Uterine Sarcoma

Challenging

Rare → Limited data Rapidly growing (doubling time is 4 weeks) tend to be increasing (Nordal & Thoresen 1997)

Epidemiology

Rare 2% to 5% of all uterine malignancies 17 per million women annually [Platz, &

Benda, 1995] Between 1989-1999, 2677 women were

diagnosed with uterine sarcoma (Brooks et al, April, 2004)

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].

Since 1978, when tamoxifen was first marketed in the United States, 159 cases of uterine sarcoma worldwide have been reported

Histologic Classification

TypeHomologousHeterologous

PureLeimyosarcomaRhabdomyosarcoma

Stromal sarcomaChondrosarcoma

(i) endolymphatic stromal sarcomaOsteosarcoma

(ii) Endometrial stromal sarcomaLiposarcoma

MixedCarcinosarcomaMixed mesodermal sarcoma

GOG , 1993

Mixed mullerian sarcomas - 50%

homologous heterologous Leiomyosarcoma (30%). Endometrial stromal sarcoma (15%) Others (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 [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 ]

Endometrial stromal Sarcoma :

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 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

Subdivided

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

heterologous (mixed mesodermal sarcoma) contain tissue element that is foreign to the uterus.

MMT

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: surgical

based on FIGO staging for endometrial cancer

StageDescription

ISarcoma is confined to the corpus

IISarcoma is confined to the corpus and cervix

IIISarcoma has spread outside the uterus but is confined to the true pelvis

IVSarcoma has spread outside the true pelvis

Lymph node Biopsy

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

should be reserved for women 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].

Treatment

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

three-year local recurrence rates

 No adjuvant treatment 62 %  Whole pelvis external beam radiation

therapy 31 % Chemotherapy alone 71 percent

[Livi et al, 2003]

Massachusetts General Hospital

1990-1999 Adjuvant therapy after optimal cytoreduction

does not decrease the rate of recurrence [Dinh et al, 2004]

  Adjuvant radiation therapy

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 TxComplications of Radiation Tx::

Acute: Perforation Fever Diarrhea Bladder spasm

Chronic: Proctitis Cystitis (a/w UTI) Fistula Enteritis

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

This is because

Adjuvant chemotherapy following complete resection (stage I and II) has not been established to be effective in RCT

But some 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

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 and/or progesterone 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 (Wade 1994)

Recurrent Disease

Most relapses occur in the pelvis, followed by lung and abdomen

currently no standard therapy for patients with recurrent disease

Doxorubcin in leiomyosarcoma ? Cisplatin in carcinosarcoma ?

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

More RCTs are needed to determine the value and regime of adjuvant therapy

Thank You