9% of fistulas in women with this disease (Andreani et al. 2007). In situ squamous carcinoma of the vagina has been reported rarely (Prezyna and Kalyanaraman 1977). Adenocarcinomas arising in rectovaginal fistulas primarily presenting as a vaginal mass may also rarely occur (Chu et al. 2010; Moore-Maxwell and Robboy 2004).
Vaginal stenosis may develop as a sequela of severe bullous erythema multiforme (Stevens–Johnson syndrome) in which extensive vulvar and vaginal ulceration occurred (Graham-Brown et al. 1981). Acantholytic intraepithelial bullae may be found when there is vaginal involvement by familial benign chronic pemphigus (Hailey–Hailey disease) (Václavínková and Neumann 1981).
Giant Cell Arteritis and Polyarteritis
Giant cell arteritis is not always limited to the temporal arteries and may be associated with either limited visceral or, much more rarely, generalized organ involvement (Bell et al. 1986). A panarteritis, with fragmentation and destruction of the internal elastic lamella and phagocytosis of elastic material by multinucleated giant cells, may be seen in the vagina as part of limited female genital tract involvement (Bell et al. 1986). Arteritis limited to the genital tract is most commonly found in the cervix and endometrium and has a favorable prognosis in the absence of an elevated sedimentation rate (Francke et al. 1998). The frequency of involvement of the vagina has not been determined, since vaginal tissues are infrequently sampled in the course of most surgical procedures.
Thrombotic Thrombocytopenic Purpura
Massive, acute hemorrhagic necrosis of the vagina has been reported as one of the initial manifestations of thrombotic thrombocytopenic purpura (Gallup et al. 1991). The disease usually is characterized by the pentad of fever, microangiopathic hemolytic anemia, thrombocytopenia, neurologic symptoms, and renal dysfunction. Numerous thrombi are found microscopically in the vaginal stroma, accompanied by superficial hemorrhage, necrosis, and sloughing of the epithelium.
Lesions that Follow Trauma, Surgery, and Radiation
Although tampons have been in use for 60 years, there had been little interest in their effects on the vagina until about 1980, when mucosal ulceration and TSS were related to their use. In several series of cases, the women presented with abnormal vaginal discharge or intermenstrual bleeding. Typically, a single ulcer with an irregular border of granulation tissue was identified in one of the vaginal fornices. After neoplasms and infectious etiologies were excluded, a more detailed history revealed the frequent use of tampons. Microscopically, some of the ulcers contained fibrillar foreign bodies within the exudate (Jimerson and Becker 1980). The lesions healed spontaneously within 2–3 months after discontinuation of tampon usage (Jimerson and Becker 1980). Subsequently, Friedrich studied the vagina during tampon use and characterized a sequence of clinically asymptomatic, colposcopic, and microscopic changes as follows: (1) mucosal dehydration, (2) layering or intraepithelial cleavage, and (3) microulceration (Friedrich and Siegesmund 1980). Ultrastructural findings include a widening of the intercellular spaces separating squamous cells and a marked reduction in the number of desmosomes. He suggested that these changes resulted from a fluid shift across the vaginal epithelium due to the absorbent qualities of the tampon. This hypothesis explains the higher frequency of mucosal alteration with the use of superabsorbent tampons. However, this explanation may be incomplete because a colposcopic study demonstrated an inverse relationship between vaginal drying and the quantity of blood absorbed by different tampon types (Raudrant et al. 1995). The great frequency with which tampons induce clinically inapparent vaginal microulcerations helps to explain their relationship to staphylococcal infections and the development of TSS.
Postoperative Spindle Cell Nodule
Vaginal Vault Granulation Tissue
Vesicovaginal and ureterovaginal fistulas may occur as a complication of hysterectomy, resulting from ischemic necrosis secondary to interruption of the vascular supply (Tancer 1980). The surgical correction usually yields small fragments of tissue with variable amounts of granulation tissue, fibrosis, chronic inflammation, and little or no epithelium. Rarely, calculi are present. These are composed of urinary salts that develop in the vagina because of continuous leakage of urine from a vesicovaginal fistula. Vesicovaginal fistula and vaginal laceration also may be a consequence of coitus.
Fallopian Tube Prolapse
Cysts of the vagina are relatively uncommon. They typically occur in reproductive-aged women with a mean age in the fourth decade, and the most common symptoms, when present, are that of a swelling or mass which may also be associated with stress incontinence, dyspareunia, or bleeding (Pradhan and Tobon 1986; Kondi-Pafiti et al. 2008). Most cysts involve the lateral and posterior vaginal wall (Pradhan and Tobon 1986; Kondi-Pafiti et al. 2008). Several classifications for cystic lesions have been proposed, reflecting a combination of good microscopic descriptions, an incomplete knowledge of embryology, and an assumption that histologic differentiation mirrors histogenesis (Kaufman et al. 1989). The most frequently encountered cyst is müllerian, followed by squamous inclusion, Bartholin duct type, and Gartner’s duct (mesonephric). A functional classification scheme follows: squamous inclusion cysts, mesonephric cysts, müllerian cysts, and Bartholin gland cysts.
Squamous Inclusion Cyst
Bartholin Gland Cyst
An extensive discussion of the features of condylomas is provided in chapters “Benign Diseases of the Vulva” and “Benign Diseases of the Cervix”. As the biologic and pathologic characteristics of vaginal condylomas are similar to those in the cervix and vulva, they are not described here.
Fibroepithelial Polyp (Mesodermal Stromal Polyp)
Tubulosquamous polyp is an uncommon entity which shows a similar morphology and immunoprofile to the so-called ectopic prostatic tissue in the cervix, with both currently considered to be derived from misplaced Skene glands (Kazakov et al. 2010; Kelly et al. 2011; McCluggage et al. 2006; McCluggage and Young 2007). These benign lesions are typically polypoid or cystic and composed of a typically minor component of tubules located at the periphery of expansile squamous nests with peripheral palisading. Central keratin pearl formation or necrotic debris may be seen within the squamous nests. Uncommonly reported findings include basaloid epithelial differentiation, microglandular proliferation, and sebaceous glands (Kelly et al. 2011; Stewart 2009). Similar to Skene glands and prostate tissue, the tubules may be positive for NKX3.1, PSA, or PrAP (McCluggage et al. 2006).
Benign smooth muscle tumors of the vagina are uncommon. The mean age at detection is about 40 years, with a reported range of 19–72 years (Sangwan et al. 1996). The tumor may occur anywhere within the vagina; however, it more commonly involves the lateral aspect and is usually in a submucosal location. Vaginal leiomyomas vary from 0.5 to 15 cm in diameter but are usually less than 5 cm (Tazvassoli and Norris 1979). Because most are relatively small, they often are asymptomatic. Larger tumors may produce pain, hemorrhage, dystocia, or dyspareunia.
The gross and microscopic appearances of vaginal leiomyomas resemble those of their uterine counterparts. They are well-circumscribed, firm masses that occasionally may contain foci of edema or hyalinization. Microscopically, they are well circumscribed without evidence of infiltration and are composed of interlacing fascicles of spindle-shaped cells, with elongated, oval nuclei with no mitotic activity or nuclear pleomorphism. Of the 60 cases of smooth muscle tumors of the vagina reviewed by Tavassoli and Norris, only 7 contained more than 5 mitoses per 10 high-power fields (HPF). Five patients developed recurrence after local excision. All the recurrent tumors were in the subset with high mitotic activity and generally moderate to marked nuclear atypia (Tazvassoli and Norris 1979). Accordingly, it is recommended that the diagnosis of vaginal leiomyoma be reserved for those tumors that are histologically well circumscribed, are cytologically bland, and have fewer than five mitoses per 10 HPF. However, it also should be noted that increased mitotic activity in the absence of aggressive behavior may be present in vaginal leiomyomas during pregnancy. A recent study suggests that uterine criteria show increased specificity over site-specific criteria for classifying vaginal smooth muscle tumors as benign (Sayeed et al. 2018).
Rhabdomyoma is a rare benign tumor displaying well-formed skeletal muscle differentiation, about 30 cases of which have been reported arising within the vagina (Gold and Bossen 1976; Hanski et al. 1991; Iversen 1996; Schoolmeester et al. 2018). The average age at diagnosis is about 45 years, with a range extending from 34 to 57 years. Patients typically present with a solitary polypoid to nodular mass that varies from 1 to 11 but is usually <3 cm in diameter. Symptoms are typically related to a mass lesion and include dyspareunia; bleeding is less common as the overlying mucosa is usually intact.
Spindle Cell Epithelioma (Benign Mixed Tumor)
Tumors that histologically bear some resemblance to salivary gland neoplasms are classified as spindle cell epitheliomas or benign mixed tumors. These neoplasms are rare and usually present as a slowly growing, painless, well-circumscribed, submucosal mass that may occur anywhere in the vagina but most frequently near the hymenal ring (Branton and Tavassoli 1993; Sirota et al. 1981). The mean age at diagnosis is 30 years. They range in size from 1.5 to 5 cm and often are diagnosed preoperatively as a polyp or cyst.
It is not uncommon for endometriosis to involve the vagina, either superficially implanted in the squamous mucosa or involving the deep stroma, particularly of the rectovaginal septum (Gardner 1966; Keyzer et al. 1982; March and Israel 1976; Venter et al. 1979; Williams 1965). A complete discussion of endometriosis is provided in chapter “Diseases of the Peritoneum.”
Miscellaneous Benign Tumors and Tumorlike Lesions
Vaginal Intraepithelial Neoplasia
In contrast to the high prevalence of intraepithelial lesions of the cervix and vulva, vaginal intraepithelial neoplasia (VAIN) is relatively rare. The reason for this discrepancy is unknown but may be related to a lesser susceptibility of the vaginal mucosa to HPV infection than the cervical transformation zone. However, similar to the cervix, the range of HPV types that can affect this area is greater than those that occur in the vulva (Sugase and Matsukura 1997; Zhang et al. 2016). Understanding the reasons for this difference may prove pivotal to understanding carcinogenesis involving the squamous epithelium of the lower female genital tract. Current terminology for intraepithelial neoplasia of the vagina follows recommendations from the recent Lower Anogenital Squamous Terminology (LAST) project (Darragh et al. 2012) in which vaginal precursors are separated into two categories – low-grade squamous intraepithelial lesion (LSIL) and high-grade squamous intraepithelial lesion (HSIL) replacing prior terms such as vaginal intraepithelial neoplasia (VAIN) or vaginal intraepithelial lesion (VAIL); this two-tiered approach is used throughout the lower genital tract and not only brings standardization and uniformity of the nomenclature but also reflects the underlying pathobiology. Irrespective of terminology, SIL displays nuclear atypia coupled with some loss of squamous maturation, disordered maturation, and increased mitotic activity, sometimes accompanied by abnormal mitotic figures, acanthosis, and dyskeratosis.
The incidence of in situ carcinoma of the vagina has been reported to be about 0.20 cases per 100,000 in Caucasian females and 0.31 cases per 100,000 in black females; this is less than 1% of the incidence for the same disease in the cervix (Cramer and Cutler 1974; Henson and Tarone 1977). A more recent study considering newer data from the CDC’s National Program of Cancer Registries and the NCI’s Surveillance, Epidemiology, and End Results (SEER) program covering 92% of the US population from 1999 to 2004 estimates the incidence to be 0.1 per 100,000 women (Watson et al. 2009). The highest incidence rates are observed in women over the age of 60, with the mean age at diagnosis of VAIN 3 about 53 years. These figures are 10 or more years greater than the age of detection of cervical intraepithelial neoplasia (CIN) 3 (Hummer et al. 1970). Risk factors for the development of VAIN paralleled that of the cervix and include immunosuppression, HPV infection or squamous neoplasia elsewhere in the lower genital tract, irradiation, and in utero exposure to DES, although this latter factor is controversial (Brinton et al. 1990). During the mid-1970s, it was first suggested that DES-exposed offspring might be at risk for increased rates of dysplasia because of the extent of metaplastic tissue present in both the cervix and vagina. Multiple studies of prevalence rates subsequently conducted indicated that the frequency of dysplasia in both the exposed and unexposed populations was approximately the same. In 1984, the DESAD Project amplified its findings on the frequency of dysplasia. The incidence rates were slightly higher in exposed women. The new occurrence of squamous cell dysplasia in women under observation developed twice as frequently in DES-exposed women in contrast to those that were never exposed in utero (Bornstein et al. 1988; Robboy et al. 1984a). Some believe that the DESAD findings may not be valid and that the increased rates of dysplasia, especially of mild form, may be caused by over- or misinterpretation of the HPV-infected tissue for dysplasia (Richart 1986), especially as the DESAD study was conducted before many of the histologic intricacies of HPV infection were fully appreciated. Regardless of interpretation, DES itself is not believed to be the etiologic cause of dysplasia. Possibly, the metaplastic squamous epithelium, which is more extensive in the vagina in DES-exposed women, may be more susceptible to agents that give rise to dysplasia, but even this is speculative.
Almost 75% of women with VAIN have preceding or coexisting squamous carcinomas of the cervix or vulva (Benedet and Sanders 1984; Kalogirou et al. 1997; Kanbour et al. 1974; Lenehan et al. 1986; Sillman et al. 1985). These observations have generated the concept of a field effect, in which the squamous epithelium of the entire lower female genital tract is at risk for neoplastic transformation. This hypothesis is appealing, because the squamous epithelia of these sites do share a common embryonic derivation from the urogenital sinus and all are susceptible to infection by various HPVs. Radiation therapy for cervical carcinoma results in exposure of the vagina to ionizing radiation, and women who have had pelvic radiation for benign as well as malignant diseases are at increased risk for the development of VAIN (Benedet and Sanders 1984; Geelhoed et al. 1976; Lenehan et al. 1986).
The differential diagnosis of SIL (VAIN) includes atrophy, radiation change, and immature squamous metaplasia in women with adenosis, all of which may display loss of glycogen and a relative increase in cellularity. The distinction rests primarily on the characteristic nuclear features of SIL (VAIN), which are absent in the other conditions. Radiation changes include nuclear enlargement, smudged chromatin, multinucleation, and vacuolization of cytoplasm, with lack of mitotic activity (Fu and Reagan 1989a). Occasionally, there may be significant nuclear atypia associated with inflammatory and reactive processes, but usually this is expressed as regular nuclear enlargement with vesicular chromatin and moderate-sized nucleoli. Such changes are referred to as reactive squamous atypia.
Clinical Behavior and Treatment
The natural history of SIL (VAIN) is uncertain. In one study, about 5% of SIL (VAIN) progressed to invasive carcinoma, with sequential changes documented by serial biopsies (Rutledge 1967), but many lesions were treated (Sillman et al. 1997). In a more recent study of 576 patients by Kim HK et al., 3.2% with HSIL developed invasive carcinoma on follow-up with a median time to cancer diagnosis of 21.4 months (Kim et al. 2018). Therapy generally is local excision, although topical 5-fluorouracil, laser vaporization, vaginectomy, and irradiation also have been successfully used (MacLeod et al. 1997; Stuart et al. 1988; Wooduff et al. 1975). In a study of 94 women with VAIN, 70% achieved remission after a single treatment of any type, but 24% required additional therapy with chemosurgery or upper vaginectomy; 5% progressed to invasive squamous carcinoma in spite of therapy and close follow-up (Sillman et al. 1997). In the recent study by Kim HK et al., rates of recurrence/progression for patients with HSIL (VAIN II/III) managed by observation (3.5%), topical management (6.5%), laser ablation (75%), excision (14.1%), and radiotherapy (0.5%) were 46.2%, 62.5%, 26.4%, 32.7%, and 0%, respectively (Kim et al. 2018). Another study has suggested that VAIN following radiation therapy may be more refractory to treatment and more likely to recur (Liao et al. 2011).
Squamous Cell Carcinoma
FIGO staging of vaginal carcinoma (2009)
Limited to vaginal wall
Extends to subvaginal tissue but not to pelvic side wall
Extends to pelvic side wall
Extends beyond the true pelvis or involves mucosa of the bladder or rectum (bullous edema does not consign the patient to stage IV)
Adjacent organs involved
Distant organs involved
The mean age at diagnosis of invasive vaginal squamous carcinoma is 64 years (Kurman et al. 1992). The presenting symptoms usually are painless vaginal bleeding or discharge, dysuria, or frequency (Al-Durdi and Monaghan 1977). There is a relationship between duration of symptoms and the size and spread of tumor. Unfortunately, about 20% of patients with vaginal cancer delay more than 7 months from the onset of symptoms to the initiation of therapy (Podczaski and Herbst 1986). Most of the tumors arise in the upper third of the vagina (Podczaski and Herbst 1986), with 57% involving the posterior wall and 27% located on the anterior wall (Plentl and Friedman 1971).
Clinical Behavior and Treatment
Historically, the survival rates for women with squamous cell carcinoma of the vagina were low. However, subsequent studies indicate a considerably better prognosis, with rates comparable to those of cervical carcinoma when corrected for stage of disease (Dixit et al. 1993; Hacker et al. 2015; Perez et al. 1988; Premptee and Amornmarn 1985). In a review of 300 women with vaginal carcinoma treated over a 40-year interval at one institution, the overall 5- and 10-year survival rates were 60% and 49%, respectively (Chyle et al. 1996). The most important prognostic indicators included FIGO stage, tumor size, and location in the vagina (with better outcomes for those with lesions in the upper vagina). Results from the National Cancer Data Base between 1985 and 1994 and the FIGO 6th annual report of results of treatment in gynecologic cancer support the prognostic importance of stage (Beller et al. 2006; Creasman et al. 1998). The relative 5-year survival rate for stage I disease was 73%, 53% for stage II tumors, and only 36% for stages III and IV (Creasman et al. 1998). In another study of 193 patients treated with radiation therapy, the 5-year disease-specific survival rates were 85% for stage I, 78% for stage II, and 58% for stages III–IVA (Frank et al. 2005). Recent studies suggest that HPV status may also be of prognostic importance including patients with early-stage disease and this may vary with viral genotype (Alonso et al. 2012; Brunner et al. 2011; Larsson et al. 2013). Unfortunately, relatively few women are diagnosed with tumors confined to the vagina. Direct spread into the soft tissues of the pelvis or to the mucosa of the bladder or rectum occurs early because the wall of the vagina is thin and is separated from these organs by only a few millimeters of connective tissue. Consequently, at initial diagnosis, most tumors have invaded the soft tissues surrounding the vaginal wall, and about 20% extend to the pelvic sidewall (Chyle et al. 1996). As discussed in the section on anatomy, the lymphatic drainage of the vagina is complex and variable, and any of the inguinal or pelvic lymph nodes may be the site of metastasis, although there is some relationship to the location of the tumor within the vagina (Marcus 1960).
Radiation therapy, including brachytherapy and external beam radiation, is the modality used primarily to treat vaginal squamous carcinoma, although radical vaginectomy may be indicated in selected instances. Although metastases may be discovered ultimately in the lungs or supraclavicular lymph nodes, recurrent disease is typically local and occurs within 2 years of diagnosis (Kurman et al. 1992). In one large study, local recurrences were identified at 5 years in 23% and distant metastases in 15% of patients (Chyle et al. 1996). Only 12% of women who suffered a recurrence survived for 5 years.
The use of the term verrucous carcinoma should be reserved for those rare vaginal tumors that display the characteristic features described by Ackerman (1948; Crowther et al. 1988). Grossly, they are exophytic, fungating masses with a coarsely granular or undulating surface. Microscopically, the characteristic feature of verrucous carcinoma is the presence of squamous cells with bland cytologic features. At the deep margin of the tumor, the squamous cells invade in a pushing fashion as broad bulbous masses, creating a so-called baggy pants appearance. On the surface of the tumor, hyperkeratosis and acanthosis are common. The distinction of verrucous carcinoma from condyloma or pseudoepitheliomatous hyperplasia may be difficult and may not be possible in a superficial biopsy specimen. Some authors have indicated that verrucous carcinoma does not display the koilocytosis or surface papillae formed from fibrovascular cores covered by squamous cells, which are typical of condylomata or warty carcinomas (Japaze et al. 1982; Kurman et al. 1992), but other investigators disagree (Dvoretsky and Bonfiglio 1986; Lucas et al. 1974). This issue, however, is not of primary importance because the diagnosis rests on the presence of bland cytologic features in the broad bulbous masses of squamous cells at the stromal interface. Verrucous carcinomas display a relatively indolent growth potential, with frequent local recurrence after incomplete excision. Lymph node metastasis occurs rarely, if ever. Because verrucous carcinomas not only are resistant to therapeutic irradiation but may actually transform to conventional squamous carcinoma after radiation therapy, the treatment is usually wide local or radical surgery (Ackerman 1948; Kraus and Perez-Mesa 1966). Tumors with a mixed pattern of both verrucous and conventional squamous carcinomas behave with the aggressiveness of typical squamous cancer and should be classified as such.
Squamous cell carcinomas in which many of the cells contain nuclear abnormalities and perinuclear cytoplasmic cavitation similar to the koilocytes in intraepithelial neoplasms have been designated warty carcinoma. These changes are not typically present in verrucous carcinoma. In addition, warty carcinomas have greater nuclear pleomorphism than verrucous carcinomas, as well as multinucleation, and an infiltrative pattern at the stromal interface. A detailed clinicopathologic analysis of warty carcinomas in the vagina has not been reported. Preliminary data from similar tumors in the vulva indicate that they behave in a low-grade malignant fashion, although metastases to regional lymph nodes occur occasionally (see chapter “Premalignant and Malignant Tumors of the Vulva”) (Kurman et al. 1993).
Papillary Squamotransitional Cell Carcinoma
There has been increased recognition that lesions involving the lower genital tract may bear a close resemblance to those arising from the urothelium. In addition to transitional cell metaplasia (Wheelock et al. 1985), malignant neoplasms have been reported, primarily in the cervix (Koenig et al. 1997; Randall et al. 1986) but with occasional cases originating in the vagina (Bass et al. 1994; Fetissof et al. 1990; Rose et al. 1998). The diagnostic terminology has been varied, including papillary squamous carcinoma, transitional cell carcinoma, and mixed squamous and transitional (squamotransitional) cell carcinoma, reflecting the less than unambiguous histologic features that discriminate such epithelia (Koenig et al. 1997). Immunohistochemical studies have usually demonstrated the presence of cytokeratin CK-7 and the frequent absence of CK-20 and GATA 3 in the papillary genital tract tumors, unlike the profile of transitional cell carcinomas of the urinary bladder, which typically react with CK-7, CK-20, and GATA 3 (Chang et al. 2012; Koenig et al. 1997).
The biologic behavior remains incompletely defined and has been described as either indolent or similar to that of conventional squamous carcinoma (Koenig et al. 1997; Randall et al. 1986). Some of the cases have followed treatment of primary papillary transitional cell carcinomas of the urinary tract or have been associated with transitional cell metaplasia, suggesting the possibility of an extended urogenital field at risk for transitional cell neoplasia (Fetissof et al. 1990).
Clear Cell Adenocarcinoma
From the 1970s to the 1990s, most cases of vaginal clear cell adenocarcinoma occurred in young women with a documented history of DES exposure in utero. The median age at the time of diagnosis in the DES-exposed US population was 19 years, and the risk of tumor development was higher when the drug was started early in pregnancy. Fortunately, clear cell adenocarcinoma developed in only about 0.1% of exposed females up to the age of 24 years. As of 2008, 757 cases of clear cell adenocarcinoma of the cervix or vagina had been accessioned worldwide to the Registry for Research on Hormonal Transplacental Carcinogenesis. Consequent to the removal of DES from the market for the treatment of high-risk pregnancy in 1971, the exposed population has aged, and between 2003 and 2008, only 35 cases of clear cell carcinomas were reported to the Registry (personal communication). Nevertheless, even though the risk of developing clear cell carcinoma was thought to decrease following age 20, long-term follow-up studies have shown the risk extending past age 40 (Hou et al. 2017; Troisi et al. 2007; Verloop et al. 2010); in addition, DES-exposed patients are at increased risk of developing melanoma before age 40 and a slightly increased risk of developing breast carcinoma after age 40 (Troisi et al. 2007; Verloop et al. 2010). Our understanding of DES-mediated carcinogenesis remains incomplete. A high frequency of microsatellite instability and overexpression of wild-type p53 has been observed (Waggoner et al. 1996; Ways et al. 1987). A bimodal age distribution with peaks in the third and eighth decade is seen even in women without DES exposure suggesting pathogenetic factors other than DES exposure in the development of vaginal clear cell carcinoma (Hanselaar et a1. 1997).
Larger tumors almost always cause symptoms such as vaginal bleeding or discharge, while many small tumors are asymptomatic and may present as an abnormal Papanicolaou smear. Approximately 60% of lesions have been confined to the vagina. The remainder have been limited to the cervix or involved both the cervix and vagina.
Atypical adenosis, characterized by glands with cellular stratification, nuclear pleomorphism, hyperchromasia, and prominent nucleoli, has been identified near the periphery of most clear cell carcinomas. The frequent finding of the tuboendometrial type of glandular cell and the rarity of the mucinous type of cell adjacent to the tumors suggest that the clear cell adenocarcinoma arises from the tuboendometrial cells (Robboy et al. 1982b, 1984b).
Microglandular hyperplasia usually occurs in the cervix but may arise in vaginal adenosis. It contains many small, closely packed glands devoid of intervening stroma (see chapter “Benign Diseases of the Cervix”). The presence of extensive nests of metaplastic squamous cells with pale eosinophilic cytoplasm may make the lesion difficult to distinguish from the solid pattern of clear cell carcinoma. A clue to the diagnosis is the presence of clefts lined by mucinous epithelium that course through the metaplastic squamous epithelium. The Arias–Stella reaction usually occurs in pregnant women. Although usually seen in the endometrium, the Arias–Stella reaction has been observed in the endocervix and occasionally in vaginal adenosis of the tuboendometrial type. Characteristically, hypersecretory glands are lined by cells with markedly enlarged nuclei resembling hobnail cells. However, in clear cell adenocarcinoma, the presence of sheets of clear cells or prominent papillae should enable the two lesions to be distinguished. In addition, the hobnail-like nuclei in the Arias–Stella reaction commonly contain smudged nuclear chromatin. Immunohistochemistry may be misleading as napsin A may be positive in Arias–Stella reaction (Fadare 2016).
Clinical Behavior and Treatment
The tumor spreads locally and also metastasizes via lymphatics and blood vessels. Clear cell carcinoma extends outside the abdominal cavity more frequently than does squamous cell carcinoma of the vagina or cervix. Thirty-six percent of the initial recurrences of clear cell carcinomas are in the lung or a supraclavicular lymph node, in contrast to less than 10% for squamous cell carcinomas.
The 5-year actuarial survival rates for all patients with clear cell adenocarcinoma are high, about 93% at 5 years and 87% at 10 years when the tumor is at stage I (Herbst 1992). Large size and/or deep invasion into the wall are associated with a poorer prognosis, but small or superficial tumors also may recur or metastasize. Recurrences develop most often within 3 years after primary therapy; however, recurrences as late as 19 years after treatment have been observed (Burks et al. 1990).
The prognosis for women with clear cell adenocarcinoma who have known exposure to DES in utero is significantly better than for those who have no history of DES exposure (5-year survival rates of 84% and 69%, respectively) (Waggoner et al. 1994). Although some of this difference could reflect earlier detection in the intensively screened exposed population, the survival advantage persists even when the comparison is adjusted for the stage of disease. Metastases to the lungs or supraclavicular lymph nodes are more frequent in the non-DES-exposed group.
Embryonal Rhabdomyosarcoma (Sarcoma Botryoides)
The most common malignant neoplasm of the vagina in infants and children is embryonal rhabdomyosarcoma, most of which is of the subtype designated sarcoma botryoides (Copeland et al. 1985a; Creasman et al. 1998; Hilgers et al. 1970; Newton et al. 1988). Nearly 90% of cases are diagnosed before 5 years of age (Creasman et al. 1998; Friedman et al. 1986). Of all rhabdomyosarcomas diagnosed in the distal female genital tract, the majority are of embryonal histology; other subtypes of rhabdomyosarcoma are typically seen in older patients (Nasioudis et al. 2017). This is a rare tumor of unknown etiology and pathogenesis although recent work suggests the role of DICER1 mutations as embryonal rhabdomyosarcoma is one of the tumors that can occur in DICER1 pleuropulmonary blastoma familial tumor predisposition syndrome (Witkowski et al. 2016) and somatic DICER 1 mutations have been shown in sporadic (non-familial) cases of embryonal rhabdomyosarcoma (Doros et al. 2012). Certainly, the distribution of embryonal rhabdomyosarcomas does not correlate with the mass of skeletal muscle, as most of these neoplasms arise in or near the mucosa of either the head and orbit or the lower urogenital system.
IRSG surgical–pathologic grouping system
Localized tumor, completely removed with pathologically clear margins and no regional lymph node involvement
Localized tumor, grossly removed with (a) microscopically involved margins, (b) involved, grossly resected regional lymph nodes, or (c) both
Localized tumor, with gross residual disease after grossly incomplete removal or biopsy only
Distant metastases present at diagnosis
The differential diagnosis includes fibroepithelial polyp, müllerian papilloma, and rhabdomyoma. The correct diagnosis can be made by considering the age at presentation and the microscopic features described above. After radiation or chemotherapy, occasionally there is difficulty in determining whether scattered mature-appearing skeletal muscle fibers represent residual tumor cells that are refractory to therapy or radiated benign muscle fibers of the pelvis. One study suggests that differentiation occurs more frequently with the botryoid variant of rhabdomyosarcoma following therapy and that it is associated with a favorable outcome (Coffin et al. 1997).
Clinical Behavior and Treatment
The tumor initially grows into the vaginal wall and soft tissue of the pelvis, bladder, or rectum and subsequently metastasizes to the lymph nodes, lungs, liver, and bone. Historically, the prognosis after radical surgery was poor, with survival rates of less than 20% (Coffin and Dehner 1992). The introduction of combined multiagent chemotherapy and in some cases radiotherapy, in addition to surgery, has dramatically improved the probability of survival (Coffin and Dehner 1992; Ghaemmaghami et al. 2008; Maharaj et al. 2008; Newton et al. 1988).
IRSG staging system
Sites of primary tumor
Tumor size (cm)
Regional lymph nodes
Orbit, non-PM head, neck; GU non-bladder/prostate; biliary tract
All other sites
All other sites
N0 or N1
N0 or N1
More than 200 cases of vaginal melanoma have been reported, representing less than 5% of the malignant neoplasms of the vagina and less than 1% of all melanomas (Creasman et al. 1998; De Matos et al. 1998; Geisler et al. 1995; Gupta et al. 2002; Huang et al. 2013; Irvin et al. 1998; Liu et al. 1987; Petru et al. 1998; Rouzbahman et al. 2015; Seifried et al. 2015; Tcheung et al. 2012; Udager et al. 2017). These tumors can occur at any age, with a range from 22 to 90 years; however, most patients are postmenopausal with a mean age of approximately 60 years (Levitan et al. 1989; Petru et al. 1998; Ragnarsson-Olding et al. 1993). Presenting symptoms include vaginal bleeding, discharge, and a mass. Although the tumors may arise anywhere within the vagina, there is a predilection for the distal third (Chung et al. 1980). The etiology and pathogenesis are unknown, but a disproportionately large number of vaginal melanomas have occurred in Japanese women, followed in frequency by Caucasian and then black women (Chung et al. 1980; Creasman et al. 1998; Levitan et al. 1989). In one autopsy study, melanocytes were identified in the basal layer of the vagina of 3 of 100 women. It has been suggested that such a condition, referred to as benign melanosis, is the setting from which melanoma occasionally may arise (Hasumi et al. 1978), and we have seen localized regions of melanosis in the vagina remote from melanomas. Unfortunately, the term melanosis also has been used to designate melanophages in the stroma and lentigo-malignum-like lesions in mucosal tissues, further obscuring interpretation of the scant available literature.
Because Clark’s levels are not appropriate for mucosal sites of melanoma, a system based entirely on tumor thickness has been proposed by Chung et al., as follows: level I, tumor confined to the surface epithelium; level II, invasion of 1 mm or less; level III, invasion of 1–2 mm; and level IV, invasion greater than 2 mm (Chung et al. 1980). Unfortunately, most of the tumors are deeply invasive. In a group of 19 patients, only 1 was at level III; the remainder were at level IV (Chung et al. 1980).
The diagnosis usually is straightforward as most vaginal melanomas are large, with gross and microscopic pigmentation. The differential diagnosis may include melanoma metastatic from other sites, poorly differentiated squamous carcinoma, sarcoma, and blue nevus. Because primary vaginal melanoma is rare, it is important to rule out metastasis from other sites. The presence of an extensive lateral junctional component is typical in melanomas arising in the vagina but relatively uncommon in metastases. A complete history is essential, and some cases can be confirmed only by postmortem examination. When large ulcerated lesions are devoid of pigment, immunohistochemistry and ultrastructural examination may permit discrimination of melanoma from other poorly differentiated neoplasms. Positive staining of malignant cells with antibodies directed against S-100 protein is a sensitive, but not specific, marker of melanocytic or neural differentiation. SOX 10, a neural crest transcription factor, appears to be more specific and sensitive than S100 (Fig. 55b) (Nonaka et al. 2008). HMB-45 is a less sensitive (negative in 23% of cases in one study (Gupta et al. 2002)) but more specific indicator of melanoma, and staining for keratin or desmin should be absent. Ultrastructural findings include premelanosomes and melanosomes, as well as abundant rough and smooth endoplasmic reticulum (Hasumi et al. 1978). A high degree of nuclear atypia and numerous mitotic figures usually permit discrimination of melanoma from the rare benign vaginal nevus.
Clinical Behavior and Treatment
The prognosis for vaginal melanoma is poor, with 5-year survival rates of less than 10–30% (Chung et al. 1980; Creasman et al. 1998; Huang et al. 2013; Levitan et al. 1989; Ragnarsson-Olding et al. 1993; Tcheung et al. 2012; Weinstock 1994). Undoubtedly, this reflects the inherent aggressiveness of melanoma coupled with the typically deep invasion found at the time of diagnosis (Chung et al. 1980; Creasman et al. 1998; De Matos et al. 1998; Reid et al. 1989. In one study, survival was inversely related to the mitotic activity (Borazjani et al. 1990). In another study, tumor thickness, ulceration status, and pathologic clearance margin were significant predictors of melanoma-specific survival (Seifried et al. 2015). Both lymphatic and hematogenous metastases are common, with the vagina and groin being the most common initial sites of spread. Primary therapy usually includes radical local excision, although pelvic exenteration has been suggested as treatment for tumors greater than 3 mm in thickness. The value of groin node dissection, radiation, and chemotherapy remains unknown (Levitan et al. 1989; Perez et al. 1992). Recent molecular studies have shown NRAS (~20%) and CKIT (~10%), but not BRAF, mutations in vaginal melanoma, which raises the possibility of targeted therapeutic approach for a subset of patients (Aulmann et al. 2014; Rouzbahman et al. 2015; Udager et al. 2017; Van Engen-van Grunsven et al. 2014.
Yolk Sac Tumor
Although the yolk sac tumor (endodermal sinus tumor [EST]) usually arises in the gonads, it can rarely occur in the vagina where it represents >90% of extragonadal yolk sac tumors (Clement et al. 1988; Ravishankar et al. 2017; Young and Scully 1984; Yuan et al. 2018; Zhang et al. 2016). It is appealing to consider that these tumors originate from germ cells that have failed to complete migration normally in the embryo from the hindgut to the gonad. However, this hypothesis does not provide an obvious explanation for the absence of other malignant germ cell tumors in the vagina or the predilection of EST for the vagina.
Most vaginal ESTs have been diagnosed in children less than 4 years of age. The presenting symptom usually is a bloody vaginal discharge with or without a prolapsing mass through the introitus; serum alpha-fetoprotein levels are typically elevated (Tao et al. 2012). The gross and microscopic features of vaginal EST closely resemble those of ovarian origin. Polypoid or sessile, soft, and tan or white vaginal masses 1–5 cm in diameter are typical (Kurman et al. 1992). A variety of histologic patterns may be present including the microcystic, reticular, papillary, and solid types of EST. Schiller–Duval bodies, composed of papillary arrangements of columnar cells separated from central vascular channels by an acellular zone of connective tissue, are characteristic findings. Extracellular hyaline droplets also are common. Although the histologic findings usually are typical, the diagnosis may not be considered initially because of the rarity of EST in the vagina. The differential diagnosis includes clear cell adenocarcinoma from which EST may be distinguished by the younger age and positive immunohistochemical reactions for alpha-fetoprotein and alpha-1-antitrypsin (Young and Scully 1984).
EST is an extremely aggressive tumor. In the past, the median survival was 11 months, and the survival rate at 5 years was less than 25% (Copeland et al. 1985b; Perez et al. 1992). Most patients developed recurrence and died within 2 years, even after radical surgery (Copeland et al. 1985b; Kurman et al. 1992). The addition of multiagent chemotherapy, usually consisting of vincristine, actinomycin, and cyclophosphamide, since 1970 has resulted in a 95% disease-free survival at 2 years (Anderson et al. 1985; Copeland et al. 1985b; Young and Scully 1984). Data suggests that combination chemotherapy and conservative surgery may permit preservation of future sexual function and fertility as well as an excellent cure rate (Perez et al. 1992; Tao et al. 2012).
Miscellaneous Malignant Neoplasms
- Ackerman LV (1948) Verrucous carcinoma of the oral cavity. Surgery (St Louis) 23:670–678Google Scholar
- Brand SR, Degenhardt TP, Person K et al. (2018). A phase 2, randomized, double-blind, placebo-controlled, dose-ranging study to evaluate the efficacy and safety of orally administered VT-1161 in the treatment of recurrent vulvovaginal candidiasis. Epub ahead of print. Am J Obstet Gynecol. 218(6):624.e1–624.e9. PMID 29534874Google Scholar
- Brinton LA, Nasca PC, Mallin K et al (1990) Case-control study of in situ and invasive carcinoma of the vagina. Gynecol Oncol 38(49)Google Scholar
- Chang A, Amin A, Gabrielson E et al (2012) Utility of GATA3 immunohistochemistry in differentiating urothelial carcinoma from prostate adenocarcinoma and squamous cell carcinomas of the uterine cervix, anus, and lung. Am J Surg Pathol 36:1472–1476. PMID: 22982890PubMedPubMedCentralCrossRefGoogle Scholar
- Charles V, Charles SX (1978) A case of vulvo-vaginal diphtheria in a girl of seven years. Indian J Pediatr 15:257–258Google Scholar
- Chattopadhyay I, Cruickshan DJ, Packer M (2001) Non diethylstilbestrol induced vaginal adenosis – a case series and review of literature. Eur J Gynaecol Oncol 22(4):p260–p262Google Scholar
- Coetzee LF (1972) Tuberculous vaginitis. South Afr Med J 46:1225–1226Google Scholar
- Coffin CM, Dehner LP (1992) The soft tissue. In: Stocker JT, Dehner LP (eds) Pediatric pathology, vol 2. Lippincott, Philadelphia, pp 1091–1132Google Scholar
- Darragh TM, Colgan TJ, Cox JT et al (2012) The lower anogenital squamous terminology standardization project for HPV-associated lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. J Lower Genit Tract Dis 16:205–242. PMID: 22820980CrossRefGoogle Scholar
- de Mundi ZA, del Alamo CM, de Blas LL, San Cristobal AA (1978) Egg of Trichuris trichiura in a vaginal smear. Acta Cytol 22:119–120Google Scholar
- de Virgiliis G, Sideri M, Rossi A et al (1985) “DES-like” anomalies. I. Biological and clinical problems. A study on 12, 285 cases. Cervix Low Female Genital Tract 3:297–312Google Scholar
- Donders GG, Bellen G, Ruban K et al (2018) Short- and long-term influence of the levonorgestrel-releasing intrauterine system (Mirena®) on vaginal microbiota and Candida. J Med Microbiol 67:308–313. PMID 29458551Google Scholar
- Droegemueller W, Herbst AL, Mishell DR Jr, Stenchever MA (1987) Comprehensive gynecology. Mosby, St. Louis, p 974Google Scholar
- Dvoretsky PM, Bonfiglio TA (1986) The pathology of vulvar squamous cell carcinoma and verrucous carcinoma. In: Sommers SC, Rosen PP, Fechner RE (eds) Pathology annual, part 2, vol 21. Appleton-Century-Crofts, Norwalk, pp 23–45Google Scholar
- Fu YS, Reagan JW (1989a) Pathology of the uterine cervix, vagina, and vulva. Saunders, Philadelphia, pp 193–224Google Scholar
- Fu YS, Reagan JW (1989b) Pathology of the uterine cervix, vagina, and vulva. Saunders, Philadelphia, pp 336–379Google Scholar
- Gaensbauer JT, Birkholz M, Smit MA et al. (2018) Epidemiology and clinical relevance of toxic shock syndrome in US children. Pediatr Infect Dis J. epub. PMID 29601458Google Scholar
- Georgiev D, Karag’ozov I, Velev M, Makaveeva V (2006) Three cases of vaginal adenosis after topical 5-fluorouracil therapy for vaginal HPV-associated lesions. Akush Ginekol 45(3):59–61Google Scholar
- Gompel C, Silverberg SG (1977) Pathology in gynecology and obstetrics. Lippincott, PhiladelphiaGoogle Scholar
- Hartmann C-A, Sperling M, Stein H (1990) So-called fibroepithelial polyps of the vagina exhibiting an unusual but uniform antigen profile characterized by expression of desmin and steroid hormone receptors but no muscle-specific actin or macrophage markers. Am J Clin Pathol 93:604–608PubMedCrossRefGoogle Scholar
- Heinz KPW (1973) Amoebic infection of the female genital tract. A report of three cases. South Afr Med J 47:1795–1798Google Scholar
- Herbst AL (1992) Vaginal clear cell cancer: incidence, survival and screening. In: Long-term effects of exposure to diethylstilbestrol (DES) (NIH Workshop), 23–24 Apr. Falls Church, pp 19–20Google Scholar
- Hill HR (1984) Group B streptococcal infections. In: Holmes KK, Mårdh P-A, Sparling PF, Wiesner PJ (eds) Sexually transmitted diseases. McGraw-Hill, New York, pp 397–407Google Scholar
- Kaufman RH, Friedrich EG, Gardner HL (1989) Cystic tumors. In: Benign diseases of the vulva and vagina, 3rd edn. Year Book, Chicago, pp 237–285Google Scholar
- Kazakov DV, Stewart CJ, Kacerovska D et al (2010) Prostatic-type tissue in the lower female genital tract: a morphologic spectrum, including vaginal tubulosquamous polyp, adenomyomatous hyperplasia of paraurethral Skene glands (female prostate), and ectopic lesion in the vulva. Am J Surg Pathol 34:950–955. PMID 20505502PubMedCrossRefGoogle Scholar
- Kelly P, McBride HA, Kennedy K et al (2011) Misplaced Skene's glands: glandular elements in the lower female genital tract that are variably immunoreactive with prostate markers and that encompass vaginal tubulosquamous polyp and cervical ectopic prostatic tissue. Int J Gynecol Pathol 30:605–612. PMID 21979599PubMedCrossRefGoogle Scholar
- Keyzer C, Lilford R, Gordon W, Bloch B (1982) Pyoderma gangrenosum, vesicovaginal fistula and endometriosis. A case report. South Afr Med J 61:843–845Google Scholar
- Komisaruk BR, Whipple B, Komisaruk BR, Whipple B (2005) Functional MRI of the brain during orgasm in women. Ann Rev Sex Res 16:62–86Google Scholar
- Kurman RJ, Norris HJ, Wilkinson E (1992) Tumors of the vagina. In: Atlas of tumor pathology, 3rd series, fasc 4. Tumors of the cervix, vagina, and vulva. Armed Forces Institute of Pathology, Washington, DC, pp 141–178Google Scholar
- Lifson AR (1992) Transmission of the human immunodeficiency virus. In: DeVita VT, Hellman S, Rosenberg SA (eds) AIDS: etiology, diagnosis, treatment, and prevention. Lippincott, Philadelphia, pp 111–117Google Scholar
- Lorenz G (1978) Adenomatoid tumor of the ovary and vagina. Zentbl Gynakkol 100:1412–1416Google Scholar
- Mårdh P-A, Holst E, Moller BR (1984) The grivet monkey as a model for study of vaginitis. In: Mårdh P-A, Taylor-Robinson D (eds) Bacterial vaginosis. Almquist and Wiksell International, Stockholm, p 201Google Scholar
- McLellan R, Spence MR, Brockman M et al (1982) The clinical diagnosis of trichomoniasis. Obstet Gynecol 60(30)Google Scholar
- Montgomery EA, Shuster DD, Burkart AL, Esteban JM, Sgrignoli A, Elwood L, Vaughn DJ, Griffin CA, Epstein JI (2006) Inflammatory myofibroblastic tumors of the urinary tract: a clinicopathologic study of 46 cases, including a malignant example inflammatory fibrosarcoma and a subset associated with high-grade urothelial carcinoma. Am J Surg Pathol 30(12):1502–1512PubMedCrossRefGoogle Scholar
- Perez CA, Gersell DJ, Hoskins WJ, McGuire WP III (1992) Vagina. In: Hoskins WJ, Perez CA, Young RC (eds) Principles and practice of gynecologic oncology. Lippincott, Philadelphia, pp 567–590Google Scholar
- Peterman TA, Stoneburner RL, Allen JR et al (1988) Risk of human immunodeficiency virus transmission from heterosexual adults with transfusion-associated infections. JAMA 259(55)Google Scholar
- Plentl AA, Friedman EA (1971) Lymphatic system of the female genitalia. The morphologic basis of oncologic diagnosis and therapy. Saunders, Philadelphia, pp 51–74Google Scholar
- Podczaski E, Herbst AL (1986) Cancer of the vagina and fallopian tube. In: Knapp RC, Berkowitz RS (eds) Gynecologic oncology. Macmillan, New York, pp 399–424Google Scholar
- Premptee T, Amornmarn R (1985) Radiation treatment of primary carcinoma of the vagina: patterns of failure after definitive therapy. Acta Radiol Oncol 24(51)Google Scholar
- Rein MF, Müller M (1990) Trichomonas vaginalis. In: Holmes KK, Mårdh P-A, Sparling PF, Wiesner PJ (eds) Sexually transmitted diseases, 2nd edn. McGraw-Hill, New YorkGoogle Scholar
- Robboy SJ, Prade M, Cunha G (1992) Vagina. In: Sternberg SS (ed) Histology for pathologists. Raven Press, New York, pp 881–892Google Scholar
- Rorat E, Ferenczy A, Richart RM (1975) Human Bartholin gland, duct, and duct cyst. Histochem Ultrastruct Study Arch Pathol 99:367–374Google Scholar
- Schoolmeester JK, Xing D, Keeney GL, Sukov WR (2018) Genital rhabdomyoma of the lower female genital tract: a study of 12 cases with molecular cytogenetic findings. Int J Gynecol Pathol epub 37(4):349–355. PMID 28700439Google Scholar
- Sunderland WA, Harris HH, Spence DA, Lawson HW (1972) Meningococcemia in a newborn infant whose mother had meningococcal vaginitis (letter to the editor). J Pediatr 81(856):310Google Scholar
- Sweet RL, Gibbs RS (1985a) Infectious vulvovaginitis. In: Infectious diseases of the female genital tract. Williams & Wilkins, Baltimore, pp 89–96Google Scholar
- Sweet RL, Gibbs RS (1985b) Perinatal infections. Infectious diseases of the female genital tract. Williams & Wilkins, Baltimore, pp 206–214Google Scholar
- Sweet RL, Gibbs RS (1985c) Toxic shock syndrome. Infectious diseases of the female genital tract. Williams & Wilkins, Baltimore, pp 78–88Google Scholar
- Tazvassoli FA, Norris HJ (1979) Smooth muscle tumors of the vagina. Obstet Gynecol 53:689–693Google Scholar
- Tjugum J, Jonassen F, Olsson JH (1986) Vaginitis emphysematosa in a renal transplant patient. Acta Obstet Gynecol Scand 65(377):378Google Scholar
- Václavínková V, Neumann E (1981) Vaginal involvement in familial benign chronic pemphigus (morbus Hailey-Hailey). Acta Dermatoveneral (Stockh) 62:80–81Google Scholar
- Vasquez R, Collini P, Meazza C, Favini F, Casanova M (2008) Ferrari A. Late relapse of embryonal rhabdomyosarcoma, botryoid variant, of the vagina Cancer 51:140–141Google Scholar
- Venter PF, Anderson JD, Van Velden DJJ (1979) Postmenopausal endometriosis. A case report. South Afr Med J 56:1136–1138Google Scholar
- Yousem HL (1961) Adenocarcinoma of Gartner’s duct cyst presenting as a vaginal lesion. A case report. Sinai Hosp J 10:112–114Google Scholar
- Yuan Z, Cao D, Yang J et al (2018). Vaginal yolk sac tumors: our experiences and results. Int J Gynecol cancer epub. PMID: 29538246Google Scholar