Uterine SarcomaProf Greta DreyerUniversity of Pretoria

Challenging Rare → Limited data

Rapidly growing (doubling time is 4 weeks)

Incidence appears to be increasing

Epidemiology Rare 2% to 5% of all uterine malignancies

17 per million women annually [Platz, & Benda, 1995]

Risk Factors prior pelvic radiation (10%-25% of

cases) 3X increase in risk among black

women (Brooks et al, April, 2004)

Data regarding parity and time of menarche and menopause as risk factors are inconclusive (Sherman & Devesa ,2003)

Long-term adjuvant tamoxifen An increase in the risk of uterine

sarcomas appears to accompany the use of long-term adjuvant tamoxifen in women with breast cancer

[Wickerham et al, 2002, Wysowski et al, 2002].

Histologic Classification

Type Homologous Heterologous

Pure Leimyosarcoma Rhabdomyosarcoma

Stromal sarcoma Chondrosarcoma

(i) endolymphatic stromal sarcoma

Osteosarcoma

(ii) Endometrial stromal sarcoma

Liposarcoma

Mixed Carcinosarcoma Mixed mesodermal sarcoma

GOG , 1993 Mixed mullerian sarcomas - 50% Leiomyosarcoma (30%). Endometrial stromal sarcoma (15%) Adenosarcoma (5%)

Leiomyosarcoma (30%)

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 [Viereck et

al, 2002].

Leiomyosarcoma

Leiomyosarcoma: Low or high grade Frequent mitotic figures significant nuclear atypia, presence of coagulative necrosis of

tumor cells. [Bell et al, 1994 ]

Zaloudek & Norris classification

Diagnosis

Mitosis/10 HPF Cytological atypia

Leiomyoma

< 5 ---------

Atypical (cellular)

< 5 present

Uncertain malignant potential

5-9 absent

Liemyosarcoma (low risk)

5-9 present

Leimyosarcoma (high risk)

> 10 Absent or present

Endometrial stromal tumors : A pure homologous neoplasm Subtypes: low and high grade Low grade : slow growing tumors with

infrequent metastasis or recurrence after therapy. [Oliva, et al, 2000].

high grade : enlarge and metastasize quickly and are often fatal.

Mixed malignant mullerian sarcomas Both carcinomatous and

sarcomatous elements must be present in this type of sarcoma.

metastasize early in the course of the disease via hematogenous and lymphatic pathways

grows as a polypoidal mass with a broad base

Mixed malignant mullerian sarcomas Mixed müllerian homologous sarcomas

(carcinosarcoma) contain only tissue elements that are endogenous to the uterus.

In contrast, if exogenous tissue is present (eg, bone, cartilage, fat), the tumor should be classified as a mixed heterologous müllerian sarcoma (mixed mesodermal sarcoma).

Carcinosarcoma or MMMT

Adenosarcoma both malignant stromal and benign

epithelial components a significantly increased occurrence

of this tumor (Seidman et al, 1999)

present as polypoid masses

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 Among 341 women with a rapidly

growing uterus by clinical or ultrasound examination, only one (0.27 percent) had a uterine sarcoma. [Parker et al, 1994].

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 [Leibsohn et al, 1990]

Evaluation Ultrasound examination, MRI, or CT

scan cannot reliably distinguish between a sarcoma, leiomyoma or endometrial cancer [Rha et al, 2003].

The diagnosis of uterine sarcomas is made from histologic examination of the entire uterus

Staging:

based on FIGO staging for endometrial cancer

Stage Description

I Sarcoma is confined to the corpus

II Sarcoma is confined to the corpus and cervix

III Sarcoma has spread outside the uterus but is confined to the true pelvis

IV Sarcoma has spread outside the true pelvis

Lymph node dissection patients with uterine sarcoma

grossly confined to the uterus/cervix showed lymph node metastases in 5 of 101 patients

should be done in all women who can tolerate the procedure?? / with clinically suspicious nodes?? [Leitao et al, 2003 ]

Further support In one series of 208 women with

uterine leiomyosarcoma, only four of 36 who underwent lymph node sampling had positive nodes [Giuntoli

et al, 2003].

Screening

because of their rarity, uterine sarcomas are not suitable for screening. (Levenback, 1996)

Surgery

is the only curative therapy for uterine sarcomas [Morice et

al, 2003]

Modalities Surgery (total abdominal

hysterectomy, bilateral salpingo-oophorectomy).

Surgery plus adjuvant chemotherapy.

Surgery plus adjuvant irradiation

Is it beneficial Interpretation of the possible benefit

of different modalities is hampered by the difficulty in comparing outcomes from series in which patients of varying stages and histologies were reported

The five year survivals Surgery alone (46 %) Surgery and radiotherapy (62 %) Surgery and chemotherapy (43 %) Radiation alone (8 %)

Weitmann et al, 2001

The three-year local recurrence rates  No adjuvant treatment 62 %  Whole pelvis external beam

radiation therapy 31 % Chemotherapy alone 71 percent

[Livi et al, 2003]

Adjuvant radiation therapy The value of pelvic radiation is not

established Some studies of postoperative radiation

suggest a survival benefit [Moskovic et al, 1993 Knocke et al, 1998, Weitmann et al, 2001].

Other studies showed cure rate was similar for those treated with surgery alone or followed by radiation, regardless of the stage of disease [Giuntoli et al, 2003]

Complications of Radiation Complications of Radiation Tx:Tx:

Acute: Fever Perforation Diarrhea Bladder spasm

Chronic:

Fistula Enteritis Cystitis (a/w

UTI) Proctitis

Adjuvant chemotherapy Current studies consist primarily of

Phase II chemotherapy trials for advanced disease

The role of chemotherapy in the treatment of uterine sarcomas has been limited

Adjuvant therapy Adjuvant chemotherapy following

complete resection (stage I and II) has not been established to be effective in a randomized trial

nonrandomized trials have reported improved survival following adjuvant chemotherapy with or without radiation therapy Piver et al, 1988 ,van Nagell , et al, 1986, Peters et al, 1989

  Leiomyosarcoma doxorubicin is an effective drug for

advanced leiomyosarcoma combinations with doxorubicin

increase the objective response rate but add substantial toxicity

A very recent small trial showed promising results with gemcitabine plus docetaxel [Hensley et al, 2002].

  Carcinosarcoma

Women with carcinosarcoma may benefit from cisplatin-based chemotherapy, particularly combinations of cisplatin with doxorubicin and ifosfamide, or single agent paclitaxel [Gallup et al, 2003 , van Rijswijk et al, 2003, Harris et al, 2003]

Mixed mesodermal tumors Cisplatin and ifosfamide appear to

have greater activity than does doxorubicin alone [Ramondetta et al,

2003]. In a very small uncontrolled trial :

cisplatin, doxorubicin, and dacarbazine give three year survivals of 51 % [Baker et al, 1991].

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

In a recent RCT 2000 ifosfamide with or without cisplatin

for recurrent sarcoma demonstrated a higher response

rate on the combination arm However,use of the combination was

not justified because of increased toxic effects [Sutton et al, 2000]

Prognosis

poor prognosis the 5-year survival : stage I less than

50% remaining stages : 0% to 20%. strongest predictor of survival was

menopausal status at time of diagnosis[Major et al, 1993]

leiomyosarcoma age over 50 years was a poor

prognostic factor, as was size greater than 5 cm [Giuntoli et al,

2003].

Conclusion Aggressive surgical cytoreduction at

the time of initial diagnosis offers the best survival

Thank You