Annotation O: The vaginal epithelium

Click here for Key Points to Annotation

The vagina is derived from the embryonic mesoderm, the urogenital sinus, making it, like the bladder and urethra, sensitive to estrogen, the dominant hormonal regulator of vaginal and pelvic floor physiology. The importance of estrogen’s role is supported by the presence of estrogen receptors (ER) in vaginal walls as well as in the uterosacral ligaments.1 The majority of androgen receptors are found in the vulva.2 There are no glands,3 so the vaginal lining is not technically mucosa; it is vaginal epithelium.

Normal vaginal epithelial lining is composed of a basal layer, several layers of parabasal cells, and multiple layers of intermediate and superficial stratified, nonkeratinized squamous cells that progressively accumulate glycogen.

From The Vulva. Farage and Maibach, Informa Healthcare, NY, 2006. P 14
From The Vulva. Farage and Maibach, Informa Healthcare, NY, 2006. P 14

The superficial layer varies in thickness depending on the degree of estrogenic stimulation. In premenopausal women, estradiol is the predominant form of circulating estrogen. Estrogen acts on receptors in the vagina, vulva, urethra, and trigone of the bladder to maintain the collagen content of epithelium, making it thick and elastic. Estradiol maintains acid mucopolysaccharides and hyaluronic acid, keeping epithelial surfaces moist, and optimizes genital blood flow.4 Consequently, the squamous epithelium of the vagina is thick, rugated, and glycogen rich.

The surface cells are cast off into the lumen of the vagina. This desquamation goes on constantly; the epithelium is replenished by mitotic division of cells in the basal layer and to a lesser extent in the parabasal layer. Using the glycogen from epithelial cell breakdown and from transudation from the serum glucose as an energy source, members of the Lactobacillus genus thrive, breaking down glycogen and glucose into lactic acid to acidify the vagina.

The vaginal pH and ecosystem are discussed under Annotation P, Vaginal Secretions, pH, microscopy, and cultures.).

Estradiol concentration fluctuates from 40 to 60 pg/mL in the early follicular phase, peaks at 200 to 600 pg/mL during ovulation, and then falls back to 100 pg/mL during the early luteal phase. Estradiol again gradually rises to peak at 200 pg/mL during the mid-luteal phase before falling to 30 to 50 pg/mL at the onset of the menses.5 These cyclic cellular changes are not grossly evident on speculum examination, although they are reflected in vaginal smear. The vaginal maturation index (VMI) is typically used by cytologists to quantify these cytologic vaginal epithelial changes.6

Clinically, the wet mount gives this information about cyclical cellular changes, making it essential to the evaluation of vulvovaginal complaints. ( pH and microscopy illustration ). The maturation index, determined from cytologic examination of a wet preparation of surface cells from the lower one third of the vagina, can be used to quantify the proportions of cell types of the vaginal epithelium. The maturation index is the proportion of parabasal, intermediate, and superficial cells in each 100 cells counted on a smear. In premenopausal women with adequate estrogen levels, intermediate and superficial cells predominate. When output of estrogen peaks immediately prior to ovulation, superficial cells predominate on the vaginal smear. Following ovulation, intermediate cells predominate. Late in the luteal phase, progesterone-induced cytolysis is evident and the cells break apart. The maturation index for premenopausal women is typically 40 to 70 intermediate cells, 30 to 60 superficial cells, and 0 parabasal cells.

As women pass through perimenopause to menopause, vaginal epithelial cells undergo less maturation and an increase in immature parabasal cells and a decrease in superficial cells are observed. Women in early menopause typically have a maturation index of 65 parabasal cells, 30 intermediate cells and 5 superficial cells. As women age and estrogen levels decline, parabasal cells will continue to increase, and the maturation index may eventually consist entirely of parabasal cells.

Parabasal cells are also a hallmark of inflammation and are seen with severe Candidal infections as well as other inflammatory vaginal conditions such as vaginal lichen planus and desquamative inflammatory vaginitis.


Vaginal infections and desquamative inflammatory vaginitis

These are discussed in Annotation P, Vaginal Secretions, pH, microscopy, and cultures..

Vaginal atrophy

This is discussed in Annotation P, Vaginal Secretions, pH, microscopy, and cultures..

Vaginal endometriosis

This is discussed in Annotation N: The vaginal architecture.

Diethylstilbestrol (DES) exposure

Besides uterine and cervical abnormalities, (Annotation M: Evaluation of the cervix, vagina, and STIs), DES exposure (1938-1971) is associated with vaginal ridges, transverse vaginal septum, and vaginal adenosis and clear cell carcinoma. (Annotation N: The vaginal epithelium).

Vaginal adenosis

Cervical adenosis is discussed in Annotation M: The Evaluation of the cervix, vagina, and STIs.

Prevalence

Vaginal adenosis was regarded as an uncommon and insignificant finding until 1971 when adenosis was frequently diagnosed in young women with prenatal exposure to diethylstilbestrol (DES).7 Vaginal adenosis in DES-exposed women was often associated with the rare clear-cell adenocarcinoma of the vagina. Prevalence in DES exposed women is variable (35-90%) depending on diagnostic technique (clinical inspection or colposcopy and biopsy).8 With the withdrawal of DES from the market in 1971, DES-related vaginal adenosis is rarely described in the medical literature.

A prevalence of 13% in unexposed women from 13-25 years has been reported in an autopsy study.9 The condition has been observed subsequent to Stevens-Johnson syndrome induced by sulfonamide,10 post-carbon dioxide laser treatment,11 and following 5-fluorouracil therapy of genital condylomata.12 These reports suggest that vaginal adenosis related to non-DES etiologies is a surprisingly frequent finding.13

Etiology

Vaginal adenosis represents, in the normally gland-free vagina, the presence of subepithelial glandular structures lined by mucinous columnar cells that resemble endocervical cells.14 In a mouse model, DES inhibited the normal replacement in the immature vagina during embryogenesis of Müllerian glandular epithelium by urogenital epithelium,15 suggesting a link to the effects of sex hormones.

In non-DES exposed women, it is thought that proliferation of remnant islets of Müllerian epithelium in the vagina can occur, either in utero under the influence of maternal sex hormones (non-DES), or after the menarche.16 Trauma and inflammation (severe inflammation, laser treatment, and 5-fluorouracil therapy) are thought to be other triggers, either from a proliferative stimulus during wound healing or through uncovering a focus of submucosal glandular structures by destruction of the overlying normal vaginal epithelium.17 A role of the oral contraceptive has been suggested but is unclear.

DES-induced adenosis is morphologically identical to the spontaneous type.18 Absence of endometrial stroma differentiates adenosis from endometriosis. Vaginal adenosis is thought to eventually transform into mature stratified epithelium,19 although it has been reported to persist past the menopause.20

It has not been possible to estimate how often any type of vaginal adenosis may transform into adenocarcinoma of the vagina.21 There is no known upper age limit for the diagnosis of DES-associated clear cell adenocarcinoma (CCA), and there is insufficient information regarding late risk in DES daughters after menopause. 22 A possible increase in incidence of DES-associated CCA at age ≥40 years has been suggested.23

Symptoms and clinical features

The clinical appearance of vaginal adenosis is varied: patchy or diffuse red stippling, granularity or nodularity, single or multiple cysts, erosions, ulcers or verrucous protruberances.24 Occasionally, the condition extends to the vulva.25

Vaginal adenosis is generally asymptomatic and of no clinical significance. Soreness of the introitus and vagina, vaginal bleeding unrelated to the menstrual cycle, post-coital bleeding and significant mucoid vaginal discharge may be seen.

Diagnosis

Vaginal adenosis is diagnosed by speculum examination of the vagina with colposcopy and biopsy of suspicious lesions. Pap smear may show atypical cells of undetermined significance (ASCUS).

Differential diagnosis

Erosive lichen planus, fixed drug eruption, erythema multiforme and bullous skin disease.

Treatment

Since spontaneous squamous differentiation is thought to occur in both DES and non-DES exposed women, isolated and asymptomatic areas may be followed with an annual examination, vaginal palpation for masses and four-quadrant vaginal Pap smear. Widespread and symptomatic involvement is rare; it has been treated successfully with cautery,26 and unsuccessfully with laser.

Erosive lichen planus of the vagina

Classical, hypertrophic, and erosive lichen planus of the vulva are discussed in the Atlas of Vulvar Disorders.

Introduction

Lichen planus (LP) is an inflammatory disease that may affect, separately or simultaneously, oral and genital mucosa, skin, scalp, and nails.27 LP has been reported in the esophagus, conjunctivae, bladder, nose, larynx, stomach, and anus.28 The presence of vaginal epithelial disease distinguishes lichen planus from lichen sclerosus, in which vaginal involvement almost never occurs.29

Etiology

The etiology of lichen planus is not known. Recent data suggest the disease may be a T-cell mediated autoimmune condition involving activated T cells directed against basal keratinocytes.30 Weak circulating basement membrane zone antibodies have been shown to be present in 61% of patients with erosive lichen planus of the vulva.31 This activity represents response to altered self-antigens or heterogeneous foreign antigens.32 An association of oral and cutaneous LP with HLA-DR1 suggests a genetic component.33

A drug-induced form of this disorder usually develops insidiously and can affect any area of the body surface to cause or worsen LP; the disease may improve when the offending drug is withdrawn. Oral lesions occur in 30 to 70 percent of cases; the mucosa may be painful and ulcerated.34 Information on the percentage of vulvovaginal cases is lacking. Over one hundred medications that have caused LP or lichenoid eruption have been documented by case reports: methyldopa, penicillamine, quinidine, angiotensin converting enzyme (ACE) inhibitors, sulfonylurea agents, carbamazepine, gold, lithium, and quinine have all been associated with lichen planus35 Drugs most frequently involved in induction of LP or worsening of LP are hydrochlorthiazide and nonsteroidal anti-inflammatory drugs (NSAIDs).36 Patients with mucosal LP are more likely to be on NSAIDs and beta blockers, although no association was found with oral LP and beta-blockers.37 Regarding the clinical forms and site of involvement, a statistically significant difference was only found for the clinical erosive form of oral lichen planus (OLP), seen more frequently in non-drug induced lichenoid reaction (DILR) (P = 0.04) and non-medicated OLP patients (P = 0.02) than in DILR OLP patients. Daily use of topical oral medication was reported by two (1.8%) OLP patients and one (1.3%) control subjects.38 In our experience, a trial of three to four weeks off a questionable drug offender results in clearance or significant improvement if the drug is involved.

Hepatitis C virus: The association of hepatitis C virus (HCV) with lichen planus is controversial, and a cause and effect relationship is uncertain.39

Prevalence

Oral LP is found in 0.5-2.3% of the general population.40 Vulvovaginal LP may occur in isolation, in association with oral involvement or in association with a generalized cutaneous eruption.41 Concurrent involvement of oral and genital sites, previously thought to be a low percentage,42 has recently been confirmed by biopsy in 31/41(75.6%) women in one study.43 Prevalence of vulvar lichen planus has probably been underestimated because physicians and dentists do not routinely examine the genitalia of their patients with lichen planus, and because genital lesions may be asymptomatic and subtle.44 In a specialized vulva clinic in Norway, 49/58 women with genital erosive lichen planus were found to have vaginal involvement with synechiae in 29 and total obliteration of the vagina in nine.45

Symptoms and clinical features

The typical symptoms of erosive vulvovaginal lichen planus are burning, pain, and pruritus, often accompanied by abnormal discharge.46 However, women with vaginal LP may indicate that they have had no symptoms such as itching, burning, pain, or discharge until the development of dyspareunia with pain on penetration and/or pain with speculum examination.

There may be no history of oral or vulvar disease in a woman with vaginal obliteration by asymptomatic LP. There may be a past history of oral or vulvar involvement, or there may be current oral lesions and/or vulvar lesions. Symptomatic women with vaginal LP often report irritative, yellow to serosanguinous discharge, spotting or post-coital bleeding. Women report that speculum examination and/or sexual relations have become painful, but often attribute these changes to the menopause.

Diagnosis

Vaginal LP is diagnosed by history of LP elsewhere, a history of dyspareunia, pain with speculum, vaginal lesions, vaginal scarring, and inflammatory discharge. Biopsy is important in clarifying the diagnosis if the characteristic signs are seen on pathology, but, depending on the stage of disease, may not be confirmatory. (See below). Cervical involvement can also occur in these patients.47

Physical exam findings will vary depending on whether vaginal LP is active or inactive and “burned out.” Active vaginal disease may or may not be accompanied by active vulvar disease: tender erosions in the vestibule and vulvar scarring (flattening or varying degrees of loss of labia minora, obliteration of prepuce and clitoris, and stenosis of the introitus from synechial formation.  (Atlas of Vulvar Disorders). The scarring of vaginal LP is thought to distinguish it from desquamative inflammatory vaginitis.

With active disease, insertion of the speculum can be painful. Adequate examination, however, can usually be achieved with use of eutectic mixture of lidocaine 2.5% and prilocaine 2.5% (EMLA) to the vestibule and hymenal ring for 15 minutes prior to speculum use. (If vaginal samples for pH and wet preparation can be taken with a Q-tip prior to application of the EMLA, a more accurate picture is obtained). With active disease, the vagina is erythematous, may have tender erosions or friable telangiectatic areas with patchy erythema on the sidewalls, or in the fornices. Varying amounts of yellow secretions with pH higher than 4.5 are seen in the vault. There may be synechial formation making opening of a speculum limited or impossible. If synechial scarring develops high in the vault, it causes narrowing of the vagina (telescoping). The cervix can be palpated beyond the narrowing, and may be involved with friable erythema.48 . Asymptomatic cervical involvement with LP has been documented.49 More advanced synechial formation can obliterate the vagina at any level, leaving a few centimeters of length or, in the worst cases, a dimple at the introitus.

If the disease is burned out, there may be no erythema, tenderness, or discharge, but vaginal scarring remains to cause dyspareunia and pain with speculum.

Pathology and laboratory findings

  • Vaginal pH, microscopy
    pH is elevated above 4.4 and may be as high as 7.0. Wet mount shows greater than one white blood cell per epithelial cell, reduction in squamous cells, the presence of immature parabasal cells, and reduction or loss of the lactobacilli.wet-mount-slide
    Overgrowth of other flora may or may not be present. The wet mount of lichen planus may be identical to that of atrophy or desquamative inflammatory vaginitis (DIV); a trial of adequate local estrogen is essential to differentiate these conditions.50 If increased white cells and parabasal cells persist after a four-week trial of adequate local estrogen, atrophy is ruled out or controlled. (See Microscopy section Principles of vaginal microscopy or synopsis illustration: pH and microscopy illustration for more information on using pH and microscopy to diagnosis.)
  • Biopsy
    Achieving definite histological proof of LP in mucosal sites is difficult compared with classic cutaneous LP,51 and biopsy is often inconclusive.52 The biopsy should be taken from the edge rather than the center of erosion. Most often, the histology is returned as “lichenoid dermatitis” consistent with but not diagnostic of lichen planus.53 The diagnosis of these diseases is clinical, and strongly associated with other cutaneous lesions.54 Dermatology consult is essential for diagnosis and treatment of bullous disease or any condition in question.
    Pathological findings in LP, first described in 1909, consist of irregular acanthosis of the epidermis, liquefactive degeneration of the basal cell layer, and a band-like dermal infiltrate composed almost entirely of lymphocytes. Colloid bodies, representing degenerate keratinocytes, are frequently seen in the lower epidermis and upper dermis.55 The inflammatory band at the dermo-epithelial junction is the most powerful predictor of LP; it is not seen with LS or eczema.56

Differential diagnosis

The discharge of LP may be difficult to distinguish from atrophy and desquamative inflammatory vaginitis (DIV) since all three conditions produce small to large amounts of yellow, pus-like or serosanguinous discharge characterized by multiple white blood cells, parabasal cells, and loss of the lactobacillus. Atrophy responds to adequate local estrogen and treatment of atrophy helps to clarify the diagnosis. Persistence after treatment for atrophy of more than one white blood cell per epithelial cell and more than the occasional parabasal cell suggests DIV. If there is scarring in the vagina, with or without scarring and erosion in the vulvar vestibule, LP is suspected.

Overlap between lichen sclerosus and LP is well recognized on the vulva;57 vaginal lichen sclerosus has been reported in only one case.58

Agglutination of the labia minora from lack of estrogen is found in 1.8% of infants of 13-23 months but scarring attributed to atrophy in both children and adults is often caused by lichen sclerosus, not atrophy. Vaginal obliteration from atrophy is not reported in children or adults.

Bullous and cicatricial pemphigoid, Stevens-Johnson syndrome, drug reaction, graft-versus-host disease may also erode, scar, and/or obliterate the vagina. Vaginal adenosis may cause erosions or ulcers.

Association with squamous cell carcinoma

Malignant transformation of vulvar lichen planus has been reported but its incidence is unclear. No cases were found in 58 cases of erosive genital lichen planus evaluated in a Norwegian vulvar clinic between the years 2003-2009.59 Seven of 114 women developed vulvar intraepithelial neoplasia and three women developed squamous cell carcinoma during a five-year study in the United Kingdom.60 There was one case of vulvar carcinoma among 44 women with LP in another case series.61 To date, vaginal cancer with vaginal lichen planus has not been reported.

Treatment

The treatment of stenosing vaginal LP is challenging to the physician, and treatment results are often disappointing, possibly because of the rigor demanded of both patient and physician. The intravaginal inflammation must be controlled to prevent scarring. Scarring existing at the time of presentation will need addressing after inflammation is treated if patency of the vagina is a goal. Subsequent to control of inflammation and release of scarring, ongoing close monitoring, intravaginal anti-inflammatory therapy, and maintenance of architecture using dilators or regular intercourse are all essential. Failures often occur with cessation of therapy by the patient herself or on the recommendation of her provider.

Intravaginal steroids, intramuscular triamcinolone, intravaginal tacrolimus

Intravaginal hydrocortisone

In our experience, intravaginal LP can usually be brought into control with

  • 10-30% hydrocortisone in petrolatum, one gram vaginally nightly for 30 days with a follow up visit in one month.

Repeat evaluation in four weeks with speculum, digital exam, and wet mount will give information on regression of inflammatory lesions and friability, and, if the patient is improved, will show diminished white cells and parabasal cells on microscopy. If there is improvement, the hydrocortisone can be spaced out gradually with ongoing monitoring to once or twice weekly. If there is no improvement, the nightly therapy can be extended another four to eight weeks. With the use of intense intravaginal steroid, prophylaxis against Candida is often important. We use 150 mg of fluconazole weekly orally or combine clotrimazole 2% with the compounded hydrocortisone.

If there is inadequate improvement after 12 weeks of intravaginal hydrocortisone, it is important to ascertain that Candida is not present. Options we have used successfully to treat recalcitrant disease include:

  • Prednisolone 5 mg vaginal suppository compounded, nightly for 30 days, then re-evaluation
  • Intramuscular triamcinolone 60 mg IM, monthly for four months. This vastly under-utilized treatment modality is safe and effective for inflammatory dermatoses,62 especially in women who do not tolerate topical steroids. The depot of steroid gives peak levels from one to two days, which fall rapidly to a steady state. The steroid is gone by the end of the third week,63 but its anti-inflammatory effects remain long after its disappearance from the plasma. The episodic exposure may be less harmful than continuous low-dose oral therapy.64 Only one report in the literature links avascular necrosis with IM triamcinolone.65 Patients have (and must be counseled about this) adrenal suppression for 30-40 days following an intramuscular injection;66 but do not experience long-term suppression. The majority have normal adrenocorticosteroid function six weeks after their last injection.67
  • Tacrolimus, 2 mg compounded vaginal suppository, nightly for 30 days, then re-evaluation. Tacrolimus is a topical calcineurin inhibitor immunosuppressant, which has been reported to be effective in erosive lichen planus.68 Its mechanism of action works through inhibition of the activation and proliferation of T lymphocytes. The advent of tacrolimus potentially heralds a new era of effective management of erosive lichen planus.
  • Systemic treatments are surprisingly unhelpful, with poor response to methotrexate, cyclosporine, and azathioprine and hydroxychloroquine sulfate.69 Other immunosuppressives (mycophenylate mofetil, etanercept, adalimumab), and retinoids have been reported as helpful. In general, patients who are not responding to steroids or tacrolimus should be seen and managed in specialized units run by multidisciplinary teams in an academic center.
Steroid absorption and complications

Ultrapotent steroids have been in use for inflammatory dermatoses since 1988. When used appropriately, they have marked clinical efficacy and do not atrophy the skin or suppress the adrenal axis.70 Unfortunately, drug manufacturers have not changed their package literature so that patients continue to be informed that ultra-potent steroids are unsafe for the genitals and must be limited to two weeks of treatment.

The vagina is an excellent route for steroid absorption.71 The mucosa of both the small intestine and the colon are statistically significantly less permeable to estradiol than human vaginal epithelium.72 However, there are no studies of corticosteroid absorption from the vagina. Topical usage of clobetasol propionate 0.05% is recommended not to exceed 50 g/week73 and a topical dose of 2 g per day of 0.05% clobetasol propionate can measurably suppress the hypothalamic-pituitary- adrenal axis.74 Such doses per vaginam are not used in our practice; vulvar regimens involve a fraction of this amount.

The intravaginal treatment of vaginal lichen planus is often achieved with the much weaker hydrocortisone (LINK to treatment), and treatment regimens with ultrapotent steroids can be achieved using less than the level known to suppress the axis. When there is concern, a normal early morning cortisol level is reassuring. In our experience, the few patients who have come into question regarding cortisol abnormalities have had an endocrinopathy rather than ultra-potent steroid use as the source of their abnormal cortisol levels.

Release of intravaginal adhesions and vaginal dilator therapy

Intravaginal scarring can be addressed when active, inflammatory disease is brought under control so that no erosions or ulcers are present in the vagina. Scarring may involve total obliteration of the vault or partial strictures of varying degrees. It has been our experience with vaginal strictures of this nature, that dilator use is ineffective as treatment but is extremely valuable in maintenance, once the adhesions have been released operatively. Pre-operative preparation includes education for risk of recurrence of the lesions and the on-going need to manage the inflammation with topical steroids and dilators.

  • Surgical release of adhesions: At the beginning of the procedure, we place a foley catheter and a rectal probe. We use a hand-held carbon dioxide laser without microscope under general anesthesia in the operating room. Small laser-compatible retractors, or a pediatric speculum disassembled to two blades are used for visualization of the vaginal adhesions. These are visible as grey-white fiber bundles seen when the vagina is put on stretch. A short burst of 12 watts releases these; the next bundle is located and the process continues with laser, sharp, and blunt dissection to eliminate as many adhesions as possible without endangering the bowel or bladder. At the end of the procedure, the vagina is filled with silvadene or petrolatum to prevent adherence over the next 24 hours.The patient is seen again within 24 hours to make sure that patency persists; any adhesions can be separated manually.
  • Postoperative course and dilator use: During the first postoperative week, the patient uses two grams of estrogen nightly into the vagina with an applicator and is started on a small, rigid, Syracuse dilator nightly for 20 minutes.During the second week, she switches to the steroid or tacrolimus that brought her active disease into remission. She is seen every two weeks, advancing to a large dilator as appropriate. (Annotation D: Patient tolerance for genital exam, section on dilators). Her management will eventually lead to steroid use 2-3 times a week with dilator or intercourse 2-3 times a week. Our experience has been similar to the report of 13 women similarly treated who reported good relief, although to a varying degree, with some recurrence.75Other experts have used foam dilators covered with condoms inserted into the newly patent vagina. The labia minora are sewn together to keep the dilator in place; sutures and foam dilator are removed after 48 hours and high dose intravaginal steroids are started.76The combination of surgical dilatation, methotrexate, and local treatments with an ultrapotent corticosteroid cream and tacrolimus has also been reported effective in the treatment of patients with severe, stenosing vulvovaginal LP; the beneficial effect of methotrexate, in this study, extended also to oral lesions.77

Graft versus host disease

Introduction

Graft versus host (GVH) disease, a systemic immune disorder, is the most common late complication of allogeneic hematopoietic stem cell transplantation.78 The incidence of chronic GVH disease has increased with peripheral blood stem cell transplantation that yields faster engraftment, earlier hematopoietic recovery and improved anti-leukemic effects. 79 Because it is insidious in onset, often developing months after the transplant, it evades the attention of transplant experts and presents to primary providers or other caregivers less likely to be familiar with the problem. Many areas of the body can be affected, including the vulva and the vagina.

Prevalence

Chronic GVHD occurs in at least 30% to 50% of recipients of transplants from human leukocyte antigen–matched siblings and at least 60% to 70% of recipients of transplants from unrelated donors.80 Risk factors include older age of patient or donor, higher degree of histoincompatibility, unrelated versus related donor, use of hematopoietic cells obtained from the blood rather than the marrow, and previous acute GVHD.81

Etiology

Allogeneic hematopoietic cell transplantation involves ablation of the patient’s lymphohematopoietic system by chemotherapy and radiation and its replacement by healthy hematopoietic stem cells and lymphocytes transfused from a related or unrelated donor. Mismatches at histocompatibility loci may lead to activation of minor histocompatibility antigen-specific donor T cells, despite prophylactic administration of immunosuppressive medications. These activated T cells, through dysregulated cytokine production and recruitment of additional effector cells, cause damage to a variety of epithelial tissues, a syndrome called acute GVHD.82

Symptoms and clinical features

The syndrome typically occurs 4 to 7 months after transplantation but may begin as early as two months or as late as two or more years after transplantation.

The onset of the syndrome may be abrupt but is frequently insidious, with manifestations evolving gradually for several weeks. The extent of involvement varies significantly, from mild involvement limited to a few patches of skin to severe involvement of numerous organ systems and profound immunodeficiency. The most commonly involved tissues are the skin (27%), liver (10%), mouth (26%), and eyes (23%).83 Chronic GVH is often more protracted, less responsive to steroids and more commonly involves the vagina (14%) and vulva (28%).84 Signs include an erythematous, papular, lichenoid eruption on the skin, lichen planus in the mouth, and lichen planus-like findings on the vulva and in the vagina, including erythema, tender gland openings, vulvar fissures and erosions, clitoral agglutination, vaginal synechiae, and vaginal fasciitis. GVH can also produce vaginal stenosis with partial to complete agglutination.85

Diagnosis

Diagnosis is made by history involving a transplant and physical examination followed by biopsy.

Differential diagnosis

Fixed drug eruption, lichen sclerosus, lichen planus, and pemphigus.

Treatment

Patients with chronic GVHD should be cared for in cooperation with the transplant physician’s team. Treatment is related to the dysregulated immune cells and cytokines causing damage to various tissues, and the immunodeficiency state that is associated with an increased risk of severe infection. Patients who develop chronic GVHD require reinstitution of immunosuppressive medication (if already discontinued) or an increase in dosage and, possibly, addition of other agents.86 Localized skin, mouth or vulvar involvement may respond to topical corticosteroids such as clobetasol 0.05% twice daily. Cyclosporine 10 mg/kg/day is often added to the steroid regime. Consultation with infectious disease experts may be necessary if infection is an issue.

Moderate to severe involvement may require oral prednisone from 20-30 mg/day to 1 mg/kg/day, tapered after two weeks if response is observed to a dose of 1 mg/kg on alternate days. After 3 months of successful treatment, the cyclosporine and prednisone can be tapered.

Vaginal stenosis in GVHD can be managed surgically with lysis of adhesions followed by a rigid dilator for 12 hours a day.87 (See above under treatment of vaginal lichen planus).

Vaginal polyps

For a discussion of vaginal polyps, refer to (Annotation N: The vaginal architecture).

Vaginal intraepithelial neoplasia

For cervical intraepithelial neoplasia (CIN): (Annotation M: Speculum exam and evaluation of the cervix)

For vulvar intraepithelial neoplasia (VIN): (Annotation F: The vulvar architecture)

*This topic is also covered in Annotation N: The vaginal architecture

Introduction

Vaginal intraepithelial neoplasia (VaIN), a rare condition, far less common than cervical intraepithelial neoplasia (CIN), has increased over the past few decades.

Prevalence

The incidence of VaIN is estimated to be 0.2-0.3 cases per 100,000 women in the USA or 0.4% of lower genital tract intraepithelial disease.88 It is now found in younger women; this rise seems to be associated with the increased prevalence of human papilloma virus infections of the genital tract.89 VaIN is more common in patients who have previously been treated for cervical or vulvar neoplasia. Therefore aceto-white vaginal lesions may appear in tissue contiguous to previously involved areas, i.e., at the vaginal apex, in the fornices, or about the vestibule and lower vagina. Lesions are often multifocal.90

Classification

VaIN represents the presence of squamous cell atypia without invasion; the depth of involvement of the vaginal epithelium with atypia determines the classification. Vaginal pre-malignant lesions are classified as VaIN I: lower one third of the epithelium, VaIN II: involving the lower two thirds, or VaIN III: involving more than two-thirds of the epithelium. The propensity for these lesions to progress to a higher grade is less well established than for CIN, but progression to invasive vaginal carcinoma is reported.91

Symptoms and clinical features

The disease is often asymptomatic but post-coital bleeding or vaginal discharge may be present. The Pap smear may be abnormal.

Diagnosis

VaIN is diagnosed by colposcopy and biopsy

Treatment

Patients with VaIN are referred to a gynecologist with VaIN treatment experience or to a gynecologic oncologist. VaIN may be treated by a variety of modalities, depending on its classification and extent. Surgical excision (vaginectomy), CO2 laser ablation, topical application of 5% imiquimod cream or 5-fluorouracil are all successful. Recurrent disease is common, approximately 44% with any modality and long-term follow up is essential.92

Malignant epithelial vaginal lesions

Introduction

Primary invasive cancer is rare and most (80-90%) vaginal carcinoma is secondary to an occurrence elsewhere. Metastatic tumors to the vagina most commonly occur among women with concurrent or previously treated endometrial or cervical cancer.93 Metastases from the vulva, ovary, breast, rectum, and kidney and kidney may also occur.94

*This topic is also covered in Annotation N: The vaginal architecture.

Prevalence

The incidence of invasive squamous cell cancer of the vagina is one per 100,000 women.95 The majority of vaginal cancers are squamous, although adenocarcinoma and others (melanoma) are reported.96 Because of the rarity of the disease, the etiology of vaginal cancer is unknown.

Symptoms and clinical features

Women with vaginal cancer may be symptom free,97 but the majority of those with invasive lesions present with vaginal bleeding, either post-coital or postmenopausal. Discharge may also be watery, blood-tinged, or malodorous.98 Abnormalities that may be seen include granular red lesions, white epithelium with or without abnormal vessels, ulceration, or tumor formation; intraepithelial or sub-epithelial hemorrhage, or urinary or bowel symptoms may occur.

Diagnosis

Vaginal carcinoma can be obscured by the blades of the speculum, adding greater significance to routine bimanual palpation for vaginal masses. Biopsy of a mass, plaque, or ulcer makes the diagnosis.

Treatment

Patients with suspected or biopsy-proven malignant lesions need to be referred to a gynecologic oncologist for evaluation and treatment. Treatment usually includes radiation and/or surgery.99

Vaginal fixed drug eruption

For vulvar fixed drug eruption, see Annotation F: The vulvar architecture and Atlas of Vulvar Disorders.

Introduction

A fixed drug eruption (FDE) is an uncommon reaction to drug and occasionally food ingestion that recurs in the same site or sites each time the drug is administered. Since the genital area in women is a common site of eruption, FDE may present as acute, recurrent, or chronic vaginitis that resolves rapidly when the offending drug is withdrawn.

Prevalence

Vaginal fixed drug eruption is rare.

Etiology

Fixed drug eruption is a type of allergic reaction to a medicine. Usually just one drug is involved, although independent lesions (patches) from more than one drug have been described. Cross-sensitivity to related drugs may occur and there are occasional reports of recurrences at the same site induced by drugs that appear to be chemically unrelated. Sometimes the inducing drug may be re-administered without causing reappearance of the patch(es) and there may be a refractory period during which no reaction will occur after the occurrence of FDE. The pathogenesis of FDE remains undetermined. However, results of a recent study suggested that activation of effector memory T cells residing in the epidermis contributes to tissue injury.100

The most common causative agent is trimethoprim-sulfamethoxazole.101

The number of drugs capable of causing fixed eruptions is large and includes over-the-counter medications as well as prescription drugs. Most FDE lesions are due to the following:102

  • Paracetamol (acetaminophen)/phenacetin and other pain killers
  • Tetracycline antibiotics: doxycycline, minocycline
  • Sulphonamide antibiotics including cotrimoxasole (Bactrim, Septrin, Apo-Sulfatrim, Trimel, Trisul), sulfasalazine (Colizine, Salazopyrin)
  • Acetylsalicylic acid/aspirin
  • Nonsteroidal anti-inflammatories (NSAIDs) including ibuprofen
  • Sedatives including barbiturates, benzodiazepines and chlordiazepoxide (Novapam)
  • Hyoscine butylbromide (Buscopan, Scopoderm) – see halogenodermas
  • Dapsone
  • Phenolphthalein (an old-fashioned laxative for constipation)
  • Quinine (Q-200, Q-300, Quinoc), taken for leg cramps)

Symptoms and clinical manifestations

The eruption appears usually within 30 minutes to 8 hours after drug exposure. The diagnostic hallmark is its recurrence at the previously affected sites. Characteristically, fixed drug eruptions recur at the same sites with repeated exposure to the offending drug. In one group, 24/28 (89%), the lesions were vulvar only; in 3/28 they were vulvovaginal.103

Mucositis progressing to erosion and ulceration has been documented in one study.104

Diagnosis

There are no definitive laboratory tests to confirm the diagnosis of FDE. Oral provocation with the suspected agent is the only reliable method in most cases.105 The clinical pattern of FDE may provide useful information to determine the most likely causative drug, especially when the details of the drugs to which the patient has been exposed are known. Fixed drug eruption is characterized by well-circumscribed, erythematous patches and plaques, occasionally associated with bulla formation. The lips, genitalia, and sacral area are favored involvement sites; however, FDE lesions can appear on any part of the body.106

Treatment

The main goal of treatment is to identify the causative agent and avoid it. In addition, symptoms must be treated. Systemic antihistamines and topical corticosteroids may be all that are required. In cases in which infection is suspected, antibiotics and proper wound care are advised. Desensitization to medications has been reported in the literature, but this should be avoided unless no substitutes exist.107

Bullous erythema multiforme (Stevens-Johnson syndrome (SJS),toxic epidermal necrolysis (TEN))

Vaginal fistulas

Rectovaginal fistulas

Introduction

A rectovaginal fistula (RVF) is an abnormal connection between the rectum and the vagina. Bowel contents can leak from the fistula with the passage of gas or stool through the vagina.

Etiology

  • Injuries in childbirth. Obstetric injuries cause up to 88% of rectovaginal fistulas,108 occurring in 0.1% of vaginal deliveries in Western countries.109 Fistula formation typically occurs as a result of a high-grade perineal body laceration caused during delivery. In Western counties, primiparity, midline episiotomies, increased birth weight, and the use of vaginal forceps are the risk factors associated with severe perineal lacerations.110 Often such lacerations are recognized and primarily repaired at the time of childbirth. Unrecognized deep tears or inadequate healing can generate a persistent aberrant connection between the rectum and vagina, allowing passage of gas, mucus, and stool to the vagina.
  • Crohn disease. The second most common cause of rectovaginal fistulas is the transmural inflammation of the gastrointestinal tract in Crohn disease.111 Most women with Crohn disease never develop a rectovaginal fistula, but having Crohn disease does increase the risk of the condition.
  • Vaginal, perineal, or ano-rectal surgery. Prior surgery in the lower pelvic region, such as removal of the uterus (hysterectomy), can lead to development of a fistula in rare cases. The incidence of RVF after operative treatment for low rectal cancer is reported to be 0.9% to 10%.112 Low and very low anterior proctosigmoidectomy, use of the double-staple technique, and combined resection of the uterus and/or partial vaginectomy during proctectomy are identified as risk factors for the development of RVF. Use of diverting ostomies in the setting of rectal cancer construction do not completely eliminate fistula risk, as RVF can occur in up to 11% of patients despite complete enteric diversion.113
  • Pelvic cancer or radiation treatment. Malignancy of the rectum, cervix, vagina, uterus, or anal canal can lead to development of a rectovaginal fistula. Radiation therapy for cancers in these areas can also increase the risk of developing such fistulae.114 A fistula caused by radiation usually forms within two years following the treatment.
  • Other causes. Less commonly, a rectovaginal fistula may be caused by infections in the anus or rectum, diverticulitis, or vaginal trauma. Abscesses arising from the crypts of Morgagni, Bartholin gland abscesses, and diverticulitis can cause intense inflammation that culminates in a fistulous tract with the vagina.115 Vaginal trauma induced by retained foreign bodies, such as pessaries, sexual objects,116 and coitus can result in RVF.117118

 

Symptoms and clinical features

Women may present with complaint of gas, stool, or malodorous discharge per vagina. There may be rectal incontinence, dyspareunia, or perineal pain. Recurrent vaginal infection may be part of the history. Besides medical, surgical, and obstetric history, questions regarding Crohn symptomatology and surgical records are important. Physical examination includes gastrointestinal signs consistent with Crohn disease. Visual inspection of the anoderm should follow pelvic examination, noting unusual findings, such as atypical fissures or mucosal irregularities. Irregular masses may be palpated on digital rectal examination. RVFs are often felt as an irregular mass arising from the rectovaginal septum on bimanual examination. Proctoscope or anoscopy allows inspection for mucosal irregularities, stricture, or active proctitis.119 A colonoscopy may be necessary.

If a fistula is not found during the physical exam, further work-up is necessary with specialized diagnostic imaging. Since MRI is more accurate in diagnosing anorectal fistula and RVF than surgical examination, ultrasound, and digital rectal examination,120 with accuracy approaching 100%,121 MRI is rapidly becoming the diagnostic modality of choice.

Diagnosis

  • Ultrasound

Standard endoanal ultrasound can be used to locate internal openings and to define sphincter anatomy of anorectal fistula and RVF with 7% to 73% accuracy.122 In women with obstetric injuries, performing an ultrasound is a routine part of the workup to evaluate for a sphincter defect.

  • Computerized tomography

A study nearly 2 decades ago found 60% accuracy in diagnosing RVF with early generation CT scanners; the accuracy of modern-day multislice scanners in localizing RVF is unknown.123

  • Contrast studies

Contrast studies with basic fluoroscopic equipments are available at most institutions; however, vaginography and proctography have relatively low sensitivity at 79% and 35%, respectively.124

  • MRI

MRI is more accurate in diagnosing anorectal fistula and RVF than digital rectal examination, surgical examination, or ultrasound, approaching 100%. It is rapidly becoming the diagnostic modality of choice.

If the suspicion for RVF is high but a lesion is elusive on examination, the patient should be referred for a more thorough examination under anesthesia.

Treatment

The diagnostic challenges imposed by RVFs are only superseded by the difficulty of achieving successful long-term repair, and patients are referred to a gynecologic or rectal surgeon with expertise in this area. Obstetric and traumatic fistulas can usually be approached by the transanal or transperineal route, depending on the presence of incontinence. Reasonable outcomes can be expected in those patients who typically have normal rectal and vaginal tissue in close proximity to the defect. Radiation-induced and Crohn-related fistulas are particularly problematic because of the inherent poor tissue quality associated with these conditions. Early diagnosis of intestinal disease and appropriate treatment will minimize Crohn-related complications. A systemic workup is mandatory, and surgical approaches include abdominal and local repairs for these often high rectovaginal defects. There are a paucity of data to support specific techniques and the need for diversion in the management of RVFs. Hopefully, ongoing studies will help produce universally accepted approaches that may enhance long-term outcomes.125

Vesicovaginal fistula

Introduction

Vesicovaginal fistula (VVF)126 is a subtype of female urogenital fistula (UGF). VVF is an abnormal fistulous tract extending between the bladder and the vagina that allows the continuous involuntary discharge of urine into the vaginal vault.

In developing countries, the predominant cause of VVF is prolonged, obstructed labor (97%). VVFs are associated with marked pressure necrosis, edema, tissue sloughing, and cicatrization. VVF can be due to sexual aggression.127 It can also result from female genital cutting.128 (See Annotation N: The vaginal architecture for information on female genital cutting).

In contrast to developing countries, countries that practice modern obstetrics have a low rate of UGFs and VVF remains the most common type. Less frequently, UGFs may occur (1) between the bladder and cervix or uterus; (2) between the ureter and vagina, uterus, or cervix; and (3) between the urethra and vagina. Of note, a ureteric injury is identified in association with 10-15% of VVFs.

The majority of UGFs in developed countries are a consequence of gynecological surgery. Consequently, the incidence likely changes as surgical management changes.

Prevalence

The incidence of VVF in the United States is debated. Although most authors quote an incidence rate of VVF after total abdominal hysterectomy (TAH) of 0.5-2%, others suggest only a 0.05% incidence rate of injury to either the bladder or ureter. Therefore, if injuries to the bladder and ureters occur in roughly 1% of major gynecologic procedures and approximately 75% are associated with hysterectomy, and if there are about 500,000 hysterectomies performed each year then about 5,000 women a year will experience an injury.

The literature on risk factors for developing an obstetric VVF is abundant. Rural, poorly educated women of short stature have the highest risk. The fact that these pregnant women who are at risk are not detected by prenatal care, and that no preventative cesarean sections are being performed, suggests the failure of initiatives in trying to reduce the maternal mortality in many African and Asian regions.

Symptoms and clinical features

Fistulas between the urinary tract and vagina are painless. A woman will present with either constant or intermittent incontinence. In particular, positional leakage can be a sign of vesicovaginal fistulas. Vulvar irritation and recurrent infections are common associated problems. Potential secondary effects include chronic pyelonephritis leading to renal insufficiency.

On vaginal examination, the fistula may appear as a small, red area of granulation tissue with no visible opening, or an actual hole may be seen. To find small fistulas, it may be necessary to instill methylene blue through a Foley catheter into the bladder, place three cotton swabs or a tampon in the vagina, and then have the patient cough or perform the Valsalva maneuver.129 More than one fistula may be found, so a split speculum examination using one blade must be carefully performed, and the speculum moved slowly and meticulously to allow visualization of the entire vagina. Fistulas usually occur in the upper third of the vagina, or at the cuff. In developing countries, patients are sometimes found to have a total amputation of the proximal urethra (TAPU). Upon digital palpation in the vagina, the finger can directly touch the pubic bone.

Diagnosis

Aside from the methylene blue test, cystoscopy with retrograde pyelography is an integral part of assessing lower urogenital tract fistulas.

The diagnosis of a VVF is a clinical diagnosis. Vaginal examination will allow a good assessment of the size, the extent, and the associated fibrosis. The patient needs referral to a urologist for both diagnosis and treatment.

Eventually, clinicians involved in fistula care will classify the fistula using one of the existing classification systems. Systems based on the anatomical appearance of the fistula do not necessarily predict the difficulty of repair, nor the post-operative prognosis.130

Treatment

In practiced hands, skilled fistula surgeons routinely achieve a closure rate of over 80% for simple fistulas at the time of first operation.131 Accepted principles of closure include identification and protection of the ureters, wide mobilization of the fistula, and closure without tension.132 A successful closure of the fistula does not necessarily mean that the patient will be continent. Especially when the urethra is involved in the fistula, postoperative urethral incontinence can persist.133

Urethrovaginal fistula

Introduction

It is a conceptual mistake to consider urethrovaginal fistulas synonymous with vesicovaginal fistulas.134 Urethrovaginal fistulas are quite different in terms of the complications because of the risk of sphincteric involvement in vesicovaginal fistulas.

Prevalence

Urethrovaginal fistulas are a rare condition.

Etiology

In the developing world, the vast majority of urethrovaginal fistulas result from obstructed labor.135 In the United States, only 5% of genitourinary fistulae are of obstetric origin compared with Nigeria, India, and Pakistan. In the developed world, more common causes of urethral injury include trauma, iatrogenic injury during urethral diverticulectomy, bladder neck suspension, endoscopic surgery, and gynecologic surgery, such as vaginal hysterectomy or anterior vaginal repair. Urethral erosion can result from synthetic materials used in these procedures or from anti-incontinence surgery, or it may be due to long-term indwelling catheters in neurologically impaired or comatose patients.136

Symptoms and clinical features

The presentation of the fistula will depend on the location and size. If the fistula involves the distal third of the urethra, the patient may be continent and often minimally symptomatic, complaining of urinary drainage per vaginam during or after voiding. A fistula in the middle or proximal urethra causes intermittent positional wetness with skin irritation, recurrent urinary tract infection, and vaginal fungal infection.

Diagnosis

A careful vaginal exam, using different probes with simultaneous cystoscopy, helps identify small or multiple fistulae. Larger lesions can be seen easily during the vaginal exam. In cases of extensive post-delivery damage, fistulae may be combined – urethrovesicovaginal – so special care is required to evaluate ureteric orifices. The possibility of stress or urgency incontinence, resulting from sphincteric damage, should also be considered, and directed testing should be done to exclude these diagnoses.137 The identification of smaller fistulae can be facilitated by distention of the bladder with methylene blue-dyed saline.

Treatment

The patient will need referral to a urologist for diagnosis and treatment. Direct primary anatomical repair may be advised for the patient with minimal anatomical disruption.

Sjögren syndrome

Introduction

Sjögren syndrome (SS) is a chronic, inflammatory autoimmune disease in which the salivary and lachrymal glands are progressively destroyed by lymphocytes and plasma cells. The patient with SS will complain of dryness, grittiness, or the sense of having a foreign body in the eye due to a decrease in the production and quality of tears. They will also complain of a very dry mouth, difficulty speaking for long periods, hoarse voice, dry throat, and an increase in dental caries. Chewing and swallowing are also affected by the decreased production of saliva. Peripheral neuropathy is present in 10% to 60%.138

Prevalence

According to the Sjögren Syndrome Foundation, the condition affects as many as 4 million Americans. Women are affected 10 times more often than men are. The average age of onset is upper 40’s, but the syndrome may develop at any age.

Symptoms and clinical features

In addition to the dry eyes and dry mouth described above, vaginal dryness and dyspareunia are also complaints; in fact, chronic dyspareunia can be a presenting feature of Sjögren, predating ocular or oral symptoms by many years in a few reported cases.139 There are more complaints of both dyspareunia and vaginal dryness in women with primary SS than in healthy patients. In a study of 36 female outpatients with SS and 43 healthy women who were in a control group, all with a comparable frequency of sexual activity, dyspareunia was present in 61% of primary SS patients and 39% of women in the control group.140 Such a symptom was significantly more frequent in postmenopausal SS patients than in women in the control group. Vaginal dryness was found in 52% of SS patients and 33% of controls. When the pre- and postmenopausal patients were compared, it was found that vaginal dryness was reported in 33% of premenopausal patients compared with 72% of the post- menopausal patients.

Etiology

Although insufficient vaginal lubrication has many causes, researchers looking specifically at the vaginal tissue of SS patients found that they all had perivascular infiltration with chronic inflammatory cells.141 It is believed that this lymphocytic vasculitis could be involved in the development of the dyspareunia caused by a dry vagina. Therefore, any increase in vaginal dryness in women with SS beyond that associated with estrogen deficiency or vaginal infection may be related to an underlying autoimmune effect of SS on the vascular supply to the vagina.

Treatment

There is no treatment specific for vaginal manifestation of Sjögren. The disease itself is sometimes treated with immunosuppressant drugs; whether these affect vaginal dryness symptoms is not known. Withdrawal of any drugs that may induce xerostomia such as tricyclic antidepressants or atropine may be considered. The compound polycarbophil, found in Replens (LDS Consumer Products, Cedar Rapids, IA) and Durex Sensilube (SSL International, Knutsford, Cheshire, UK) has the ability to cling to epithelial surfaces and to be effective for up to 72 hours.142 Furthermore, it releases water that rehydrates the epithelial cells and keeps the vagina moist for longer periods. Estrogen creams, which can increase capillary blood flow to the vagina and vulvar area, and hormone replacement therapy, are also helpful.

Radiation injury

Introduction

External beam radiation therapy and brachytherapy for gynecologic tumors (endometrial and vaginal) and for rectal cancer143 can cause radiation injury of the vulva and vagina with symptomatic shortening and narrowing of the vagina, dryness, and dyspareunia in up to 70 percent of patients.144 145 Vaginal stenosis after treatment for cervical cancer occurs in 55% of post radiated patients.146 Radiation damage involves fibrosis, vascular toxicity, neurotoxicity, and psychological factors.147

Symptoms and clinical features

External beam radiation to the vagina initially causes extreme pain and moist desquamation to the entire genital/perineal area. There is loss of pubic hair. Later changes manifest as circumferential whitening and rigidity of the vaginal vault (fibrosis) with foreshortening or stenosis. Cystitis, proctitis, and rectovaginal or vesicovaginal fistulae are also possible.

Treatment

Many women receiving radiation therapy do not receive education about potential sexual side effects and resultant pathology, including vaginal stenosis, has received little attention. Significant sexual dysfunction for treated women may be a consequence.148 If not addressed, the problems compound over time.149

To prevent vaginal stenosis, some clinicians have recommended dilator use150 following radiation treatment and topical estrogen cream to prevent and treat symptomatic shortening and narrowing of the vagina.151 The UK Gynaecological Oncology Nurse Forum recommends using vaginal dilators three times weekly for an indefinite time period.152
A 2010 Cochrane review, however, raises controversy regarding dilator use. During or immediately after radiotherapy, dilators in two reported cases caused recto-vaginal fistula.153 In the review, the authors found no persuasive evidence from any study to demonstrate that dilator use prevents stenosis,154 including one randomized, controlled trial that showed no improvement in sexual scores in women who were encouraged to practice dilation. The review authors suggest that gentle vaginal exploration might separate the vaginal walls before they can stick together. Some women may benefit from dilation therapy once inflammation has settled, but there are no good supporting data.

If there is an intact urinary and intestinal tract, some experts offer surgical treatment to widen the vagina with laterally placed flaps.155 156 However, neovaginal reconstruction following pelvic irradiation is a difficult procedure that has a high risk of complications and limited success, since fibrosis can be ongoing after the reconstruction.157

Because vaginal stricturing is common after radiation therapy, and because good alternatives to dilators do not exist, we continue to work in our practice with local care, adequate local estrogen, and dilators. Treatment starts with education. A woman needs to know to ask what to expect regarding physical changes, discomfort, and sexual functioning, if this information is not offered. She needs to understand that continuing sexual function in the presence of vaginal stricturing involves a lifetime commitment. During the acute treatment period, comfort measures include sitz baths, moisturization with a film of vaseline, and adequate pain control. Vaginal intercourse may substitute for the dilator use, but therapeutic intervention appears to be superior to regular sexual intercourse alone.158 In a woman who already has radiation changes, comfort measures with sitz baths and moisturization with a film of Vaseline, regular vaginal dilatation and topical estrogen cream may also be useful.

Dilators are prescribed with instruction, initial demonstration to the patient, and returned demonstration from the patient. It is never helpful to give a set of dilators without this education. A dilator must be rigid in order to do the job, not soft and flexible. An appropriate size is selected with circumference that fits snugly with lubrication. Xylocaine 5% ointment is used prior to insertion. Use of xylocaine is essential to prevent sensitizing pain with vaginal insertion. In order to achieve dilation, the dilator must stay in place at least 20 minutes three times weekly. We suggest reading or television during this time in the evening or at a quiet portion of the day. Once the dilator fits in loosely and comfortably, the patient advances to the next size. (Annotation D: Patient tolerance of genital exam, section on dilators).

It is important to recognize that some genital cancers develop in association with lichen sclerosus. In addition to the treatment for radiation pathology, the dermatosis will require ongoing treatment with observation for possible signs of recurrence as thickened, indurated areas unresponsive to steroid management. Biopsy may need to be repeated.

Mesh erosion after midurethral sling

Introduction

Polypropylene midurethral slings are a minimally invasive approach that has become the gold standard operation for stress urinary incontinence. Midurethral slings can be placed using a retropubic (TVT), suprapubic (SPARC), transobturator (TOT), or single incision approach. Midurethral slings provide a resistant platform under the midurethra to counteract increased abdominal pressure. Synthetic polypropylene mesh or tape is used. This is thought to promote ingrowth of collagen over time.159

Within the past decade, complication rates (e.g., graft rejection, erosion into the urethra, fistulae) were high with ePTFE (Gore-Tex®) slings. In the largest series of women with SUI treated with polyethylene terephthalate (Mersilene®) pubovaginal slings, 19 percent of patients had complications.160

Prevalence

Midurethral slings with polypropylene mesh are associated with low erosion rates of 0.5%. In a systematic review, the overall rate of erosion for retropubic and transobturator midurethral slings was 2.8 percent161

In addition, tape rejection has not been reported for polypropylene midurethral slings.

Symptoms and clinical features

Vaginal erosion over implanted mesh may be asymptomatic and noted on examination. Alternatively, it can present with new, minimal vaginal discharge, or pain and a sensation of scratching for the partner during intercourse.162 Recurrent urinary tract infection, serosanguinous staining, or constitutional symptoms of fever or malaise suggesting infection are also reported.163 The mesh may be visualized by careful vaginal speculum examination of the anterior or posterior vaginal wall; the defect can also be palpated.

Treatment

The patient will need to consult with the surgeon who placed the mesh. Excision of fibers may be done in the office. A large erosion may require advancing the vaginal epithelium to cover it.

References

  1. Chen GD, Oliver RH, Leung BS, Lin LY, Yeh J. Estrogen receptor and expression in the vaginal walls and uterosacral ligaments of premenopausal and postmenopausal women. Fertil Steril. 1999; 71;1099-1102
  2. Hodgins M, Spike R, Mackie R, MacLean A. An immunohistochemical study of androgen, oestrogen and progesterone receptors in the vulva and vagina. Br J Obstet Gynaecol. 1998; 105(2):216-222.
  3. Katz V. Reproductive Anatomy. In: Katz VL, Lentz GM, Lobo RA, Gershenson DM, eds. Comprehensive Gynecology. Philadelphia, Mosby Elsevier, 2007. 47.
  4. Castelo-Branco., C, Cancelo, MJ, Villero, J, et al. Management of post-menopausal vaginal atrophy and atrophic vaginitis. Maturitas 2005; 52 Suppl 1:S46.
  5. Bachmann G, Santen R. Clinical manifestations and diagnosis of vaginal atrophy. In: UpToDate Basow DS (Ed), UpToDate, Waltham, Massachusetts, 2015.
  6. Ballagh SA. Vaginal hormone therapy for urogenital and menopausal symptoms. Semin Reprod Med. 2005;23:126-140.
  7. Herbst L, Ulfelder H, Poscanzer DC. Association of maternal stilbestrol therapy with tumor appearance in young women. N Engl J Med 1971; 284:878-881.
  8. Stafl A, Mattingly RM, Foley D. Clinical diagnosis of vaginal adenosis. Obstet Gynecol. 1974; 43:118-128.
  9. Kurman RG, Scully RE. The incidence and histogenesis of vaginal adenosis: an autopsy study. Hum Pathol. 1974; 5:265-276.
  10. Bonafe JL, Thibaut I, Hoff J. Introital adenosis associated with the Stevens-Johnson syndrome. Clin Exp Dermatol. 1990; 15:356-357.
  11. Sedlacek TV, Riva JM, Magen AB, et al. Vaginal and vulvar adenosis: an unsuspected side effect of carbon dioxide laser vaporization. J Reprod Med. 1990; 35:995-1001.
  12. Goodman A, Zukerberg LR, Mikrui N, Scully RE. Vaginal adenosis and clear cell carcinoma after 5-fluorouracil treatment for condlyomas. Cancer. 1991; 68:1628-1632.
  13. Kranl C. Zelger B, Kofler H, et al. Vulval and vaginal adenosis. Br J Dermatol. 1998; 139:128-131.
  14. Sandberg EC, Danielson RW, Prince E. Benign vaginal adenosis. Obstet Gynecol. 1967; 30(1):93-98.
  15. Forsberg JG. Estrogen, vaginal cancer and vaginal development. Am J Obstet Gynecol. 1972: 113:83-87.
  16. Herbst AL, Jurman RJ, Scully RE. Vaginal and cervical abnormalities after exposure to stilbestrol in utero. Obstet. Gynecol 1972; 40:287-298.
  17. Kranl C. Zelger B, Kofler H, et al. Vulval and vaginal adenosis. Br J Dermatol. 1998; 139:128-131.
  18. Robboy SL, Hill EB, Sandberg EC, Czernobilsky B. Vaginal adenosis in women born prior the diethylstilbestrol era. Hum Pathol. 1986; 17:488-492.
  19. Ng, ABP, Regan JW, Nadji M, Greening S. Natural history of vaginal adenosis in woman exposed to diethylstilbestrol in utero. J Reprod Med. 1977; 18:1-13.
  20. Antonioli D, Burke L. Vaginal adenosis. Am J Clin Pathol. 1975; 64:625-638.
  21. Kranl C. Zelger B, Kofler H, et al. Vulval and vaginal adenosis. Br J Dermatol. 1998; 139:128-131.
  22. Hatch E. Outcome of diethlstilbestrol (DES), exposed individuals. In: UpToDate, Basow DS (Ed), UpToDate, Waltham, Massachusetts, 2015.
  23. Verloop J, van Leeuwen FE, Helmerhorst TJ, et al. Cancer risk in DES daughters. Cancer Causes Control. 2010; 21:999.
  24. Kranl C. Zelger B, Kofler H, et al. Vulval and vaginal adenosis. Br J Dermatol. 1998; 139:128-131.
  25. Sandberg EC, Danielson RW, Prince E. Benign vaginal adenosis. Obstet Gynecol. 1967; 30(1):93-98.
  26. Cebesoy Kutlar I, Aydin A. Vaginal adenosis successfully treated with simple unipolar cauterization. J Nat Med Assoc. 2007; 99(2):166-167.
  27. Goldstein A, Metz A. Vulvar lichen planus. Clin Obstet Gynecol. 2005; 48:818-823.
  28. Scully, C, el-Kom, M. Lichen planus: review and update on pathogenesis. J Oral Pathol. 1985; 14:431.
  29. Cooper S. Influence of treatment of erosive lichen planus of the vulva and it prognosis. Arch Dermatol. 2006; 142:289-294.
  30. Cooper S, Baldo M, Wojnarowska F. The association of lichen sclerosus and erosive lichen planus of the vulva with autoimmune disease: a case control study. Arch Dermatol. 2008; 144:1432-1435.
  31. Cooper S, Dean D, Allen J, et al. Erosive lichen planus of the vulva: weak circulating basement membrane zone antibodies are present. Clin Experiment Dermatol. 2005; 30:551-556.
  32. Thornhill M. Immune mechanisms in oral lichen planus. Acta Odontol Scand. 2001: 59:174-177.
  33. LaNasa G, Cottoni F, Mulargia M, et al. HLA antigen distribution in different clinical subgroups demonstrates genetic heterogeneity in lichen planus. Br J Dermatol. 1996; 132:897-900.
  34. Thompson, DF, Skaehill, PA. Drug-induced lichen planus. Pharmacotherapy. 1994; 14:561.
  35. Litt, J. Litt’s Drug Eruption Reference Manual, 10th edition. London: Informa Healthcare; 2004.
  36. Gunes, AT, Fetil E, Ilknur T, et al. Naproxen-induced lichen planus: report of 55 cases. Int J Dermatol. 2006; 45:709.
  37. Clayton R, Chaudhry S. Ali I, Cooper S, Hodgson T, Wojnarowska F. Mucosal (oral and vulval) lichen planus in women: are angiotensin-converting enzyme inhibitors protective, and beta-blockers and non-steroidal anti-inflammatory drugs associated with the condition? Clin Exp Dermatol. 2010 Jun;35(4):384-387.
  38. Hirota SK, Moreno RA, dos Santos CH, Seo J, Migliari DA. Analysis of a possible association between oral lichen planus and drug intake. A controlled study. Med Oral Patol Oral Cir Bucal. 2011 Sep 1;16(6):e750-756.
  39. Goldstein B, Goldstein A. Lichen planus. In: UpToDate, Baslow DS (Ed), UpToDate, Waltham, Massachusetts, 2015.
  40. Huber M. Oral lichen planus. Quintessence Int. 2004; 35:731-752.
  41. McPherson T, Cooper S. Vulval lichen sclerosus and lichen planus. Dermatol Ther. 2020; 23:523-532.
  42. Rogers R, Eisne D. Erosive oral lichen planus with genital lesions: the vulvovaginal-gingival syndrome and the penogingival syndrome. Dermatol Clin. 2003; 21:91-98.
  43. DiFede O, Belfiore P, Cabibi D, et al. Unexpectedly high frequency of genital involvement in women with clinical and histological features of oral lichen planus. Acta Derm Venereol. 2006; 86:433-438.
  44. Clayton R, Chaudhry S. Ali I, Cooper S, Hodgson T, Wojnarowska F. Mucosal (oral and vulval) lichen planus in women: are angiotensin-converting enzyme inhibitors protective, and beta-blockers and non-steroidal anti-inflammatory drugs associated with the condition? Clin Exp Dermatol. 2010 Jun;35(4):384-387.
  45. Helgesen A, Gjersvik P, Jebsen P, Kirschner R, Tanbo T. Vaginal involvement in genital erosive lichen planus. Acta Obstet Gynecol. 2010; 89:966-970.
  46. Kirtschig G, Wakelin SH, Wojnarowska F. Mucosal vulval LP: outcome, clinical and laboratory features. J Eur Acad Dermatol Venereol. 2005;19(3):301-307.
  47. Pelisse M. The vulvo-vagino-gingival syndrome: a new form of erosive lichen planus. Int J Dermatol. 1989; 28:381-384.
  48. Eisen D. The vulvovaginal gingival syndrome of lichen planus. Arch Dermatol. 1994; 120:424-426.
  49. Gupta R, Bansal B, Singh S, et al. Lichen planus of uterine cervix- the first report of a novel site of occurrence: a case report. Cases J. 2009;2:9306.
  50. The North American Menopause Society. The role of local vaginal estrogen for treatment of vaginal atrophy in postmenopausal women: 2007 position statement of The North American Menopause Society. Menopause. 2007;14:355-369.
  51. Pelisse M. Erosive vulvar lichen planus and desquamative vaginitis. Semin Dermatol. 1996;15:47-50.
  52. Cooper S, Dean D, Allen J, et al. Erosive lichen planus of the vulva: weak circulating basement membrane zone antibodies are present. Clin Experiment Dermatol. 2005; 30:551-556.
  53. Edwards L. Erosions and vesiculobullous diseases. In: Edwards L, Lynch P. Genital Dermatology Atlas, 2nd edition.Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins, 2011, 124.
  54. Goldstein A, Metz A.Vulvar lichen planus. Clin Obstet Gynecol. 2005; 48:818-823.
  55. Lever W, Schaumburg-Lever G. Lichen planus. In: Histopathology of the Skin, 7th ed. Philadelphia: JB Lippincott, 1990: 168.
  56. Niamh L, Naveen S. Hazel B. Diagnosis of vulval inflammatory dermatoses: a pathological study with clinical correlation. Int J Gynecol Pathol. 2009; 28:554-558.
  57. Marren P, Millard P, Chia Y, Wojnarowska F. Mucosal lichen sclerosus/lichen planus overlap syndromes. Br J Dermatol. 1994; 131:118-123.
  58. Longinotti M, Schieffer Y, Kaufman R. Lichen sclerosus involving the vagina. Obstet Gynecol. 2005; 106(5 Pt 2):1217-1219.
  59. Helgesen A, Gjersvik P, Jebsen P, Kirschner R, Tanbo T. Vaginal involvement in genital erosive lichen planus. Acta Obstet Gynecol. 2010; 89:966-970.
  60. Cooper S, Dean D, Allen J, et al. Erosive lichen planus of the vulva: weak circulating basement membrane zone antibodies are present. Clin Experiment Dermatol. 2005; 30:551-556.
  61. Kirtschig G, Wakelin SH, Wojnarowska F. Mucosal vulval LP: outcome, clinical and laboratory features. J Eur Acad Dermatol Venereol. 2005;19(3):301-307.
  62. Robins D. Intramuscular triamcinolone: a safe, effective and underutilized dermatologic therapy. J Drugs Dermatol. 2009; 8(6):580-585.
  63. Kusama M, Sakauchi N, Kumaoka N. Studies of plasma levels and urinary excretion after intramuscular injection of triamcinolone acetonide. Metabolism. 1071; 20(6):590-596.
  64. Robins D. Intramuscular triamcinolone: a safe, effective and underutilized dermatologic therapy. J Drugs Dermatol. 2009; 8(6):580-585.
  65. Nasser S. Ewan P. Depot corticosteroid treatment for hay fever causing aseptic necrosis of both hips. Br Med J. 2001; 322(7302):1589-92.
  66. Kenalog-40 package insert. Princeton, New Jersey, Bristol-Myers Squibb, 2006.
  67. Droszcz W, Malunowicz E. Leon B, et al. Assessment of adrenocortical function in asthmatic patients on long-term triamcinolone acetonide treatment. Thorax. 1979; 42(1):41-43.
  68. Kirtschig G, Van Der Meulen A, Ion Lipan J, Stoof T. Successful treatment of erosive vulvovaginal lichen planus with topical tacrolimus. Br J Dermatol. 2002; 147:625-26.
  69. Cooper S, Dean D, Allen J, et al. Erosive lichen planus of the vulva: weak circulating basement membrane zone antibodies are present. Clin Experiment Dermatol. 2005; 30:551-556.
  70. Dalziel K, Millard P, Wojnarowska F. The treatment of vulval lichen sclerosus with a very potent topical steroid (clobetasol propionate 0.05%) cream. Br J Dermatol. 1991; 124(5):461-464.
  71. Dezarnaulds f, Fraser I. Vaginal ring delivery of hormone replacement therapy- a review. Exper Opin Pharmacother. 2003;4(2):201-212.
  72. van der Biji P, van Eyk A. Comparative in vitro permeability of human vaginal, small intestinal and colonic mucosa. Int J Pharm. 2003; 11;2611-20:147-152.
  73. McKay M. Topical therapy of gynecologic skin disorders. In:Black M, McKay M, Braude P, Vaughan Jones S, Margesson L, eds. Obstetric and Gynecologic Dermatology, 2nd edition. London, Mosby, 2002, 212.
  74. Ohman E, Rogers S, Meenan F, et al. Adrenal suppression following low dose topical clobetasol propionate. J R Soc Med. 1987;80:422-423.
  75. Helgesen A, Gjersvik P, Jebsen P, Kirschner R, Tanbo T. Vaginal involvement in genital erosive lichen planus. Acta Obstet Gynecol. 2010; 89:966-970.
  76. Stalburg C, Haefner K. Vaginal stenosis in lichen planus. Surgical treatment tips for patients in whom conservative therapies have failed. J Pelvic Med Surg. 2008;14:193-198.
  77. Kortekangas-Savolainen O, Kiilholma P. Treatment of vulvovaginal erosive and stenosing lichen planus by surgical dilatation and methotrexate. Acta Obstet Gynecol Scand. 2007;86(3):339-343.
  78. Bhushan V, Collins R. Chronic graft-vs.-host disease. JAMA. 2003; 290:2599-2603.
  79. Eapen M, Horowitz M, Klein J, Champlain R, Loberiza F, Ringden O, et al. Higher mortality after allogeneic peripheral blood transplantation compared with bone marrow in children and adolescents: the Histocompatibility and Alternate Stem Cell Source Working Committee of the International Bone Marrow Transplant Registry. J Clin Oncol. 2004; 22:4872-4880.
  80. Lee SJ, Vogelsang G, Flowers ME. Chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2003;9:215-233.
  81. Cutler C, Giri S, Jeyapalan S, et al. Acute and chronic graft-versus-host disease after allogeneic peripheral-blood stem-cell and bone marrow transplantation: a meta-analysis. J Clin Oncol. 2001;19:3685-3691.
  82. Ferrara JL, Deeg HJ. Graft-versus-host disease. N Engl J Med. 1991;324:667-674
  83. Lee SJ, Vogelsang G, Flowers ME. Chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2003;9:215-233.
  84. Flowers ME, Parker P, Johnston L, Matos A, Storer B, Bensinger W, et al. Comparison of chronic graft-vs.-host disease after transplantation of peripheral blood stem cells versus bone marrow in allogeneic recipients: long-term follow-up of a randomized trial. Blood. 2002; 100:415-9.
  85. Bradbury C. Gynecologic complications. In: Atkinson K, ed. Clinical Bone Marrow Transplantation. Cambridge, United Kingdom: Cambridge University Press 2000:1002-1008.
  86. Bhushan V, Collins R. Chronic graft-vs.-host disease. JAMA. 2003; 290:2599-2603.
  87. Constantin S, Di Capua S. the management of severe vaginal obstruction from genital chronic graft-versus-host disease: diagnosis, surgical technique and follow-up. Minerva Ginecol. 2006; 58:11-16.
  88. Singer A, Monaghan JM, Swee CQ, Deery AR. Lower genital tract precancer: colposcopy, pathology, and treatment, 2nd ed. Oxford. Wiley Blackwell. 2000:214.
  89. Sugase, M, Matsukura, T. Distinct manifestations of human papillomaviruses in the vagina. Int J Cancer. 1997; 72:412.
  90. Diakomanolis E, Stefanidis K, Rodolakis a, Haidopoulos D, Sindos M, Chatzipappas I Michalas S.Vaginal intraepithelial neoplasia: report of 102 cases. Eur J Gynaecol Oncol. 2002; 23(5):457-459.
  91. Wharton, JT, Tortolero-Luna, G, Linares, AC, et al. Vaginal intraepithelial neoplasia and vaginal cancer. Obstet Gynecol Clin North Am. 1996; 23:325.
  92. Ait Menguellet, S, Collinet, P, Houfflin Debarge, V, et al. Management of multicentric lesions of the lower genital tract. Eur J Obstet Gynecol Reprod Biol. 2007; 132:116.
  93. Kirkbride, P, Fyles, A, Rawlings, GA, et al. Carcinoma of the vagina–experience at the Princess Margaret Hospital (1974-1989). Gynecol Oncol. 1995; 56:435.
  94. Elkas JC, Berek JS. Vaginal cancer. In:  UpToDate, Basow DS (Ed), UpToDate, Waltham, Massachusetts. 2015.
  95. Daling JR, Madeleine MM, Schwartz SM, et al. A population-based study of squamous cell vaginal cancer: HPV and cofactors. Gynecol Oncol. 2002; 84:263.
  96. Lilic V, Lilic G, Flilpovic S, Visnjic M, Zivadinovic R. Primary carcinoma of the vagina. J BUON. 2010; 15(2):241-247.
  97. Gallup DG, Talledo OE, Shah KJ, Hayes C. Invasive squamous cell carcinoma of the vagina: a 14-year study. Obstet Gynecol. 1987; 69:782.
  98. Orient JM. Sapira’s Art and Science of Bedside Diagnosis, 4th ed. Philadelphia. Lippincott Williams & Wilkins: 2009:470
  99. Lian, J, Dundas, G, Carlone, M, et al. Twenty-year review of radiotherapy for vaginal cancer: an institutional experience. Gynecol Oncol. 2008; 111:298.
  100. Shiohara T, Mizukawa Y, Teraki Y. Pathophysiology of fixed drug eruption: the role of skin-resident T cells. Curr Opin Allergy Clin Immunol. 2002 Aug;2(4):317-323.
  101. Ozkaya-Bayazit E, Bayazit H, Ozarmagan G. Drug related clinical pattern in fixed drug eruption. Eur J Dermatol. Jun 2000;10(4):288-291
  102. Edwards L. Erosive and vesicobullous diseases. In: Edwards L, Lynch P, eds. Genital Dermatology Atlas, 2nd edition. Philadelphia. Wolters Kluwer/Lippincott Williams & Wilkins:2011, 148.
  103. Meneaux E, Oanuek BJ, Revuz J, Roujeau JC, Wolkenstein P. Vulvovaginal sequelae in toxic epidermal necrolysis, J Reprod Med.1997; 42(3):153-156.
  104. Sehgal VH, Gangwani OP. Genital fixed drug eruptions. Genitourin Med. 1986; 62:56-58.
  105. Stubb S, Heikkila H, Kauppinen K. Cutaneous reactions to drugs:a series of inpatients during a five-year study. Acta Derm Venereol. 1994 Jul;74(4):289-91;74:289-291
  106. Breathnach SM. Drug reactions. In: Burns T, Breathnach SM, Cox N, Griffits C (editors). Rook’s Textbook of Dermatology. 7th edition. Oxford. Blackwell Science: 2004; 73:28.
  107. Kelso JM, Keating RM. Successful desensitization for treatment of a fixed drug eruption to allopurinol. J Allergy Clin Immunol. May 1996; 97(5):1171-1172.
  108. Senatore PJ Jr. Anovaginal fistulae. Surg Clin North Am. 1994;74:1361–1375.
  109. Venkatesh KS, Ramanujam PS, Larson DM, et al. Anorectal complications of vaginal delivery. Dis Colon Rectum. 1989; 32:1039–1041.
  110. Angioli R, Gomez-Marin O, Cantuaria G, et al. Severe perineal lacerations during vaginal delivery: the University of Miami experience. Am J Obstet Gynecol. 2000; 182:1083–1085.
  111. Saclarides TJ. Rectovaginal fistula. Surg Clin North Am. 2002;82:1261–1272.
  112. Kosugi C, Saito N, Kimata Y, et al. Rectovaginal fistulas after rectal cancer surgery: incidence and operative repair by gluteal-fold flap repair. Surgery. 2005;137:329–336.
  113. Kosugi C, Saito N, Kimata Y, et al. Rectovaginal fistulas after rectal cancer surgery: incidence and operative repair by gluteal-fold flap repair. Surgery. 2005;137:329–336.
  114. Kasibhatla M, Clough RW, Montana GS, et al. Predictors of severe gastrointestinal toxicity after external beam radiotherapy and interstitial brachytherapy for advanced or recurrent gynecologic malignancies. Int J Radiat Oncol Biol Phys. 2006;65:398–403.
  115. Hamilton S, Spencer C, Evans A. Vagino-rectal fistula caused by Bartholin’s abscess. J Obstet Gynaecol. 2007;27:325–326.
  116. Ahmad M. Intravaginal vibrator of long duration. Eur J Emerg Med. 2002;9:61–62.
  117. Purwar B, Panda SN, Odogwu SO, et al. Recto-vaginal sex leading to colostomy and recto-vaginal repair. Int J STD AIDS. 2008;19:57–58.
  118. Singhal SR, Nanda S, Singhal SK. Sexual intercourse: an unusual cause of recto-vaginal fistula. Eur J Obstet Gynecol Reprod Biol. 2007;131:243–244.
  119. Champagne B, McGee M. Rectovaginal fistula. Surg Clin N Amer. 2010;90:69-82.
  120. Sudol-Szopinska I, Jakubowski W, Szczepkowski M. Contrast-enhanced endosonography for the diagnosis of anal and anovaginal fistulas. J Clin Ultrasound. 2002;30:145–150.
  121. Dwarkasing S, Hussain SM, Hop WC, et al. Anovaginal fistulas: evaluation with endoanal MR imaging. Radiology. 2004;231:123–128.
  122. Sudol-Szopinska I, Jakubowski W, Szczepkowski M. Contrast-enhanced endosonography for the diagnosis of anal and anovaginal fistulas. J Clin Ultrasound. 2002;30: 145–150.
  123. Kuhlman JE, Fishman EK. CT evaluation of enterovaginal and vesicovaginal fistulas. J Comput Assist Tomogr. 1990;14: 390–394.
  124. Giordano P, Drew PJ, Taylor D, et al. Vaginography–investigation of choice for clinically suspected vaginal fistulas. Dis Colon Rectum. 1996;39:568–572.
  125. Champagne B, McGee M. Rectovaginal fistula. Surg Clin N Amer. 2010;90:69-82.
  126. Kirkbride, P, Fyles, A, Rawlings, GA, et al. Carcinoma of the vagina–experience at the Princess Margaret Hospital (1974-1989). Gynecol Oncol. 1995; 56:435.
  127. Onsrud M, Sjoveian S, Luhiriri R, Mukwege D. Sexual violence-related fistulas in the Democratic Republic of Congo. Int J Gynaecol Obstet. 2008; 103:265 –269.
  128. Banks E, Meirik O, Farley T, et al. Female genital mutilation and obstetric outcome: WHO collaborative prospective study in six African countries. Lancet. 2006; 367:1835–1841.
  129. Moir, JC. Personal experiences in the treatment of vesicovaginal fistulas. Am J Obstet Gynecol. 1956; 71:476.
  130. Arrowsmith SD. The classification of obstetric vesico-vaginal fistulas: a call for an evidence-based approach. Int J Gynecol Obstet. 2007; 99 (Suppl 1):S25 – S27.
  131. Raassen TJ, Verdaasdonk EG, Vierhout ME. Prospective results after first-time surgery for obstetric fistulas in East African women. Int Urogynecol J Pelvic Floor Dysfunct. 2008; 19:73–79.
  132. De Ridder D. Vesicovaginal fistula: a major healthcare problem. Curr Opin Urolo. 2009;19:358-361.
  133. Carey MP, Goh JT, Fynes MM, Murray CJ. Stress urinary incontinence after delayed primary closure of genitourinary fistula: a technique for surgical management. Am J Obstet Gynecol. 2002; 186:948–953.
  134. Pushkar Y, Sumerova N, Kasyan G. Management of urethrovaginal fistulae. Curr Opin Urol. 2008, 18:389–94.
  135. Ahmad S, Nishtar A, Hafeez GA, Khan Z. Management of vesico-vaginal fistulae in women. Int J Gynecol Obstetr 2005; 88:71–75.
  136. Golomb J, Leibovitch I, Mor Y, et al. Fascial path technique for repair of complicated urethrovaginal fistula. Urology. 2006; 68:1115–1118.
  137. Hilton P. Urodynamic findings in patients with urogenital fistulae. Br J Urol. 1998; 81:539–542.
  138. Chai J, Logigian E. Neurological manifestations of primary Sjögren’s syndrome. Curr Opin Neurol. 2010; 23(5):509-513.
  139. Mulherin D, Sheeran T, Kumaratne D, Speculand B, Luesley D, Situnayake R. Sjögren’s syndrome in women presenting with chronic dyspareunia. BJOG. 1997;104(8):1019-1023.
  140. Marchesoni, D., Mozzanega, B., De Sandre, P., Romagnolo, C., Gambari, P. F., & Maggino, T. Gynaecological aspects of primary Sjögren’s syndrome. European Journal of Obstetrics & Gynecology and Reproductive Biology. 1995; 63: 49-53.
  141. Skopouli, F. N., Papanikolaou, S., Malamou-Mitsi, V., Papanikolaou, N., & Moutsopoulos, H. M. Obstetric and gynaecological profile in patients with primary Sjögren’s syndrome. Annals of the Rheumatic Diseases. 1994; 53, 69-73.
  142. Gelfand, M. M., & Wendman, E. Treating vaginal dryness in breast cancer patients: Results of applying a polycarbophil moisturizing gel. Journal of Women’s Health. 1994; 3(6): 427-434.
  143. Lange MM, Marijnen C, Maas C, Putter H, Rutten H, Stiggelbout AM, Meerchoek-Klein Kranenbarg E, van de Velde CJH. Risk factors for sexual dysfunction after rectal cancer treatment. Eur J Cancer. 2009;45(9): 1578-1588.
  144. Potter R, Knocke TH, Fellner C, et al. Definitive radiotherapy based on HDR brachytherapy with iridium 192 in uterine cervix carcinoma: report on the Vienna University Hospital findings (1993-1997) compared to the preceding period in the context of ICRU 38 recommendations. Cancer Radiother. 2000; 4:159.
  145. Lange MM, Marijnen C, Maas C, Putter H, Rutten H, Stiggelbout AM, Meerchoek-Klein Kranenbarg E, van de Velde CJH. Risk factors for sexual dysfunction after rectal cancer treatment. Eur J Cancer. 2009;45(9): 1578-1588.
  146. Brand AH, Lanciano R, Keegan M. et al. Vaginal stenosis in patients treated with radidotherapy for carcinoma of the cervix. Int J Gynecol Cancer. 2006; 16:288-293.
  147. Morgantaler A. Male impotence. Lancet. 1999; 354:1713-1718.
  148. Mannaerts G, Schijven M, Hendrikx A, Martijn H, Rutten H, Wiggers T. Urologic and sexual morbidity following multimodal treatment for locally advanced primary and locally recurrent rectal cancer. Eur J Surg Oncol. 2001; 27:265-272.
  149. Wolf J. Prevention and treatment of vaginal stenosis resulting from pelvic radiation therapy. Community Oncology. 2006; 3(10):665-671.
  150. American Cancer Society www.cancer.org/…/ETO_1_4X_Side_Effects_of_Radiation_Therapy.asp
  151. Weiss, E. Clinical manifestations and treatment of radiation-induced fibrosis. In: UpToDate, Basow DS (Ed), UpToDate, Waltham, Massachusetts, 2015.
  152. National Forum of Gynaecological Oncology Nurses. Best practice guidelines on the use of vaginal dilators in women receiving pelvic radiotherapy. Oxon, United Kingdom, Own Mumford Ltd, 2005, 4.
  153. Hoffman M, Wakeley K, Cardosi R. Risks of rigid dilation for a radiated vaginal cuff: two related rectovaginal fistulas. Obstet & Gynecol. 2003; 101(5):1125-1126.
  154. Miles T, Johnson N. Vaginal dilator therapy for women receiving pelvic radiotherapy. Cochrane Database Syst Rev. 2010 Sep 8;(9):CD007291.
  155. Knapstein PG, Hawighorst-Knapstein S, Stief C. Rehabilitation as an integrative model: Surgical and psychological approaches. In: Hoskins WJ, Perez CA, Young RC, eds. Principles and practice of gynecologic oncology. 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2000:599.
  156. Zenn M, Fowler W, Bos G. Introital stenosis requiring pelvic resection and soft tissue reconstruction. Obstet Gynecol. 2001; 98:972-974
  157. Micha JP, Goldstein BH, Rettenmaier MA, Brown JV. Neovagina Reconstruction Utilizing the Bladder and Urethra Following Radical Radiation Therapy. J Gynecol Surg. 2006;22:73.
  158. Wolf J. Prevention and treatment of vaginal stenosis resulting from pelvic radiation therapy. Community Oncology. 2006; 3(10):665-671.
  159. Young, SB, Rosenblatt, PL, Pingeton, DM, et al. The Mersilene mesh suburethral sling: A clinical and urodynamic evaluation. Am J Obstet Gynecol. 1995; 173:1719.
  160. Young, SB, Rosenblatt, PL, Pingeton, DM, et al. The Mersilene mesh suburethral sling: A clinical and urodynamic evaluation. Am J Obstet Gynecol. 1995; 173:1719.
  161. Latthe, P, Foon, R, Toozs-Hobson, P. Transobturator and retropubic tape procedures in stress urinary incontinence: a systematic review and meta-analysis of effectiveness and complications. BJOG. 2007;114:522.
  162. Kobasjo K, Govier F. Management of vaginal erosion of polypropylene mesh slings. J Urol. 2003; 169:2242-2243.
  163. Kobashi, K. C., Dmochowski, R., Mee, S. L., Mostwin, J., Nitti,V. W., Zimmern, P. E. et al: Erosion of woven polyester pubovaginal sling. J Urol. 162: 2070, 1999