Uniwersytet Mikoaja Kopernika w Toruniu Collegium Medicum w

Uniwersytet Mikołaja Kopernika w Toruniu Collegium Medicum w Bydgoszczy Infections of the Urinary & Reproductive Systems dr hab. n. med. Marek Szymański KATEDRA i KLINIKA POŁOŻNICTWA, CHORÓB KOBIECYCH i GINEKOLOGII ONKOLOGICZNEJ

Structures of Reproductive System • Females – Urinary and reproductive systems are distinct

23. 2 Normal Biota of the Urinary Tract • Outer region of the urethra harbors some normal biota • Nonhemolytic streptococci, staphylocci, corynebacteria, and some lactobacilli • Normal Biota of the Male Genital Tract – Same as described for urethra, since the urethra is the terminal “tube” • Normal Biota of the Female Genital Tract – The vagina harbors a normal population of microbes • Lactobacillusi species • Candida albicans at low levels

Cystitis • Cystitis: sudden onset of symptoms – Pain in the pubic area – Frequent urges to urinate even when the bladder is empty – Burning pain accompanying urination (dysuria) – Cloudy urine – Orange tinge to the urine (hematuria) – Fever and nausea – Back pain indicates kidneys may also be involved

23. 4 Reproductive Tract Diseases Caused by Microorganisms • Many are transmitted through sexual contact, but not all are • Three broad categories of sexually transmitted diseases – Discharge diseases – Ulcer diseases – Wart diseases

Vaginitis and Vaginosis • • Inflammation of the vagina Vaginal itching to some degree Burning and sometimes a discharge occurs Symptoms depend on the etiologic agent

Candida albicans • Normal biota living in low numbers • If grows rapidly and causes a yeast infection, white vaginal discharge occurs

Gardnerella species • Infection called vaginosis rather than vaginitis because inflammation in the vagina does not occur • Vaginal discharge with a very fishy odor, especially fater sex • Itching is common

Trichomonas vaginalis • Asymptomatic infections in approximately 50% of females and males • Some people experience long-term negative effects

Discharge Diseases with Major Manifestation in the Genitourinary Tract • Increase in fluid discharge in male and female reproductive tracts • Includes trichomoniasis, HIV, gonorrhea, and Chlamydia infection

Gonorrhea • N. gonorrhoeae is the etiologic agent- also known as the gonococcus • Symptoms in the male – Urethritis, painful urination and a yellowish discharge – Can occasionally spread from the urethra to the prostate gland epididymis – Scar tissue in the spermatic ducts during healing can render a man infertile (rare)

Symptoms in the Female • Likely that both urinary and genital tracts will be infected • Mucopurulent or bloody vaginal discharge • Painful urination if urethra is affected • Major complications occur when the infection ascends from the vagina and cervix to higher reproductive structures – Salpingitis – Pelvic inflammatory disease

Chlamydia • Most common reportable infectious disease in the U. S. • Majority of cases are asymptomatic • Symptoms in males – Inflammation of the urethra – Symptoms mimicking gonorrhea – Untreated infections may lead to epididymitis • Symptoms in females – – Cervicitis Discharge Salpingitis May lead to PID

Genital Ulcer Diseases • Three common infectious conditions resulting in lesions on a person’s genitals • Syphilis, chancroid, and genital herpes • Having one of these diseases increases the chances of infection with HIV because of the open lesions

Syphilis • Three distinct clinical stages: primary, secondary, and tertiary • Latent periods of varying duration also occur • Transmissible during the primary and secondary stages, and the early latency period between secondary and tertiary • Largely nontransmissible during latent and tertiary stages

Primary Syphilis • Appearance of a hard chancre at the site of entry of the pathogen (after an incubation period of 9 days to 3 months) • Lymph nodes draining the affected region become enlarged and firm • Chancre filled with spirochetes • Chancre heals spontaneously in 3 to 6 weeks but by then the spirochete has moved into the circulation

Secondary Syphilis • 3 weeks to 6 months after the chancre heals • Many systems have been invaded • Fever, headache, sore throat, followed by lymphadenopathy and a red or brown rash that breaks out on all skin surfaces • Hair often falls out • Lesions contain viable spirochetes and disappear spontaneously in a few weeks • Major complications occur in bones, hair follicles, joints, liver, eyes, and brain

Latency and Tertiary Syphilis • Highly varied latent period, can last for 20 years or longer • Tertiary syphilis is rare because of the use of antibiotics • Major complications occur by this stage • Cardiovascular syphilis- weakens the arteries in the aortic wall • Gummas develop in tissues such as the liver, skin, bone, and cartilage

Congenital Syphilis • From a pregnant woman’s circulation into the placenta and fetal tissues • Inhibits fetal growth • Disrupts critical periods of development

Chancroid • No systemwide effects • Infection usually begins as a soft papule at the point of contact • Develops into a soft chancre (painful in men, but may be unnoticed in women) • Inguinal lymph nodes can become swollen and tender

Wart Diseases • Human papillomavirus (HPV) – Causative agents of genital warts – An individual can be infected with HPV without having warts, however • Molluscum Contagiosum – Unclassified virus in the pox family – Can take the form of skin lesions – Wartlike growths on the mucous membranes or skin of the genital area

Group B Streptococcus “Colonization”- Neonatal Disease • 10% to 40% of women in the U. S. are colonized asymptomatically by group B Streptococcus • When these women become pregnant, about half of their infants become colonized by the bacterium during passage through the birth canal • Small percentage of infected infants experience life-threatening bloodstream infections, meningitis, or pneumonia

• Normally urine and urinary tract above bladder are sterile – Urethra contains normal resident flora • Lactobacillus, Staphylococcus, Corynebacterium and Streptococcus • Normal flora varies in female genital tract – Depends on hormones • Lactobacillus

Urinary Tract Infections May include any or all of the organs • • Urethritis – inflammation of urethra Cystits – inflammation of the urinary bladder Ureteritis –inflammation of the ureters Pyelonephritis – inflammation of the kidneys

• Causative agents: – Usually intestinal flora • E. coli – most common • Proteus and Klebsiella • Psudomonas – Typically nosocomial – Non-enteric bacteria – Non-invasive and opportunistic

• Signs and Symptoms – Dysuria – frequent, painful urination – cloudy urine with foul odor; may have pale red color 9 due to blood in urine) – Tenderness of pelvic area – May have slight fever

• Prevention – – Adequate fluid intake (2 -4 liters daily) Cranberry juice may help prevent attachment of bacteria Void urine immediately after sex Proper personal hygiene • Treatment – Sulfonamides or cephalosporins

Bacterial Vaginosis • Causative agent: – May be caused by multiple anaerobic bacteria – Gardnerella vaginalis • Change in vaginal flora – p. H increases and allows overgrowth of pathogen

• Signs & Symptoms – Thin, grayish-white vaginal discharge • Can be slightly bubbly – Pungent ‘fishy’ odor – Some itching and irritation – 50% asymptomatic

• Prevention – No proven prevention – Associated with multiple sexual partners, vaginal douching, anti-microbial therapy • Treatment – Metronidazole – Vinegar douche – Reestablishment of lactobacilli

Vaginal Candidiasis • Causative agent – Candida albicans • Normal flora for up to 80% women • Opportunistic pathogen • Dimorphic of

• Signs & Symptoms – White mucoid colonies on vaginal mucus membranes and labia – Severe itching and burning – White curd-like discharge

Vaginal Cancer

Vaginal Cancer • Rare tumor representing only 1 -2% of all gynecologic malignancies • 80 -90% are metastatic • Mean age of patients with primary vaginal cancer is 60 -65 years • Most primary tumors are squamous cell in origin • HPV DNA identified in VAIN

Vaginal Cancer precursors • • VAIN – avg age of VAIN 3 is 53 Ratio of VAIN to CIN is 1: 23 5% progress to Vaginal Ca Hallmark of VAIN – cytologic atypia-Pleomorphisim, irreg nuclear contours and chromatin clumping – Abnormal maturation – nuclear enlargement

Vaginal Cancer precursors • VAIN 3 – usually occurs in upper third of vagina and is multifocal and diffuse in half the cases. – 1/3 of patients have a hx/o CIN – CIN coexists w/ VAIN in 10 -20% of pts – Colposcopic findings are similar to those of CIN (aceto white epithelium with punctations and mosaic patterns)

Vaginal Cancer precursors VAIN 1 Proliferation of basal layer Koilocytotic atypia Enlarged pleomorphic nuclei vacuolated cytoplasm

Vaginal Cancer precursors VAIN 2 Proliferation of basal layer, crowding and loss of polarity Koilocytotic atypia Enlarged pleomorphic nuclei vacuolated cytoplasm

Vaginal Cancer precursors VAIN 3 Increased proliferation of abnormal basal and parabasal cells replacing full thickness of epithelium

Vaginal Cancer precursors • Treatment Options for VAIN – Excisional Bx for small lesions – Partial Vaginectomy – Laser Vaporization – Intravaginal 5 FU cream

Vaginal Cancer: Predisposing Factors • • Low socioeconomic status History of genital warts Vaginal discharge or irritation Previously abnormal Pap smear Early hysterectomy Previous pelvic radiation (? ) In-utero exposure to DES

Anatomy of the Vagina • Muscular dilatable tube averaging 7. 5 cm in length • Vaginal wall composed of three layers: mucosa, muscularis, adventitia. • Epithelium normally contains no glands and changes little during reproductive cycle • Lymphatic drainage of upper vagina via pelvic nodes while lower vagina drains via femoral and inguinal nodes.

Natural History and Patterns of Spread • Lesions usually found in the upper vagina on the posterior wall • Vaginal primary tumors may spread along mucosa to cervix or vulva (changes diagnosis) • Direct extension to bladder, parametria, paracolpos, rectum, cardinal ligaments, uterosacral ligaments

Gross and microscopic Findings • 50% of Vag Ca ulcerative • 30% are exophytic • 20%are annular and constricting

Natural History and Patterns of Spread • Any of the nodal groups may be involved regardless of the location of the tumor • Inguinal nodes most often involved if lesion is in the lower 1/3 of the vagina • Clinically apparent inguinal node mets seen in 5 -20% of patients • Incidence of pelvic nodes varies with stage and location of the tumor

Lymphatic Drainage of Vagina

Clinical Presentation • Abnormal vaginal bleeding – 50 -75% of patients with primary tumors • Dysuria • Pain

Diagnostic Work-up • Complete history and physical • Speculum examination and palpation of the vagina • Bimanual pelvic and rectovaginal examination • Pap smear, colposcopy, directed biopsies

Diagnostic Work-up • • Cystoscopy Proctosigmoidoscopy Chest X-ray IVP Barium enema Computed Tomography MRI (84% PPV, 97% NPV)

Staging • Stage I - Lesions confined to the mucosa • Stage II- Subvaginal tissue involved but no extension to pelvic sidewall – IIA: Subvaginal infiltration only – IIB: Parametrial extension • Stage III- Pelvic sidewall extension • Stage IV- Bladder or rectal extension and/or direct extension outside of true pelvis

Staging

Natural History and Patterns of Failure • Stage I – 10 -20% pelvic recurrence, 10 -20% distant • Stage II – 35% pelvic recurrence, 22% distant • Stage III – 25 -37% pelvic recurrence, 23% distant • Stage IV – 58% pelvic recurrence, 30% distant

Pathology • Squamous Cell CA represents 80 -90% of primary tumors • Vaginal SCCA may be considered primary if there is neither cervical or vulvar CA at diagnosis or for 10 years prior • No correlation between grade and survival

Verrucous Carcinoma • Variant of well-differentiated SCCA that rarely occurs in the vagina • Relatively large, well-circumscribed, soft cauliflower-like mass • Cytologic features of malignancy are lacking • May recur locally after surgery but rarely, if ever, metastasizes

Pathology • Melanoma – 2 nd most common vaginal cancer – Most frequently found in the lower third – Cells may be spindle shaped, epithelioid, or small lymphocyte-like, pigmented or nonpigmented – Junctional activity helps exclude the possibility of a metastasis – Depth of invasion best predictor of survival

Pathology • • • Smooth muscle tumors Small Cell Carcinoma Endodermal Sinus Tumor Rhabdomyosarcoma (Sarcoma Boytrioides) Malignant lymphoma Clear Cell Adenocarcinoma

Management • Radiation therapy is the preferred treatment for most carcinomas of the vagina • Surgical therapy – Irradiation failures – Non-epithelial tumors – Stage I Clear cell adenocarcinomas in young women

Management • Surgery – Stage I tumors of the middle or upper third of vagina treated with radical hysterovaginectomy and PLND – Stage I tumors of the lower third of vagina which may encroach on the vulva treated with radical vulvovaginectomy and bilat. groin node dissection – Pelvic exenteration possible for more invasive lesions

Management • Stage I – Usually managed with RT – Superficial lesions (<1 cm) may be treated with vaginal cylinder covering the entire vagina (6 -7 Gy mucosal dose + 2 -3 Gy dose to tumor) – Thicker lesions may be treated with vaginal cylinder + single plane implant – EBRT reserved for aggressive lesions (infiltrating or poorly differentiated)

Vaginal Cylinder + Single Plane Implant

Management • Stage I – Radical hysterectomy, partial vaginectomy, PLND may be used for lesions of the posterior and lateral vaginal fornices • Stage IIA – WPRT (2000 c. Gy) + parametrial boost for 4500 c. Gy-5, 000 c. Gy total

Management • Stage IIA – WPRT (2000 c. Gy) + parametrial boost for 4500 c. Gy-5, 000 c. Gy total – WPRT + combination of intracavitary and interstitial implants for 5000 to 6000 c. Gy total • Stage IIB, III, IVA – WPRT (4000 c. Gy) + parametrial boost (2500 c. Gy)

Management • Small Cell Carcinoma – Reasonable local control may be obtained with surgery or irradiation followed by systemic chemo – Cyclophosphamide, Adriamycin, Vincristine (CAV) X 12 cycles (some prior to initiation of RT) – Doses of RT similar to SCCA

Management • Rhabdomyosarcoma – Generally treated with a combination of surgery, RT, and chemotherapy – Vincristine, Dactinomycin, Cyclophosphamide (VAC) X 1 -2 years effective adjuvant treatment for stage 1 dz – Local excision + interstitial/intracavitary RT + systemic chemo has replaced radical pelvic surgery as therapy of choice

Sarcoma Botryoides

Sarcoma Botryoides Strap cell

Management • Malignant Lymphoma – Vaginectomy and radical hysterectomy or pelvic exenteration has been used for localized vaginal tumors – Satisfactory results with pelvic RT (tele and brachytherapy) + systemic chemo – Cyclophosphamide, adriamycin, vincristine, prednisone (CHOP) X 6 cycles most often used

Clear Cell Adenocarcinoma and DES Exposure • Incidence is between 0. 14 to 1. 4/1000 women exposed to DES • Median age at diagnosis 19 years • Lesions found mainly in the upper 1/3 of the anterior vaginal wall • 90% of patients with early stage disease (I and II) at diagnosis

Management • Clear Cell Adenocarcinoma – Surgery for stage I lesions has advantage of ovarian preservation and better vaginal function following skin graft – Vaginectomy, radical hysterectomy PLND, paraaortic LNBx (frozen section of distal margin) – Intracavitary or transvaginal radiation can be used for small lesions – More extensive lesions: EBRT

Clear cell adenocarcinoma

FAVORABLE FACTORS IN SURVIVAL OF PATIENTS WITH CLEAR CELL ADENOCARCINOMA • • Low stage Older age Tubulocystic Pattern Small tumor diameter Reduced depth of invasion Negative nodal mets Positive ho/o DES

Radiation Therapy Techniques • EBRT delivered through AP: PA portals or using 4 field “box technique” • 15 cm X 15 cm or 15 cm X 18 cm portals usually adequate • Inguinal nodes should be electively covered (4500 -5000 c. Gy) for tumors of the lower 1/3 of vagina • Additional 1500 c. Gy (4 -5 cm depth) delivered for palpable inguinal nodes

Radiation Therapy Techniques Portal for pelvic RT and elective groin coverage Portal for groin coverage with palpable inguinal

Radiation Therapy Techniques • Intracavitary therapy utilizes vaginal cylinders (Burnett, Bleodorn, Delclos, or MIRALVA applicators) • Upper 1/3 lesions can be treated with tandem and ovoids • Interstitial therapy with 137 Cs, 226 Ra, or 192 Ir needles have been used • High dose rate brachytherapy (>1200 c. Gy/hour) also used

Summary • Superficial stage I lesions may be treated with RT or radical hysterovaginectomy • Stage IIA-IVA treated with WPRT and intracavitary RT • Role of chemotherapy in advanced SCCA presently unknown • Pelvic failures and distant metastases occur in 1/2 of pts with advanced dz

5 Year Survival

• Epidemiology – Can be spread person to person • Mother to newborn • Rarely sexually transmitted – Antibacterial medications increases risk – Other risk factors include birth control, hormone therapy, AIDS, diabetes, invasive hospital procedures and cancers – Changes in vaginal flora and p. H

• Prevention – minimizing risk factors • Treatment – Intra-vaginal treatment with nystatin and clotrimazole • Cream azoles may weaken latex condoms – Oral fluconazole

Vulvar cancer is a rare disease in which malignant (cancer) cells form in the tissues of the vulva. Vulvar cancer forms in the external genitalia. The vulva includes:

Vulvar Carcinoma • Majority are of epidermal origin • Age: 60 -75 years. • 90 -95% of Vulval cancer are of Squamous origin. • Melanoma of the vulva is second most common type (4 -9%).

Aetiology • Vulval dermatomes (lichen sclerosis): a common Vulval inflammatory dermatosis (HPV 16 & 33) affecting older women with ↑chance of malignant progression. • Vulval Intraepithelial Neoplasia (VIN) : 80% will lead to invasive cancer at 10 years if not treated & 7 -8% if treated. VIN 3 is a pre-invasive condition. • Human papilloma virus (HPV): associated with 30% of Vulval cancer & with 80 -90% of Vulval cancer in women less than 50 years of age. • Smoking: co-factor of HPV & VIN development. v VIN affects mainly L. minora & perineum.

Classification of VIN • VIN I - mild dysplasia with hyperplastic vulvar dystrophy with mild atypia • VIN II - Moderate dysplasia, hyperplastic vulvar dystrophy with moderate atypia • VIN III - Severe dysplasia; hyperplastic vulvar dystrophy with severe atypia (it replaces the term carcinoma in situ, Bowen’s disease). Carcinoma in situ

VIN Dx & Rx • Dx: colposce + biopsies • Rx: - low grade VIN: observation. - VIN 3: local excision or laser vaporization - Topical immunomodulator: imiquimod

Vulval Carcinoma Clinical Staging (F. I. G. O. ): • Stage I : 1 a: confined to vulva with <1 mm invasion. 1 b: confined to vulva with a diameter < 2 cm & no inguinal lymph nodes affection. • Stage II : limited to vulva with diameter > 2 cm) & no inguinal lymph nodes affection. • Stage III : adjacent spread to the lower urethra and/or vagina and/or anus and/or unilateral lymph nodes affection. • Stage IV : A. Bilateral inguinal nodes metastases, involvement of mucosa of rectum, urinary bladder, upper urethra or pelvic bones. B. Distant metastasis.

Treatment of Vulval Carcinoma • Stage I & II : Radical local excision with 1 cm disease–free margin. • Stage III & IV : - According to the general health. - Chemotherapy & radiotherapy to shrink the tumour to permit surgery which may preserve the urethral & anal sphincter function. - radical vulvectomy + inguinal L. nodes dissection. - reconstructive surgery with skin grafts or myocutaneous flaps for healing.

Vaginal Intraepithelial Neoplasia (Va. IN) • Extremely uncommon (150 times < CIN). • 70% associated with CIN (extension of the transformation zone into the vaginal fornices). • Predisposing factors: similar to those of CIN (HPV), but the age of Va. IN is higher than CIN, diethylstilboesterol in utero (metaplastic transformation into the vagina), previous history of CIN), radiotherapy of CA cervix. • Va. IN is graded 1 -3 but is less invasive than CIN: - Va. IN 1: mild dysplasia. - Va. IN 2: moderate dysplasia. - Va. IN 3: severe dysplasia. • Dx: V. smear, colposcopy, biopsy (even after hysterectomy). • Rx: low grade: observation. high grade: excision, 5 fluoroyracil, diathermy. Alternatively, Radiotherapy.

Vaginal Carcinoma • Incidence: 1 -2% of all gyn. Cancer. • Classification: 1. primary: squamous (common, 85%), adenocarcinoma (17 -21 years of age, metastasis to L. Ns), clear cell adenocarcinoma (DES). 2. secondary: metastasis from the cervix, endometrium, …. . others. • 50% in the upper 3 rd, 30% in lower 3 rd & 19% in middle 3 rd. • Posterior V. lesions more common than anterior & the anterior are more common than lateral lesions. • Spread: direct & lymphatic.

Vaginal Carcinoma Clinical Staging (F. I. G. O. ): • Stage I: tumour confined to vagina. • Stage II : tumour invades paravaginal tissue but not to pelvic sidewall. • Stage III : tumour extends to pelvic sidewall. • Stage IV : a) tumour invades mucosa of bladder or rectum and/or beyond the true pelvis. b) Distant metastasis.

TREATMENT • Stage 1: 1. Tumour < 0. 5 cm deep: a. surgery: local excision or total vaginectomy with reconstruction. b. radiotherapy. 2. Tumour > 0. 5 cm deep: (a) wide vaginectomy, pelvic lymphadenectomy + reconstruction of vagina. (b) radiotherapy • stage 2: (a) radical vaginectomy, lymphadenectomy (b) radiotherapy • Stage 3: radiotherapy.

Risk factors • Having vulvar intraepithelial neoplasia (VIN). • Having human papillomavirus (HPV) infection. • Having a history of genital warts. • Having many sexual partners. • Having first sexual intercourse at a young age. • Having a history of abnormal Pap tests (Pap smears).