Vesicobullous disorders of female genitalia.

Blistering over the vulval region can be due to multiple causes, each having nearly a similar presentation. Thus, a thorough understanding of the various etiologies is necessary to make a correct diagnosis. Clinically, there always remains some ambiguity as to the precise diagnosis, thus investigations, such as biopsy, play a very essential role in clinching the correct diagnosis. Most of these disorders are amenable to treatment and thus an early intervention is a must to prevent morbidity associated with these diseases.

INTRODUCTION

Disorders of female genitalia can present with varying manifestations, being present either as an isolated disorder or as part of a systemic disease. Disorders of female genitalia have always proved confusing to the clinicians as majority of the problems are dermatological, but patients tend to present to other specialties, especially gynecologists, who have had little or no training in dermatology. Almost all types of cutaneous diseases can affect the vulval region.

Vesicobullous diseases are a group of disorders in which a patient presents with fluid-filled lesions.

These can be classified into following types depending upon the etiology:

Autoimmune bullous disorders: Pemphigus vulgaris (PV), pemphigus vegetans, paraneoplastic pemphigus, bullous pemphigoid (BP), mucous membrane pemphigoid, linear IgA disease, and epidermolysis bullosa acquisita (EBA).

Genetic bullous disorders: Epidermolysis bullosa (EB) and Hailey-Hailey disease (HHD).

Inflammatory disorders: Contact dermatitis (CD).

Drug induced: Acute disseminated epidermal necrolysis (ADEN) and bullous fixed drug eruption (FDE).

Infectious: Herpes simplex and herpes zoster.

Miscellaneous: Lymphangiectasia, lymphangioma, mucinous cysts, erythema multiforme (EM), and lichen sclerosus (LS).

Autoimmune bullous diseases

These diseases are characterized by pathogenic autoantibodies directed against antigens which are important adhesion molecules in the skin. These are primarily classified into intraepidermal and subepidermal depending upon the level of split.

Pemphigus vulgaris

These disorders are characterized by intraepidermal flaccid blisters and a positive Nikolsky's sign. PV is the most common immunobullous disorder and is primarily a disease of middle age. Its incidence is 0.1-3.2 cases per 100,000 individuals per year.[1] Antibodies are directed primarily against the desmoglein 3 antigen,[2] but antibodies to desmoglein 1 are also found. Blisters in PV are confined to the suprabasal level. All patients have mucosal lesions. Although oral mucosa is most commonly involved (50%-70%), involvement of vulva[3] [Figure 1] and cervix[4] is also seen in some cases. Localized vulvar pemphigus has been reported due to topical tacrolimus therapy.[5] In a study done on 77 females with PV, genital lesions were observed in 39 (51%) patients. Of these, the labia minora were involved in 36 patients (92%), the labia majora in 11 (28%), the vagina in 14 (36%), and the cervix in 6 (15%) patients.[6] PV clinically presents as flaccid blisters filled with clear fluid over a normal or an erythematous base which soon rupture to produce painful erosions [Figure 1]. Unusual presentations of genital PV such as desquamative inflammatory vaginitis[7] and chronic vaginal discharge have also been described.[8] Such cases usually pose a diagnostic dilemma as even histopathology may be inconclusive. Direct immunofluorescence (DIF) plays an essential role in diagnosing such cases. The lesions heal without scarring. Corticosteroids, both topical and systemic, are the mainstay of treatment. A case of squamous cell carcinoma (SCC) arising from vulval pemphigus has been reported in the literature. The patient also had associated systemic lupus erythematosus, an association described only in five cases till date.[1]

Figure 1

Vulvar involvement in pemphigus vulgaris

Pemphigus vegetans is a variant of pemphigus vulgaris that is characterized by primarily a flexural involvement. Oral mucosa is involved in majority and few cases may have genital involvement as well. Pemphigus vegetans has also been reported as a cause of localized vulvar acantholytic dermatoses. This girl presented with warty lesions over the labium majus whose histopathology and DIF showed typical features of pemphigus.[9]

Pemphigoid

It is clinically characterized by presence of tense bullae. Mucous membrane involvement is less common than PV; however, intact blisters are also seen rather than only erosions, as in case of PV.

Localized vulvar pemphigoid is a variant of bullous pemphigoid and is a rarely reported entity. It is characterized by recurrent blistering confined to the vulva of young girls and does not result in scarring.[1011]

Mucous membrane pemphigoid, also known as “cicatricial pemphigoid” or “benign mucosal pemphigoid,” causes recurrent blistering of the mucous membrane or of the skin near one of the orifices along with a tendency to form scars.[12] Genitalia are involved in half of the female patients.[3] Mucous membrane pemphigoid of the genitalia is manifested by nonspecific erosions, skin fragility, and sometimes intact blisters over clinically hair-bearing skin.[7] Complications that ensue are labial fusion, introital shrinkage, and scarring, indistinguishable from LS.[13] These can further lead to sexual and urinary problems. Initial therapy is with oral corticosteroids. Lesions may respond to potent topical steroids or to the combination of topical steroids and tetracycline. Adhesions may require surgical division. Success has also been reported with sulfapyridine, minocycline, mycophenolate mofetil, and intravenous immunoglobulin (IVIg).[14] Linear IgA mucous membrane pemphigoid is an entity in which patients have typical clinical signs of mucous membrane pemphigoid along with linear IgA on direct immunofluorescence.[15] The disease has been described in both children and adults.[16]

Linear IgA disease of adults

It commonly occurs after the age of 60 years and is characterized by IgA basement membrane antibodies.[17] There is a strong association between linear IgA disease and the extended autoimmune haplotype HLA-B8, -CW7, and -DR3. The major antigen in linear IgA disease is BP180/collagen XVII. Symptoms may vary from mild to severe pruritus and burning. The trunk is almost always affected. Mucosal lesions are common[17] and involvement of the genitalia can also occur. Spontaneous remission occurs in the majority after an average of 3-6 years, the TNF genotype of the patient affects disease duration.[18] The disease responds favorably to dapsone.

Genetic bullous diseases

These are characterized by genetically determined structural abnormalities in the dermoepidermal junction.

Epidermolysis bullosa

EB comprises a group of genetically determined skin fragility disorders characterized by blistering of skin and mucosae following mild mechanical trauma, thus they are also known as “mechanobullous diseases.” Involvement of the genitourinary tract has been described in many types of EB.[19] Depending upon the ultrastructural level of tissue cleavage, they are grouped into three types: EB simplex (split through basal layer), junctional EB (split through lamina lucida), and dystrophic EB (split through sublamina-densa).

EB simplex, inherited in an autosomal dominant manner, usually does not involve the mucosae except for the Dowling-Meara type which is the most severe form of EB simplex. Early involvement of mucous membranes is there, which heal with scarring and milia formation.

Mucosal involvement is seen in both types of junctional EB, i.e., Herlitz and non-Herlitz variety, an autosomal recessive disorder.

Dystrophic EB is the most severe variety in which there's a mutation in the anchoring fibril protein, type VII collagen. It is characterized by skin fragility, blistering, scarring, nail changes, and milia formation. In the severe generalized recessive dystrophic EB (Hallopeau-Siemens type), blistering, erosions, and painful fissures may develop which later lead to stenosis due to scarring. An important sequel of this form is the development of SCC; these are aggressive and often metastasize.[2021] In the non-Hallopeau-Siemens dystrophic EB, findings are similar but milder.

Although skin biopsy may clinch the diagnosis in a few cases but electron microscopy (EM) is diagnostic. No specific treatment is as yet available but gene therapy might prove to be helpful in the near future.[22-25] Till then, the most important approach to such children is prevention of trauma.

Hailey-Hailey disease

Also known as familial benign chronic pemphigus, it is an autosomal dominant intraepidermal blistering disease characterized by recurrent vesicles and erosions affecting the neck, axillae, and groins.[26] The disease is caused by mutations in the ATP2C1 gene. The disease usually presents in the 3rd or 4th decade with flaccid vesicopustules, crusted erosions, or expanding circinate plaques in areas exposed to friction.[2728] Mucosal involvement is rare but vaginal involvement has been described.[28] Lesions presenting exclusively in the vulval region have also been described.[29] HHD at times may also present atypically as leukoplakia[30] or candidiasis.[31] Rarely SCC arising both in the skin[32] as well as vulvar lesions[33] of HHD has been reported. A report of SCC following topical tacrolimus therapy has also been described.[30]

Inflammatory diseases

Contact dermatitis

Contact dermatitis of the vulva is common, with irritant CD occurring more frequently than allergic CD.[34] CD usually occurs when there is an impairment of the barrier function.[3536] This may occur because of dampness and maceration secondary to a heavy vaginal discharge, or increased contact with urine in an incontinent patient. Agents usually responsible for irritant dermatitis are cleansing agents, bubble baths, disinfectants, lubricants, perfumed products, deodorants, and medicaments. Mostly, it presents as an eczematous eruption but in severe cases, vesicobullous lesions may be seen.

Drug induced

Acute disseminated epidermal necrolysis

The term ADEN was first proposed by Ruiz-Maldonado[37] to encompass two life-threatening mucocutaneous reactions: Steven-Johnsons syndrome (SJS) and toxic epidermal necrolysis (TEN). SJS involves<10% of body surface area (BSA), whereas TEN involves >30% BSA. ADEN clinically begins within 8 weeks of drug exposure (usually 4-30 days). Nonspecific constitutional symptoms may precede the mucocutaneous lesions by 1-3 days. Mucosal involvement is seen in nearly 90% of cases.[38] Genital lesions are frequent leading to dysuria; retention of urine may occur, as may involvement of the bladder. Renal damage may occur as a complication of genital lesions, and can prove fatal if not recognized in time. Systemic steroids are the most commonly employed agents for treatment. IVIg is the most specific treatment, but is expensive. Immunosuppression by these agents may minimize severity if instituted in the first 24-48 hours.[39]

Bullous-fixed drug eruption

FDE occurs more commonly over the penis than vulva. The most common medications responsible include acetaminophen, barbiturates, nonsteroidal anti-inflammatory drugs including salicylates, oral contraceptives, penicillins, tetracyclines, phenolphthalein, and sulfonamides.[4041] One or a few blisters or erosions ranging from 1 to 3 cm appear within 1-2 days following ingestion of the offending medication. Subsequent exposure to the medication produces recurrence of lesions precisely at the same location and occasionally at additional areas as well. FDE of the genitalia preferentially affects non-hair-bearing skin of the vulva. Postinflammatory hyperpigmentation generally does not occur on these areas.

Infectious disease

Vulval herpes

It is caused by herpes simplex virus type I and II, latter being more commonly found. 95% infections are acquired sexually. Typical lesions are closely aggregated vesicles, filled with clear fluid, which later rupture to form erosions or ulcers [Figure 2]. Lesions are symptomatic most of the times in the form of pain, burning, or itching. Urinary retention may occur either due to affection of the nerve segments S2-4 or due to pain and edema. A case report of atypical genital herpes simulating PV has been published, where DIF and indirect immunofluorescence studies were consistent with diagnosis of pemphigus.[42]

Figure 2

Vesicles and erosions in herpes genitalis

Definitive diagnosis is possible only by a viral culture. Treatment involves prescribing acyclovir 400 mg three times a day or acyclovir 200 mg five times a day, for 5-7 days. Recalcitrant and recurrent cases may require prolonged doses of antivirals.

Herpes Zoster

It is caused by reactivation of the Varicella-Zoster virus leading to eruption of vesicobullous lesions in a dermatomal fashion. Involvement of the vulva may occur if the 3rd sacral dermatome is involved and may also be accompanied by bladder and bowel dysfunction.[43]

Miscellaneous

Lymphangioma

Lymphangiomas are malformations of the lymphatic system giving rise to vesicles filled with clear fluid. Vulval lymphangiomas are of two types: Lymphangioma circumscriptum and cavernous lymphangioma. The former appear as localized thin-walled vesicles which are aggregated together and the latter one arises in childhood and presents as a soft compressible mass. It may even involve the whole vulva.[44] Vulval lymphangiomas are rare. Thirteen cases of the congenital and 24 cases of acquired form of lymphangiomas have been reported in the literature presently.[45] Surgical resection is an effective and well-tolerated therapy for vulval lymphangioma circumscriptum in most women. Lesion recurrence is frequent but resection can be repeated several times with no adverse effects.[46]

Lymphangiectasia

It is an acquired dilatation of the cutaneous lymphatics secondary to obstruction of the lymphatic vessels. It may occur secondary to treatment of cervical carcinoma with surgery and/or radiotherapy,[47-49] Crohn's disease and in pregnant females. A case report of lymphangiectasia as a sequel of primary chylous reflex has also been published.[50] Repeated episodes of cellulitis may also occur in lymphangiectasia; however, there may be an underlying abnormality of the lymphatics that predisposes to cellulitis.

Mucinous cysts

Vulval mucinous cysts are not uncommon. They are usually found on the vestibule where they develop secondary to obstruction of the duct of one of the many minor vestibular mucus-secreting glands. They are of urogenital sinus origin.[5152]

Erythema multiforme

It is an acute self-limited, usually mild, and often recurrent mucocutaneous disease. There are four subtypes:[53]

EM minor: Only cutaneous lesions.

EM major: Cutaneous lesions with mucosal involvement.

Herpes associated EM.

Mucosal EM (Fuchs syndrome): Only mucosal involvement.

Most common cause of EM is infection, most commonly herpes simplex. M. pneumoniae is the most common cause in children.[5455] Cutaneous lesions present typically as “target or iris” lesions. Mucosal lesions occur in 70% of cases, most commonly limited to the oral mucosa. Genitalia are rarely involved in EM. “Ectodermosis pluriorificialis” or “Fuchs syndrome” is characterized by severe involvement of two or three mucosal sites in the absence of skin lesions.

Lichen sclerosus

The condition was initially described as a variant of lichen planus and was earlier known by varied names such as “leukoplakia,” “leukoplakic vulvitis,” and “kraurosis vulvae.”[56] These terms have now been abandoned to avoid any confusion. Exact etiology of the condition is not known, but it is believed to be an autoimmune disorder which is genetically determined.[57] The disease can affect females of any age but majority are either prepubertal or postmenopausal. Presenting symptom is usually severe itching, but few cases might be asymptomatic. The disease usually presents with atrophic whitened epithelium [Figure 3], but rarely bullae may occur. These later ulcerate and heal with scarring. Complications thereby ensue such as disfigurement and introital narrowing. Vulval LS is also associated with malignancy such as SCC.[58] Topical steroids are the mainstay of treatment.

Figure 3

Atrophic whitish plaque of lichen sclerosus

Pyodermatitis-pyostomatitis vegetans

The disorder is also known as “blastomycosis-like pyoderma.”[59] It most commonly presents as a verrucous plaque studded with pustules, thus mimicking pyoderma gangrenosum, especially of the vegetans type. When the lesions are localized to the oral mucosa, it is known as “pyostomatitis vegetans.” Such cases mostly occur in association with IBD. Besides oral mucosa, involvement of vulval mucosa has also been described. It may be the presenting symptom or may get involved later during the course of the disease.[60] Histology shows eosinophilic spongiosis with eosinophilic microabscesses and pseudoepitheliomatous hyperplasia. Direct immunofluorescence is negative. A predominant neutrophilic infiltrate may also be seen.

Vesicobullous disorders of the female genitalia can include a multitude of dermatological entities with nearly similar presentation. Thus, a careful and watchful approach toward such patients is necessary in order to arrive at the correct diagnosis. Besides clinical examination, histopathology and DIF also plays an important role in making a diagnosis.

Multiple Choice Questions

Q1. Urinary retention in cases of genital herpes may occur following involvement of which nerves?

S1-3

S2-4

S3-5

S4-6

Q2. All of the following can present as vesicular lesions in the vulvar region except

Lichen sclerosus

Psoriasis

Fixed drug eruption

Contact dermatitis

Q3. A 27-year-old pregnant female presented with multiple asymptomatic vesicles over her labia majora, for the past 1 month. The probable diagnosis in this patient is

Lymphangiectasia

Contact dermatitis

Folliculitis

Pemphigus vulgaris

Q4. A 50-year-old female presented with severely pruritic vesicular eruption on the 2nd postoperative day after a vaginal hysterectomy. The most likely cause is

Pemphigus vulgaris

Scabies

Contact dermatitis

Lichen planus

Q5. Which of the following vesicobullous disorder of vulva is genetically determined?

Pemphigus vulgaris

Hailey-Hailey disease

Pyodermatitis-pyostomatitis vegetans

Fuchs syndrome

Q6. All of the following vesicular conditions of the vulva have been reported to develop secondary malignancy except

Lichen sclerosus

Hailey-Hailey disease

Pemphigus vulgaris

Erythema multiforme

Q7. Steroids, oral or topical, are the preferred modality of treatment in all of the following except

Linear IgA disease of adults

Mucous membrane pemphigoid

Lichen sclerosus

Contact dermatitis

Q8. DIF (direct immunofluorescence) is a useful investigation in diagnosis of following vesicobullous disorders involving genitalia

Pemphigus vulgaris

Bullous pemphigoid

Linear IgA disease

Dystrophic epidermolysis bullosa

Q9. Which statement isn't true for vulvar mucinous cysts?

Usually found on vestibule

Develop secondary to obstruction of minor mucus secreting gland

Originate from the urogenital sinus

None of these

Q10. Dapsone is the preferred treatment for which of the following vesicobullous disease?

Linear IgA disease

Pemphigus vulgaris

Bullous pemphigoid

Hailey-Hailey disease

Answers:

(b)

(b)

(a)

(c)

(b)

(d)

(a)

(a)

(d)

(a)