UTERINE CARCINOMAUTERINE CARCINOMA

DR. SALWA NEYAZI

CONSULTANT OBSTETRICIAN GYNECOLOGIST

PEDIATRIC & ADOLESCENT GYNECOLOGIST

11--ENDOMETRIAL HYPERPLASIA & ENDOMETRIAL HYPERPLASIA & CARCINOMACARCINOMA

Endometrial cancer is the most common pelvic Endometrial cancer is the most common pelvic genital cancer in womengenital cancer in women

In the US the life time risk of developing In the US the life time risk of developing endometrial Ca is 2.4% in white women & 1.3% in endometrial Ca is 2.4% in white women & 1.3% in blackblack

It is a disease of postmenopausal women with a It is a disease of postmenopausal women with a peak incidence in the 6peak incidence in the 6thth & 7 & 7thth decade of life decade of life

Only 2-5% occur before 40 yearsOnly 2-5% occur before 40 years Prognosis is better than other Gynecological Ca Prognosis is better than other Gynecological Ca

due to early Dx ---75% due to early Dx ---75% Dx Stage IDx Stage I Estrogen has been implicated as a causative Estrogen has been implicated as a causative

factorfactor

RISK FACTORSRISK FACTORS Age 65-75 Y , only 2-5% < 40 YAge 65-75 Y , only 2-5% < 40 Y Excessive endogenous / exogenous estrogensExcessive endogenous / exogenous estrogens-Early menarche < 12 Y-Early menarche < 12 Y- Late menopause > 52 Y - Late menopause > 52 Y 2 X risk 2 X risk-Nulliparity 2X > women with 1 child / 3X > women -Nulliparity 2X > women with 1 child / 3X > women

with with ≥5≥5-Chronic anovulation as in PCO-Chronic anovulation as in PCO-Obesity -Obesity aromatization of adrenal androgens in fat aromatization of adrenal androgens in fat

tissue risk is 3X for Pt 21-50 pounds overweight tissue risk is 3X for Pt 21-50 pounds overweight 10 X for Pt 10 X for Pt > 50 P overweight> 50 P overweight -Granulosa-thicka cell tumors of the ovary (a rare -Granulosa-thicka cell tumors of the ovary (a rare

estrogen secreting ovarian tumor) estrogen secreting ovarian tumor) endometrial endometrial hyperplasia & Ca in 10% of Pthyperplasia & Ca in 10% of Pt

-Cirrhosis of the liver -Cirrhosis of the liver degradation of estrogen degradation of estrogen-Endometrial hyperplasia-Endometrial hyperplasia

RISK FACTORSRISK FACTORS

Unopposed estrogen therapy in postmenopausal Unopposed estrogen therapy in postmenopausal women women risk of E Ca 6-8 X risk of E Ca 6-8 X

Tamoxifen Tamoxifen an anti-estrogen used in the Rx of an anti-estrogen used in the Rx of breast Ca breast Ca has weak estrogenic activity on the has weak estrogenic activity on the genital tractgenital tract

2 X 2 X risk of E Ca when used risk of E Ca when used ≥≥ 5 Y 5 Y risk in women with breast, ovarian risk in women with breast, ovarian

(endometrial type) & colorectal Ca (endometrial type) & colorectal Ca Diabetes Diabetes 3X 3X risk risk HypertensionHypertension Previous pelvic radiation therapyPrevious pelvic radiation therapy Family Hx of endometrial CaFamily Hx of endometrial Ca

ENDOMETRIAL HYPERPLASIAENDOMETRIAL HYPERPLASIA

Excessive proliferation of the endometrial glands Excessive proliferation of the endometrial glands & to a lesser extent endometrial stroma& to a lesser extent endometrial stroma

Due to excessive estrogen stimulationDue to excessive estrogen stimulation Only 25% of Pt with E Ca have Hx of hyperplasiaOnly 25% of Pt with E Ca have Hx of hyperplasiaCLASSIFICATIONCLASSIFICATION1-Hyperplasia without atypia (not premalignant)1-Hyperplasia without atypia (not premalignant) 1-A-Simple1-A-Simple Microscopically Microscopically crowding of the glands in the crowding of the glands in the

stromastroma Glands are cystically dilated & give a “Swiss Glands are cystically dilated & give a “Swiss

cheese” appearance cheese” appearance Commonly asymptomaticCommonly asymptomatic 1% progress to Ca over 15 Y 1% progress to Ca over 15 Y 80% regress80% regress

ENDOMETRIAL HYPERPLASIAENDOMETRIAL HYPERPLASIA

1-B-Complex hyperplasia without atypia1-B-Complex hyperplasia without atypia A complex crowded appearance of the glands A complex crowded appearance of the glands

with very little stromawith very little stroma Epithelial stratification & mitotic activityEpithelial stratification & mitotic activity 3% progress to Ca over 13 Y3% progress to Ca over 13 Y 80% regress80% regress 85% reversal with progestin Rx85% reversal with progestin Rx

ENDOMETRIAL HYPERPLASIAENDOMETRIAL HYPERPLASIA

2-Hyperplasia with atypia (premalignant)2-Hyperplasia with atypia (premalignant) Histologically Histologically endometrial glands are lined by endometrial glands are lined by

enlarged cells with enlarged cells with nuclear : cytoplasmic ratios nuclear : cytoplasmic ratios

The nuclei are irregular with coarse chromatin The nuclei are irregular with coarse chromatin clumping & prominent nucleoliclumping & prominent nucleoli

50-94% regress with progestin therapy50-94% regress with progestin therapy A higher rate of relapse after stopping Rx A higher rate of relapse after stopping Rx

compared to that of lesions without atypiacompared to that of lesions without atypia

2-A-Simple 2-A-Simple Progression to carcinoma occur in 8%Progression to carcinoma occur in 8%

2-B- Complex2-B- Complex Progression to carcinoma occur in 29%Progression to carcinoma occur in 29%

ENDOMETRIAL HYPERPLASIAENDOMETRIAL HYPERPLASIA

3-CARCINOMA IN SITU3-CARCINOMA IN SITU

Histologically differentiated from carcinoma byHistologically differentiated from carcinoma by

Presence of intervening stroma between Presence of intervening stroma between abnormal glandsabnormal glands

There is no evidence of invasionThere is no evidence of invasion

It is difficult to differentiate from Ca It is difficult to differentiate from Ca

PRESENTATION OF ENDOMETRIAL PRESENTATION OF ENDOMETRIAL CACA

Abnormal vaginal bleeding Abnormal vaginal bleeding most common 90% most common 90% Premenopausal Pt Premenopausal Pt usually c/o heavy flow at the usually c/o heavy flow at the

time of menses time of menses may present with may present with persistent intermenstrual bleedingpersistent intermenstrual bleeding pre or post menstrual spottingpre or post menstrual spotting polymenorrhea that fails to respond to polymenorrhea that fails to respond to

hormonal Rxhormonal Rx Postmenopausal bleeding is the most common Postmenopausal bleeding is the most common

type of abnormal bleeding type of abnormal bleeding 12-15% due to E Ca 12-15% due to E Ca 5-8% due to other cancers like uterine sarcoma, 5-8% due to other cancers like uterine sarcoma,

ovarian Ca, Cx, tubal or vaginal Caovarian Ca, Cx, tubal or vaginal Ca Postmenopausal Pt Postmenopausal Pt commonly c/o intermittent commonly c/o intermittent

spottingspotting Postmenopausal vaginal discharge 10%Postmenopausal vaginal discharge 10%

PRESENTATION OF ENDOMETRIAL PRESENTATION OF ENDOMETRIAL CACA

Asymptomatic women with glandular Asymptomatic women with glandular abnormalities on routine PAP smear/ abnormalities on routine PAP smear/ abnormalities found in 50% of Pt with E Ca abnormalities found in 50% of Pt with E Ca

Advanced disease Advanced disease symptoms due to local or symptoms due to local or distant metastases distant metastases

Sever cramps due to hematometra or pyometra Sever cramps due to hematometra or pyometra occur in postmenopausal Pt with Cx stenosis occur in postmenopausal Pt with Cx stenosis ----10%----10%

HISTOPATHOLOGYHISTOPATHOLOGY

Microscpically Microscpically hyperplasia & anaplasia of hyperplasia & anaplasia of glands glands

Invasion of stroma, myometrium, or vascular spacesInvasion of stroma, myometrium, or vascular spaces

1-Adenocarcinomas 1-Adenocarcinomas 80-85% 80-85%

Grade 1 Grade 1 well differentiated & difficult to well differentiated & difficult to distinguish from atypical complex hyperplasiadistinguish from atypical complex hyperplasia

Grade 2Grade 2 Grade 3 Grade 3 anaplastic Ca (poorly differentiated) anaplastic Ca (poorly differentiated)

HISTOPATHOLOGYHISTOPATHOLOGY

2-Adenocarcinoma with squamous differentiation 2-Adenocarcinoma with squamous differentiation 5%5%

Malignant glands with benign squamous Malignant glands with benign squamous metaplasiametaplasia

Also subdivided into 3 gradesAlso subdivided into 3 grades

3-Adenosquamous Ca 3-Adenosquamous Ca 10-20% 10-20% Malignant glands & malignant squamous Malignant glands & malignant squamous

epitheliumepithelium Often grade 3Often grade 3

HISTOPATHOLOGYHISTOPATHOLOGY

4-Papillary Serous Ca 4-Papillary Serous Ca 10% 10% Older women Older women Less likely to have hyperestrogenic stateLess likely to have hyperestrogenic state Simillar to Papillary Serous Ca of the ovariesSimillar to Papillary Serous Ca of the ovaries Spread early through peritoneal surfaces of the Spread early through peritoneal surfaces of the

pelvis & abdomenpelvis & abdomen Invasion of the myometrium & lymphaticInvasion of the myometrium & lymphatic Prognosis unfavorablePrognosis unfavorable

HISTOPATHOLOGYHISTOPATHOLOGY

5-Clear cell Ca 5-Clear cell Ca 4% 4% Microscopic appearance Microscopic appearance clear cells / solid, clear cells / solid,

papillary, tubular, & cystic pattern are possiblepapillary, tubular, & cystic pattern are possible Commonly high grade & aggressiveCommonly high grade & aggressive Seen in advanced stagesSeen in advanced stages Older womenOlder women Not associated with hyperestrogenic statesNot associated with hyperestrogenic states Behaves like ovarian CaBehaves like ovarian Ca

HISTOPATHOLOGYHISTOPATHOLOGY

6-Mucinous Ca 6-Mucinous Ca 9% 9% PAS- positive intracytoplasmic mucinPAS- positive intracytoplasmic mucin

7-Secretory Ca 7-Secretory Ca 1-2% 1-2% Exhibit sub-nuclear or supra-nuclear vacuoles Exhibit sub-nuclear or supra-nuclear vacuoles

resembling early secretory endometriumresembling early secretory endometrium Behaves like typical E CaBehaves like typical E Ca

8-Squamous cell Ca 8-Squamous cell Ca extremely rare extremely rare Associated with Associated with Cx stenosis, pyometra & Cx stenosis, pyometra &

inflammationinflammation

SPREADSPREAD

1-Direct spread 1-Direct spread Through the endometrial cavity Through the endometrial cavity to Cx to Cx Through the fallopian tubes Through the fallopian tubes to ovaries & to ovaries &

peritoneal cavityperitoneal cavity Through invading the myometrium Through invading the myometrium to serosal to serosal

surface ,parametrium & pelvic wallsurface ,parametrium & pelvic wall Rarely Rarely direct invasion of the pubic bone direct invasion of the pubic bone

SPREADSPREAD

2- Lymphatic spread 2- Lymphatic spread Never occurs without myometrial invasion Never occurs without myometrial invasion The incidence of involvement is related to the The incidence of involvement is related to the

degree of differentiation & depth of myometrial degree of differentiation & depth of myometrial involvementinvolvement

Pelvic lymphnodes Pelvic lymphnodes common 35% common 35% Para-aortic lymphnodes Para-aortic lymphnodes 10-20% 10-20%

Rarely involved without pelvic nodes involvementRarely involved without pelvic nodes involvement Inguinal lymphnodes Inguinal lymphnodes rare rare

SPREADSPREAD

3-Hematogenous spread to the lungs3-Hematogenous spread to the lungs Uncommon with the 1ry tumor limited to the Uncommon with the 1ry tumor limited to the

uterusuterus Occurs with recurrent or disseminated diseaseOccurs with recurrent or disseminated disease

4-Vaginal metastasis 4-Vaginal metastasis 3-8% of clinical stage I 3-8% of clinical stage I Occur through direct spread, submucousal Occur through direct spread, submucousal

lymphatics or hematogenous spreadlymphatics or hematogenous spread More common with high grade & lower uterine More common with high grade & lower uterine

segment or Cx involvementsegment or Cx involvement

PROGNOSTIC FACTORSPROGNOSTIC FACTORS

Stage Stage overall survival depends on the stage at overall survival depends on the stage at DxDx

-Stage I -Stage I 72% 72%

-Stage II -Stage II 56% 56%

-Stage III -Stage III 32% 32%

-Stage IV -Stage IV 11% 11% Depth of myometrial invasion Depth of myometrial invasion correlates with correlates with

lymph nodes involvement in early diseaselymph nodes involvement in early disease

-also correlates with tumor grade-also correlates with tumor grade Malignant cells in peritoneal washingsMalignant cells in peritoneal washings

PROGNOSTIC FACTORSPROGNOSTIC FACTORS

Tumor grade Tumor grade as it as it depth of invasion & depth of invasion & LN involvementLN involvement

-grade I -grade I 90% limited to endometrium or inner ½ 90% limited to endometrium or inner ½ of the myometrium of the myometrium

-grade III -grade III 50% invading the outer half of the 50% invading the outer half of the myometriummyometrium

Histological typeHistological type-adenocarcinoma -adenocarcinoma best prognosis best prognosis-clear cell & papillary serous types -clear cell & papillary serous types poorer poorer

prognosisprognosis-absence of estrogen receptors -absence of estrogen receptors poorer prognosis poorer prognosis Lymphovascular space involvement Lymphovascular space involvement important important

prognostic factor in terms of survival & prognostic factor in terms of survival & recurrence for stage I disease recurrence for stage I disease

INVESTIGATIONINVESTIGATION

Any Pt with signs or symptoms suggestive of E Ca Any Pt with signs or symptoms suggestive of E Ca should be investigatedshould be investigated

All Pt should have endometrial sampling in the All Pt should have endometrial sampling in the clinic clinic false -ve 10%false -ve 10%

If continues to be symptomatic in spite of –ve If continues to be symptomatic in spite of –ve biopsy or suspicious finding on biopsy biopsy or suspicious finding on biopsy D&C D&C

In the past the “gold standard” was D&C In the past the “gold standard” was D&C The current “gold standard” is hystroscopy with The current “gold standard” is hystroscopy with

targeted endometrial biopsytargeted endometrial biopsy

INVESTIGATIONINVESTIGATION

As an alternative As an alternative endometrial sampling with a endometrial sampling with a pipelle + transvaginal U/S to assess endometrial pipelle + transvaginal U/S to assess endometrial thickness, presence of endometrial polyp or thickness, presence of endometrial polyp or ovarian massesovarian masses

Endometrium < 5 mm in thickness Endometrium < 5 mm in thickness high –ve high –ve predictive valuepredictive value

U/S also helpful in assessing the depth of U/S also helpful in assessing the depth of endometrial invasionendometrial invasion

MRI MRI depth of E invasion, Cx, & LN involvement depth of E invasion, Cx, & LN involvement Chest X-Ray Chest X-Ray exclude pulmonary spread exclude pulmonary spread

STAGINGSTAGING

Surgical staging Surgical staging TAH + BSO + pelvic washings TAH + BSO + pelvic washings +abdominal exploration + selective pelvic & PA LN +abdominal exploration + selective pelvic & PA LN biopsiesbiopsies

I ---------------------confined to the body of the uterusI ---------------------confined to the body of the uterus

Ia-------------------confined to the endometriumIa-------------------confined to the endometrium

Ib-------------------myometrial invasion < 50%Ib-------------------myometrial invasion < 50%

Ic-------------------myometrial invasion > 50%Ic-------------------myometrial invasion > 50%

II --------------------- Cx involvedII --------------------- Cx involved

IIa-----------------endocervical gland involvement onlyIIa-----------------endocervical gland involvement only

IIb-----------------Cx stromal invasionIIb-----------------Cx stromal invasion

does not extend beyond the body of the does not extend beyond the body of the uterusuterus

STAGINGSTAGING

III ----------------spread to serosa of uterus, peritoneal III ----------------spread to serosa of uterus, peritoneal cavity or LNcavity or LNIIIa --------------Ca involving serosa of uterus, adnexae,IIIa --------------Ca involving serosa of uterus, adnexae, +ve ascites or +ve peritoneal washings+ve ascites or +ve peritoneal washingsIIIb --------------vaginal involvement either direct or IIIb --------------vaginal involvement either direct or metastaticmetastaticIIIc --------------para-aortic or pelvic LN involvementIIIc --------------para-aortic or pelvic LN involvement

IV ----------------local or distant metastasis IV ----------------local or distant metastasis IVa ---------------Ca involving the mucosa of the bladder orIVa ---------------Ca involving the mucosa of the bladder or rectumrectumIVb ---------------distant metastasis & involvement if other IVb ---------------distant metastasis & involvement if other abdominal or inguinal LN abdominal or inguinal LN

DIFFERENTIAL DIAGNOSISDIFFERENTIAL DIAGNOSIS

Various causes of abnormal bleedingVarious causes of abnormal bleeding Premenopausal Pt Premenopausal Pt exclude pregnancy exclude pregnancy

complications complications abortion abortion Endometrial hyperplasiaEndometrial hyperplasia Endometrial & Cx polypsEndometrial & Cx polyps FibroidFibroid Ovarian, Cx or tubal neoplasmsOvarian, Cx or tubal neoplasms Postmenomausal Pt Postmenomausal Pt atrophic vaginitis, atrophic vaginitis,

endometrial atrophy, exogenous estrogens endometrial atrophy, exogenous estrogens Urethral caruncles Urethral caruncles Trauma Trauma

COMPLICATIONSCOMPLICATIONS

Severe anemia 2ry tochronic blood loss or acute Severe anemia 2ry tochronic blood loss or acute hemorrhage hemorrhage high dose bolus radiation therapy high dose bolus radiation therapy is effective in controlling the hemorrhageis effective in controlling the hemorrhage

Hematometra Hematometra Cx dilatation for adequate Cx dilatation for adequate drainage drainage

Pyometra Pyometra Cx dilatation for adequate drainage Cx dilatation for adequate drainage + antibiotics+ antibiotics

Perforation of the uterus at the time of D&C or Perforation of the uterus at the time of D&C or endometrial sampling endometrial sampling laparoscopy or laparoscopy or laparotomy toevaluate &repair the damage + laparotomy toevaluate &repair the damage + antibioticsantibiotics

TREATMENTTREATMENT

1-SURGERY1-SURGERY

TAH & BSO TAH & BSO stage I & II stage I & II may require may require radiotherapyradiotherapy

Surgery alone Surgery alone ≤≤ stage Ib /grade 1or stage Ib /grade 1or 2/adenocarcinoma 2/adenocarcinoma

Stage III Stage III radical surgery (TAH/BSO + max radical surgery (TAH/BSO + max debulking) followed by radio therapy debulking) followed by radio therapy

TREATMENTTREATMENT

2-RADIOTHERAPY2-RADIOTHERAPY Stage I or II Stage I or II most Pt require surgery + most Pt require surgery +

radiotherapy if they have any adverse featuresradiotherapy if they have any adverse features Radiotherapy regime :Radiotherapy regime :

- high dose intracavitary brachytherapy - high dose intracavitary brachytherapy risk of risk of vault recurrencevault recurrence

- low dose external beam radiotherapy - low dose external beam radiotherapy risk of risk of pelvic recurrencepelvic recurrence

Advanced disease Advanced disease as palliative Rx as palliative Rx bone bone pain & vaginal bleedingpain & vaginal bleeding

TREATMENTTREATMENT

3-HORMONE THERAPY3-HORMONE THERAPY Progestogens (medroxyprogestrone acetate 200-Progestogens (medroxyprogestrone acetate 200-

400mg/D)400mg/D) Will not prevent recurrenceWill not prevent recurrence Used in the management of recurrent disease Used in the management of recurrent disease

response rate 30% response rate 30% Response is higher in estrogen progestrone Response is higher in estrogen progestrone

receptor +ve tumorsreceptor +ve tumors Other hormonal agents Other hormonal agents tamoxifen & GnRH tamoxifen & GnRH

limited responcelimited responce

TREATMENTTREATMENT

4-CHEMOTHERAPY4-CHEMOTHERAPY

Not commonly used Not commonly used Should be considered in fit Pt with systemic / Should be considered in fit Pt with systemic /

advanced diseaseadvanced disease Epirubicin, doxorubicin, cisplatin, carboplatin Epirubicin, doxorubicin, cisplatin, carboplatin

response rate 25-30% / short lived responseresponse rate 25-30% / short lived response

PROGNOSISPROGNOSIS

The 5 Y survival rate for endometrial Ca :The 5 Y survival rate for endometrial Ca : Stage I Stage I 75% 75% Stage II Stage II 58% 58% Stage III Stage III 30%30% Stage IV Stage IV 10%10% Overall 5 Y survival Overall 5 Y survival 70% 70% most Pt present most Pt present

early due to abnormal vaginal bleedingearly due to abnormal vaginal bleeding