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Endometrial Hyperplasia

Complex hyperplasia Atypical simple hyperplasia Atypical complex hyperplasia defines an endometrium with dilated glands that may contain some outpouching and abundant endometrial stroma Glands cystically dilated and focal crowding

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Endometrial hyperplasia is believed to result from an excess of estrogen or an excess of estrogen relative to progestin, such as occurs with anovulation.

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Lined by psuedostratified tall columnar epithelium Glands separated by abundant cellular stroma term has been used to describe dilation of the endometrial glands, which often occurs in a hyperplastic endometrium in a menopausal or postmenopausal woman (cystic atrophy). It is considered to be weakly premalignant.
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this condition, glands are crowded with very little endo-metrial stroma and a very complex gland pattern and outpouching formations this is a variant of adenomatous hyperplasia with moderate to severe degrees of architectural atypia but with no cytologic atypia. These hyperplasias have a low premalignant potential.
A i l H l x y t p a p e r p y c a s a i

refers to hyperplasias that contain glands with cytologic atypia and are considered premalignant an increase in the nuclear/cytoplasmic ratio with irregularity in the size and shape of the nuclei Cytologic atypia occurs primarily with complex hyperplasia, and simple hyperplasia with atypia is rarely seen. Complex atypical hyperplasia has the greatest malignant potential. Crowding of glands with disparity in their size and irregularity in their shape. Budding with fingerlike outpouching in the adjacent endometrial stroma Nuclear Atypia Loss of polarity Increased N:C Ratio Irregular size and shape Prominent nucleoli Thick nuclear membrane Atypia Crowding of glands Epithelial stratification, scalloping and tuffin Cytomegaly, loss polarity, hyperchromatism, prominence of nucleoli Altered N/C ratio Mitosis is common Symptoms of Endometrial Hyperplasia Abnormal Vaginal Bleeding is the most frequent symptom of endometrial hyperplasia Younger patients hyperplasia may develop during anovulatory cycles and maybe even detected after a prolonged periods of oligomenorrhea or amenorrhea Can occur anytime in reproductive age group

Most common in perimenopausal period Diagnosis of Endometrial Hyperplasia Premenopausal women with irregular vaginal bleeding and post menopausal women with any vaginal bleeding should be evaluated with endometrial sampling and D&C Office sampling: thin plastic pipelle, introduced through the cervical os into the endometrial cavity and can provide very accurate information. Many patients tolerate office endometrial sampling without an analgesic agent, but paracervical block can be an effective anesthetic aid, partic-ularly in nulliparous women. Some patients benefit from an oral nonsteroidal antiinflammatory drug taken approximately 30 minutes before biopsy. Transvaginal ultrasonongraphy: - an adjunct for the diagnosis of endometrial hyperplasia and cancer. - Greater use was eliminating the diagnosis of neoplasia for those with endometrial thickness less than 5mm (negative predictive value of 99%) - Less than 4mm had a 100% negative predictive value - Routine screening with transvaginal ultrasound was not of value, and authors concluded that sampling should be done if the patient experiences bleeding - Normal Endometrial Thickness Ultrasonography: Postmenopause: <5mm Reproductive Age: *Proliferative Phase: 5-8mm *Periovulatory Phase: 6-10mm *Secretory Phase: 7-14mm D&C Hysteroscopy Diagnostic Procedures and Tests when Appropriate: - CBC, Serum iron, Ferritin - Coagulation Profile - HCG assay - Thyroid function test - Prolactin - Serum progesterone - HSG, HSSG Thickened Endometrium A measurement of >5mm in the postmenopausal woman and > 15mm in the premenopausal woman warrant further investigation with sonohysterography, transvaginal color Doppler and/or endometrial tissue sampling Schematic Diagram of Endometrial Management for Reproductive Patients

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age 35-55: 12% age >56: 28%

Endometrial Cancer most common in 50-65 y/o th 15 most common overall #1 in gynecologic cancer; #2 cancer in women Incidence starts rising steeply at age 50. Route of Spread:
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1. A small lymphatic branch along the round ligament that runs to the inguinal femoral nodes 2. Lymphatic branches from the fallopian tubes 3. Ovarian pedicles (infundibulopelvic ligaments), which are large lymphatics that drain into the paraaortic nodes 4. The broad ligament lymphatics that drain directly to the pelvic nodes
D i P i l S e r c t e r t n o e a p e r

1. 2.

Through the uterine wall Lumen of the fallopian tube

Medical Management of Endometrial Hyperplasia Combined oral contraceptive pills Medroxyprogesterone Acetate Megestrol Acetate LNG Containing IUD Surgical Management of Endometrial Hyperplasia D&C Endometrial ablation - indicated for bleeding unresponsive to therapy - when hysterectomy is contraindicated - women who do not want to take medications - women who refuse hysterectomy - no desire for pregnancy Hysterectomy - treatment for atypical hyperplasia - age <35: 11%

 Histologic Types Typical endometrioid adenocarcinoma Adenocarcinoma with squamous elements Clear cell carcinoma Serous carcinoma Secretory carcinoma Mucinous carcinoma Squamous carcinoma Adenocarcinoma with Squamous Differentiation Used with description of the degree of differentiation of both the glandular and squamous components Adenoacanthoma: previously used to describe a well differentiated tumor Adenosquamous Carcinoma: described a poorly differentiated carcinoma with squamous elements Clear Cell Carcinoma Resemble clear cell adenocarcinoma of the ovary, cervix and vagina Tend to develop in postmenopausal women Prognosis much worse than typical endometrial adenocarcinoma Survival rates of 39% - 55% have been reported, much less the 65% or better usually recorded for endometrial carcinoma Uterine Papillary Serous Carcinoma Uncommon (5-10%) Highly virulent Histologically resemble papillary serous carcinoma of the ovary (epithelial anaplasia and papillary growth) High risk of extrauterine disease (+) progestational stimulation and corpus luteum is frequently detected in the ovary Good prognosis Mucinous Carcinoma Extremely rare Confused with mucinous carcinoma of the ovary, cervix or bowel
[*]
E d i l P i A d o m e t r r m a y r e n o c a c r i o m a n a n s

With good prognosis

Degree of Differentiation G1 Well differentiated G2 Moderately differentiated G3 Poorly differentiated

Less than 6% solid components 6%-50% solid components More than 50% solid components

Hyperestrogenic States Unopposed estrogen stimulation Unopposed menopausal estrogen (4-6x) replacement therapy Menopausal after 52 year (2-4x) Obesity (2-5x) Nulliparity (2-3x) Diabetes (2-8x) Feminizing ovarian tumors Polycystic ovarian syndrome Tamoxifen therapy for breast cancer Diminished Risk: 1. ovulation 2. progestine therapy 3. combination oral contraception 4. menopause before 49 years 5. normal weight 6. multiparity Steroid Hormone Receptors 1. The steroid leels in endometrial carcinoma is lowest than in normal endometrium 2. Highest levels of estrogen and progesterone receptors in tumors have been found in the well differentiated (grade 1) tumors and the lowest (grade 3) tumors 3. Survival rate is better for women with receptor rich tumors
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S I a t e g S I a t e g I
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Schematic for surgical staging for endometrial carcinoma according to 1988 International Federation of Gynecology and Oncology definitions Signs and Symptoms of Endometrial Carcinoma Post menopausal bleeding Abnormal premenopausal bleeding

Perimenopausal bleeding Diagnosis Endometrial Biopsy: - With ECC: to rule out invasion to endocervix and the patient is GOOD risk for surgery - Without ECC Pap Smear detects endometrial cancer in only 50% D&C Hysteroscopy Prognostic Factors I. Clinical determinants: patient age at diagnosis: older > young race: white > black clinical tumor stage II. Pathologic determinants tumor grade histologic type uterine size depth of myometrial invasion microscopic involvement of vascular spaces in the uterus by tumor spread of tumor outside the uterus to the retroperitoneal lymph nodes, perito-neal cavity, or uterine adnexa. III. Histologic Grade major determinant of prognosis IV. Histolohic Type Best Prognosis: - Typical Adenocarcinoma - Secretory carcinoma Poor Prognosis - Papillary serous carcinoma - Clear cell carcinoma - Poorly differentiated carcinoma V. Myometrial Invasion Deepest myometrial penetration: higher grade, higher stage VI. Peritoneal Cytology Results are conflicting Stratify Low Risk, Intermediate Risk and High Risk Stage IA Stage IB Stage IC StageIIA G1 G1 G1 G1 G2 G2 G2 G2 G3 G3 G3 G3 <50% G3 >50%

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Yellow Low Risk Green Intermediate Risk Red High Risk Lymph Node Evaluation Definition of adequate lymphdenectomy needs further investigation 21-25 lymph nodes (pelvic & paraaortic): significantly increases the probability of detecting at least 1 positive lymph node in endometrioid uterine cancer Indication for Aortic Node Sampling 1. suspicious para-aortic or common iliac nodes 2. grossly positive adnexa 3. grossly positive pelvic nodes 4. high grade tumors showing full thickness myometrial invasion 5. clear cell or papillary serous or carcinosarcoma 6. lower uterine segment involvement 7. cervical involvement Guidelines lymph node dissection may be ommited *Low risk corpus cancer (level2B) *Surface dimension < 2cm Routine omentectomy is not *As part of surgical staging recommended *For seemingly early stage endometrioid type adenocarcinoma ADJUVANT treatment for adenocarcinoma with squamous differentiation Results of PORTEC 2 (Phase III RCT) Srudy *Depend on the histological grade of the Glandular component *Vaginal brachytherapy vs pelvic EBRT alone *Vaginal brachytherapy provides a better result than pelvic EBRT in terms of QOL (initial) *Predictive of NODAL SPREAD for endometrioid histologic type tumors (odds ratio: 5) *Prognostic significance, however remains unknown *Strong predictor of distance and lymphatic recurrence *Warrants adjuvant therapy *Associated with a 2 fold risk of death *Adjuvant therapy chemotherapy

(doxorubicin-based) radiotherapy Management: Stage I: Confined to the Corpus Surgery: EHBSO, PFC, Lymph Node Evaluation Adjuvant: Radiation (not for low risk patients) IA G1, G2 No Adjuvant G3 Vaginal Brachytherapy IB G1, G2 No Adjuvant G3 Pelvic EBRT IC G1, G2, G3 Pelvic EBRT

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Stage II: Tumor extension to the cervix (occult/microscopic) Occult Stage II: is defined as (+) ECC with histologic continuity but with no gross evidence of cervical involvement IIA RHBSO, PFC, LNE No Adjuvant IIB EHBSO, PFC, LNE Pelvic EBRT, there is no apparent benefit for additional brachytherapy Stage III: Tumor extension to the cervix For good surgical risk (radical) Surgico Pathologic Staging Surgery Adjuvant IIA/IIB G1,G2,G3 RHBSO, PFC, No Adjuvant LNE For poor surgical risk (pre operative brachytherapysurgery Stage II Pre operative pelvic RT and vaginal brachytherapy followed G1, G2, G3 by PFC and EHBSO with selective lymphadenectomy (common iliac and para-aortic) Guidelines for Stage III Tumor Extended to the Endocervix Patients who underwent RHBSO Lines of resection are negative Brachytherapy is not necessary RH is the recommended With > 50% myometrial invasion Grade 3 tumors Cevical involvement (+) LVSI Give adjuvant therapy

Lower uterine segment involvement

Positive LVSI (regardless of stage and grade)

Stage III: Tumor extension outside the uterus within the pelvis Surgery (primary): EHBSO, PFC, LNE, Debulking Adjuvant: Chemotherapy followed by RT staging adjuvant IIIB Chemotherapy Pelvic EBRT IIIC EFRT
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Vaginal Brachytherapy

Every 3 weeks for a maximum of 7 cycles or until disease progression or unacceptable toxicity occurs. No dose reduction is required even if there is previous RT
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:

9. Lymph node (location and number) 10. Peritoneal fluid Persistent or Recurrent Disease Treatment Options 1. Should be individualized 2. Depend on site, extent of disease and receptor status 3. May give irradiation 4. May give chemotherapy Other Treatment Options 1. Laparoscopy 2. Vaginal Hysterectomy Hormonal Treatment
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Every 3 weeks for a maximum of Doxorubicin 500mg/m2 or until disease progression or unacceptable toxicity occurs
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Every 4 weeks for 6 cycles

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Stage IV: Tumor invades bladder and/or bowel mucosa. +/- distant metastasis Surgery (primary) EHBSO, Tumor Debulking Adjuvant Chemotherapy followed by EFRT and vaginal brachytherapy Poor Histologic Types: Uterine Papillary Serous/Clear Cell Carcinoma Surgery (primary treatment) EHBSO, PFC, BLND, PALS, IO, RPB (extended surgical staging) Stage Adjuvant IA Observation IB-IV ChemotherapyAbdominopelvic RT Final Histopathologic Report of Endometrial Cancer Specimens 1. Histologic Type 2. Histologic Grade 3. LVSI 4. Depth of myometrial invasion 5. Type of cervical involvement 6. Adnexal involvement 7. Parametria 8. Vaginal rim/cuff

Megestrol Acetate MPA DMPA Side effects: Weight gain Edema Thromboplebitis Headache Occasional hypertension Response Rate: 30-50% *poorly differentiated tumors or hormone-receptor negative tumors have significantly lower response rates *should be considered in patients with recurrent endometrial cancer
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1 Generation: tamoxifen nd 2 Generation: raloxifen rd 3 Generation: arzoxifen 3. Aromatase Inhibitors (anastrazole) An oral steroidal aromatase inhibitor Response Rate: - unselected population 9% - endometrioid G1, G2 30% Follow-Up after Completion of Treatment Every 3-4 mo for the first 2 years, every 6 months for the next 3 years and yearly thereafter *Pap Smear at least yearly *MRI or CT Scan annual for the first 3 years

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*Ultrasonography +/- Color Doppler option *Annual CXR does not contribute to early detection of recurrence *Isolated vaginal vault recurrence curable in up to 87% of cases in patients not previously exposed to radiation *CA 125 -recommended in cases with advanced surgical stage (stage 3-4) -or high risk histologic subtypes every 6 months on the first year -annually thereafter up to 5 years Sarcomas

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Histologic Features: comparable with a 12-week pregnancy or larger risk of sarcoma increased with age, determination of malignancy is made in part by ascertaining the number of mitoses in 10 hpf as well as the presence of cytologic atypia, abnormal mitotic figures, and nuclear pleomorphism finding of more than five mitoses per 10 hpf with cytologic atypia leads to a diagnosis of leiomyosarcoma; when there are four or fewer mitoses per 10 hpf, the tumors usually have a more benign clinical course Prognosis: Vascular invasion and extrauterine spread of tumor are associated with worse prognoses. prognosis worsens for tumors with more than 10 mitoses per 10 hpf. presence of bizarre cells may not necessarily establish the diagnosis because they can occasionally be seen in benign leiomyomas and in patients receiving progestational agents. it is important to note that an increase in mitotic count in leiomyomas occurs in pregnancy as well as during oral contraceptive use Clinical Features: patient has an enlarged pelvic mass, occasionally accompanied by pain or vaginal bleeding Leiomyosarcomas are suspected if the uterus undergoes rapid enlargement, partic-ularly in patients in the perimenopausal or postmenopausal age group. Treatment Primary treatment includes total hysterectomy, bilateral salpingooophorectomy, and staging recurrence in most of these patients is outside the pelvis Cisplatin, Adriamycin, paclitaxel (Taxol), ifosfamide actinomycin D, and cyclophosphamide (Cytoxan) (VAC protocol
E d i l S l o m e t r t r o m a S c r o m a n a a

Histological Feature: behavior correlates primarily with mitotic rate these tumors were once divided into low grade and high grade, more recently all ESSs are considered low grade. If high-grade elements are present, these tumors would be classified as undifferentiated high-grade sarcomas. Undifferentiated sarcomas have a greater degree of anaplasia and lack the branching vasculature characteristic of ESSs. ESSs have a peak incidence in the fifth decade of life.

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 Histologically, ESS most resembles proliferative endometrial stroma. Prognosis: Prognosis depends on the extent of disease and ability to remove all of the tumor at the time of surgery ESSs are indolent, slowly progressing tumors. Clinical Features: Recurrent disease may be diagnosed as many as 30 years after diagnosis ESS tends to recur locally in the pelvis or peritoneal cavity and frequently spreads to the lungs Treatment: In treating metastatic disease, it should be remembered that these tumors contain estrogen and progestin steroid hormone receptors and are sensitive to hormone therapy Complete resolution has been reported with megestrol acetate (Megace), medroxyprogesterone (Provera), letrozole (Femara), tamoxifen, and 17hydroxyprogesterone caproate (Delalutin). Radiation has also been used to treat recurrences of these tumors, especially in the pelvis, with resolution of all residual tumors, but extensive experience with radiation therapy is not available. Systemic chemotherapy with cytotoxic agents has not been reported generally to be effective, although good responses to doxorubicin (Adriamycin) have been reported.
U d i f f i d n e e r n t e t a S c r o m a a s

Clinical Features: carcinosarcoma tend to be older and primarily postmenopausal, usually beyond the age of 62 years. These tumors spread into the myometrium and then to the pelvis, to the abdomen including the peritoneum, and frequently to the lungs and pleura, a pattern similar to the spread of endometrial carcinoma. A common symptom is postmenopausal bleeding, often accompanied by a large uterus. Method of Diagnosis: Occasionally, the diagnosis is made in tissue removed with D&C, and the tumor may appear to be a polypoid excrescence from the cervix; diagnosis may be made also by vaginal ultrasound examination. Those with deep myometrial invasion are more likely to have spread to pelvic or paraaortic nodes, as in endometrial carcinomas. Prognosis: The extent of the tumor and the depth of myometrial invasion are important prognostic factors. Treatment: primary treatment is surgical removal of the uterus. Total abdominal hysterectomy and bilateral salpingo-oophorectomy are completed with stage I tumors More extensive procedures are occasionally attempted for stage II tumors as well as for those with early extrauterine spread.
M l l i A r n e d n o a s c r o m a e a

Prognosis: These high-grade tumors behave aggressively and have a poor prognosis. Method of Diagnosis: These tumors must be evaluated carefully as they are often confused with other large cell undifferentiated tumors (lymphoma, leukemia, high-grade endometrial cancer, carcinosarcoma). Histological Feature: Microscopically, more than 10 mitoses per 10 hpf are present, and frequently 20 or more mitoses per 10 hpf are present. Clinical Features: Recurrences are common in the pelvis, lung, and abdomen If there is disseminated disease, multiple-agent chemotherapy is used.
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Mllerian adenosarcoma is a rare low-grade malignancy composed of both a sarcomatous stroma (homologous) and a proliferation of benign glandular elements that are intimately associated. occurs predominantly in women older than 60 years. Total abdominal hysterectomy with bilateral salpingo-oophorectomy is the streatment of choice patients with advanced-stage disease or recurrent disease, there was a moderate rate of response to platinum-based chemotherapy and chemosensitizing radiation.
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M l i M i d M l l i T a c r o a s c r o m a a n g a n t e x r n u m o r n e

Histological Features: consist of carcinomatous and sarcomatous elements native to the uterus that may resemble the endometrial stroma of smooth muscle (homologous) or of sarcomatous tissues foreign to the uterus (heterologous).

M d i f i o e

involvement of the uterus may be the initial presentation of disseminated lymphoma usually treated by radiation after hysterectomy
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Carcinosarcoma (malignant mixed mullerian tumor)

Homologous (Carcinosarcoma): Carcinosarcoma + Homologous Sarcoma Heterologous Carcinsarcoma + Heterologous Sarcoma Mullerian Adenosarcoma Lymphoma
K E Y P O I N T S

stage, histologic type, and degree of myometrial invasion. Older patients with atypical hyperplasia are at increased risk of malignant progression compared with younger patients. Computed tomography scans may miss as many as 50% of patients with nodal disease. A key determinant of the risk of nodal spread of endometrial carcinoma is depth of myometrial invasion, which is often related to tumor grade. Well-differentiated (grade 1) endometrial carcinomas usually express steroid hormone receptors, whereas poorly differentiated (grade 3) tumors usually do not express receptors. Uterine papillary serous carcinoma is an aggressive histologic subtype associated with metastatic disease even in the absence of myometrial invasion. Ninety percent of recurrences of adenocarcinoma of the endometrium occur within 5 years. Overall survival rates for patients with adenocarcinoma of the endometrium by stage are as follows: stage I, 86%; stage II, 66%; stage III, 44%; stage IV, 16% (overall 72.7% 5-year survival rate combining clinical and operative staging systems). Histologic variants of endometrial carcinoma with a poor prognosis include uterine papillary serous carcinoma and clear-cell carcinoma. Patients with uterine papillary serous or clear-cell carcinoma of the endometrium should have a full staging laparotomy similar to that for ovarian carcinoma. The most frequent sites of distant metastasis of adenocarcinoma of the endometrium are the lung, retroperitoneal nodes, and abdomen. Primary treatment of endometrial cancer includes hysterectomy, bilateral salpingo-oophorectomy, pelvic cytology, bilateral pelvic and paraaorotic lymphadenectomy, and resection of all disease. The exceptions include young perimenopausal women with stage I and grade 1 endometrial carcinoma associated with endometrial hyperplasia, and women with increased risk of mortality secondary to medical comorbidities. Postoperative adjuvant radiation has not been shown to improve overall survival.

Endometrial carcinoma is the most common malignancy of the female genital tract. In the United States, the lifetime risk of endometrial cancer is 3%. Most women who develop endometrial cancer are between 50 and 65 years of age. Women with Lynch syndrome (hereditary nonpolyposis colorectal cancer syndrome) have a 40% to 60% lifetime risk of endometrial cancer, which is similar to their lifetime risk of colon cancer. Chronic unopposed estrogen stimulation of the endometrium leads to endometrial hyperplasia and in some cases adenocarcinoma. Other important predisposing factors include obesity, nulliparity, late menopause, and diabetes. The risk of a woman developing endometrial carcinoma is increased three times if her body mass index is greater than 30. Tamoxifen use increases the risk of endometrial neoplasia two- to threefold. The primary symptom of endometrial carcinoma is postmenopausal bleeding. Women with abnormal bleeding should undergo an endometrial sampling to rule out endometrial pathology. Cytologic atypia in endometrial hyperplasia is the most important factor in determining malignant potential. Simple hyperplasia will develop into endometrial cancer in 1% of patients, whereas complex hyperplasia will develop into cancer in 29% of patients. Recent studies have found that there is a 40% concurrent rate of endometrial cancer in patients with a preoperative diagnosis of complex atypical hyperplasia. Prognosis in endometrial carcinoma is related to tumor grade, tumor

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Patients with high stage or recurrent disease should be treated in a multimodality approach including chemotherapy, radiation, and/or hormone therapy. Uterine sarcomas comprise less than 5% of uterine malignancies. Uterine sarcomas are treated primarily by operation including removal of the uterus, tubes, and ovaries. Endometrial stromal sarcomas are low-grade sarcomas with an indolent course. Multiagent chemotherapeutic regimens are usually prescribed for metastatic sarcomas; complete responses are rare and usually temporary.

IA IB IIA IIB IIIA IIIB IIIC IVA

Tumor limited to uterus < 5 cm Tumor limited to uterus > 5 cm Tumor extends to the pelvis, adnexal involvement Tumor extends to extra-uterine pelvic tissue Tumor invades abdominal tissues, one site More than one site Metastasis to pelvic and/or para-aortic lymph nodes Tumor invades bladder and/or rectum Distant metastasis
S t I D i f f f O t h U t i n o s a r c o m a a e g e r s r o m r e r e S a r c o m a e n s

m e

IVB IA IB II IIIA IIIB Tumor confined to the uterus, no or < myometrial invasion
A e d

Tumor confined to the uterus, > myometrial invasion IA Cervical stromal invasion, but not beyond uterus IB Tumor invades serosa or adnexa IB Vaginal and/or parametrial involvement Invasion to > myometrium Invasion to < myometrium Tumor limited to endometrium/endocervix

IIIC1 Pelvic node involvement IIIC2 Para-aortic involvement IVA IVB Tumor invasion bladder and/or bowel mucosa Distant metastases including abdominal metastases and/or inguinal lymph nodes

Uterine sarcomas were staged previously as endometrial cancers, which did not reflect clinical behavior. Therefore, a new corpus sarcoma staging system was developed based on the criteria [2] used in other soft tissue sarcomas. This is described as a best guess staging system, so data will need to be collected and evaluated for further revision.

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