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DISEASES OF THE VULVA and VAGINA

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					                       DISEASES OF THE VULVA and VAGINA
                              JANICE M. LAGE, MD


Basic Pathology (8th ed): pages 712-716

Objectives:

      Be familiar with common inflammatory conditions affecting the vulva and vagina.
       Know which are infectious and which are frequently transmitted sexually.

      Understand the relationship between HPV, VIN, VAIN, and squamous cell
       carcinoma.

      Be familiar with “Bowen’s disease” and “extramammary Paget’s disease.”

      Understand the relationship between DES, vaginal adenosis and clear cell
       carcinoma of the vagina.

      Know which mesenchymal tumors (benign and malignant) can involve the
       vagina.


I. Introduction: Disease processes affecting the vulva include dermatologic conditions

of the skin and its adnexal structures and diseases of mucous membranes. There are,

in addition, conditions peculiar to Bartholin’s glands and the vestibular glands.

Nomenclature of the inflammatory skin diseases can be confusing because of

differences between dermatologic and gynecologic terminology.



II. Non- infectious inflammatory skin disease: Although there are a large number of

inflammatory dermatologic conditions which can involve vulvar skin, there are two which

are of particular importance. Squamous hyperplasia, also known as “hyperplastic

dystrophy” is the vulvar equivalent of chronic spongiotic dermatitis or lichen simplex

chronicus. This pruritic skin condition can result from a contact allergy, although many

instances are of unknown etiology. Morphologically, there is orthohyperkeratosis,

irregular epidermal hyperplasia, and a lymphomononuclear infiltrate surrounding the




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Janice M. Lage, MD                                                    Vulva/Vagina

superficial dermal vessels. Often, the epidermis is edematous (spongiotic) and contains

scattered lymphocytes (exocytosis).

       Lichen sclerosis (et atrophicus) occurs predominantly in post- menopausal

women and presents as multiple, white macules which coalesce to form atrophic

plaques. Ultimately, there may be distortion and obliteration of much of the normal

vulvar architecture (chronic atrophic vulvitis or kraurosis vulvae). Microscopically

there is usually epidermal atrophy which results from destruction of the basal layer of

the epidermis. The underlying dermis is marked by a zone of dense sclerosis which is

almost acellular. Beneath the sclerotic layer is a lymphomononuclear infiltrate.

       Although squamous hyperplasia and lichen sclerosis are not considered pre-

malignant, a small percentage of patients develop vulvar intraepithelia neoplasia

(VIN) which may evolve into invasive carcinoma.



III. Infectious inflammatory skin disease: Vulvar skin is subject to a variety of

infections. These include fungal, viral, bacterial, chlamydial, and spirochetal diseases.

Of the fungal infections, candidiasis is the most common. Microscopically, the

epidermis often shows a little spongiosis. The presence of neutrophils in the stratum

corneum is often a clue to the presence of fungal organisms which can be

demonstrated through the use of special stains. In the case of candidiasis, spores and

pseudohyphae are usually confined to the horn.

       Herpes simplex and molluscum contagiosum are common viral infections of

vulvar skin. The former is characterized by painful vesicles which ulcerate.

Histologically there is intracellular edema of keratinocytes with vesiculation and

ulceration accompanied by an intense mixed inflammatory infiltrate. Characteristic

multinucleate giant cells with “ground-glass” nuclear inclusions can be found in both

histologic sections and scrapings (Tzanck preps). Eosinophilic inclusions are less

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Janice M. Lage, MD                                                    Vulva/Vagina

commonly encountered. The causative agent is usually HSV II.

       Molluscum contagiosum causes asymptomatic firm, pearly papules which often

become umbilicated. Distinctive cytoplasmic inclusions (molluscum bodies) are

diagnostic of this pox virus.

       Human papilloma viruses are important in the etiology of VIN and will be

discussed in the section of neoplasia.

       Granuloma inguinale, caused by a gram- negative bacterium

Calymmatobacterium granulomatis causes a chronic, progressive granulomatous skin

disease of the genital, inguinal, and perianal regions. It, and lymphopathia venereum,

an infection by Chlymydia trachomatis are extremely rare in our patient population,

being more prevalent in the tropics. They can be transmitted venereally. Gonorrhea,

infection by Neisseria gonorrhoeae, is venereally transmitted and causes infection of the

urethra, paraurethral glands, or Bartholin’s glands. It can ascend to involve the

endocervix, uterus and fallopian tubes.

       Syphilitic chancre, the primary lesion of infection by Treponema pallidum,

occurs about 3 weeks following inoculation. It is a firm painless ulcer and is often

located on the fourchette or labia. The ulcer bed is densely infiltrated by plasma cells.

Spirochetes can be demonstrated through special stains. Condyloma lata are raised

lesions and are a manifestation of secondary syphilis. In addition to an intense plasma

cell infiltrate, there is epidermal hyperplasia, and the epidermis and dermis contain

numerous spirochetes.

IV. Bartholin’s cyst and abscess: Blockage of the excretory duct of a Bartholin’s

gland results in cystic dilation of the gland. Infection of a gland by any of a number of

bacteria (i.e. E. Coli, gonococcus, streptococcus or staphylococcus) can result in

adenitis with abscess formation.



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Janice M. Lage, MD                                                     Vulva/Vagina

V. Vestibular adenitis: Vestibulitis is of unknown etiology. It results in severe

vestibular tenderness. Microscopically there is a lymphoplasmacytic infiltrate within the

superficial stroma and surrounding the vestibular glands.



VI. Benign tumors: In addition to melanocytic nevi, fibroepithelial polyps (skin

tags), and other benign cutaneous neoplasms, there is a peculiar benign sweat gland

tumor, the papillary hidradenoma which presents as a mass lesion of the vulva and

can mimic a malignancy because of its tendency to ulcerate. The lesion microscopically

often appears as an encapsulated, sometimes partially cystic mass of acini, tubules and

papillary excrescences lined by one or two layers of cuboidal cells. They are

histologically similar to certain intraductal papillomas of the breast (to which they might

be histogenetically related).



VII. Malignant tumors: Melanomas and other cutaneous malignancies can involve

vulvar skin. However, of most importance is squamous cell carcinoma which arises in

the setting of vulvar intraepithelial neoplasia and which is often associated with HPV

infections, particularly types 16 and 18 and extramammary Paget’s disease, an

intraepithelial adenocarcinoma. The latter is only rarely associated with underlying

malignancy unlike mammary Paget’s disease which is virtually always associated with

underlying breast carcinoma.

       Squamous cell carcinoma of the vulva is most often associated with human

papilloma virus infection and preceded by vulvar intraepithelial neoplasia. VIN can be

graded histologically from I-III based upon degree of nuclear atypia and the extent of

disruption of the normal maturation sequence of the keratinocytes. Adjacent changes of

condyloma (venereal wart) and cytologic findings of viral cytopathic effect

(koilocytosis) often accompany the VIN. VIN III or squamous cell carcinoma in situ

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Janice M. Lage, MD                                                   Vulva/Vagina

is carcinoma confined to the epidermis or squamous mucosa by the epithelial basement

membrane. It can take the form of a flat erythematous cutaneous plaque, a

presentation also known as Bowen’s disease, or localized to smaller verrucous wart-

like lesions (Bowenoid papulosis).     Similar erythematous plaques of VIN III involving

the mucosa of the vestibule are sometimes termed erythroplasia of Querat. A few

vulvar carcinomas arise in the setting of squamous hyperplasia or lichen sclerosis.

      The risk of invasive squamous cell carcinoma increases with age. Risk of

metastatic spread (seen only in invasive tumors) is linked to tumor size and depth of

invasion. Small tumors (<2cm in diameter) without palpable nodes (stage I) have a

98% survival at 5 years. Stage II tumors which are >2 cm, confined to the

vulva/perineum, without palpable nodes have a 87% survival. Stage III tumors can be

of any size and show spread to the lower urethra, and/or vagina, and/or anus, and/or

have unilateral node metastasis. 5 year survival is 75%. Stage IV tumors have invaded

the upper urethra (or bladder), rectum, pelvic bones, and/or have bilateral node

metastasis. Survival is 29% at 5 years.

      Verrucous carcinomas are extremely well differentiated squamous cell

carcinomas which lack an infiltrative growth pattern and show virtually no cytologic

atypia. They have the appearance of large condylomas and are deemed malignant by

their destruction of normal structures. They seldom metastasize.

      Extramammary Paget’s disease, an intraepithelial adenocarcinoma manifests

as a pruritic, erythematous plaque and is sometimes associated with a mass. Large

neoplastic cells, often containing mucin, are found scattered throughout the epidermis.

Most cases are unassociated with underlying malignancy although epidermotropic

spread from endocervical adenocarcinoma, skin adnexal carcinoma, rectal

adenocarcinoma and carcinoma of the bladder must be ruled out.



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Janice M. Lage, MD                                                    Vulva/Vagina

                               DISEASES OF THE VAGINA

I. Introduction: The vagina is subject to a variety of developmental defects and

infectious diseases (sexually and nonsexually transmitted). Neoplasms of the vagina,

however, are relatively uncommon.

II. Developmental disorders: Imperforate hymen, vaginal agenesis, transverse

vaginal septum, and complete duplication of the vagina result from defective

development. Vaginal adenosis, a common complication of in utero exposure to

diethylstilbesterol (DES) and related drugs presents clinically as excessive mucous

vaginal discharge. Colposcopically and histologically it appears as glandular mucosa

replacing the native vaginal mucosa and usually involves the anterior upper 1/3 of the

vagina. The glandular mucosa is histologically similar to endocervical mucosa and

frequently undergoes metaplastic change.

III. Inflammatory conditions: Fungal, bacterial, viral, and protozoal infections can

involve the vagina. Candidiasis is the most common of the fungal infections.

Bacterial vaginosis (?-itis) may not represent infection by a single organism, but to be

overgrowth of multiple bacterial strains. It is clinically often associated with malodorous

vaginal discharge or pruritis. On pap smear clue cells, squamous epithelial cells with a

coating of attached bacteria are seen. Trichomonas vaginitis, infection by a motile

protozoan T. vaginalis leads to a yellow- green vaginal discharge. The mucosa is

erythematous and may show punctate hemorrhages. Microscopically, the oval

organisms can be seen on pap smears, or in saline preparations. There is associated

acute inflammation, often with a neutrophilic infiltrate.

       Toxic shock syndrome, an acute, potentially life- threatening disease is usually

associated with infection by certain strains of S. aureus which produce toxic shock

syndrome toxin 1 a.k.a. staphylococcal enterotoxin F. The syndrome consists of fever,

hypotension, diffuse or palmar erythema, hyperemia of mucous membranes, and

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Janice M. Lage, MD                                                   Vulva/Vagina

multisystem dysfunction (headache, vomiting, diarrhea, and oliguria). The histologic

findings are of mucosal desquamation with underlying vascular fibrin thrombi and

perivascular inflammation. The use of certain types of tampons is said to be a

predisposing factor.

IV. Neoplasms: Among benign epithelial neoplasms of the vagina are condylomas,

caused by one of several strains of human papilloma virus. Leiomyoma is the most

common mesenchymal neoplasm of the vagina in adult women. Squamous cell

carcinoma and clear cell adenocarcinoma are the most important vaginal

carcinomas. Embryonal rhabdomyosarcoma is the most common malignant

neoplasm of the vagina seen in infants and children.

      Vaginal intraepithelial neoplasia (VAIN) is the precursor to squamous cell

carcinoma of the vagina. Most cases are thought to be HPV related although

immunosuppression and in utero DES exposure are other predisposing factors. VAIN is

graded histologically with criteria being similar to those used for VIN and CIN. SCC

represents the overwhelming majority of malignant tumors of the vagina (>90%). Most

arise in the proximal 1/3 of the vagina and present as painless vaginal bleeding. The

average age at diagnosis is 63 years. Stage I carcinoma is limited to the vaginal wall

(71% survival @ 5 yrs.) Stage II tumors extend to the subvaginal soft tissues, but not to

the pelvic side wall (47% survival @ 5 yrs.). Stage III tumors extend to the pelvic side

wall (25% 5 year survival). Stage IV carcinoma extends beyond the true pelvis or

involves the bladder or rectal mucosa. IV a tumors involve adjacent organs and IV b

tumors involve distant organs. The overall survival for stage IV is 8% @ 5 yrs.

      Clear cell adenocarcinoma of the vagina is an extremely rare tumor usually

seen in young women 15- 20 years of age. There is a strong statistical link with DES

exposure although the risk for an individual woman exposed in utero to DES is

extremely low (<0.14%). 5 yr. survival rates for stage I disease are about 93%, but late

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Janice M. Lage, MD                                                   Vulva/Vagina

recurrence have been reported. This tumor is more likely to spread hematogenously

(lung metastases) than vaginal squamous cell carcinoma.

      Sarcoma botryoides (embryonal rhabdomyosarcoma) is a rare vaginal

sarcoma affecting infants and children. It forms an exophytic polypoid mass which often

protrudes through the introitus. Near the surface there is often a densely cellular

cambium layer of neoplastic cells. Elsewhere, the tumor is myxomatous. The spindled

rhabdomyoblasts sometimes have cytoplasmic cross striations which can be seen at the

light microscopic level. Although survival after radical surgery alone has been poor,

combined multiagent chemotherapy in addition to surgery has dramatically improved the

survival rate (96% in one recent study).




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Janice M. Lage, MD                                                   Vulva/Vagina

                                       Sample Questions

1. Which of the following is an STD?

      A.   Lichen simplex chronicus
      B.   Lichen sclerosis (et atrophicus)
      C.   Herpes simplex type II
      D.   Psoriasis
      E.   Kraurosis vulvae

2. Which of the following is a known etiologic factor in the development of clear cell
carcinoma of the vagina?

      A.   HPV
      B.   Molluscum contagiosum
      C.   HSV
      D.   DES
      E.   T. vaginalis

3. Extramammary Paget’s disease is best described as:

      A.   Intraepithelial squamous cell carcinoma
      B.   Intraepithelial adenocarcinoma
      C.   Cutaneous candidiasis
      D.   Lichen simplex chronicus
      E.   Lichen sclerosis et atrophicus


For review questions of the female genital system, please go to:

http://www-medlib.med.utah.edu/WebPath/EXAM/MULTORG/fem1frm.html




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Janice M. Lage, MD             Vulva/Vagina

      NOTES




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