Malignant diseases of the uterus

Dr.Omar Aldabbas Assisstant prof.

MUTA university OBGYN specialist

Endometrial cancer

Endometrial cancer

Epidemiology:

1. Age: 1.

Median age

(or mean age? Which is more accurate?)

is 61 y. 2.

75-80% of women are postmenopausal, and 3-5% being less than 40 years old, it peaks in the years before the menopause and plateau after that.

“Another peak of EC is in the 40s” 2. Country variations: Highest in north America.

3. Racial variations: MORE IN Whites.

Endometrial cancer

• •

Aetiology:

Unknown.

Unopposed estrogen. So it is more in women with:

1. Nulliparity 2. Anovulation 3. PCOS (during their life) (because it comprises hyeprestrogenism and failure of ovulation) 4. Late Menopause 5. Functioning ovarian tumor. Estrogen producing. Granulose and theca cell tumor.

6. Unopposed estrogen therapy 7. Obesity

Endometrial cancer

8. Personal or family history of breast or colon cancer, and family history of endometrial cancer.

9. Tamoxifen therapy

(Has estrogenic-type effect on the uterus in particular. Anti estrogen effect on other organs … Only on the uterus it is agonist).

•

HRT While Combined oral contraceptive pills and progesterone decreases the incidence of endometrial cancer (Only because they contain progesterone which antagonizes the action of estrogen. Even in the combined pill, progesterone counteracts the action of estrogen.)

Endometrial cancer

Pathology

1. Endometrial adenocarcinoma: Is the commonest about 90%.

2. Endometrial adenocarcinoma with squamous metaplasia (adenoacanthoma) 3. Adenosquamous carcinoma 4. Papillary serous and clear cell carcinoma are very rare.

Uterus Cervix

90%

Adenocarcinoma Squamous

10%

Squamous Adenocarcinoma

Endometrial hyperplasia

• •

1.

2.

3.

Cystic hyperplasia:

The most common type, rarely seen in association with endometrial cancer. risk of progression to cancer is 0.4-1.1%. Benign hyperplasia because the chance of changing into malignant. Not precancerous lesion.

Adenomatous hyperplasia:

Rate of progression to cancer or coexistence with cancer is 0-3.4%

Cystic and adeomatous are benign forms of endometrial hyperplasia

Atypical hyperplasia:

Carcinoma may coexist in 25-50% of cases. And progression to cancer occurs in the rate of 22-33%.

Precancerous lesion. If she completed her family, Considered as “stage 0” endometrial cancer”

Or given progesterone for 9 months, take biospy. If the abnormality disappeared, the problem ended and she can get pregnant.

Endometroid ovarian cancer may co-exist

Endometrial hyperplasia Presentation of hyperplasia:

• Post-menopausal women will present with abnormal bleeding.

• Before the menopause: irregular or heavy periods • Perimenopausal bleeding.

Endometrial hyperplasia

Investigations:

1.

2.

3.

4.

D&C Ovarian ultrasound to exclude Estrogen producing and endometroid tumor.

CA 125 Estradiol estimation.

Endometrial hyperplasia

• • •

Management:

depends on the severity of the condition and her fertility aspirations.

Cystic and adenomatous hyperplasia:

No special follow up and management depends on further symptoms of abnormal bleeding.

– Benign forms of hyperplasia

Atypical hyperplasia

: Hysterectomy and bilateral salpingo-oophorectomy. However, in young women who want to keep the uterus, give Progesterone for 8 12 months and repeat D&C.

– It is considered to be “Stage 0 endometrial cancer”.

• • • •

Endometrial cancer

Diagnosis and investigations: Presenting symptoms:

– Abnormal bleeding. Postmenopausal bleeding in 75-80% of women,.

– A woman who is 60 and gets a single drop of blood, she will doubt it because 10 years since last menses… So better survival rate because most of the cases are discovered at early stage. Only one single drop of blood is enough to make the woman worry. If you examined her. – Next common cause: Senile vaginits. But even if you saw senile vagina, yo have to do diagnostic biopsy. – Pain in late stages.

Clinical examination:

Rarely helpful.

Look for:

enlarged lymph nodes in the groin or supraclavicular area, metastasis in the posterior vaginal wall, uterus may be enlarged,

Endometrial cancer: Investigations

• Endometrial biopsy can be done as an outpatient procedure with special cannula (failure rate 20%) • Ultrasound: vaginal USS to detect tick endometrium in post-menopausal women, ovarian pathology • D&C under GA • Hysteroscopy

Endometrial cancer: Spread of invasive disease:

• • •

Direct:

Myometrium,

Lymphatic:

Para-aortic Lymph nodes – Spread to the cervix may occur by extension, but more commonly through lymphatic.

Blood:

rarely •

Mode of spreading depends on the type of tumor:

– – Any epithelial tumor spreads by lymphatics and is slower Sarcoma: Spreads by blood (Very rapid and can kill quickly and will go quickly to the brain, liver, etc. )

Endometrial cancer

Prognostic factors:

1. Stage of the disease 2. Myometrial invasion 3. Degree of differentiation 4. Tumor size 5. Age

FIGO staging of Endometrial cancer

Stage

• IaG123 tumor limited to the endometrium.

• Ib G123 Invasion <0.5 cm myometrium • Ic G123 Invasion >0.5 cm myometrium • IIa G123 endocervical glandular involvement only • IIbG123 Cervical stromal invasion • IIIaG123:Tumor involves serosa or adnexa (ovaries or tubes) or + ve peritoneal cytology.

• IIIbG123:Vaginal metastasis • IIIc G123:Metastasis to pelvic and/or Para-aortic lymph node.

• Iva: tumor invades bladder and or bowel mucosa • IVb: Distant metastasis including intra-abdominal or inguinal lymph nodes.

• • • G123:referred to the grade of differentiation tumor (1 = well differentiated, 2=moderately, 3 poorly differentiated).

a, b, c: Depends on invasion of the tumor to the myometrium. If stage II: it reached cervix and is treated as cervical cancer.

Endometrial cancer: Management

•

Stage I

: TAH+BSO which could be done either vaginally or abdominally.

•

Radiotherapy:

vault radiation or

external radiation

the whole pelvis. • Vaginal radiation to the vault to minimize vault recurrence.

to • Pelvic radiation advised in women with poor prognostic factors such as invasion more than half way through the myometrium, high grade and large tumor • Adjuvant progesterone therapy: can be used in advanced and recurrent disease.

• III and IV: no place for surgery. Because you are not aiming at treating the patient. Radiotherapy only. Some give progesterone but is hopeless. • Stage II: Only limited to uterus. Luckily , this is the most common presentation. Total abdominal hysterectomy, and bilateral salpingectomy, and maybe omenectomy. If histopathology, showed it involved > 50% of wall or poorly differentiated tumor of deposits in cervix or tubes, you need to give them post-operative radiotherapy. Otherwise, no need for radiotherapy.

• • •

Management: ???

Stage II. Treated as cervical cancer : Radical Hysterectomy (Whertimes) and pelvic lymph nodes removal + Radiation

Endometrial cancer

Management

Stage III

: If there is parametrial extension of the disease or vaginal involvement, patient should have CT scan of the pelvis and upper abdomen. If the tumor is confined to the pelvis, radiation is the choice. If there is spread to the adnexa, do pelvic clearance + Omentectomy as for primary ovarian tumor.

Endometrial cancer

•

Stage IV. The lung are most common sites of metastasis followed by peripheral lymph nodes. Radiation or cytotoxic drugs and hormonal treatment may be required.

• • • • • •

Endometrial cancer

Hormone replacement therapy: It safe to use estrogen in women with stage I-II. If the disease has been removed surgically or by radiation, then Estrogen has no bad effect on the disease.

Stage II: Cervical tumor is considered as. The cornerstone stone of treatment. Ia: only cone biospy or simple hysterectomy.

1b or 2a: Radical or Wertheim hysterectomy. Ovaries, tubes, parametrial tissue until you reach the ureters. Block dissection of all of pelvic LNs c(Common iliac, internal iliac, external iliac, obturator, and presacral LNs)

– –

Why remove ovaries: EC is estrogen dependent tumor.

Also, they share the same lymphatics. So there is cross spread of the two tumors. If endometrial cancer, it might spread via the lymphatics to the ovaries. Vice versa, an ovarian cancer can spread via lymphatic to endometrium. Treatment of ovarian cancer and stage Ia??? Is the same (hysterectomy, bilateral salpingo-oophorectomy, and maybe omentectomy.

–

Paraaortic drainage 2b and above: radiotherapy alone.

Wertheim (veer-time) operation (Austrian gynecologist): a radical operation for carcinoma of the uterus in which as much as possible of the vagina is excised and there is wide lymph node excision.

Endometrial cancer

5 years survival rate

Stage 1 =83%, (in some studies, the doctor saw up to 92%) stage 2= 71%, stage 3=39%, stage 4=27%, all stages= 60%, IN UK, 73%

• When does a patient need post-operative radiation: – Poor differentiation – More than 50% of myometrium or more than 0.5 cm – Microscopic deposits in … – What is the aim of radiation? Because more chance of lymphatics involvement in such cases .

Endometrial cancer

•

Recurrent disease:

70% of all recurrences occurred in the first 2-3 years. Early recurrence carry poor prognosis.

• Can be in any site, but mainly is in the pelvis

Endometrial cancer

•

Sites of recurrence:

Pelvis, vagina, peritoneal cavity, lungs, liver, bone, inguinal and supraclavicular lymph nodes.

• Vault recurrence is more common after surgical treatment which can be cured.

• Progesterone therapy has a response rate of 15-20%, G1 will respond better than G2&3 • Cytotoxic drugs has small role following failure of hormonal therapy. • Radiation maybe the only therapy. Very poor prognosis.

Uterine Sarcoma

Challenging

• Rare → Limited data 2% to 5% of all uterine malignancies – Prognosis, behavior  Not enough data – EC: 2-3 cases/ year… US once in 10 years because is very rare.

• Rapidly growing (doubling time is 4 weeks) – Rapidly spreading: Kill quickly because is through BC • tend to be increasing

Risk Factors

• Prior pelvic radiation (10%-25% of cases) – Women with cervical cancer, stage Ib or more, this lady might come 20 30 years later with US. Generally, all stage of cervical cancer can be treated by radiation (either surgery alone or surgery + radiation) Surgery without radiation in stage 1b and IIa (because you can simply do cone biopsy or simple hysterectomy) • 3X increase in risk among black women • An increase in the risk of uterine sarcomas appears to accompany the use of long-term adjuvant tamoxifen in women with breast cancer.

– Tamoxifen on uterus: poly, ??/ and cancer • Should be considered in postmenopausal women with a pelvic mass, abnormal bleeding, and pelvic pain, where the incidence of sarcoma is 1 to 2 percent – Menopause is a treatment for fibroids!

– If post-menopausal, it is very likely to be cancer. If there is a mass with post menopausal, almost always sarcoma

• Cervical cancer and pregnancy: - T1 + t2: as if she is not pregnant  Wertheim (pron.: veer-time) operation “radical” Not total hysterectomy. After radiation, she will abort. - Late: wait until end of pregnancy and then Wertheim. After 2 weeks, radiation.

Types

• Mixed mullerian sarcomas - 50% • Leiomyosarcoma (30%): De-novo, starts alone. Sarcomatous chance in fibroids is rare. Mostly, de-novo.

• Endometrial stromal sarcoma (15%) • Adenosarcoma (5%):

Leiomyosarcoma

• Arise from smooth muscles of the uterus usually de novo • appear grossly as a large (>10 cm) yellow or tan solitary mass with soft, fleshy cut surfaces exhibiting hemorrhage and necrosis

Leiomyosarcoma

Yellowish, necrosis, and hemorrhagic area. It reaches 10 cm

Leiomyosarcoma: Low or high grade

• Frequent mitotic figures • significant nuclear atypia • presence of coagulative necrosis of tumor cells

Endometrial stromal tumors

:

• A pure homologous neoplasm – Because there is no other tissue • Subtypes: low and high grade malignancies – Based on the number of atypia • Low grade : slow growing tumors with infrequent metastasis or recurrence after therapy. • high grade : enlarge and metastasize quickly and are often fatal.

Mixed mullerian sarcomas

• Both carcinomatous and sarcomatous elements must be present in this type of sarcoma. – CT tumor and epithelial tissue trauma at the same time. – Behavior of sarcoma wins again behavior of carcinoma (because it is blood not lymphatics) • metastasize early in the course of the disease via hematogenous and lymphatic pathways • grows as a polypoidal mass with a broad base

Mixed mullerian sarcomas

• Mixed mullerian homologous sarcomas ( carcinosarcoma ) contain only tissue elements that are indigenous to the uterus. • In contrast, if exogenous tissue not normally found in the uterus is present (eg, bone, cartilage), the tumor should be classified as a mixed heterologous mullerian sarcoma ( mixed mesodermal sarcoma ).

MMT Mixed mesodermal tumor (you can find bone and calcifications)

Adenosarcoma

• both malignant stromal and benign epithelial components • a significantly increased occurrence of this tumor • present as polypoid masses in the uterus • Sarcoma and adenocarcinoma

Clinical Diagnosis

• Vaginal bleeding is the most common presenting symptom of a uterine sarcoma. • On pelvic examination, the uterus is enlarged and, in some patients, part of the tumor may protrude from the uterine cavity through the cervical os.

• Rapidly growing!

• Spreads mainly by blood

Evaluation

• Ultrasound examination, MRI, or CT scan cannot reliably distinguish between a sarcoma, leiomyoma or endometrial cancer • The real diagnosis of uterine sarcomas is made from histologic examination of the entire uterus – Make histology and take the whole sample for examination

Staging: surgical

based on FIGO staging for endometrial cancer

Stage I Description Sarcoma is confined to the corpus II Sarcoma is confined to the corpus and cervix III IV Sarcoma has spread outside the uterus but is confined to the true pelvis Sarcoma has spread outside the true pelvis

Treatment

Surgery:

is the only curative therapy for uterine sarcomas

Modalities:

• Surgery (total abdominal hysterectomy, bilateral salpingo oophorectomy). • Surgery plus adjuvant chemotherapy. • Surgery plus adjuvant irradiation • Aggressive surgical cytoreduction at the time of initial diagnosis offers the best survival • Surgery and chemotherapy is the best combination. Never leave any part of the tumor: Cytoreduction: remove as much as you can of the tumor. Cytoreductive therapy: therapy with the intention of reducing the number of cells in a lesion, usually a malignancy.

The five year survivals: What adds to the survival rate?

• Surgery alone (46 %) • Surgery and radiotherapy (62 %) [improved by 16% so it is something!) • Surgery and chemotherapy (43 %) • Radiation alone (8 %)

three-year local recurrence rates

• No adjuvant treatment 62 % – If you did not use anything • Whole pelvis external beam radiation therapy 31 % – Radiation: recurrence is worse than primary tumor • Chemotherapy alone 71 percent – Technically, it is not useful. It may be harmful.

Complications of Radiation Tx: like what you took in the past!!!

Acute:

• Perforation • Fever • Diarrhea • Bladder spasm

Chronic:

• Proctitis • Cystitis (a/w UTI) • Fistula (Fistulas can be caused by either surgery or radiation) • Enteritis

Adjuvant chemotherapy

• The role of chemotherapy in the treatment of uterine sarcomas has been limited – Or at least, try new chemotherapeutic agents

Hormone therapy

• Estrogen, progesterone, and other hormone receptors are present in leiomyosarcomas and endometrial stromal sarcomas but do not predict hormone responsiveness. • In fact, only one of 28 patients with residual or recurrent disease following surgery had an objective response to hormone therapy

Recurrent Disease

• Most relapses occur in the pelvis, followed by lung and abdomen • • Currently, no standard therapy for patients with recurrent disease Most will go for radiotherapy because they are not aiming at curing the patient!!!

Prognosis

Poor prognosis:

• The 5-year survival : stage I less than 50% • Remaining stages : 0% to 20%.

Poor prognostic factor of leiomyosarcoma:

• Age over 50 years • Size greater than 5 cm