Carcinosarcoma of the uterus

1. Dorothea Greiner, MD

2.  Carcinosarcoma of the ovary accounts for 1-5% of all ovarian
cancers
 Carcinosarcoma of the uterus accounts for less than 5 % of
uterine corpus cancers
 The uterus is the most common gynecologic site for
carcinosarcoma
 80% in postmenopausal women of low parity, mostly aged
50-70
 A higher percentage of patients with carcinosarcoma are
African-American as compared to endometrioid endometrial
cancer (28% as compared to 8%) (Zelmanowicz A. et al. 1998)

3.  Carcinosarcoma tumors contain both
sarcomatous
malignant epithelial and sarcomatous epithelial
(mesenchymal) elements
 epithelial component:
◦ serous
◦ endometrioid
◦ undifferentiated adenocarcinoma
◦ clear cell adenocarcinoma
◦ squamous cell carcinoma
 sarcomatous element:
◦ homologous tissue native to the ovary/
uterus
◦ heterologous tissue not native to the
ovary/uterus
 The carcinomatous (epithelial)
portion predominates within
metastatic sites, and thus,
determines the clinical course of
advanced carcinosarcoma

4.  Biclonal  Monoclonal  1 stem cell precursor
 2 different stem cells  1stem cell  Differentiation in 1 cell type
 Then differentiation in the
second cell type
Combination Conversion
Collision theory theory theory

5.  A study of 30 ovarian
carcinosarcoma performed
comparative genomic
hybridization and fluorescence in
situ hybridization (Schipf A. et al., 2008) .
 Chromosomal amplification of
the c-myc proto-oncogene on
chromosomes 8q and 20q was
 genetic analysis of 12 uterine observed suggesting a
and 3 ovarian carcinosarcomas monoclonal origin for these
(Jin Z. et al., 2003) analyzing X-
tumors.
chromosome inactivation,  It was also noted that genetic
identification of p53 mutations, aberrations were similar to
and microsatellite analysis led serous carcinomas in that these
to the conclusion of all ovarian tumors could also be metaplastic
carcinosarcomas being consistent with the conversion
monoclonal in origin supporting theory .
the combination theory  An evaluation of loss of
 1 case of carcinosarcoma was heterozygosity, p53 mutation,
reported where clonal loss of and microsatellite analysis in 2
BRCA2 allele and a somatic ovarian serous epithelial
mutation in p53 were found in carcinomas which recurred as
both carcinoma and carcinosarcomas showed
sarcomatous components. identical findings in the primary
These results lend further tumor and recurrent
support to the combination carcinosarcoma, thus lending
theory (Sonoda Y., et al., 2000) support to the conversion theory
(Gallardo A. et al., 2002)
Collision theory Combination theory Conversion theory

6. Of the Uterus

7.  In the United States the incidence is approximately 7 per 100,000 women
over age 35 and comprises only 1.2 % of uterine neoplasms [Brooks, SE, 2002].
 The median age at diagnosis is 62 to 67 years old [Gadducci A. et al., 2007].
 Blacks in the United States have a twofold increase in uterine carcinosarcoma
incidence compared with non-Hispanic whites [Sherman ME et al., 2003; Bansal N et al., 2008].
 Uterine carcinosarcomas share similar risk factors with endometrial
carcinomas. Both neoplasms are associated with obesity, nulliparity, and use
of exogenous estrogen and tamoxifen. Oral contraceptives are protective
against both types of neoplasms
 A history of exposure to pelvic radiation appears to be associated with an
increased risk of developing uterine carcinosarcoma
 Approximately 30 % of women have extrauterine disease at time of diagnosis

8.  vaginal bleeding
 abdominal distention
 symptoms related to distant metastases (eg,
pulmonary symptoms)
 On pelvic examination, the uterus is often
enlarged, and in some patients, part of the
tumor may protrude through the cervical os

9. Uterine carcinosarcoma is staged surgically according to the International
Federation of Gynecologists and Obstetricians staging system for endometrial
carcinoma International Federation of Gynaecology and Obstetrics (FIGO)
staging for carcinoma of the endometrium
Stage 1 Confined to the corpus uteri
1a Tumour limited to endometrium
1b Invasion to less than one half of the myometrium
1c Invasion to greater than one half of the myometrium
Involves the corpus and the cervix, but has not extended
Stage 2
outside the uterus
2a Endocervical glandular involvement only
2b Cervical stromal invasion
Stage 3 Extends outside the uterus but is confined to the true pelvis
Tumour invades serosa and / or adnexa and / or positive peritoneal
3a
cytology
3b Vaginal metastases
3c Metastases to pelvic and / or para-aortic lymph nodes
Involves the bladder or bowel mucosa or has metastasised to
Stage 4
distant sites
4a Tumour invasion of bladder and / or bowel mucosa
Distant metastases, including intra-abdominal and / or inguinal lymph
4b
nodes

10.  Total extrafascial hysterectomy with
bilateral salpingo-oophorectomy is the
standard surgical procedure for uterine
carcinosarcoma [Gadducci A et al., 2007].
 As with other endometrial
malignancies, complete staging also
includes cytology of peritoneal
washings and biopsy of any areas
where metastases are suspected. Some
surgeons also perform omentectomy
due to the relatively high risk of upper
abdominal spread.
 There are no data regarding the
benefits of optimal cytoreduction in
women with advanced carcinosarcoma.
However, debulking is a reasonable
approach based upon evidence from
histologically similar advanced
endometrial tumors.

11.  The incidence of regional lymph node
metastases is approximately 20 %, thus,
pelvic and paraaortic lymphadenectomy are
indicated for complete intraoperative
evaluation for metastatic disease. The number
of lymph nodes collected correlates to risk of
recurrence and survival. Disease-free and
overall survival are greater in patients with
higher lymph node count. (FIGO I and II)
[Gadducci A et al., 2007; Temkin SM et al. 2007]
 A study using data from a United States
national cancer database (Surveillance
Epidemiology and End Results) demonstrated
an association between lymphadenectomy
and significantly improved survival (54
months in women who underwent
lymphadenectomy versus 25 months in those
who did not) [Nemani D et al., 2008]

12.  Chemotherapy with either pelvic radiation therapy or vaginal brachytherapy
for adjuvant treatment for women with stage Ib-IVa optimally resected
carcinosarcoma (Grade 2 C). Adjuvant whole abdominal irradiation is also an
option.
 Cisplatin-based adjuvant chemotherapy regimens such as cisplatin and
doxorubicin or cisplatin, doxorubicin, and paclitaxel (TAP) (Grade 2C).
Hematopoietic growth factor support is given with the three-drug regimen,
TAP
 cisplatin, doxorubicin, and paclitaxel (TAP) for palliative chemotherapy in
women with recurrent or metastatic disease (Grade 2C). Ifosfamide regimens,
such as ifosfamide/paclitaxel, or carboplatin/paclitaxel are also commonly
used

13.  There is a significant risk, approaching 60 %, that carcinosarcoma will recur
following surgery and adversely affect survival [Arrastia CD et al., 1997; Yamada SD et al., 2000; Major FJ et
al., 1993; Callister M et al., 2004].
 With many recurrences occurring in the pelvis (40 to 55 %), it is reasoned that
adjuvant pelvic radiation therapy (RT) might improve survival by decreasing
recurrences [Arrastia CD et al., 1997; Yamada SD et al., 2000; Callister M et al., 2004].
 Limited prospective data suggest a possible decrease in local recurrences,
but no survival benefit with RT.

14.  A high rate of recurrences outside of the pelvis (45 to 60 %) suggests a
potential role for adjuvant chemotherapy [Yamada SD et al., 2000; Major FJ et al., 1993; Callister M et al., 2004].
 There is little evidence, much of it from uncontrolled studies, regarding the
effectiveness and choice of agents for adjuvant chemotherapy.
 Both single agent ifosfamide and the combination of cisplatin, ifosfamide,
and mesna have demonstrated tolerability and favorable survival endpoints in
uncontrolled studies [Sutton G et al., 2005; Kushner DM et al., 2000].
 No improvement in progression-free survival or overall survival was gained
from adjuvant single agent doxorubicin in the adjuvant setting in a trial of
resected, early stage uterine sarcoma, in which carcinosarcoma patients
represented nearly half of the study population [Omura GA et al., 1985].
 Despite the lack of data demonstrating clear superiority over other agents,
we and others favor a cisplatin-containing regimen [Gonzalez Bosquet J et al., 2010,Gadducci A et al.,
2001]. We approach adjuvant therapy for carcinosarcomas as we would for
women with high-grade endometrial carcinomas. Although we favor cisplatin,
doxorubicin, and paclitaxel (TAP), which requires hematopoietic growth
factor (G-CSF) support, others use cisplatin and doxorubicin.

15.  In light of the poor prognosis of patients with early stage resected
carcinosarcoma, many centers manage carcinosarcoma patients with
multimodality therapy.
 These include protocols of adjuvant chemotherapy, including cisplatin and
ifosfamide or carboplatinum and paclitaxel, followed by pelvic radiotherapy.
 Favorable survival outcomes with sequential or multimodality therapy have
been suggested by retrospective reviews of patients treated in this manner
[Gonzalez Bosquet J et al., 2010; Wong L et al., 2006; Manolitsas TP et al., 2001; Menczer J et al., 2005; Makker V et al., 2008].
 However, prospective, randomized trials are lacking.

16.  Doxorubicin, ifosfamide, paclitaxel, cisplatin, pegylated liposomal
doxorubicin, and topotecan all have reasonable single-agent activity in
advanced or recurrent carcinosarcoma. No trial has directly compared these
drugs to each other
 Several combination regimens are active, including ifosfamide plus
paclitaxel [67], ifosfamide plus cisplatin [61,68], ifosfamide, cisplatin and
doxorubicin [69], doxorubicin plus cyclophosphamide [59], doxorubicin,
cisplatin, and dacarbazine [70], and paclitaxel plus carboplatin [71-73
 Though some of these trials have prospectively compared multiagent and
single-agent regimens, the superiority of any one approach has not been
demonstrated [59,61,67]. It is clear that multiagent therapy is associated with
greater toxicity.].
 With the recognition of carcinosarcoma as poorly differentiated epithelial
carcinoma, interest has focused on chemotherapy regimens used for high-
grade endometrial carcinoma rather than sarcoma. These are predominately
platinum-containing regimens, paclitaxel plus carboplatin, and cisplatin plus
doxorubicin and paclitaxel (TAP).

17.  Surveillance commonly consists of
physical exam and vaginal cytology
every three months for two years,
then every six months for a total of
five years.
 Optimal radiologic follow-up is not
determined; however, some
centers include whole body PET-CT
or computed tomography of the
chest, abdomen, and pelvis every
six months for two years and then
annually until five years.
 The poor prognosis associated
with recurrent disease should be
borne in mind when
recommending a plan of post
treatment surveillance.

18.  Uterine carcinosarcomas are associated with a less favorable outcome than
uterine carcinomas; estimated five year overall survival rates are 25 to 39
percent. Recurrences tend to occur early, usually within 12 months of
treatment .
 The extent of tumor spread or surgical stage has been consistently found to
be the most important prognostic factor [Sartori E. et al., 1997; Nemani, D. et al., 2008].
 Five-year disease-specific survival rates stratified according to the new FIGO
staging system
◦ Stage I or II (n = 67) — 59 percent
◦ Stage III (n = 19) — 22 percent
◦ Stage IV (n = 33) — 9 percent
 Other factors associated with
prognosis: depth of myometrial
invasion, lymphovascular space
invasion, age, late onset menopause,
race (African-Americans have a poorer
prognosis than Caucasians), marital
status, and the presence of gross
residual disease Kaplan Meier Analysis by FIGO stage

19.  Rare tumor with poor prognosis, most
common location: uterus
 Risk factors: Obesity, nulliparity, TAM,
exogenous estrogen, pelvic radiation,
 Staging according to endometrium carcinoma
 Treatment: Surgery (TAH-BSO, OE,
paraaort/pelv. LNE), CTX (TAP or AP), (RTX)
 Follow up: Cytology and pelvic exams,
imaging

20. Of the ovary

21.  Abdominal distension and bloating
 Palpable pelvic mass on examination
 67-100% present with aszites
 >50% have metastastic nodal disease at
presentation
 Unlike uterine carcinosarcoma, metastases
(5%) are rarely found in the lungs or brain

22.  reports in the literature
estimate median survivals
of 7 to 27 months
 Advanced stage, older age
and suboptimal debulking
worsen prognosis
 Recurrence rates of 50%
were noted for stage I,
100% for stage II, 90% for
stage III, and 100% for
stage IV disease
 CA125 provides prognostic
information and correlates
with disease stage
Harris MA et al., 2003

23.  Optimal surgical cytoreduction
 Platinum-based CTX
 Whether platinum agents should be administered alone or in
combination is undetermined.
 Common treatment combinations utilized to date include
platinum and/or paclitaxel and platinum and/or ifosfamide
 No radiation therapy