• Information
  1. Introduction
  2. Lichen Sclerosis
  3. Squamous Hyperplasia
  4. Overview
  5. Human Papillomavirus (HPV)
  6. Vulvar Intraepithelial Neoplasia (VIN)
  7. Squamous Cell Carcinoma of the Vulva
  8. Malignant Melanoma
  9. Extramammary Paget's Disease

• VAGINA
  1. Normal Histology
  2. Vaginal Inflammation
  3. Vaginal Prolapse
  4. Vaginal Adenosis
  5. Diethylstilbestrol (DES) Exposure
  6. Malignant Tumors of the Vagina

• CERVIX
  1. Transformation Zone
  2. Papanicolaou Cytologic Test (PAP smear)
  3. Cervical Intraepithelial Neoplasia (CIN)
  4. Cervical Dystonia

A. Introduction

1. Vulvar Dystrophy is new term for non-neoplastic epithelial disorders of vulva
2. These disorders lack malignant potential
3. Usually present as white lesions of vulva, usually in middle-aged to older women
4. All suspicious lesions should be biopsied to rule out neoplastic and other diseases
5. Vulvodynia [1]
   1. Chornic burning and/or pain of vulva
   2. No objective physical findings to explain symptoms
   3. 5% lignocaine ointment, gabapentin, tricyclic antidepressants have been used
6. Vestibular Papillomatosis [13]
   1. Flesh-colored, shiny, soft pearly papules 1-2mm in diamter
   2. Papules may be singular (discrete) or grouped
   3. Grouped papules are easily separated from each other
   4. No whitening on application of 5% acetic acid (which does whiten HPV lesions / warts)
   5. Normal vulvar anatomical condition (counterpart of male pearly penile papules)

B. Lichen Sclerosis [2]

1. Epidemiology
   1. May occur in women or men
   2. Female to male ration 6-10 to 1
   3. Incidence is ~14 per 100,000 per year
   4. Uncommon under age 2 years
   5. Lichen sclerosis of the vulva is associated with vulvar squamous cell carcinoma
   6. Also called lichen sclerosis et atrophicus, lichen albus, leukoplakia
2. Lesion Occurrance
   1. Anogenital area in ~90% of cases
   2. Extragenital lesions in ~10% of cases
3. Most commonly found in women in figure eight pattern around vulva and anus
4. Symptoms
   1. Pruritus
   2. Dyspareunia (painful intercourse)
   3. White plaques on vulva due to hyperkeratosis
   4. Skin thinning, parchment or crinkled appearance
   5. Hyperkeratosis with blunting or loss of rete ridges
5. Pathology
   1. Development of an acellular zone in upper dermis
   2. Chronic inflammation usually lies beneath this layer
   3. Includes T cells of CD4 and CD8 lymphocytic infiltrates
   4. Macrophages and mast cells are also
   5. Immature collagen fibrils and increased tenascin has been found
   6. Difficult to distinguish from morphea
6. Pathophysiology
   1. Possible HLA DQ7 association (Class II MHC)
   2. Polymorphisms of interleukin 1 receptor antagonist may affect disease severity
   3. About 40% of patients with lichen sclerosis also have autoantibodies
   4. Antibodies to extracellular matrix protein 1 (ECM 1) in 67% of patients [3]
   5. Autoantibodies to other skin and mucous membrane proteins also found
   6. Antibodies against thyroid and parietal cell proteins in some patients
   7. Increased incidence of thyroid disease and pernicious anemia in lichen sclerosis
   8. Increased infections with bacteria including E. coli and streptococci
7. Treatment
   1. Specialized dermatology (vulvar) clinic
   2. Confirm histology with punch biopsy
   3. Full blood counts
   4. Autoantibody screen and thyroid function and glucose (for diabetes)
   5. Swab skin if concurrent infection is suspected
   6. Treat patient (even asymptomatic) with potent topical steroids
   7. Apply potent topical steroid twice daily for three months, then taper off
   8. Steroids should be used as needed thereafter
   9. Check for cancer: non-healing erosive or warty lesions
   10. Circumcision is treatment of choice for phimosis in male patients
   11. Educate patient about condition

C. Squamous Hyperplasia

1. Proliferation of epithelium (acanthosis)
2. Enlargement and confluence of epidermal rete ridges
3. White appearance on vulva (hyperkeratosis, leukoplakia)
4. Must distinguish between hyperplasia, intraepithelial neoplasia, and true cancer

1. 3200 cases in USA in 1998 with 800 deaths
2. Two Separate Disease
   1. Type 1 from vulvar intraepithelial neoplasia (VIN) due to human papilloma virus (HPV)
   2. Type 2 develops from vuvlvar non-neoplastic epithelial disorders (usually older women)
3. Any suspicious lesions of the vulva must be biopsied

B. Human Papillomavirus (HPV)

1. DNA virus, replication as episome
2. Large number of serotypes with spectrum of oncogenicity
   1. Little / No Risk of Malignancy: Most serotypes
   2. Intermediate risk of Malignancy: Serotypes 31, 33, 35
   3. High Risk of Malignancy: Serotypes 16 and 18
3. Has two potential oncogenes, E6 and E7 (early genes)
   1. E6 from oncogenic HPV strains binds to the anti-oncogene p53 and inactivates it
   2. E7 from oncogenic HPV strains binds to the anti-oncogene Rb and inactivates it
   3. Thus, mechanism of transformation appears to be 2 hit antioncogene inactivation
4. Major Role in Vulvar and Cervical Dysplasia and Neoplasia in these areas

C. Vulvar Intraepithelial Neoplasia (VIN)

1. Formerly called Dysplasia and Carcinoma in Situ (CIS)
2. Disease spectrum from minimal cellular atypia leads to marked cellular changes
3. VIN is a precursor for squamous cell CA
   1. Human papilloma virus (HPV) plays major role in etiology
   2. Majority of VIN contain HPV 16, but found in only ~35% of vulvar CAs
4. HIV-1 infection is the major risk factor for developing VIN and invasive carcinoma [5]
5. Gross Appearance
   1. Single or multiple lesions
   2. Macular, papular, or plaque-like
6. Grading System
   1. Grades I (low) through 3 (high)
   2. Based on qualitative and quantitative changes
   3. Nuclear atypia and size, mitoses, cytoplasmic differentiation towards surface
7. Treatment
   1. Local excision
   2. Imiquimod
8. Imiquimod Cream (Aldara®) [12]
   1. Applied to lesions twice weekly for 16 weeks
   2. 80% of patients have lesion size reduce >25% at 20 weeks; 35% complete response
   3. HPV was cleared in 58% of lesions
   4. Pain and pruritus of lesions reduced
9. Local Excision
   1. Recurrence in ~25% of women
   2. Progression to invasive CA
   3. Frequently associated with other cancers
10. Quadravalent HPV vaccine (Gardasil®) is ~97% effective in preventing new HPV associated vulvar and vaginal lesions (VIN 2/3, ValN2/3) [10,11]

D. Squamous Cell Carcinoma of the Vulva

1. Accounts for ~5% of all genital cancers in women; 86% of vulvar cancers
2. Occurs in both younger and older women, mainly in setting of HIV-1 infection [5]
3. Appearance
   1. Usually presents as white patches, especially when small
   2. About 65% are exophytic; 35% are ulcerative and endophytic
   3. Slow growing tumors, with direct extension to surrounding areas
4. Symptoms
   1. Pruritus of long duration
   2. Ulceration, bleeding, and secondary infection may develop
5. Staging
   1. Stage 0: Tis - carcinoma in situ, intraepithelial neoplasia
   2. Stage I: T1 N0 M0 - tumor confined to vulva/perineum, greatest dimension 2cm or less
   3. Stage II: T2 N0 M0 - tumor confined to vulva/perineum, greatest dimension >2cm, no nodes
   4. Stage III: T1-T3 N1 M0 or T3 N0 M0 - unilateral regional LN or adjacent spread to lower urethra and/or vagina or the anus
   5. Stage IVA: T any N2 M0 or T4; bilateral regional metastases or tumor invades any of the following: upper urethra, bladder mucosa, rectal mucosa, pelvic bone
   6. Stage IVB: T any N any M1: any distant metastasis including pelvic lymph nodes
6. Treatment
   1. Surgical resection with goal to remove all tumor
   2. Chemotherapy has generally been ineffective
7. Prognosis
   1. Stage is main determinant: 5 year survival ~90% for Stages I and 2
   2. Tumor grade
   3. Presence of HIV-1 infection is poorer prognosis

E. Malignant Melanoma

1. Represents ~5% of vulvar cancers
2. Usually occurs in older women (>50)
3. Highly aggressive

F. Extramammary Paget's Disease

1. Rare neoplasm, similar to cancers of the nipple
2. Paget's cells present, with positive staining for carcinoembryonic antigen
3. Metastases are rare, and treatment usually requires wide local excision

1. Stratified, non-cornified squamous epithelium
2. No mucosal glands

B. Vaginal Inflammation [6]

1. Candidiasis (Monillia) - most common cause of itching, vaginal symptoms
2. Trichomonis vaginalis - usually with odor
3. Bacterial vaginosis (usually Gardnerella vaginalis) - usually with odor
4. Papillomavirus
5. History and physical do not adequatly differentiate causes of vaginal symptoms
6. Microscopic examination of vaginal discharge is most effective modality for diagnosis

C. Vaginal Prolapse [7]

1. Also called cervical or uterine prolapse, more recently "Pevlic Organ Prolapse" or POP
   1. "Tissue coming out of vagina"
   2. Protrusion of pelvic organs into or out of vaginal canal
   3. Tissue protruding may be uterus, small bowel, colon, or bladder
2. POP due to loss of support of anterior or posterior vaginal wall or vaginal apex
   1. Present in ~14% of women
   2. Usually correlated with vaginal delivery
   3. 11X increase in risk with >3 vaginal deliveries
3. Symptoms (Table 1, Ref [7])
   1. Tissue protruding from vagina
   2. Urinary hesitancy and/or incomplete voiding
   3. Urinary frequency, urgency or frank dysuria
   4. Urinary incontinence
   5. Defacatory dysfunction, fecal incontinence
   6. Sexual dysfunction - dyspareunia, reduced sensation, libido dysfunction
4. Staging
   1. Stage 0: perfect support
   2. Stage 1: no point lower than 1cm above hymenal ring
   3. Stage 2: lowest point within 1cm of hymenal ring
   4. Stage 3: lowest point >1cm below hymenal ring but not completely prolapsed
   5. Stage 4: complete prolapse
5. Treatment
   1. Observation with pelvic floor strengthening exercises ("Kegel exercises")
   2. Pessaries: supportive or insertive device
   3. Ring pessary with or without floor is a common supportive pessary
   4. Gelhorn and cube pessaries are common space-occupying devices
   5. Surgical repair - require repeat procedure in ~30% of cases
   6. Most obstetricians recommend hysterectomy at time of surgical repair

D. Vaginal Adenosis

1. Red, granular patches on vaginal mucosa. Usually asymptomatic
2. Histology (in addition to normal squamous epithelium)
   1. Mucinous columnar cells similar to those in endocervix
   2. Ciliated cells with eosinophilic cytoplasm (similar to fallopian tube)
   3. Replacement of these cells with metaplastic squamous cells in healing lesions
3. Basis of Pathology is embryological.
   1. At 10th week of gestation, urogenital sinus epithelium normally replaces glandular epithelium lining vagina and endocervix
   2. DES exposure between 10th and 18th weeks, arrests this replacement process
   3. Thus, some glandular tissue remains
4. One third of DES exposed women have adenosis or metaplastic squamous cells

E. Diethylstilbestrol (DES) Exposure [2,5]

1. DES is a synthetic estrogen analog originally used for recurrent spontaneous abortions
2. Banned in 1971 due to lack of efficacy and side effects in exposed mothers and children
3. DES exposure in early prenatal life leads to multiple changes in daughters, including:
   1. Vaginal Adenosis: glandular tissue in vagina
   2. Cervical ectropion: glandular tissue in cervix
   3. Gross structural changes in vagina and cervix
   4. Structural and functional abnormalities of upper GU tract
   5. Clear Cell Adenocarcinoma (~0.1% of exposed women) of the cervix
   6. No other cancers in daughters associated with DES exposure in utero [5]
4. There also appears to be increase in breast cancer risk in DES exposed mothers
5. Probable Effects of DES exposure include:
   1. Ectopic pregnancy increase in DES daughters
   2. Infertility in DES daughters
   3. Reproductive tract anomalies in DES sons
6. Possible Effects of DES exposures include:
   1. Cervical dysplasia and carcinoma in situ in DES daughters
   2. Testicular Cancer but not infertility [5] in DES sons
   3. Autoimmune disorder increase in DES daughters
7. Monitoring Persons with DES Exposure (ACOG Recommendations)
   1. DES Mothers: Monthly breast self examinations, annual physical, usual mamography
   2. DES Daughters
   3. Pelvic examination with Lugol solution, PAP smear, internal by a Gynecologist
      1. High risk obstetric clinic evaluation and followup
   4. DES Sons: usual testicular examinations, including self examinations

F. Malignant Tumors of the Vagina

1. Rare tumors, ~2% of all genital tract tumors
2. About 80% of vaginal malignancies represent spread from cervix and vulva
3. Symptoms
   1. Vaginal discharge, often foul smelling
   2. Bleeding with coitus
   3. Depending on spread, symptoms may include pelvic or abdominal pain and swelling
4. Squamous Cell Vaginal CA
   1. Typically in older women, 60-70 years
   2. Usually in posterior wall of upper third of vagina, as exophytic mass
   3. Precursor appears to be vaginal intraepithelial neoplasia (VAIN) associated with HPV
   4. Quadravalent HPV vaccine (Gardasil®) is ~97% in preventing new HPV associated vulvar and vaginal lesions (VIN 2/3, ValN2/3) [10,11]
   5. Vaginal squamous cell CA often associated with cervical or vulvar CA (carcinogen)
   6. Routine use of PAP smears used for diagnosis
   7. Prognosis for Stage I (local tumor) excellent; Stages III and IV is poor
5. Clear Cell Adenocarcinoma
   1. Associated with DES exposure, 0.1% of exposed women develop after adolescence
   2. Most commonly appears between 17 and 22 years
   3. Usually occurs on anterior wall of upper third of vagina
   4. Associated with Vaginal adenosis (simply because of association of DES and VA)
   5. Histology: clear cell cytoplasm due to glycogen
   6. Early detection leads to survival rate ~100%
6. Embryonal Rhabdomyosarcoma
   1. Rare vaginal tumor also called Sarcoma Botryoides (botrys = "grapes")
   2. Confluent polypoid masses resembling bunch of grapes
   3. Usually in children <4 years
   4. Stromal origin (mesenchyme), primitive muscle cells in lamina propria
   5. Usually detected because of vaginal spotting; chemotherapy of small tumors good
7. Treatment of localized vaginal tumors usually by radical hysterectomy and vaginectomy
8. Prolonged labor (especially in developing countries) increases risk of vesicovaginal fistula [9]

1. Cervix remodels continuously during life due to vaginal pH changes
2. Prenatal life and infancy
   1. Columnar epithelium normally in endocervical canal
   2. This may extend to exocervix or vagina
   3. Thus, original squamocolumnar junction located on exocervix
   4. Normally, the columnar epithelium regresses to the endocervical canal
   5. The area between original and new squamocolumnar junction = Transformation Zone
   6. This is critical zone because nearly all cancers arise here (usually anterior area)
3. Columnar epithelium also undergoes replacement by metaplastic squamous cells
   1. Local pH
   2. Hormone action
   3. Increased estrogen will increase glycogen, change pH by altering flora

B. Papanicolaou Cytologic Test (PAP smear)

1. Cytology of female genital tract
2. Cells, mostly epithelial, are scraped with spatula, brush or swab
3. Early detection for premalignant and malignant cervical lesions
4. Recommend beginning smears at age 18, or with sexual activity, annually thereafter

C. Cervical Intraepithelial Neoplasia (CIN)

1. Cervical Cancer is 8th cause of cancer mortality in USA
2. Due to screening methods, marked increase incidence of precursor lesions
3. These precursors are called cervical intraepithelial neoplasia (CA in situ; CIN)
   1. Carcinoma in situ is malignant lesion confined to epithelium
   2. CIS must involve the full thickness of the epithelium
   3. Neoplasia most common in anterior lip of cervix
   4. Neoplasia are due to human papilloma virus (HPV) infection in >95% of cases
4. Risk factors for development of CIN
   1. Number of lifetime sexual partners
   2. Probably related to presence of high risk serotypes of HPV
   3. Low socioeconomic status, other STDs, and some contraceptive methods
5. Grades of CIN
   1. CIN 1: mild dysplasia (low grade squamous intraepithelial lesions, condylomata)
   2. CIN 2: moderate dysplasia (high grade, along with CIN 3)
   3. CIN 3: severe dysplasia and Carcinoma in Situ
6. HPV
   1. CIN is a manifestation of HPV infection
   2. These agents cause genital warts (condylomata acuminata) and cancers
   3. Warts are usually associated with low risk HPV serotypes (6 or 11)
   4. High grade CIN usually contain HPV types 16, 31, 33, or 35
   5. Invasive cancers (70%) contain HPV 16 or 18
   6. Screening for high risk HPV serotypes is a reasonable alternative to Pap smear
   7. Quadravalent HPV vaccine (Gardasil®) is ~98% in preventing new HPV associated cervical lesions (also prevents vulvar and vaginal lesions) [10]

D. Cervical Dystonia [8]

1. Also called spasmodic torticollis
2. Sustained, intermittent, involuntary muscle contractions
3. Often painful
4. Botulinum Toxin (Botox®, Myobloc®)
   1. Standard treatment for cervical dystonia
   2. Block cholinergic junctions at motor endplate (inhibit release of acetylcholine)
   3. Leads to weakening or paralysis of muscle
   4. Multiple muscles are injected
   5. >80% effectiveness and duration of 3-4 months
   6. Type B (Myobloc®) toxin can be used in patients resistant to Type A (Botox®)
   7. Main side effect is dysphagia, which is severe in rare cases
5. Alternative Treatments
   1. Physical therapy
   2. Muscle relaxants
   3. Anticholinergic agents
   4. Tricyclic antidepressants
   5. Surgical denervation

References

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2. Powell JJ and Wojnarowska. 1999. Lancet. 353(9166):1777
3. Oyama N, Chan I, Neill SM, et al. 2003. Lancet. 362(9378):118
4. Canavan TP and Cohen D. 2002. Am Fam Phys. 66(7):1269
5. Conley LJ, Ellerbrock TV, Bush TJ, et al. 2002. Lancet. 359(9301):108
6. Anderson MR, Klink K, Cohrssen A. 2004. JAMA. 291(11):1368
7. Cundiff GW. 2005. JAMA. 293(16):2018
8. Botulinum Toxin for Cervical Dystonia. Med Let. 43(1109):63
9. Wall LL. 2006. Lancet. 368(9542):1201
10. Recombinant HPV Vaccine. 2006. Med Let. 48(1241):65
11. Joura EA, Leodolter S, Hernandez-Avila M, et al. 2007. Lancet. 369(9574):1693
12. Van Sters M, van Beurden M, ten Kate FJ, et al. 2008. NEJM. 358(14):1465
13. Chan CC and Chiu HC. 2008. NEJM. 358(14):1495