UTERINE CARCINOMA DR. SALWA NEYAZI CONSULTANT OBSTETRICIAN GYNECOLOGIST PEDIATRIC & ADOLESCENT GYNECOLOGIST

1-ENDOMETRIAL HYPERPLASIA & CARCINOMA Endometrial cancer is the most common pelvic genital cancer in women Endometrial cancer is the most common pelvic genital cancer in women In the US the life time risk of developing endometrial Ca is 2.4% in white women & 1.3% in black In the US the life time risk of developing endometrial Ca is 2.4% in white women & 1.3% in black It is a disease of postmenopausal women with a peak incidence in the 6 th & 7 th decade of life It is a disease of postmenopausal women with a peak incidence in the 6 th & 7 th decade of life Only 2-5% occur before 40 years Only 2-5% occur before 40 years Prognosis is better than other Gynecological Ca due to early Dx ---75%  Dx Stage I Prognosis is better than other Gynecological Ca due to early Dx ---75%  Dx Stage I Estrogen has been implicated as a causative factor Estrogen has been implicated as a causative factor

RISK FACTORS Age Y, only 2-5% < 40 Y Age Y, only 2-5% < 40 Y Excessive endogenous / exogenous estrogens Excessive endogenous / exogenous estrogens -Early menarche < 12 Y - Late menopause > 52 Y  2 X risk -Nulliparity 2X > women with 1 child / 3X > women with ≥5 -Chronic anovulation as in PCO -Obesity  aromatization of adrenal androgens in fat tissue risk is 3X for Pt pounds overweight 10 X for Pt > 50 P overweight 10 X for Pt > 50 P overweight -Granulosa-thicka cell tumors of the ovary (a rare estrogen secreting ovarian tumor)  endometrial hyperplasia & Ca in 10% of Pt -Cirrhosis of the liver  degradation of estrogen -Endometrial hyperplasia

RISK FACTORS Unopposed estrogen therapy in postmenopausal women  risk of E Ca 6-8 X Unopposed estrogen therapy in postmenopausal women  risk of E Ca 6-8 X Tamoxifen  an anti-estrogen used in the Rx of breast Ca  has weak estrogenic activity on the genital tract Tamoxifen  an anti-estrogen used in the Rx of breast Ca  has weak estrogenic activity on the genital tract 2 X  risk of E Ca when used ≥ 5 Y 2 X  risk of E Ca when used ≥ 5 Y  risk in women with breast, ovarian (endometrial type) & colorectal Ca  risk in women with breast, ovarian (endometrial type) & colorectal Ca Diabetes  3X  risk Diabetes  3X  risk Hypertension Hypertension Previous pelvic radiation therapy Previous pelvic radiation therapy Family Hx of endometrial Ca Family Hx of endometrial Ca

ENDOMETRIAL HYPERPLASIA Excessive proliferation of the endometrial glands & to a lesser extent endometrial stroma Excessive proliferation of the endometrial glands & to a lesser extent endometrial stroma Due to excessive estrogen stimulation Due to excessive estrogen stimulation Only 25% of Pt with E Ca have Hx of hyperplasia Only 25% of Pt with E Ca have Hx of hyperplasiaCLASSIFICATION 1-Hyperplasia without atypia (not premalignant) 1-A-Simple 1-A-Simple Microscopically  crowding of the glands in the stroma Microscopically  crowding of the glands in the stroma Glands are cystically dilated & give a “ Swiss cheese ” appearance Glands are cystically dilated & give a “ Swiss cheese ” appearance Commonly asymptomatic Commonly asymptomatic 1% progress to Ca over 15 Y 1% progress to Ca over 15 Y 80% regress 80% regress

ENDOMETRIAL HYPERPLASIA 1-B-Complex hyperplasia without atypia A complex crowded appearance of the glands with very little stroma A complex crowded appearance of the glands with very little stroma Epithelial stratification & mitotic activity Epithelial stratification & mitotic activity 3% progress to Ca over 13 Y 3% progress to Ca over 13 Y 80% regress 80% regress 85% reversal with progestin Rx 85% reversal with progestin Rx

ENDOMETRIAL HYPERPLASIA 2-Hyperplasia with atypia (premalignant) Histologically  endometrial glands are lined by enlarged cells with  nuclear : cytoplasmic ratios Histologically  endometrial glands are lined by enlarged cells with  nuclear : cytoplasmic ratios The nuclei are irregular with coarse chromatin clumping & prominent nucleoli The nuclei are irregular with coarse chromatin clumping & prominent nucleoli 50-94% regress with progestin therapy 50-94% regress with progestin therapy A higher rate of relapse after stopping Rx compared to that of lesions without atypia A higher rate of relapse after stopping Rx compared to that of lesions without atypia2-A-Simple Progression to carcinoma occur in 8% Progression to carcinoma occur in 8% 2-B- Complex Progression to carcinoma occur in 29% Progression to carcinoma occur in 29%

ENDOMETRIAL HYPERPLASIA 3-CARCINOMA IN SITU Histologically differentiated from carcinoma by Presence of intervening stroma between abnormal glands Presence of intervening stroma between abnormal glands There is no evidence of invasion There is no evidence of invasion It is difficult to differentiate from Ca It is difficult to differentiate from Ca

PRESENTATION OF ENDOMETRIAL CA Abnormal vaginal bleeding  most common 90% Abnormal vaginal bleeding  most common 90% Premenopausal Pt  usually c/o heavy flow at the time of menses Premenopausal Pt  usually c/o heavy flow at the time of menses may present with may present with  persistent intermenstrual bleeding  persistent intermenstrual bleeding  pre or post menstrual spotting  pre or post menstrual spotting  polymenorrhea that fails to respond to hormonal Rx  polymenorrhea that fails to respond to hormonal Rx Postmenopausal bleeding is the most common type of abnormal bleeding  12-15% due to E Ca Postmenopausal bleeding is the most common type of abnormal bleeding  12-15% due to E Ca  5-8% due to other cancers like uterine sarcoma, ovarian Ca, Cx, tubal or vaginal Ca  5-8% due to other cancers like uterine sarcoma, ovarian Ca, Cx, tubal or vaginal Ca Postmenopausal Pt  commonly c/o intermittent spotting Postmenopausal Pt  commonly c/o intermittent spotting Postmenopausal vaginal discharge 10% Postmenopausal vaginal discharge 10%

PRESENTATION OF ENDOMETRIAL CA Asymptomatic women with glandular abnormalities on routine PAP smear/ abnormalities found in 50% of Pt with E Ca Asymptomatic women with glandular abnormalities on routine PAP smear/ abnormalities found in 50% of Pt with E Ca Advanced disease  symptoms due to local or distant metastases Advanced disease  symptoms due to local or distant metastases Sever cramps due to hematometra or pyometra  occur in postmenopausal Pt with Cx stenosis % Sever cramps due to hematometra or pyometra  occur in postmenopausal Pt with Cx stenosis %

HISTOPATHOLOGY Microscpically  hyperplasia & anaplasia of glands Microscpically  hyperplasia & anaplasia of glands Invasion of stroma, myometrium, or vascular spaces 1-Adenocarcinomas  80-85% Grade 1  well differentiated & difficult to distinguish from atypical complex hyperplasia Grade 1  well differentiated & difficult to distinguish from atypical complex hyperplasia Grade 2 Grade 2 Grade 3  anaplastic Ca (poorly differentiated) Grade 3  anaplastic Ca (poorly differentiated)

HISTOPATHOLOGY 2-Adenocarcinoma with squamous differentiation  5% Malignant glands with benign squamous metaplasia Malignant glands with benign squamous metaplasia Also subdivided into 3 grades Also subdivided into 3 grades 3-Adenosquamous Ca  10-20% Malignant glands & malignant squamous epithelium Malignant glands & malignant squamous epithelium Often grade 3 Often grade 3

HISTOPATHOLOGY 4-Papillary Serous Ca  10% Older women Older women Less likely to have hyperestrogenic state Less likely to have hyperestrogenic state Simillar to Papillary Serous Ca of the ovaries Simillar to Papillary Serous Ca of the ovaries Spread early through peritoneal surfaces of the pelvis & abdomen Spread early through peritoneal surfaces of the pelvis & abdomen Invasion of the myometrium & lymphatic Invasion of the myometrium & lymphatic Prognosis unfavorable Prognosis unfavorable

HISTOPATHOLOGY 5-Clear cell Ca  4% Microscopic appearance  clear cells / solid, papillary, tubular, & cystic pattern are possible Microscopic appearance  clear cells / solid, papillary, tubular, & cystic pattern are possible Commonly high grade & aggressive Commonly high grade & aggressive Seen in advanced stages Seen in advanced stages Older women Older women Not associated with hyperestrogenic states Not associated with hyperestrogenic states Behaves like ovarian Ca Behaves like ovarian Ca

HISTOPATHOLOGY 6-Mucinous Ca  9% PAS- positive intracytoplasmic mucin PAS- positive intracytoplasmic mucin 7-Secretory Ca  1-2% Exhibit sub-nuclear or supra-nuclear vacuoles  resembling early secretory endometrium Exhibit sub-nuclear or supra-nuclear vacuoles  resembling early secretory endometrium Behaves like typical E Ca Behaves like typical E Ca 8-Squamous cell Ca  extremely rare Associated with  Cx stenosis, pyometra & inflammation Associated with  Cx stenosis, pyometra & inflammation

SPREAD 1-Direct spread Through the endometrial cavity  to Cx Through the endometrial cavity  to Cx Through the fallopian tubes  to ovaries & peritoneal cavity Through the fallopian tubes  to ovaries & peritoneal cavity Through invading the myometrium  to serosal surface,parametrium & pelvic wall Through invading the myometrium  to serosal surface,parametrium & pelvic wall Rarely  direct invasion of the pubic bone Rarely  direct invasion of the pubic bone

SPREAD 2- Lymphatic spread  Never occurs without myometrial invasion Never occurs without myometrial invasion The incidence of involvement is related to the degree of differentiation & depth of myometrial involvement The incidence of involvement is related to the degree of differentiation & depth of myometrial involvement Pelvic lymphnodes  common 35% Pelvic lymphnodes  common 35% Para-aortic lymphnodes  10-20% Para-aortic lymphnodes  10-20% Rarely involved without pelvic nodes involvement Rarely involved without pelvic nodes involvement Inguinal lymphnodes  rare Inguinal lymphnodes  rare

SPREAD 3-Hematogenous spread to the lungs Uncommon with the 1ry tumor limited to the uterus Uncommon with the 1ry tumor limited to the uterus Occurs with recurrent or disseminated disease Occurs with recurrent or disseminated disease 4-Vaginal metastasis  3-8% of clinical stage I Occur through direct spread, submucousal lymphatics or hematogenous spread Occur through direct spread, submucousal lymphatics or hematogenous spread More common with high grade & lower uterine segment or Cx involvement More common with high grade & lower uterine segment or Cx involvement

PROGNOSTIC FACTORS Stage  overall survival depends on the stage at Dx Stage  overall survival depends on the stage at Dx -Stage I  72% -Stage II  56% -Stage III  32% -Stage IV  11% Depth of myometrial invasion  correlates with lymph nodes involvement in early disease Depth of myometrial invasion  correlates with lymph nodes involvement in early disease -also correlates with tumor grade Malignant cells in peritoneal washings Malignant cells in peritoneal washings

PROGNOSTIC FACTORS Tumor grade  as it    depth of invasion & LN involvement Tumor grade  as it    depth of invasion & LN involvement -grade I  90% limited to endometrium or inner ½ of the myometrium -grade III  50% invading the outer half of the myometrium Histological type Histological type -adenocarcinoma  best prognosis -clear cell & papillary serous types  poorer prognosis -absence of estrogen receptors  poorer prognosis Lymphovascular space involvement  important prognostic factor in terms of survival & recurrence for stage I disease Lymphovascular space involvement  important prognostic factor in terms of survival & recurrence for stage I disease

INVESTIGATION Any Pt with signs or symptoms suggestive of E Ca should be investigated Any Pt with signs or symptoms suggestive of E Ca should be investigated All Pt should have endometrial sampling in the clinic  false -ve 10% All Pt should have endometrial sampling in the clinic  false -ve 10% If continues to be symptomatic in spite of – ve biopsy or suspicious finding on biopsy  D&C If continues to be symptomatic in spite of – ve biopsy or suspicious finding on biopsy  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 targeted endometrial biopsy The current “ gold standard ” is hystroscopy with targeted endometrial biopsy

INVESTIGATION As an alternative  endometrial sampling with a pipelle + transvaginal U/S to assess endometrial thickness, presence of endometrial polyp or ovarian masses As an alternative  endometrial sampling with a pipelle + transvaginal U/S to assess endometrial thickness, presence of endometrial polyp or ovarian masses Endometrium < 5 mm in thickness  high – ve predictive value Endometrium < 5 mm in thickness  high – ve predictive value U/S also helpful in assessing the depth of endometrial invasion U/S also helpful in assessing the depth of endometrial invasion MRI  depth of E invasion, Cx, & LN involvement MRI  depth of E invasion, Cx, & LN involvement Chest X-Ray  exclude pulmonary spread Chest X-Ray  exclude pulmonary spread

STAGING Surgical staging  TAH + BSO + pelvic washings +abdominal exploration + selective pelvic & PA LN biopsies I confined to the body of the uterus Ia confined to the endometrium Ia confined to the endometrium Ib myometrial invasion < 50% Ib myometrial invasion < 50% Ic myometrial invasion > 50% Ic myometrial invasion > 50% II Cx involved IIa endocervical gland involvement only IIa endocervical gland involvement only IIb Cx stromal invasion IIb Cx stromal invasion does not extend beyond the body of the uterus does not extend beyond the body of the uterus

STAGING III spread to serosa of uterus, peritoneal cavity or LN cavity or LN IIIa Ca involving serosa of uterus, adnexae, +ve ascites or +ve peritoneal washings +ve ascites or +ve peritoneal washings IIIb vaginal involvement either direct or metastatic metastatic IIIc para-aortic or pelvic LN involvement IV local or distant metastasis IVa Ca involving the mucosa of the bladder or rectum rectum IVb distant metastasis & involvement if other abdominal or inguinal LN abdominal or inguinal LN

DIFFERENTIAL DIAGNOSIS Various causes of abnormal bleeding Various causes of abnormal bleeding Premenopausal Pt  exclude pregnancy complications  abortion Premenopausal Pt  exclude pregnancy complications  abortion Endometrial hyperplasia Endometrial hyperplasia Endometrial & Cx polyps Endometrial & Cx polyps Fibroid Fibroid Ovarian, Cx or tubal neoplasms Ovarian, Cx or tubal neoplasms Postmenomausal Pt  atrophic vaginitis, endometrial atrophy, exogenous estrogens Postmenomausal Pt  atrophic vaginitis, endometrial atrophy, exogenous estrogens Urethral caruncles Urethral caruncles Trauma Trauma

COMPLICATIONS Severe anemia 2ry tochronic blood loss or acute hemorrhage  high dose bolus radiation therapy is effective in controlling the hemorrhage Severe anemia 2ry tochronic blood loss or acute hemorrhage  high dose bolus radiation therapy is effective in controlling the hemorrhage Hematometra  Cx dilatation for adequate drainage Hematometra  Cx dilatation for adequate drainage Pyometra  Cx dilatation for adequate drainage + antibiotics Pyometra  Cx dilatation for adequate drainage + antibiotics Perforation of the uterus at the time of D&C or endometrial sampling  laparoscopy or laparotomy toevaluate &repair the damage + antibiotics Perforation of the uterus at the time of D&C or endometrial sampling  laparoscopy or laparotomy toevaluate &repair the damage + antibiotics

TREATMENT 1-SURGERY TAH & BSO  stage I & II  may require radiotherapy TAH & BSO  stage I & II  may require radiotherapy Surgery alone ≤ stage Ib /grade 1or 2/adenocarcinoma Surgery alone ≤ stage Ib /grade 1or 2/adenocarcinoma Stage III  radical surgery (TAH/BSO + max debulking) followed by radio therapy Stage III  radical surgery (TAH/BSO + max debulking) followed by radio therapy

TREATMENT 2-RADIOTHERAPY Stage I or II  most Pt require surgery + radiotherapy if they have any adverse features Stage I or II  most Pt require surgery + radiotherapy if they have any adverse features Radiotherapy regime : Radiotherapy regime : - high dose intracavitary brachytherapy   risk of vault recurrence - low dose external beam radiotherapy   risk of pelvic recurrence Advanced disease  as palliative Rx   bone pain & vaginal bleeding Advanced disease  as palliative Rx   bone pain & vaginal bleeding

TREATMENT 3-HORMONE THERAPY Progestogens (medroxyprogestrone acetate mg/D) Progestogens (medroxyprogestrone acetate mg/D) Will not prevent recurrence Will not prevent recurrence Used in the management of recurrent disease  response rate 30% Used in the management of recurrent disease  response rate 30% Response is higher in estrogen progestrone receptor +ve tumors Response is higher in estrogen progestrone receptor +ve tumors Other hormonal agents  tamoxifen & GnRH limited responce Other hormonal agents  tamoxifen & GnRH limited responce

TREATMENT 4-CHEMOTHERAPY Not commonly used Not commonly used Should be considered in fit Pt with systemic / advanced disease Should be considered in fit Pt with systemic / advanced disease Epirubicin, doxorubicin, cisplatin, carboplatin  response rate 25-30% / short lived response Epirubicin, doxorubicin, cisplatin, carboplatin  response rate 25-30% / short lived response

PROGNOSIS The 5 Y survival rate for endometrial Ca : Stage I  75% Stage I  75% Stage II  58% Stage II  58% Stage III  30% Stage III  30% Stage IV  10% Stage IV  10% Overall 5 Y survival  70%  most Pt present early due to abnormal vaginal bleeding Overall 5 Y survival  70%  most Pt present early due to abnormal vaginal bleeding