Metastatic Uterine Carcinosarcoma: A Case
Report and Literature Review
Erica Testani OMSIII1*, Michael Smith DO1, Richard Hwang MD2, Ali Chaudri MD2 and Leacroft Green MD1
1Department of Surgery, St. Barnabas Hospital, USA
2Department of Pathology, St. Barnabas Hospital, USA
Submission: February 19, 2017; Published: May 30, 2017
*Corresponding author: Erica Testani OMSIII, Department of Surgery, St. Barnabas Hospital, Bronx, New York, USA, Email: email@example.com
How to cite this article: Erica T O, Michael S D, Richard H M, Ali C M, Leacroft G M. Metastatic Uterine Carcinosarcoma: A Case Report and Literature Review. JOJ Case Stud 2017; 2(5) : 555599. DOI:10.19080/JOJCS.2017.02.555599.
Uterine carcinosarcoma (UCS) is a highly aggressive malignancy with a poor prognosis. Metastasis of UCS is seen most frequently in the abdomen, pelvis and lungs. This report discusses a rare case of a post-menopausal female with recurrent UCS who was diagnosed with metastasis to the soft tissue of the left anterior neck. In 2011, the patient was initially diagnosed with stage III UCS and successfully treated with a total abdominal hysterectomy, bilateral salpingo-oophorectomy, and regional lymphadenectomy, followed by adjuvant radiation and chemotherapy. The patient was in clinical remission and screening PET scans were negative for a 2.5-year period. In 2015, a PET scan and biopsy revealed metastatic spread of UCS to the anterior neck, pulmonary parenchyma and axillary lymph nodes. The present review discusses UCS, a rare presentation of distant metastasis and the mechanisms underlying cancer dormancy.
A 56 year old G4P3013 Hispanic female presented to outpatient clinic in November 2011 with a 6 month history of daily postmenopausal bleeding. The patient’s medical history included a Papanicolaou test demonstrating atypical squamous cells of unknown significance (ASCUS) within the past year. She denied any medical conditions or history of hormone replacement therapy. She reported menarche at age 12 and menopause at age 46.
Initial physical exam revealed a firm cervix and a firm anteriorly fixed uterus consistent with 6-8 weeks gestation. Transvaginal ultrasound demonstrated a thickened endometrial stripe of 5.6 centimeters (cm) and an endometrial biopsy revealed moderately differentiated endometrial adenocarcinoma. Subsequent total body CT scan showed several areas of lymphadenopathy, specifically in the left internal iliac nodes and left external iliac nodes and multiple retroperitoneal locations, including the para-aortic lymph nodes. Pelvic scans showed endometrial expansion with a heterogeneous mass measuring 9.3x 6.4x10.0cm.
In February 2012, the patient underwent an exploratory laparotomy, radical total abdominal hysterectomy, bilateral salphingo-oophorectomy and regional lymphadenectomy. Intra-operative findings included invasion into the uterine serosa and cervix with greater than 50% myometrial invasion. On gross examination the cervix and uterus measured 12.0x 9.0x 8.0cm. The cervix showed an irregular papillary growth occupying the entire cervical canal and extension into the lower segment of the uterus.
The endometrium was completely occupied by a soft variegated and hemorrhagic tumor mass. Histology of the specimen demonstrated poorly differentiated malignant neoplasm morphologically compatible with metastatic uterine carcinosarcoma (UCS), demonstrating S-100 protein immunohistochemical staining for the chondrosarcomatous component and myogenin immunohistochemical stain of the rhabdomyosarcomatous component, (Figures 1-3). Only one of
eleven lymph nodes, specifically the right obturator lymph node,
was positive for metastatic disease. Pelvic washing cytology was
negative for malignant cells. TMN staging was determined to
be pT2 pN1 pMX, Fédération Internationale de Gynécologie et
d’Obstétrique (FIGO) stage IIIC1.
During an 18-month period following surgical resection,
the patient underwent 6 cycles of radiation therapy and
chemotherapy including four cycles of taxane/anthracycline/
platinum (TAP) and two cycles of carboplatin/paclitaxel. PET
scans in May 2013 confirmed absence of disease with complete
remission. Recurrence was monitored with serial CT scans
every six months and tumor marker (CA 125, CA 19-9 and CEA)
screening every three months.
In October 2015 a PET scan revealed pulmonary parenchymal
metastasis, left axillary adenopathy and left cervical adenopathy
lateral to the thyroid gland. Tumor marker CA 125 was increased
to 40 units per milliliter, a significant elevation above the normal
threshold (<35U/mL). Left supraclavicular lymph node FNA
confirmed metastatic recurrence of carcinosarcoma. The patient
received 4 cycles of carboplatin/paclitaxel chemotherapy in
November 2015. PET scan in February 2016 demonstrated good
response to treatment, follow up CT in April 2016 did not reveal
any masses, (Figure 4).
In October 2016 a CT with contrast demonstrated a new soft
tissue mass on the left neck with vascular supply originating
from a branch of the subclavian artery, (Figure 5). One month
later, the patient underwent a modified neck dissection. The
specimen was an 8.5x7.0x4.5cm soft tan-yellow mass with areas
of hemorrhage and necrosis, (Figure 6 & 7). Histopathology
demonstrated metastatic carcinosarcoma with identical
histopathologic features as the previous uterine tumor. Consent
was obtained from the patient for intra operative photography
and the production of this manuscript was approved by our
institution’s internal review board.
Uterine carcinosarcoma (UCS), also known as a malignant,
mixed Müllerian tumor (MMMT) is a highly aggressive cancer
that accounts for approximately 3% of all uterine malignancies
. The majority of cases are seen in post-menopausal women
with a median age of 65 . Fewer than 5% of cases are diagnosed
in women younger than 50 years old. Data from the National
Cancer Institute indicates that black females have significantly
higher incidence rates of UCS and poorer treatment outcomes
compared with white non-Hispanic females .
UCS grossly presents as a bulky, polypoid mass with necrotic
and hemorrhagic foci. The tumor often fills the endometrial
cavity, invades deep into the myometrium and can protrude into
the cervix . The most common initial presenting symptom is
abnormal postmenopausal uterine bleeding. Additional signs
and symptoms include gradual weakness, increasing abdominal
girth, pelvic pain and pressure, and a protuberant cervical mass.
Risk factors are similar to that of endometrial carcinoma and
are associated with an excess estrogen environment as seen
in obesity, nulliparity, menstrual irregularities and long-term
unopposed estrogen therapy. There is some evidence to suggest
that UCS is also associated with previous pelvic irradiation
and prolonged Tamoxifen use . Carcinosarcoma is unique in
that it is biphasic and contains both malignant epithelial and
mesenchymal components . Microscopically the epithelial
elements are typically high grade endometrial adenocarcinoma
that can be serous, endometrioid, clear cell, mucinous or
The histology of the mesenchymal component can be
subdivided into homologous or heterologous types of uterine
tissue. Homologous mesenchyme usually resembles endometrial
stromal sarcoma or fibrosarcoma. The heterologous subtype is
derived from undifferentiated sarcoma and contains components
of skeletal muscle, cartilage or bone. The most common
variant is rhadbomyosarcoma, followed by chondrosarcoma,
osteosarcoma and liposarcoma . The prognostic significance
of the mesenchymal histology is controversial however, most
studies suggest that the homologous or heterologous elements
do not influence the behavior of the tumor . Conversely,
tumors with an epithelial component composed of grade III
endometroid, serous or clear cell type are associated with a
higher incidence of metastasis and deep myometrial and cervical
Clinical and pathological evidence suggests that MMMT
derives from an endometrial carcinoma that has undergone a
metaplastic change resulting in the acquisition of sarcomatous
features . This theory explains why UCS behaves like an
aggressive subtype of endometrial carcinoma rather than a
uterine sarcoma. Despite its similarities, clinical evidence
suggests that UCS is biologically distinct from endometrial
carcinoma because of its significantly worse prognosis and
potential for hematogenous spread . At the time of diagnosis,
approximately 50% of all cases are FIGO stage III or stage IV and
present with either extra uterine spread or distant metastasis.
The pattern of UCS spread is primarily governed by the
carcinomatous component of the tumor. Immunohistochemical
analysis has demonstrated the majority of metastatic foci contain
predominantly carcinomatous elements . Sarcomatous
elements can be found in metastatic tumors however
purely sarcomatous tissue is uncommon . Therefore, like
endometrial carcinoma, MMMT predominantly spreads through
the lymphatic system.
The most common sites of metastasis are the lung,
peritoneum and pelvic and para-aortic lymph nodes . Forty
to sixty percent of women will experience disease recurrence,
which often presents in the abdomen, pelvis, vagina, and lungs
. In most cases the median survival is approximately 21
months and overall 5 year survival ranges from 33-39% .
Surgery is the primary treatment for uterine carcinosarcoma
and includes total abdominal hysterectomy, bilateral salpingoophrectomy,
lymph node dissection, omentectomy or omental
biopsy and resection of all gross disease. Several studies
demonstrate that lymphadenectomy confers a measurable
survival benefit by removing microscopic lymphatic metastasis.
Therefore, research suggests that the number of lymph nodes
resected is an important predictor of prognosis and survival .
Other prognostic factors include degree of lymphovascular space
involvement, depth of myometrial invasion, adnexal and serosal
involvement, lymph node metastasis and positive peritoneal
cytology . Regardless of the aforementioned factors or stage,
adjuvant chemotherapy or radiation therapy is recommended in
all women because of the high rate of disease recurrence .
This case demonstrates a clinical phenomenon known as
cancer dormancy, in which a patient experiences a period of
asymptomatic remission after resection of the primary tumor.
Latent cancer cells persist below a detectable threshold for
months to decades until the disease eventually recurs, often in
the form of metastatic relapse. Dormancy is well documented in
cases of recurrent breast, prostate, thyroid, brain and pancreatic
cancers . Research shows that disseminated tumor cells
(DTCs) have been detected in asymptomatic patients with a
history of breast cancer, even decades after removal of the
primary tumor. Some studies suggest that many patients who
are considered cured still house latent cancer cells .
The precise mechanism underlying cell dormancy is
unknown. It is likely due to a combination of mutations in genes
modulating cell proliferation and alterations in the surrounding
microenvironment. There are three prevailing models for
understanding this phenomenon: angiogenic dormancy,
immunologic dormancy and cellular dormancy .
Angiogenic dormancy occurs when the proliferation
of malignant cells is restricted by a finite blood supply. An
enlarging tumor mass must rely on neo vascularization to
provide sufficient nutrients and oxygen to sustain growth
. Without an increasing vascular supply, DTCs will exist in
a state of equilibrium in which rapid proliferation is balanced
by a comparable rate of cell death. Malignant cells escape
dormancy when genetic alterations initiate an angiogenic shift
which results in the up regulation of proangiogenic factors, such
as VEGF, which restores the potential for tumor growth .
Research has shown that augmented VEGF expression correlates
with rapid induction of tumor growth, while withdrawal of VEGF
results in the regression of tumor vessels and extensive cell
Immunologic dormancy occurs when the immune
system eradicates or impedes the growth of malignant cells.
Immunosurveillance mechanisms detect transformed cancer
cells via distinct inflammatory signals and tumor-specific
markers. The presence of malignant cells will activate the innate
and adaptive immune systems and initiate a cascade of events
which ultimately suppress tumor growth . T cells are critical
to the induction of cancer dormancy.
T cells release cytokines, such as INF-γ and TNF-α, which
inhibit cell growth, prevent angiogenesis, and regulate cell cycle
progression. In a mouse model of sarcoma, depletion of CD8+
and CD4+ T cells resulted in the growth of previously dormant
cancer cells and decreased the overall time to metastasis [17,18].
The immune system is capable of inducing a state of
equilibrium between healthy cells and tumor cells. In an
immunocompetent host, immune cells will monitor tumor
mass and restrict malignant proliferation using a combination
of cytostatic and cytolytic factors . Tumor mass will remain
constant and the patient will be clinically asymptomatic [13,16].
Over time cancer cells can adapt to the immune environment and
accumulate genetic mutations that promote immune evasion,
neovascularization and proliferation. Ultimately these changes
will enable DTCs to escape dormancy resulting in metastatic
Cellular dormancy is a quiescent state in which tumor
cells are arrested in the G0 phase of the cell cycle. Latent cells
remain in distant tissues and neither divides nor undergoes
apoptosis. Cell cycle arrest is driven by a number of intrinsic
and extrinsic factors . For example, changes in the tumor
microenvironment, such as hypoxia, can prompt cancer cell
latency. Radiation therapy can also induce cellular quiescence
via the upregulation of cyclin dependent kinase (CDK) inhibitors,
which prevent cell cycle progression at the G1 and S phase .
Under certain circumstances, such as changes in growth factors,
cytokines or nutrients, dormant cells can reenter the cell cycle
and resume proliferation .
Tumor dormancy presents a number of obstacles to
cancer treatment. Latent tumor cells are clinically silent and
are resistant to conventional therapy, which primarily targets
actively dividing cells. Current research is exploring the use of
novel therapeutics designed to shift cells in and out of dormancy.
The goal is to encourage DTCs to reenter the cell cycle in order
to increase sensitivity to chemotherapeutic agents . The
behavior of dormant cancer cells can be highly divergent from
that of the primary tumor.
Tumor cells that disseminate early during the course
of the disease may eventually evolve and develop different
characteristics compared to the primary tumor. Recent evidence
shows that DTCs have different genetic variations compared
with primary tumor cells . Therefore, metastatic cancers
may be resistant to treatments which were designed exclusively
for the primary tumor .
Dormant DTCs are believed to be the cause of recurrence
and metastasis. There are still many unknowns regarding the
mechanism of dormancy. Understanding this process is crucial
to preventing metastatic relapse. Future research must explore
ways of identifying DTCs and eliminating them before they
escape dormancy and cause disease recurrence.
Our patient is currently undergoing palliative treatment with
radiation and chemotherapy. Despite aggressive treatment with
carbo/taxol, weekly gemcitabine and radiation therapy, imaging
studies reveal persistent and increasing metabolic uptake in the
left neck although no new masses have been identified to date.