Mesenchymal Neoplasms of the Female Genital Tract
Case 3 -
Teri Longacre, Esther Oliva and Robert Soslow
Carcinosarcoma, also referred to as "malignant mixed Mullerian tumor" or "MMMT" is a neoplasm composed
of malignant-appearing epithelial and mesenchymal elements . Although they can arise in any genital
organ, they are found most frequently in the uterus where they represent less than 5% of malignant
neoplasms. These tumors are increasingly thought of as carcinomas that demonstrate sarcomatoid
although many gynecologists persist in classifying them as sarcomas. Regardless,
they are extraordinarily heterogeneous, clinically aggressive neoplasms. Their morphologic heterogeneity
is responsible for difficulties in accurate diagnosis.
The mean age of patients with endometrial carcinosarcoma is in the 7th decade, but the age range spans
from the 4th through 9th decades. The disease tends to present like other
endometrial cancers, with vaginal bleeding being common. Another typical presentation of carcinosarcoma
is a polypoid mass that protrudes through the cervical os.
The 5-year survival for carcinosarcoma is around 30% and the 5 year survival in surgical stage I
disease (confined to uterus)
is approximately 50%
This very aggressive profile contrasts with
that of other high grade endometrial cancers where 5 year survivals in stage I disease are approximately
80% or better
This has led to toxic treatment protocols that usually include ifosphamide and
cisplatin along with whole pelvic irradiation. There are no data that suggest that treating the
predominant tumor component (i.e. rhabdomyosarcoma, when present) is preferable to standard therapy.
There have been numerous studies that have sought to define prognostic factors in carcinosarcoma, but
many are compromised by including at least 2 groups of patients, some of whom were clinically staged and
others who were surgically staged
Despite that, there is general agreement that surgical stage is
the most important prognostic indicator. In common with some of the older literature, our group has
recently found that the presence of heterologous elements is a statistically significant poor prognostic
factor in Stage I patients . 30% of patients with heterologous elements survive 5 years as compared
to 80% of patients with homologous elements. Other factors that have been proposed include the grade of
the carcinomatous and sarcomatous elements, the percentage of tumor demonstrating sarcomatous
differentiation, the depth of myometrial invasion and the presence of lymphovascular invasion
The cardinal rule of carcinosarcoma is that it is a biphasic tumor, composed of distinctive and
separate, but admixed, malignant-appearing epithelial and mesenchymal elements. The epithelial and
mesenchymal elements should not merge with one another. This definition essentially excludes from
consideration all monophasic tumors such as undifferentiated carcinomas and undifferentiated sarcomas and
tumors that display either malignant-appearing epithelial elements
(endometrioid adenocarcinoma with spindle cell features) or malignant-appearing mesenchymal elements
Carcinomatous and sarcomatous elements are generally easy to find, but occasional cases show sarcoma
or carcinoma almost exclusively. About one-third of carcinosarcomas harbor a carcinoma with endometrioid
differentiation and two-thirds contain carcinomas that are serous or undifferentiated . The former
tumors may be associated with complex atypical hyperplasia and endometrial intraepithelial carcinoma may
be found in the latter tumors. Clear cell, mucinous and squamous carcinomas have also been described.
In our series , 10% of the carcinomatous components were FIGO grade 1, 10% were grade 2 and 80% were
grade 3. The sarcomatous components were also heterogeneous. The homologous components of
carcinosarcoma are usually spindle cell tumors without obvious differentiation; many resemble
fibrosarcomas or pleomorphic sarcomas. In our experience, it is uncommon to find a carcinosarcoma
containing areas that closely resemble leiomyosarcoma or endometrial stromal sarcoma. Almost all are
histologically high grade. The most common heterologous elements are chondroid or rhabdomyoid
(constituting something that resembles either pleormorphic rhabdomyosarcoma or embryonal
rhabdomyosarcoma). Occasional cases showing lipoblastoid, osteoid, neural/neuroectodermal and
angiomatoid elements have been described.
Most carcinosarcoma metastases are epithelial only or, less commonly, epithelial predominant. It is
uncommon, but not extraordinary, to find sarcoma-only metastases from carcinosarcoma.
The immunophenotype of carcinosarcoma should closely follow that of the individual elements present in
the tumor. For example, the serous component should express keratins and p53, while the rhabdomyoblastic
component should express desmin and myogenin. It is a well known diagnostic pitfall that the sarcomatous
component of carcinosarcoma can express keratins, but the same is true of leiomyosarcoma, in particular.
Given this and the adherence to the cardinal rule of carcinosarcoma (see above), immunohistochemistry
should not be needed for diagnosis and should only be used in exceptional circumstances. I essentially
restrict the use of immunohistochemistry to cases where I want to support my impression of a heterologous
element, particularly rhabdomyosarcoma. I will rarely perform immunohistochemistry to support my
impression of a malignant epithelial component (p53 in epithelium that looks neoplastic and probably
malignant) or to support a morphologically distinct epithelial component where the overwhelming
impression is that of a monophasic undifferentiated tumor. Pleomorphic, monophasic neoplasms with patchy
keratin expression should not necessarily be diagnosed as carcinosarcomas.
As mentioned earlier, most monophasic tumors should not be considered candidates for a carcinosarcoma
diagnosis, although many pathologists believe that uterine pleomorphic rhabdomyosarcomas represent
carcinosarcomas in which the epithelial component has not been sampled or has been overgrown by sarcoma.
This leaves the biphasic tumors.
The four most important biphasic tumors to consider in the differential diagnosis are adenosarcoma,
endometrioid adenocarcinoma with spindle cell elements
so-called dedifferentiated endometrial
and composite or collision tumors.
Mullerian adenosarcoma vs carcinosarcoma
Mullerian adenosarcomas are typically polypoid tumors with the appearance of phyllodes tumor. The
epithelial component is benign appearing, whereas the mesenchymal component is malignant, although it is
usually low-grade in appearance. Therefore, the typical adenosarcoma does not bear resemblance to
carcinosarcoma, although occasional carcinosarcomas can contain areas that are histologically
indistinguishable from adenosarcoma . Some adenosarcomas display sarcomatous stromal overgrowth; the
sarcomatous component of these tumors is usually high grade and, on occasion, can efface the epithelial
components. It is a natural tendency to consider carcinosarcoma (or leiomyosarcoma) in such a case, but,
again, carcinosarcoma requires elements, at least focally, that are histologically carcinoma. Very rare
adenosarcomas can manifest complex atypical hyperplasia in the epithelial compartment, leading to
confusion with carcinosarcoma . The phyllodes-like growth pattern, the absence of overt carcinoma,
and epithelium showing low histologic grade are all against a carcinosarcoma diagnosis. Last, be aware
that adenosarcoma can contain heterologous elements.
Endometrioid adenocarcinoma with spindle cell elements vs carcinosarcoma
Endometrioid adenocarcinoma with spindle cell elements has long been recognized, although it was only
recently given a name and an in-depth description
In this tumor, the endometrioid elements,
frequently showing squamous metaplasia, fuse imperceptibly with spindle cell elements that are never
histologically high grade. In most cases, the endometrioid component is no more than FIGO grade 2 and
the spindle cell component is cellular and sometimes mitotically active, but not markedly atypical. If
there is confusion between this entity and carcinosarcoma, use the tumor grade and the presence or
absence of "element fusion" to inform the decision. Carcinosarcoma contains easily separable epithelial
and mesenchymal elements whereas this type of endometrioid adenocarcinoma shows seamless fusion of the
two (i.e. element fusion). Be aware here as well that endometrioid adenocarcinomas can contain chondroid
and osteoid elements. Heterologous elements by themselves do not signify carcinosarcoma.
"Dedifferentiated" endometrial carcinoma vs carcinosarcoma
"Dedifferentiated" endometrial carcinoma is a recently described entity that includes a well or
moderately differentiated endometrioid adenocarcinoma juxtaposed with an undifferentiated carcinoma
These tumors usually look biphasic and the undifferentiated component is distinct from the
differentiated component, theoretically leading to confusion with carcinosarcoma. The undifferentiated
component characteristically shows only focal or weak keratin expression, potentially compounding
difficulties with the differential diagnosis. In contrast to carcinosarcoma, the undifferentiated
component is made of small rounded cells instead of spindle shaped or obviously pleomorphic cells.
Collision tumor vs carcinosarcoma
Last are the composite or collision tumors. These are extremely uncommon. We have seen the following
very rare examples: endometrial adenocarcinoma with adenosarcoma; endometrial adenocarcinoma with
endometrial stromal nodule; endometrial adenocarcinoma with metastatic poorly differentiated carcinoma;
endometrial adenocarcinoma with lymphoma.
A Managerial Approach
A) Monophasic tumors:
As stated previously, monophasic tumors should not be diagnosed as carcinosarcoma. However, either
the mesenchymal or epithelial components of carcinosarcoma may predominate in small sample biopsies or
scant curettage specimens. Therefore, the possibility of carcinosarcoma should be mentioned whenever a
highly pleomorphic sarcoma, a high-grade carcinoma that is difficult to subclassify, or heterologous
elements are encountered in a small sampling. Although a diagnosis of carcinosarcoma often cannot be
made given the material at hand, the final diagnosis in such cases can be deferred to the hysterectomy
specimen. From a clinical perspective, the next logical intervention is hysterectomy, regardless of
B) Biphasic tumors:
To reiterate, a carcinosarcoma diagnosis can only be made confidently when distinct, high grade
epithelial and mesenchymal components are found. Carcinosarcoma is also a reasonable diagnosis when both
elements are high grade, but fused. When both elements are low grade and merge with one another, the
diagnosis of endometrioid adenocarcinoma with spindle cell elements is warranted. Tumors showing high
grade epithelial components and separate low grade spindle cell areas are difficult to subclassify as are
tumors with low grade epithelial components and separate high grade mesenchymal zones. Fortunately,
these tumors are uncommon. In general, the higher grade component should probably drive the diagnosis.
A reasonable differential diagnosis for the latter tumors includes adenosarcoma with low grade
carcinomatous elements and high grade sarcomatous elements, and an unusual carcinosarcoma. The type of
epithelial elements present and whether they predominated would probably influence my final decision.
What constitutes "low" and "high grade" appearing mesenchymal components and the extent of mesenchymal
differentiation sufficient for a carcinosarcoma diagnosis are probably not reproducible. These are the
guidelines (admittedly subjective and empirical) that we use for separating "high grade" from "low grade"
mesenchymal proliferations in the context of a biphasic uterine tumor: cellularity greater than that
seen in typical ovarian fibroma; easily found mitotic figures in 3 to 5 fields at intermediate
magnification; any atypical mitotic figure; nuclear hyperchromasia; nuclear pleomorphism recognizable at
scanning magnification; 3X nuclear enlargement relative to non-neoplastic myometrial muscle fibers or
non-neoplastic endometrial stroma. "High grade" mesenchymal elements usually feature almost all of these
elements, but atypical mitotic figures can be scarce or absent. Regarding the extent of mesenchymal
differentiation sufficient for a carcinosarcoma diagnosis, we would hesitate to make an outright
diagnosis of carcinosarcoma if the malignant mesenchymal component could not be circled with a pen and
measured; it would preferably measure more than 2 or 3 mm. If it did not, we would diagnose
adenocarcinoma with spindle cell elements and describe the focal high grade mesenchymal appearance in a
note. Of course, these practices are valid only when the lesion is well sampled; they are reasonable
only when the pathologist and clinician understand each other's thresholds for diagnosis and therapeutic
decisions. As patients with uterine carcinosarcoma are frequently entered onto protocols that involve
treatment with highly toxic agents and are stigmatized as having one of the most aggressive gynecologic
cancers, it is prudent to reserve an outright diagnosis of carcinosarcoma for lesions demonstrating
absolutely classic morphology.
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