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BENIGN &MALIGNANT DISEASE OF CERVIX

Benign and malignant BE diseases of cervix

PREINVASIVE DISEASE AND SCREENING

Cervical Anatomy

Smooth and pink, with clear mucoid secretion and is composed of columnar epithelium,which lines the endocervical canal,and squamous epithelium,which covers the cervix.

The point at which they meet is called squamocolumnar junction(SCJ)

Cervical intraepithelial lesion

The concept of cervical intraepethelial lesion(CIN) was introduced in 1968

Term CIN is equivalent to the term dysplasia,which means abnormal maturation,cellular disorganization,nuclear abnormalities and increased mitotic activity.

The extent mitotic activity,immature cellular proliferation and nuclear atypicality identify the degree of neoplasia.

If the mitosis are present only in 1/3 of epithelium,the lesion is designed as CINI and involvement of the middle and upper third is diagnosed as CINII and CINIII.

Most CIN I and some CINII regress spantaneously if untreated,however may progress to invasive carcinoma.

Metaplasia without mitotic activity should not be called dysplasia,and it does not progress to invasive cancer.

Morphologic changes of cervical cancer

SIL and CIN

Squamocolumnar Junction

The SCJ is a dynamic point and changes in response to puberty,pregnancy,menopause

At menarche,the production of estrogen causes the vaginal epithelium to fill with glycogen,Lactobacilli act on the glycogen to lower the PH stimulating the subclumnar reserve cells to undergo metaplasia.

Metaplasia advances from the original SCJ inward,toward external OS

The T.Z extends from the original SCJ to the physiologically active SCJ.

In most cases,CIN is originate as a single focus in the transfomation zone at the advancing SCJ. Once the metaplastic epithelium matures and forms glycogen, is called healed T.Z and relatively resistant to oncogenic stimuli. The only way to determine original SCJ are nabothian cysts or

cervical cleft opening CIN is most likely to begin during menarch or after

pregnancy and after menopause there is a lower risk of C.I.N The ant. Lip of cervix is twice post. lip. CIN I-II may regress to normal as high as %75 at five years for adults and up to %91 at 3 years in adolescents.

Types of Prevention

•Primary prevention: Keeps disease from occurring at all by removing its cause. administering folic acid to prevent neural tube defects, giving immunizations and counseling patients to adopt healthy lifestyles (such as helping patients to stop smoking, to eat foods low in saturated fats and cholesterol, to exercise appropriately, and safe sexual practices)• Secondary prevention: detects early disease when it is asymptomatic and when treatment can stop it from progressing such as Pap smears, mammograms, and fecal occult blood tests

•Tertiary prevention: refers to activities that reduce complications such as use of beta-blocking drugs to decrease the risk of death in myocardial infarction,or good control of blood glucose, regular ophthalmologic examinations and monitoring for proteinuria in diabetics.

Cervical cancer is a preventable disease

17

Primary prevention:

- Avoidance of tobacco- Safe sexual practice,avoid exposure to HPV- Use barrier contraception- High folate, beta carotene, Vit C & E diet

-ImmunizationSecondary prevention: -Screening of asymptomatic population for

premalignant conditions or early stage disease before they progress to cancer

Criteria for a good screen test

•High sensitivity:The proportion of all those with disease that the test correctly identifies as positive.•High specificity:The proportion of all those without disease (normal) that the test correctly identifies as negative.•High positive predictive value• Simplicity •Low cost• Safety• Available

THE PAPANICOLAOU SMEAR

• George N. Papanicolaou, developed a microscopic technique that involved examination of vaginal debris to study the estrous cycle of guinea pigs.• The papanicolaue smear screening test for cervical cancer was introduced in the united states in 1941

...Pap Smear

- False negative : 49% - Sensitivity for CIN detection : 51 % - Sensitivity after 3 test : 87 %This is NOT a diagnostic testDetect premalignant, malignant processes of

cervix. Sample cervical cells from T.Z Sent to cytology for review of cells. Classified according to Bethesda System.

pap test

False negative error (%49) 1- sampling error : small lesion with no

exfoliated cell, device did not pick up cell, cell did not transfer from device to slide

2- preparation error : poor fixation, bloody,thick,mucus

3- interpretation error : screener fault

sample collection

Avoiding vaginal cream ,coitus,tampon for 48 h0urs No Lubricant gelClear cervical mocus and dischargeEndocervical with swab or brushExocervical with spatulaImmidiately smearedFixation promptlyLabel smear -Conventional smear -Liquid base smear

23

Equipment

Conventional Kit Thin PrepThin Prep

CONVENTIONAL PAP SMEAR

%30- %80 sensivity and %86-%100 specifityThe conventional pap smear consist of

cells,sampled from cervix using a brush or spatula,are placed on a slide and fixed with a chemical fixative in office.

• In 1990 a new technology(LBC) replaced for sreening cervical cancer•demonstrated 65% increase in detection of cancerous lesions with LBC.

• Pre-cancerous lesions can be detected 8 to10 years earlier than old PAP Smear

• Improved sensivity without loss of specefity 1- All Cells collected (%80-%90) are preserved for

analysis. 2-Remove the blood and mucus,so clearer field of vision.

3-A single specimen for HPV 4-Reflex HPV testing of the specimen may be used to test for HPV for evaluation ASC-US in cytology 5-The slides can be read by the cytopathologist more quickly 6-Better detection glandular lesion,ASC-US,LSIL than conventional PAP 7-fewer unsatisfactory specimens 8-specimen adequacy is to be improved .

LIQUID BASE CYTOLOGY

LIQUID BASAE PAP SMEAR

Liquid base cytology consists of cells that are sampled similarly but suspended in a liquid transport medium and then cells filtered in the laboratory and plated as thin layers on slides.

Conventional Pap Smear Liquid base pap smear

Conventional Pap ThinPrep Pap Test

f

Cervical screening cytology

Guideline American society cancer

ACOG

Initial screening Age 21 or 3 years after vaginal sex

Age 21 or 3 years after vaginal sex

Interval 1/year for con.papevery 2 y. for L.B.PEvery 2-3y. after 30y with 3 normal p

Every 1 y. for L.B.P or conventional papEvery 2-3 y.after 3o y. with 3 normal

Discontinue 70 y. if 3 normal pap in 10 years

No upper limit of age

Classification of Pap smear results

Papaniculau classification:Class I-VDysplasia classification(1963)CINI,II,III(1968)Bethesda classification Squamous cell ASC : atypical squamus cell ; ASC -US , ASC -H LSIL : low grade squamus intraepithelial lesion(HPV ,CIN I) HSIL: high grade squamus intraepithelial lesion(CIN II/III/Insitu) Invasive scc Glandular Cell

Atypical Glandular cells (AG) Undetermined Significance (AG-US) or NOS Favors Neoplasm

Adenocarinoma In Situ (AIS) Adenocarcinoma

Comparison of cervical cytology classification systems

Bethesda CIN Dysplasia Papanicol. NL

NL NL I

Infection , reactive,repair

Inflammatory atypia

Inflammatory atypia

II

ASC-US Squamus+HPV atypia

Squamus+HPV atypia

IIR

LSIL CIN I Mild dysplasia

III

HSIL

CIN II CIN III CIN III

Moderate dyspl. Severe dyspl.Carcinoma insitu

III IV IV

SCC SCC SCC V

•The most common cervical cytology abnormality is ASC(ASC-H or ASC-US) and is seen in %3-%4 of smears•ASC :In Bethesda 2001 cellular atypia cannot fill criteria for dysplasia•ASC-H need to more rapid evaluation of potential CIN II or CINIII•LSIL %2 and HSIL %0.5-%1•Present of AGC or AIS on cervical cytology is a significant marker for neoplasia of endometrium as well as cervix•A smear with AGC is assosiated with a premalignant or malignant lesion of endocervix or endomertrium in %10-%40 cases.•All women with AGC or AIS should be referred for colposcopy with directed cervical biopsy and sampling endocervical canal,and >35 years should have an endometrial biopsy.

Bethesda system 2001

Specimen type (conventional pap or liquid base) Specimen adequacy:-Satisfactory(notation presence or absence of endocervical/T.Z)-Unsatisfactory for evaluation-- Lable--Squamous cellularity--Obscuring factors(inflammation,blood)--Clinical information--poor preservation General categorization-Negative for intraepithelial lesion or malignancy-Epithelial cell abnormality Atypical squamous cell (ASC,LSIL,HSIL)

…BETHESDA

Glandular cells:Atypical-Endocervical cells(NOS)-Endometrial cells(NOS)Atypical-Endocervical cells favor of neoplasm-Glandular cells favor of neoplasmEndocervical adenocarcinoma insituAdenocarcinoma-Endocervical-Endometrial

.…BETHESDA

Organisms-Trichomonas vaginalis-Fungal organisms-Shift flora suggestive Bacterial vaginosis-Bacteria morphologically consistent with Actinomyces-Cellular change consistent with herpes simplex virus Other non neoplastic finding Reactive cellular changes associated with -Inflamation(include typical repair) -Radiation -I.U.D -Glandular cells status post hysterectomy -Atrophy Other-Endometrial cells in women 40 years of age(endometrial

pathology like polyp,hyperplasia or cancer)

CHOOSING CONVENTIONAL SMEARS VERSUS LIQUID-BASED CYTOLOGY

depends upon a variety of factors, including ability to perform concurrent testing, and cost.

These factors vary by health care setting, thus, no general recommendation can be made.

Liquid-based systems provide greater specimen adequacy, particularly for women with cervical bleeding or inflammation, which may obscure interpretation of a conventional Pap smear.

Liquid-based and conventional smears appear to perform equally well for detection of HSIL

Liquid-based methods perform better for detection of glandular abnormalities, ASCUS, and LSIL.

The ability to obtain reflex HPV testing, when needed, from a single liquid-based specimen is another advantage

Satisfactory smear

Minimum of 5000 well-visualized squamous cells on a liquid-based preparation

8000 squamous cells on a conventional smear

Notation regarding the presence or absence of endocervical or T.Z

Properly labeledPatient history

Unsatisfactory smears

Unsatisfactory cervical cytology tests should always be repeated in two to four months

If the cells are obscured by inflammation, an attempt should be made to clear the inflammatory process (eg, treat cervicitis or vaginitis) prior to repeating the cytology tests.

If the test is repeatedly unsatisfactory, then additional clinical evaluation with colposcopy and/or biopsies is appropriate because women with unsatisfactory cervical cytology tests are more likely to have intraepithelial lesions or cancer on follow-up than women with satisfactory tests

Endocervical cells not present

The presence of metaplastic and endocervical cells indicates adequate sampling of the transformation zone of the cervix, the area at greatest risk for neoplasia.

The follow-up of patients whose cervical cytology tests lack these cells is controversial.

Repeat 6-12 month later

Management of abnormal Pap smear

Negative Routine smearASC-US -Colposcopy -Repeat cytology at 6-12 months -Reflex HR HPVASC-H -Colposcopy LSIL -Colposcopy -in adolescents ASC-US,LSIL repeat cytology in 12-24

months if persistant or HSIL colposcopyHSIL -ColposcopyAGC-NOS-Colposcopy +_EMB and HPV HRAGC favor neoplasm-Colposcopy +_EMBCarcinomaBiopsy +Colposcopy if no gross lesion

Management of CIN

CIN I proven with biopsy %15 risk of CIN II/III in 2 years,so expectant management(cytology month 6 and 12 or HPV rest at 12 months) if negative annual screen and HR HPV positive or ASC or greater colposcopy

CIN II/III with few exception need treatment with ablatin or excisional techniques

Exception in adolscents (%60 regression CIN II at 1 year) so cytology at 6 month interval up to 2 years with satisfactory colposcopy

o AIS cold knife conization and ECC(%20 residua with negative margin),in adolsecents conservative follow up with Pap,colposc0py,ECC,every 6 months

Other screening modalities

Visual inspection with colposcopyHPV testing HPV testing, in combination with

Pap smear testing, in women over age 30 may have better sensitivity than in younger women.

Negative HPV DNA and cytology >30 years N.P.V >%99,so until 3 years need no evaluation

HUMAN PAPILLOMAVIRUS TEST

99.7% of cervical cancer are positive for HPVNecessary but insufficient precursor,Host factorsGenital warts: HPV 6 and HPV 11Presence of high risks

HPV(16,18,31,33,35,39,45,51,52,56,58,59,68,69,82) is assosiated with an increased risk of cervical cancer

Presence of HPV appears to be necessary for development of both squamous and adenocarcinoma

HPV 16 account for %60 and HPV 18 for an additional %10-%20 of cases.(%67 16 &18 invasive cancer)

HPV 16 is seen in %16 LSIL and %14 of normal smears.

HPV 18 is seen in %23 invasive cancer,%5 CINII,III,%5 CINI and%2 normal smears.

Dysplasia and HPV

HPV related genital disease ranges from genital wart(LR) to cytologic abnormalities and cevical,vulvar,anal and vaginal cancer(HR HPV)

Gardasil Vaccine

Decrease preinvasive and cervical cancerAgainst HPV 6, 11, 16, 183 Doses: 0, 2, 6 monthsAges: 9-26 y/oEfficacy >%85 in persistant infection and

%93 cytologic abnormality Reduced vulvar and vaginal intraepithelial

neoplasia and anogenital disease Bivalent HPV 16/18 virus like particle

vaccine (Cervarix)

COLPOSCOPY

Colposcopy is initial step in evaluation abnormal pap smear, diagnostic procedure in which a colposcope(disecting microscope with various magnification lenses)is used to provide a magnified view of cervix,vagina and vulva

Target biopsy of areas with Abnormal morphology

Adequate & conclusive evaluation require: complete visualization of T - zone

INDICATION OF COLPOSCOPY

Specefic abnormal cytology--persistant ASC-US or ASC-US with high risk

HPVASC-HAGCLSILHSILAssesment of women exposed to DESEvaluation of palpably or visually abnormal

cervix,vagina or vulvaPost coital bleeding

COLPOSCOPIC FINDING

Leukoplakia(CIN,Carcinoma,HPV,Radiation)Acetowhite epitheliumIodine negative or positive schiller testAtypical vascular patternPunctationMussaism

Summary Understand the current recommendations for PAP smear

screening and follow-up Start within 3 years of onset of sexual activity or

age 21 Screening at least every 3 years after 30 years with

3 normal smear Stop at age 70 due to recommendation of American

cancer society Stop after hysterectomy for benign disease Continue screening after hysterctomy for malignant

lesion

Recognize the role of HPV in cervical cancer(%99) and determine patients who are candidates for Vaccination Approved for age 9-26

Benign conditions

Benign conditions

InfectionsEndocervical polypsNobothian cystColumnar epithelium eversion or

ectropionCervical leiomyoma( fibroma )Cervical endometriosis

Cervical polyp

Endocervical pedunculated

lesion , friable,several mm to several cm

Etiology : chronic papillary endocervicitis

D.Dx : - cervical cancer - retained tissue - prolapsing leiomyoma - endomtrial polypSymptoms : AUB ,

leukorrhea ,contact bleeding Treatment : is grasped &

twisted , send for pathology

POLYP

اکتروپیون مختلف مراحل در سرویکس حجم

و بلوغ زمان در خصوص به زندگیترشح افزایش که بارداری اولین

یابد می دارد،افزایش وجود استروژنتلیوم اپی اورزیون به منجر که

موقعیت به اندوسرویکال ای استوانه . شود می اکتوسرویکس

و اندوسرویکس مخاط اورزیونبه ای استوانه تلیوم اپی شدن نمایان

. نامند می اکتروپیون را واژن می بالینی عالئم بندرت اکتروپیون

کشف. بالینی معاینه در ومعموال دهدیا لکوره به منجر شود،گاهی می. شود می تماس از بعد خونریزی

اکتروپیون...

گرانولیشن قرمزمشابه نمای یافته اورزیون تلیوم اپی. شود پوشیده زرد ترشح با است ممکن و دارد

سنین در این adolesenseاکتروپیون از است،بعد شایعکه های خانم در می ocpسنین دیده کنند، می مصرف

شود. به منجر که مواردی در مگر ندارد درمان به نیاز اکتروپیون

از بعد خونریزی ویا بینی لکه موکوئیدی، شدید ترشحات. شود تماس

: که کرایو،کوتریزاسیون این invasiveدرمان در هستندشود رد بدخیمی شده بررسی باید بیمار موارد

: مثل اسیدی ترکیبات با ای هفته دو درمان درمان آلترناتیواسید بوریک های شبانه 600شیاف میلیگرم

سرویسیت حاد سرویسیت

است،در - واژن چرکی ترشح عالمت تنها اغلب و ترین شایعملتهب،ادماتو،شکننده مختلف درجات با سرویکس مشاهده

. است موکوپروالنت ترشحات ودارایگنوره،کالمیدیا - پارتنر - و بیمار درمان

مزمن سرویسیتهای - نمونه بیوپسی در هیستولوژیک غلط اصطالح یک

است نابالغ متاپالزی علت به سرویکس بیوپسی ) وجود) واقع در تلیال اپی ساب التهابی انفیلتراسیون

نمی عفونت علت به بیوپسی نمونه در ها لکوسیت. است متاپالزی طبیعی پروسه از قسمتی باشد،بلکه

Nobothian cyst

occlution of endocervical glands opening & mucinous retention , physiologic finding due to squamus metaplasia .

a finding in P/E , rarely causes symptom

CERVICAL CANCER

EPIDEMIOLOGY

Cervical cancer ranks as the third most common gynecologic neoplasm in the United States, behind cancer of the corpus and ovary.

Cervical cancer is a disease of sexually active women and infection with high risk HPV is central to the pathogenesis of cervical cancer

Cervical cancer has typically a long preinvasive state and the treatment is effective

500,000 new cases identified each year 80% of the new cases occur in developing countries At least 200,000 women die of cervical cancer each year %50 0f women diagnosed with cervical cancer had never

been screened,%10 no smear in last 5 years %70 reduction in deaths from cervical cancer because

of cytology

68

Epidemiology

The lifetime probability of cervical cancer is 1: 128(%0.4 in israel-%5.3 in colombia)

The mean age for cervical cancer in the United States is 52y

Distribution of cases is bimodal,with peaks at 35 to 39 years and 60 to 64 years of age.

%25 of cervical cancers and %41 of deaths occur in women over 65 years old

Risk factors

Young age at first intercourse «16 years(twice than >20 y) Multiple sexual partners of lifetime High parity Cigarette smoking in SCC (two Fold ) Race(twice in black,Hispanic and higher in native American) Lower socioeconomic status Long term O.C.P>5y ?( glandular abnormalities) two fold Barrier methods especially chemical decrease risk HPV : causal factor detected in 99% by inactivation of tumor suppressor genes ( P53 & Rb ) by

viral proteins E6 & E7 Herpes virus and Chlamydia likely acting as cofactors. The role of HIV in cervical cancer is thought to be mediated

through immune suppression.(cell mediated)

Clinical presentation

Symptoms- Most common : vaginal bleeding or

discharge most often PCB ,postmenopausal,irregular

bleeding- Advanced :Malodor vaginal

discharge ,weight loss, obstructive uropathy,Hematochezia,Hematuria,fistula,Lumbosacral Pain due to L.S nerve involvement

- Asymptomatic.

Cervical cancer

P/E :- Early stage :normal P/E , diagnosis by

colposcopy directed biopsy or conization- Cervical inspection : large cervix ulcerative

(errosive ) , tumoral exophytic , endophytic- Digital vaginal or rectovaginal exam : firm and

enlarged cervix in endophytic tumors- parametrial involvment:nodularity in T.R- Lymph node(axillary,inguinal,supraclavicular)

in advanced

Cervical cancer

Pathology

SCC : most common variety - large cell with or without keratinization,better

prognosis - Small cell , poorly differentiated - small cell anaplastic carcinoma , most aggressive -Verrucous and transitional(papillarey)rare metastasis Adenocarcinoma : increasing incidence(%10-%15) Prognose:poorer than squamous? - endocervical(mucin): 80 % - endometriod -clear cell ,intestinal type,mixture of above

types,minimal change adenocarcinoma(malignant adenoma)

- villoglandular papillary type(young ,pregnant,good prognose)

Cervical cancer pathology...

Adenosquamus

Poor prognose -Mature adenosquamous

-Glassy cell carcinoma - adenoid cystic and basal carcinoma Sarcoma - embryonal rhabdomyosarcomaMalignant melanoma : rare,prognose

related to deep invasion

Cervical cancer pathology

Metastatic cancer : - genital malignancies : endometrium , ovary , vagina ?? ( vag + cervix : cervical primary )

- adjacent organs : colon , bladder - systemic malignancies spread : lymphoma,leukemia,breast,kidney,

stomach

Rareovarian involvement occurs through the

lymphatic connections between the uterus and adnexal structures

In patients undergoing surgical treatment for early-stage disease, ovarian metastasis in <1% of SCC and slightly >1% of adenocarcinoma

Ovarian Metastasis

Patterns of spread Direct invasion into the cervical stroma,

corpus,vagina, and parametriumLymphatic metastasisBlood-born metastasis(uncommon) Intraperitoneal implantation. Pelvic lymph node the first site %20 of patients with tumor extending to pelvic wall biopsy

proven bladder invasion The upper vagina is frequently involved (50% of cases)

when the primary tumor has extended beyond the confines cervix.

Endometrium involvement in %2-%10 surgeries Ovarian involvement in %0.5-%1.7

Cervical cancer staging

FIGO staging allowed procedures :- P/E(T.R,Vaginal exam under anesthesia and

lymph node)- Radiologic studies : IVP, Barium enema ,Chest x ray, skeletal x-ray- Procedures : colposcopy, biopsy,conization,ECC,cystoscopy,

proctoscopy - Optional ( not change staging ) : CT ,MRI ,sonography, lymphangiography,

laparoscopy/laparotomy,radionucleotide

Staging

FIGO System : five stages Stage 0: Carcinoma in situStage 1 :Limited to cervixStage 2: spread out of cervixStage 3:Pelvic wall, spread to the lower part of the vagina.

Stage 4: spread to nearby organs; metastasis.

Cervical cancer staging

Stage 0 : Carcinoma in situStage I : tumor confined to cervixStage Ia : diagnosis only by microscopy ,

tumor depth< 5 mm , width< 7 microinvasive ca

- Ia1 : = 3mm depth of invasion - Ia2 : >3 - 5 mm depth, < 7mm widthStage Ib : depth > 5mm & or width >

7mm - Ib1 : lesion less or equal 4 cm - Ib2 : lesion more than 4 cm

Cervical cancer staging

Stage II : extend beyond cervix but no to pelvic wall,no involvment 1/3 lower vagina

- IIa : No obvious parametrial involve - IIb : Obvious parametrial involvementStage III : extension to pelvic wall or

hydronephros,1/3 lower vagina - IIIa :No extension to pelvic wall - IIIb : hydronephrosis or nonfunction

kidney

Cervical cancer staging

Stage IV : carcinoma extend beyond true pelvis or

to bladder or rectal mucosa - IV a : spread to adjacent organs - IV b : spread to distant organs

Clinical staging of cervical cancer

Cervical cancer staging

Staging- At diagnosis : stage I : 38 % stage II : 32 % stage III : 26 % stage IV : 4 %

Five-year survival

stage IA :97%stage IB : 70% - 85%stage II :60% to 70% stage III :30% to 45% stage IV :12% -18%

Independent prognostic variables

Tumor Histology

No difference in overall survival between SCC and adenocarcinoma.•adenosquamous histology was associated with decreased survival

Independent prognostic variables

Histologic grade :• 5-year survival in well-diff tumors :74.5%•moderately differentiated tumors :63.7%•poorly differentiated carcinomas:%51.4Lymph node status : For all stages of disease, when both pelvic and paraaortic lymph nodes are negative, the 5-year survival is 75.2% and 45.6% with positive pelvic nodes

Treatment

Primary treatment 1 - surgery : limited to stage I & IIa 2- radiation : applicable to all stages The 5-year survival rate for stage I cancer of the

cervix is approximately 85% with either radiation therapy or radical hysterectomy.

Adjuvant treatment after primary modality to decrease recurrence

risk IIB-IVA Radiation curative,preferably in

combination chemotherapy

..…TreatmentSurgery

Preinvasive cervical cancer Cryosurgery Laser surgery Conization

Invasive cervical cancer Simple hysterectomy Radical hysterectomy and pelvic lymph node dissection

Removal of entire uterus, surrounding tissue, upper part of the vagina, and lymph nodes

RadiationChemotherapy:extrapelvic metastasis,recurrence

Source: American Cancer Society

Surgery Stage 0 : conization versus HysterectomyStage IA1 : negligable possibility of lymph

node involvement , extrafascial hysterectomy,conization

Stage IA2 : Type II radical hysterectomy & pelvic lymph node dissection

Stage IB,IIA : Type III radical hysterectomy & pelvic lymph node dissection

Stage IIB-IVA:Radiotherapy+chemotherapyStage IVB:Systemic

chemotherapy+paliative radiation

Cone biopsy

Cervix Cone biopsy of the cervix serves both a diagnostic and therapeutic role in cervical cancer( stageIA1)

Because stage IA1 cancers have less than a 1% risk of lymph node metastasis, lymphadenectomy is not necessary

For effective treatment, there must be no evidence of lymph-vascular space invasion, and both endocervical margins and curettage findings must be negative for cancer or dysplasia.

IA2 class II Hysterectomy with PLNDRadical trachelectomy is a procedure for

women with stage la2 and Ibl disease who desire uterine preservation and fertility.

This procedure may be performed vaginally or abdominally and it usually is accompanied by pelvic lymphadenectomy and cervical cerclage placement.

The risk of positive pelvic lymph nodes with stage IA2 cancer may be as high as 8%, indicating the need for lymphadenectomy.

There are limited data on subsequent pregnancy outcomes after radical trachelectomy; however, successful outcomes have been reported.

Radiotherapy Can be used in all stages Cure rate :

stage I :70% stage II : 60%o stage III : 45% stage IV : 18% Standard plan:Combination of external

(teletherapy ) +internal(brachytherapy)as a boost for central tumor

Ovarian failure in all, %70 vaginal fibrosis,%8 proctosigmoiditis,%3 hemorrhagic cystitis,small bowel obstruction in %2, fistula in %1

Radical Hysterectomy

Radical hysterectomy is reserved for women in good physical condition.

With improvements in anesthesia, elderly patients withstand radical surgery almost as well as their younger counterparts

not to operate larger than 4 cm in diameter because these patients will require postoperative radiation therapy.

When selected in this manner, the urinary fistula rate is less than 2% and the operative mortality rate is less than 1%

Metastasis to the ovaries occurs in 0.5% of S.C.C and 1.7% of cases of adenocarcinomas, so ovarian preservation and transposing the ovaries out of the planned radiation field may be considered.

some studies suggest that normal ovarian function is preserved in fewer than 50% of patients.

Surgery and radiation

There are advantages to the use of surgery instead of radiotherapy, particularly in younger women for whom conservation of the ovaries is important.

Chronic bladder and bowel problems occur in up to 8% of patients undergoing radiation therapy .

Such problems are difficult to treat because they result from fibrosis and decreased vascularity.This is in contrast to surgical injuries,which in general are easily repaired and without long-term complications.

Sexual dysfunction is less likely to occur after surgical therapy than radiation because of vaginal shortening,fibrosis, and atrophy of the epithelium associated with radiation.

The epithelium does not become atrophic because it responds either to endogenous estrogen or to exogenous estrogens if the patient is postmenopausal.

Follow up

Patients who receive radiotherapy should be closely monitored

Tumors may be expected to regress for up to 3 months after radiation.

During the pelvic examination, progressive shrinkage of the cervix and possible stenosis of the cervical os and surrounding upper vagina is expected and should be noted.

During rectovaginal examination, careful palpation of the uterosacral and cardinal ligaments for nodularity

Cytologic assessment by FNA and CT of palpable pelvic mass Pelvic examination and lymph node evaluation, including

supraclavicular and inguinal nodes and smear,should be performed every 3 months for 2 years and then every 6 months for an additional 3 years

Endocervical curettage may be performed in patients with large central tumors.

Chest x Ray yearly in advanced(metastasis to the lung in 1.5% of cases)

I.V.P if pelvic mass or urinary symptom Patients who have had radical hysterectomy and who

are at high risk for recurrence routine CT urogram 6 to 12 months after surgery may be beneficial.

%50 in 1 year and %80 recurrence in 2 years after radical hysterectomy

Large mass lower time for recurrence

Host factors in outcome

Anemia(Hb 12 or less) is associated with a higher incidence of pelvic recurrences and decreased survival, primarily due to more frequent radiation therapy failures.(Tumor hypoxia)

Thrombocytosis (>400,000/mm3), which has been associated with decreased survival after controlling for cell type, stage, and age.

Whether or not patient age at diagnosis of cervical cancer is a significant and independent predictor of clinical outcome remains controversial

Medical problems(Diabete ,Hypertension) due to decreased blood supply and hypoxia

Persistant& Recurrent

•Persistant:detection within the first 6 months after therapy• recurrent disease:later diagnose• Appropriate treatment of recurrent cervical cancer is dictated by both the site of recurrence and the modality of primary therapy.• In general, patients in whom locally recurrent disease develops following primary surgery should be considered for salvage radiation therapy. Conversely, surgical treatment should be considered for those patients with recurrent central disease who initially received irradiation.• Distantly metastatic recurrent tumor is an indication for palliative chemotherapy and possibly radiation therapy for local control.

Adjuvant Therapy following Surgery

For patients with risk factors(large tumor,deep stromal invasion,tumor in capillary lymphatic space) and negative pelvic lymph nodes, adjuvant pelvic radiation associated with a statistically significant 47% reduction in the risk of disease recurrence.

Even after extensive follow-up, the addition of radiation therapy was not associated with a statistically significant improvement in overall survival.

Cervical cancer inpregnancy

Cervical cancer is one of the most common malignancies in pregnancy

Incidence ranging from 1/1,200 to 1/2,200 pregnancies.

1 /34 women diagnosed with cervical cancer is pregnant at the time of diagnosis.

The most common complaint:abnormal bleeding Delay in diagnosis.

Diagnose : In the presence of a grossly visible lesion with by biopsy.

Cervical cancer in pregnancy.....

Conization is indicated only for those patients with apparent microinvasive disease on directed biopsy or for patients with persistent cytologic evidence of invasive cancer in the absence of a colposcopically visible lesion.

The optimal time to perform conization is between 14 -20 weeks or after the time of fetal viability has been reached.

Cervical cancer in pregnancy....

Staging like nonpregnant Treatment recommendations are

individualized and are dependent on the stage of disease, gestational age at the time of diagnosis, and the desires of the patient regarding continuation of the pregnancy.

Patients with well-documented stage IA1 disease (conization with negative surgical margins) may be managed with vaginal delivery and reevaluation postpartum. If the patient has completed childbearing, a simple extrafascial hysterectomy would be appropriate

.…cervical cancer in pregnancy

For patients with stage IA2 modified radical cesarean hysterectomy with pelvic lymph node dissection is the preferred treatment.

Patients with stage IB or IIA disease may be treated with surgery in the form of radical hysterectomy and pelvic lymph node dissection, either in conjunction with cesarean section or with the fetus in situ, depending on the gestational age.

Radiation therapy is the treatment of choice for patients with stage IIB to IVA

Spantaneous abortion 4-5 after start radiationDelay treatment 6-12 weeks for stage I

HYPERPLASIA

Endometrial Hyperplasia

Classic teaching has been that endometrial hyperplasias represent a continuum of morphologic severity; the most severe form, termed atypical adenomatous hyperplasia or carcinoma in situ, was considered the immediate precursor of endometrial carcinoma .

Endometrial hyperplasia and endometrial neoplasia are two biologically different diseases.

The only important distinguishing feature is the presence or absence of cytologic atypia.

Ferenczy et al. (92) suggested that the term endometrial hyperplasia be used for any degree of glandular proliferation devoid of cytologic atypia and the term endometrial intraepithelial neoplasia for lesions with cytologic atypia. Using similar criteria in a long-term follow-up study of 170 patients with endometrial hyperplasia, Kurman et al. (91) reported a 1.6% risk of progression to carcinoma in patients devoid of cytologic atypia, compared with a 23% risk in patients with cytologic atypia.

HyperplasiaSimpleComplex (adenomatous)Atypical hyperplasiaSimpleComplex (atypical adenomatous)

Endometrial Hyperplasia

Endometrial hyperplasia represents a spectrum of morphologic and biologic alterations of the endometrial glands and stroma, ranging from an exaggerated physiologic state to carcinoma in situ.

Clinically significant hyperplasias usually evolve within a background of proliferative endometrium as a result of protracted estrogen stimulation in the absence of progestin influence.

Endometrial hyperplasias are important clinically because they may cause abnormal bleeding, be associated with estrogen-producing ovarian tumors, result from hormonal therapy, and precede or occur simultaneously with endometrial cancer.

Simple or Complex Differential point is complexity and crowding of the glandular

elements. Simple hyperplasia is characterized by dilated or cystic

glands with round to slightly irregular shapes, an increased glandular to-stromal ratio without glandular crowding, and no cytologic atypia.

Complex hyperplasia has architecturally complex (budding and infolding), crowded glands with less intervening stroma without atypia.

Atypical hyperplasia refers to cytologic atypia and can be categorized as simple or complex, depending on the corresponding glandular architecture.

Criteria for cytologic atypia include large nuclei of variable size and shape that have lost polarity, increased nuclear-to-cytoplasmic ratios, prominent nucleoli, and irregularly clumped chromatin with parachromatin clearing

The risk of endometrial hyperplasia progressing to carcinoma is related to the presence and severity of cytologic atypia.

Kurman and colleaguesretrospectively studied endometrial curettings from 170 patients with untreated endometrial hyperplasia followed a mean of 13.4 years. They found that progression to carcinoma occurred in 1% of patients with simple hyperplasia, 3% of patients with complex hyperplasia, 8% of patients with atypical simple hyperplasia, and 29% of patients with atypical complex hyperplasia. Most of the hyperplasia seemedto remain stable(18%) or regress(74%).

The premalignant potential of hyperplasia is influenced by age, underlying ovarian disease, endocrinopathy, obesity, and exogenous hormone exposure

As many as 25% to 43% of patients with atypical hyperplasia detected in an endometrial biopsy or curettage specimen will have an associated, usually well-differentiated endometrial carcinoma detected during hysterectomy.

Marked cytologic atypia, a high mitotic rate, and marked cellular stratification are features of atypical endometrial hyperplasia most often associated with the finding of an undiagnosed carcinoma at hysterectomy.

In a report of 85 menopausal women with endometrial hyperplasia treated with medroxyprogesterone acetate (10-20 mglday), 84% of 65 who did not have cytologic atypia had complete reversal of the lesions, 6% developed recurrent hyperplasia, but none developed cancer at a mean follow-up interval of 7 years (17).

By contrast, of 20 patients with cytologic atypia, only 50% responded to progestin, 25% developed recurrent hyperplasia, and 25% developed adenocarcinoma.

In another study, hyperplasia resolved in 94% of 32 patients with atypical endometrial hyperplasia who were treated with megestrol acetate (20-40 mglday); however, relapse occurred in all 7 patients who discontinued progestin therapy.

Conversely,high-dose progestin therapy (medroxyprogesterolleacetate,200 mglday, or megestrol acetate, 160 mglday) has been reported to have successfully reversed atypical hyperplasia and well-differentiated endometrial adenocarcinoma in 16 (94%) of 17 and 9 (75%) of 12 premenopausal women younger than age 40, respectively.

The average treatment course required to achieve disease regression was 9 months (range 3-18 months)

Subsequent pregnancies after progestin treatment of endometrial hyperplasia and even well-differentiated cancer have occurred and can apparently be enhanced by the use of assisted reproductive technologies.

Progestin therapy is very effective in reversing endometrial hyperplasia without atypia but is less effective for endometrial hyperplasia with atypia.

For women with endometrial hyperplasia without atypia, ovulation induction, cyclical progestin therapy(e.g., medroxyprogesterone acetate, 10-20 mg/day for 14 days per month), or continuous progestin therapy (e.g., megestrol acetate, 20-40 mg/day) appear to be effective.

Continuous progestin therapy with megestrol acetate (40-160 mg/day) is probably the most reliable treatment for reversing complex or atypical hyperplasia.

Therapy should be continued for 2 to 3 months, and endometrial biopsy should be performed 3 to 4 weeks after completion of therapy to assessresponse.

Periodic endometrial biopsy or transvaginal ultrasonography is advisable in patients being monitored after progestin therapy for atypical hyperplasia because of the presence of undiagnosed cancer in 25% of cases, the 29% progression rate to cancer, and the high recurrence rate after treatment with progestins.

For women with atypical complex hyperplasia who no longer desire fertility, hysterectomy is recommended.

Treatment

Most women with endometrial hyperplasia respond to progestin therapy. Patients who do not respond are at a significantly increased risk of progressing to invasive cancer and should be advised to have a hysterectomy. Patients who are unlikely to respond can be identified on the basis of cytologic atypia.

Ferenczy and Gelgand reported on 85 women with endometrial hyperplasia treated with medroxyprogesterone (93). The 65 patients who had no cytologic atypia received 10 mg daily for 14 days per month, whereas the 20 patients with cytologic atypia received 20 mg daily. Both groups had endometrial sampling every 3 months. In the group without cytologic atypia, 14% had persistence of their hyperplasia, but none progressed to carcinoma. Of the 20 patients with cytologic atypia, 50% had persistence of their hyperplasia, and 25% developed frank carcinoma at a mean of 5.5 years after initiation of hormonal therapy.

The type of progestin used does not appear to be important, the optimal dosage has not been investigated, and the regimens advocated are essentially arbitrary (96). High doses of progestins are often better tolerated than low doses. The main side effects are weight gain, edema, thrombophlebitis, and occasionally hypertension. The incidence of venous thrombosis and embolism may also be slightly increased.

Other approaches to hormonal therapy include levonorgestrel-releasing intrauterine devices (97), the use of danazol in a dose of 400 mg daily for 3 months (98), and the combined use of gonadotropin-releasing hormone (GnRH) analogues and progestins (99).

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