Vulvovaginal disorders Flashcards
components of the Normal Flora
- Aerobes, anaerobes, and yeast
- Anaerobes 10x > aerobes
- Lactobacillus
- Skin and GI tract flora - Exempt from normal bactericidal immune activity
- Convert glycogen in vaginal mucosal secretions to lactic acid
- Normal vaginal pH - 4.0 - 4.5
- Postmenopausal - 6.5 - 7.0
what alters the vaginal flora?
- age - low estrogen lvls = less Lactobacillus; Estrogen replacement restores vaginal lactobacilli
- menses - mainly in first days; possibly 2/2 hormonal changes; Menstrual fluid may nourish bacteria
- abx - eradication of normal flora
- Changes in reproductive tract - hysterectomy, pregnancy
- Foreign substances
- Dec overall health
- Poor eating habits - esp sugary foods
- Meds - BC, abx, steroids
- Immunosuppression
how to restore vaginal flora
- Avoidance of aggravating or predisposing factors
- Antimicrobial regimen for treatment or prophylaxis of overgrowth
- Probiotic dosing
MCC of Candidal Vulvovaginitis
Candida albicans - 90%
Candidal Vulvovaginitis
often associated with what other causes/conditions:
- Systemic disorder - DM, HIV, obesity
- Pregnancy
- Meds - abx, steroids, BC
- Chronic debilitation
- Intense vulvar pruritus +/- excoriations
- Thick, white, “cottage cheese” discharge
- Usually with minimal odor
- Vulvar erythema and possible edema
- Burning sensation may follow urination
Candidal Vulvovaginitis
w/u for candidal vulvovaginitis
- Vaginal pH - mildly elevated (pH 4-5)
-
Saline Prep
- 1 drop vaginal discharge with 1 drop normal saline
- Apply coverslip and examine under microscope
- Candidiasis - branching filaments, pseudohyphae - KOH Prep
- 1 drop discharge w/ 10% aq KOH
- Dissolves epithelial cells and debris and facilitates visualization of fungal mycelia - Cx - gold standard for diagnosis
on microscopy you see budding yeast, pseudohyphae, dx?
candidiasis
tx for Candidal Vulvovaginitis
- Topical or oral antifungals, boric acid, gentian violet - Most respond to 1-3 days of topical azole creams or a single dose of fluconazole 150 mg PO
what is considered “complicated” in candidal vulvovaginitis?
tx?
4+ episodes/yr, severe sx, non-albicans, uncontrolled DM, HIV, steroids, pregnancy
- 7-14 d of topical therapy or 2 doses of oral fluconazole
- Cx to confirm dx
- Consider boric acid
Available OTC and rx
Less risk for systemic SE
Messy application
Weaken latex
May provide more rapid s/s relief
which type of antifungal tx?
Intravaginal antifungal creams
Available by rx only
Higher risk for systemic SE
More convenient
Overuse → resistance?
Delayed relief of symptoms
Cannot use in 1st trimester
which type of antifungal tx?
Oral antifungal therapy
Available OTC
Work better for non-candidal infections
Cannot use in pregnancy
Harmful if taken orally by mistake
which tx?
Boric acid intravaginal
Available OTC
Does not work well with other topical therapies
Caution in pregnancy - no studies
Discoloration of skin
which tx?
Gentian Violet
inserted into vagina qhs using applicator
Cream or suppository; often also can use externally
Varying treatment lengths depending on medication - single-dose, 3 day, 7 day, 14 day
Vaginal Antifungal Therapy
MOA of Vaginal Antifungal Therapy
inhibit enzyme for cell membrane synthesis
which vaginal antifungal therapy increases permeability of cell walls
nystatin
SE and DDI of Vaginal Antifungal Therapy
- SE - burning, itching, swelling, rash, discharge; rare - HA, cramps
- DDI - rarely may potentiate warfarin
MOA of Oral Antifungal Therapy
inhibits enzyme for cell membrane synthesis
SE and DDI of PO antifungal therapy
- SE - GI upset, abd pain, dizziness, HA, drowsiness, allergic rxn; Rare - dysrhythmia/palpitations (prolongs QT)
- DDI - erythromycin, clopidogrel, warfarin, theophylline, sulfonylureas, thiazides, cimetidine, hepatotoxic drugs
new drug in triterpenoid class
Better long-term prevention of recurrent VVC than azoles
inhibits glucan synthase enzyme, used to make cell wall
Ibrexafungerp (Brexafemme)
SE and DDI of Ibrexafungerp
- SE - GI upset (N/V/D), abdominal pain
- Rare - elevated AST/ALT, rash, back pain, vaginal bleeding
- CI in pregnancy - DDI - grapefruit, anticonvulsants, azole antifungals
- Most helpful in non-candidal infections
- Cannot be used in pregnancy
- 1 capsule intravaginally (PV) QHS x 7 d
- interferes with fungal metabolism
Boric Acid Intravaginal
Size 0 gelatin capsules filled with boric acid, which is about ? mg
600
SE and DDI of boric acid intravaginal
- SE - local irritation or inflammation
- Toxic if taken internally - DDI - not common
how to use gentian violet
Apply 1% topically QD x once (acute) or x 10-14 d (recurrent)
- May apply to clean tampon and insert
- Remove 3-4 hrs after tampon insertion
- Should not use tampons for menstrual
flow while performing this therapy
MOA of gentian violet
may inhibit protein synthesis
SE and DDI of gentian violet
- SE - topical irritation, staining or
- discoloration of clothing and skin
- DDI - none known
tx for Recurrent cases of candidal vulvovaginitis
May use prophylactic antifungals for up to 6 months
- Azoles - PO 1x/week or PV 1-2x/week
- Boric acid - PV once every two weeks
- Gentian violet - PV/externally QD x 10-14 d, then PRN
prevention for Candidal Vulvovaginitis
- Keep vulvovaginal area dry - Avoid non-absorbent undergarments
- Control underlying systemic disease
- Avoid excessive glucose dietary intake
- DC complicating meds
- Consider prophylactic antifungals with abx
Overgrowth of abnormal bacterial flora
Often polymicrobial - Gardnerella vaginalis often present
Not considered STI, but rare in nonsexually active patients
Bacterial Vaginosis
Milky, homogenous, malodorous vaginal discharge, often with minimal inflammation
More noticeable after unprotected intercourse
“Fishy” smell, enhanced after KOH prep
Lack of vaginal mucosal inflammation on exam
Bacterial Vaginosis
BV is Associated with increased risk of ?
preterm delivery
w/u for BV
- Vaginal pH - usually elevated (pH 5.5 - 7)
-
Saline Prep
- 1 drop vaginal discharge with 1 drop normal saline
- Apply coverslip and examine under microscope
- BV - “clue cells” - epithelial cells covered with bacteria -
KOH Prep
- 1 drop discharge with 10% aqueous potassium hydroxide
- BV - fishy odor present or increased after KOH (“whiff test”) - Can also do Gram stain and culture of discharge
- Cx often not helpful - polymicrobial condition
tx for BV
- Metronidazole (Flagyl/Metrogel)
- Clindamycin (Cleocin)
- PO Tinidazole (Tindamax) - avoid in preg
- PO Secnidazole (Solosec) - avoid in preg
MOA of nitroimidazoles
binds to and deactivates enzymes
best nitroimidazoles for pregnant pts
PO metronidazole or clindamycin
SE of Nitroimidazoles
dizziness, HA, false lab results (LFTs and TG)
- GU - dark colored urine, local irritation (vaginal)
- GI - abdominal pain, GI upset, dry mouth, glossitis, altered taste
- Rare - neurotoxicity, anaphylaxis, serotonin syndrome
DDI of nitroimidazoles
alcohol (up to 3 days after use), disulfiram (up to 2 weeks before/after use), anticoagulants, phenytoin, lithium
MOA of clinda
binds to ribosomes blocking protein synthesis
SE of clinda
C. diff and pseudomembranous colitis, local irritation (vaginal)
- GI - abdominal pain, GI upset, altered taste
- Rare - blood dyscrasias, hepatotoxicity, anaphylaxis, polyarthritis
DDI of clinda
macrolides, neuromuscular drugs, antiperistaltic drugs
how to prevent BV
Avoidance of factors altering nml vaginal flora
Under investigation:
1. Probiotic supplements - oral or intravaginal
1. Boric acid with EDTA suppositories
1. Microbiome transplant
1. Acidifying vaginal douches - Vaginal douching not recommended
- Unicellular flagellate protozoan
- Most prevalent non-viral STD in the US - Rarely transmitted outside of sexual activity
- Associated with perinatal complications and increased HIV transmission
Trichomonal Vaginitis
- Profuse, extremely frothy, greenish, at times foul-smelling vaginal discharge
- possible vulvar pruritus, urinary sx
- generalized vaginal erythema with multiple small petechiae - “strawberry cervix;” edema/tenderness of labia minora, vestibule
Trichomonal Vaginitis
w/u for Trichomonal Vaginitis
- Vaginal pH - elevated (pH >5-5.5)
-
Saline Prep
- 1 drop vaginal discharge with 1 drop normal saline
- Apply coverslip and examine under microscope
- Trichomonas - actively motile trichomonads -
Other tests - can give false + results
- Immunochromatographic rapid test - 10 minutes
- Nucleic acid probe - 45 minutes
- Pap smears may reveal infection
- Cx - most sensitive and specific method
tx for trichmonal vaginitis
- metronidazole OR secnidazole OR tinidazole
- Resistant - tinidazole
- Partner should also be treated! Also screen for other STIs - G&C, HIV, syphilis
Gonorrheal Vulvovaginitis Mc infects glands of ?
cervix, urethra, vulva, perineum, anus
?% of Gonorrheal Vulvovaginitis are asx
80-85%
w/u and tx for gonorrheal vulvovaginitis?
- Dx - nucleic acid probe or culture of discharge; G- diplococci within leukocytes
- Tx - ceftriaxone + doxycycline/azithromycin (chlamydia)
- Partner should also be treated!
s/s of Chlamydial Vulvovaginitis
often asx
May see mucopurulent cervicitis, dysuria, and/or postcoital bleeding
Can progress to PID or lymphogranuloma venereum
w/u and tx for Chlamydial Vulvovaginitis
- Dx - Cx, immunoassay, nucleic acid
- Can be found on Pap smear as well
- Tx - doxycycline (preferred), azithromycin; Usually also receive tx for gonorrhea
- Partner should also be treated!
causes of Noninfectious Vaginitis
- Topical irritants - sanitary supplies, spermicides, feminine hygiene supplies, soaps, perfumes
- Allergens - latex, antimycotic creams
- Atrophy - s/p menopause or premature ovarian failure
- Excessive sexual activity
- Poor hygiene, stress, sweat, heat
s/s of Noninfectious Vaginitis?
tx?
- Varying degrees of pruritus, irritation, burning, erythema, and vaginal discharge
- remove offending agent; Atrophy - lubricants, moisturizers, HRT or ospemifene (a SERM); Warm sitz baths; Topical steroid therapy (minimal duration)
CAM Treatment of Vaginitis
- Intravaginal therapies - white vinegar, herbals (oregano leaf, goldenseal root, echinacea), povidone iodine, tea tree oil suppositories
- Probiotic supplementation
- Daily oral supplements - green tea, cat’s claw, milk thistle, grapefruit seed extract, garlic
MC type of HSV
60% - HSV type 2
s/s of herpes genitalis
vesicles that become painful erosions or ulcers surrounded by an erythematous halo
- Prodrome - tingling, itching, burning, flu-like symptoms
- +/- inguinal lymphadenopathy
- +/- urinary symptoms (dysuria, urinary retention)
w/u for herpes genitalis?
viral culture, PCR, DFA, Tzanck smear
tx for herpes genitalis
-
Initial - antivirals for 7-10 days
- Valacyclovir, Famciclovir, Acyclovir - Recurrent - antivirals for 1-5 days
- Prophylaxis - re-evaluate need periodically
Prevention - barrier contraception, suppressive antivirals
MCC of Condyloma Acuminatum?
HPV 6 and 11
- white exophytic or papillomatous growth
- Tend to coalesce and form large cauliflower-like masses
- May also see flat lesions with granular surfaces - Can affect vagina, cervix, vulva, perineum, perianal areas as well as other areas of body
Condyloma Acuminatum
w/u for Condyloma Acuminatum
- Before tx, should do Pap and colposcopy
- bx to r/o neoplasia
- screen for STIs
tx for Condyloma Acuminatum
- Provider - topical application of bichloracetic acid, trichloroacetic acid, podophyllin; cryotherapy, electrosurgery, simple excision, laser
- Pt - topical podofilox, imiquimod, topical interferon, or sincatechins
- Recurrence after treatment is common!
Benign epithelial tumors caused by poxvirus
Size varies - up to 1 cm
Often multiple and contagious
microscopy: numerous inclusion bodies in cell cytoplasm
dx?
tx?
Molluscum Contagiosum
Tx - desiccation, freezing, curettage, chemical cauterization, topical imiquimod; Frequently cause scarring; May choose to observe
STI caused by Treponema pallidum
Syphilis
the 4 types of Syphilis
- Primary - lone painless ulcer (chancre) +/- LAD
- Secondary - generalized rash, malaise, F
- Latent - asx w/ positive serology
- Tertiary - systemic involvement (e.g. cardiac, neural)
tx for Syphilis
- PCN (benzathine penicillin)
- If pregnant - still use PCN (desensitization for PCN-allergic pts) - Primary, secondary, or < 1 yr latent
Benzathine PCN G x 1 dose
- PCN allergic, nonpregnant women - doxy - > 1 yr latent, tertiary, CV
Benzathine PCN G x 3 wk
- PCN allergic, nonpregnant women - doxycycline x 4 wk
Located near vaginal orifice
Secrete mucus for lubrication
Bartholin’s Glands
problems with Bartholin’s Glands
- Infection - important cause of obstruction
- Other causes - inspissated mucus, congenital narrowing
- Postmenopausal - may reflect cancer; Consider bx of lesion
- Pain, tenderness, dyspareunia
- Difficulty walking with adducted thighs
- Usually will have fluctuant, tender mass
- If cystic only - swelling with no pain or minimal discomfort
- Systemic signs of infection are unlikely
Bartholin Gland Disease
tx for Bartholin Gland Disease
- Drainage of cyst or abscess
- 1st line - marsupialization or insertion of Word catheter
- Simple aspiration or I&D - temporary relief - Excision - if recurrent or postmenopausal
-
abx - if significant inflammation
or signs of systemic illness
Benign, chronic, inflammatory disorder
MC non-neoplastic epithelial vulvar disorder
Lichen Sclerosus
causes of lichen sclerosus
Multifactoral
- Vit A def, autoimmune, excess of elastase, dec 5-alpha-reductase
- > 60 years
- Childhood pts → 50% have spontaneous resolution at adolescence
s/s of Lichen Sclerosus
pruritus (MC)
May see vulvar pain, dyspareunia, asx white lesions
Typical characteristics and progression of Acute Lichen Sclerosus:
- Erythema and edema of vulvar skin
- Development of white plaques - lichenification and hyperkeratosis
- Uniting of white plaques
- Intense pruritus → scratch–itch cycle
- Telangiectasias and subepithelial hemorrhages 2o scratching
- Erosions, fissures, and ulcerations
Typical characteristics and progression of Chronic Lichen Sclerosus:
- Thin, wrinkled, white skin (“cigarette-paper”)
- Agglutination of anterior bilateral labia minora → cover the clitoris → phimosis
- Contraction of the vulvar structures → introital stenosis
- Involvement of the perianal region
- Some women develop islands of hyperplastic epithelia within the atrophic lichen sclerosus epithelium
complications of lichen sclerosus
- High rate of SCC (3-5%)
- bx indicated for all new lesions
- Cancer mainly in pts who continue to suffer itching or who neglect treatment
goals of lichen sclerosus therapy
- Stop itch-scratch cycle
- Minimize dermal inflammation
- Improve vulvar hygiene
- Avoid tight undergarments
- Daily cleansing with mild soap
- Drying skin with hair dryer
tx for lichen sclerosus
-
Clobetasol propionate 0.05% (Dermovate)
- intralesional injection for refractory areas with thickened, hypertrophic plaques (monthly x 3 months) - Adjunct - oral antihistamines QHS, topical emollient
- 2nd-line - tacrolimus cream, retinoids (topical or oral), phototherapy
- Surgery - for introital narrowing causing dyspareunia or invasive SCC
- Refractory - oral acitretin (retinoid), MTX, laser/UVA therapy
- Surgical undermining of affected skin (Mering procedure)?
tx that are no longer used for lichen sclerosus
- Topical testosterone cream - Less effective than steroids; virilization
- Topical progesterone cream
- Intralesional alcohol injection
- Vulvectomy
Emerging/Investigational therapies for lichen sclerosus
- Silk underpants
- Tretinoin, cyclosporine, adalimumab
- Cryotherapy and/or focused US
- Platelet-rich plasma
prognosis of lichen sclerosus
- Chronic disease - recurs when tx stopped
- Steroids resolve symptoms in most patients - Can reverse skin changes in 50%
- Benign epithelial thickening and hyperkeratosis
- Chronic irritation (perfumed pads, chronic infection)
- 26-75% association w/ atopic disorders (hyperplastic dystrophy, squamous cell hyperplasia)
- Chronic pruritus leads to rubbing and scratching which becomes involuntary over time
Lichen Simplex Chronicus
- Lichenified, scaly, localized plaque
- Initially may present as red papules that later coalesce
- +/- excoriations, hypopigmentation, or hyperpigmentation
- Can develop secondary cellulitis
- Patients usually complain of itching
Lichen Simplex Chronicus
w/u for Lichen Simplex Chronicus
bx
- Required to rule out intraepithelial neoplasia or invasive CA
- Absence of dermal inflammatory infiltrate distinguishes from lichen sclerosus
mgmt for Lichen Simplex Chronicus
- General vulvar hygiene
- Sitz baths and topical lubricants
- Oral antihistamines
- Topical medium-potency steroids (fluocinolone, triamcinolone)
- Intractable cases -
- steroid injection
- Oral antidepressants (TCA such as amitriptyline)
- Mucocutaneous dermatosis
- Skin - sharply marginated flat-topped papules
- Mucous membranes - less sharply marginated white plaques - Rare to find on vulva
- Erosive lesions (more common) or leukoplastic lesions
- May have introital stenosis or vaginal adhesions
dx?
tx?
Lichen Planus
- Initial - topical hydrocortisone foam for vagina (Colifoam)
- Secondary - higher potency topical steroids or topical tacrolimus
- Severe - systemic steroids
- Introital stenosis or adhesions - vaginal dilators or surgical release
Dark vulvar lesions
- Melanosis / Lentigo - darkly pigmented flat lesion; mistaken for melanoma
- Vulvar melanoma - only 1-3% of vulvar cancer - extremely aggressive
- Capillary hemangioma
- Childhood - small strawberry hemangiomas or large cavernous; often become static or regress after 18 months
- Senile - small, dark blue, asx papules
- excision (if repetitive bleeding is an issue), laser, cryotherapy - Other lesions - vaginal neoplasia, Kaposi’s sarcoma, dermatofibroma, SKs, vulvar varicosities
- Varicose veins involving the vulvar anatomy
- May be aggravated during pregnancy
- Rare outside of pregnancy - May signify underlying vascular dz, pelvic tumor - Rupture can cause profuse hemorrhage
- Can have phlebitis or thrombosis of a vulvar varicosity causing pain and tenderness
dx?
tx?
- Vulvar Varicosities
- seldom necessary unless there is a complication; Supportive compression undergarments during pregnancy; If persistent postpartum - sclerosing agent
Vulvar intraepithelial neoplasia (VIN) often associated with multifocal lower genital tract disease
May involve vagina, vulva, cervix, perineum, perianal areas
Preinvasive Vulvar Disease
Preinvasive Vulvar Disease has a strong association with ?
HPV (90% of lesions)
Also associated with HIV
what increases risk of high-grade lesions of preinvasive vulvar disease
smoking
- white, hyperkeratotic papules
- Discrete or diffuse, single or multiple, flat or raised
- vary in color from white to velvety red or black
- pruritus (60%); Often asx!
dx?
w/u?
- Preinvasive Vulvar Disease
- inspection of vulva with colposcopy (+/- green filter) followed by bx of suspicious lesions
tx for preinvasive vulvar disease
Based on bx
- Wide local excision
- Laser ablation
- Topical 5-fluorouracil or imiquimod
- Superficial vulvectomy
f/u for Preinvasive Vulvar Disease
- Thorough pelvic exam with colposcopy every 3-4 months until patient is disease free for 2 years
- After 2 years - pelvic exam every 6 months
- Intraepithelial neoplasia (adenocarcinoma in situ)
- < 1% of all vulvar malignancies
- MC Caucasian women in 60s-70s
- May be extensive but MC confined to epithelial layer - Often extends to perirectal, buttocks, thighs, inguinal, mons
Extramammary Paget’s Disease
- pruritus, vulvar soreness
- Pruritic, slowly spreading velvety-red discoloration - Initial lesion may be confused with other chronic vulvar lesions
- Eventually becomes eczematoid with maceration and development of white plaques
- “Red Velvet Cake” appearance
dx?
w/u?
tx?
- Extramammary Paget’s Disease
- bx
- wide local excision
prognosis of extramammary paget’s disease
High chance for recurrence
- multiple local excisions of recurrent disease after tx of primary disease
- If invasive, (-) node metastases - good prognosis
- If invasive, (+) node metastases - almost always fatal
MCC of Vulvar Cancer
- SCC
- 2nd MC - malignant melanoma (5%)
- MC cause in younger women - HPV
- MC cause in older women - chronic inflammation
vulvar cancer is MC in who?
- MC in poor and elderly
- Uncommon overall - 4% of GYN cancers
- infrequent medical exams
- 10% - DM
- 30-50% - obese, HTN or other CV disease
s/s of vulvar cancer
-
Vulvar pruritus and/or mass - >50% pts
- Bleeding or vulvar pain also possible
- 20% - asx; mass found on exam
- 25% have seen physician and received tx w/o bx done - SCC - 65% in labia, 25% clitoris or perineum
- > ⅓ midline or BL vulva
- Varies from large, exophytic, cauliflower-like lesion to small ulcers to elevated red velvety tumor - Exophytic lesions may become very large, necrotic, and become infected
tx for vulvar cancer
- remove all tumor wherever possible
- Wide radical local excision with inguinal LN excision; (+) LN metastasis - radiation
- Imaging depends on presentation
- Pelvic exenteration - if involvement of anus, rectum, rectovaginal septum, proximal urethra or bladder
- Chemotherapy - depends on cancer extent and type
f/u for vulvar CA
- Every 3 months for 2 years - 80% of recurrences in 1st 2 yrs
- Every 6 months thereafter
Most Vaginal Intraepithelial Neoplasia (VAIN) are where?
in the upper ⅓ of the vagina
s/s of preinvasive vaginal disease
- History similar to cervical neoplasia (CIN)
- May present as abnormal cytology or as a visible lesion
- Condylomatous lesions usually associated with dysplasia
- Lesions usually on vaginal ridges; may be raised, have spicules
w/u for preinvasive vaginal disease
colposcopy and biopsy
- 3-5% acetic acid solution used to identify areas
- May be difficult to do colposcopy of vaginal cuff
tx for preinvasive vaginal disease?
- VAIN I: regresses; do not require tx
- VAIN II/III: surgery / CO2 laser; topical 5-FU
- Hysterectomy if CIS of cervix extends to upper ⅓ of vagina
- hard to resolve w/ only one tx modality/session; close monitoring q 4-6 mo
MC type of cancer to cause vaginal cancer?
SCC - 85%
when is vaginal CA considered primary?
no cervical involvement/minimal involvement
MC form of vaginal malignancy is extension of ?
cervical cancer
RF for vaginal CA
similar to cervical neoplasia
- Smoking
- Hx of HPV infection or lower genital tract neoplasia
- Multiple sexual partners
- In-utero DES - risk of primary vaginal adenocarcinoma
May be exophytic or ulcerative
involves posterior wall of upper ⅓ of vagina
which type of vaginal CA?
SCC
MC primary vaginal cancer in young patients?
adenocarcinoma
MC form is highly aggressive tumor in infancy or early childhood with polypoid, edematous “grape-like” masses at vaginal introitus
May also see in older pts - upper anterior vaginal wall
which type of vaginal CA?
sarcoma
Rare - MC arise from anterior surface and lower ½ of vagina
which type of vaginal CA?
melanoma
s/s vaginal CA
- MC asx and found on exam
- MC sx - postmenopausal and/or postcoital bleeding
- vaginal discharge, vaginal mass, urinary sx possible
- Pain or leg edema if advanced tumor present
w/u, mgmt, prognosis for vaginal CA?
- Dx - Colposcopy and bx
- hysterectomy, vaginectomy, lymphadenectomy
- Localized - pelvic exenteration
- 5-yr survival - 77% stage I, 45% stage II, 31% stage III, 18% stage IV; Melanomas - highly malignant, do not respond well to therapy