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Uterus Carcinosarcoma Pathology 

  • Author: Peggy S Sullivan, MD; Chief Editor: Ramya Masand, MD  more...
 
Updated: Nov 13, 2013
 

Definition

Carcinosarcoma of the uterus is a biphasic neoplasm composed of malignant epithelial and mesenchymal elements.

Although carcinosarcoma is the preferred term for this group of tumors, according to the International Society of Gynecological Pathologists (ISGyP)/World Health Organization (WHO) classification, it is also referred to as malignant müllerian mixed tumor. These tumors are currently thought to be monoclonal carcinomas with sarcomatous differentiation.

Various synonyms have been used to distinguish those with only homologous mesenchymal elements (carcinosarcoma) from those with only heterologous mesenchymal elements (malignant mesodermal mixed tumor or malignant müllerian mixed tumor [MMMT]).

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Epidemiology

Carcinosarcoma comprises less than 5% of malignant neoplasms of the uterine corpus.[2] It is typically seen in postmenopausal women, although rare cases occur in younger women and even children. The median age at presentation is 65 years,[3, 4] and it may be more common in blacks than in non-Hispanic whites.[5, 6, 7, 66]

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Etiology

Risk factors for carcinosarcoma include excessive weight, exogenous estrogen use, and nulliparity,[5] which are similar risk factors for (but not as strongly linked to) endometrial carcinoma.[8] Oral contraceptives and smoking are thought to be protective.[5] Some cases may result from prior pelvic radiation.[9, 10] In recent years, an association between long-term tamoxifen treatment and the development of carcinosarcoma has been suggested.[3, 12, 13, 67]

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Location

Carcinosarcomas typically arise within the endometrial cavity. In rare cases, neoplasms may arise in the cervix or within an endometrial polyp.[14, 68]

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Clinical Features and Imaging

Most patients with uterine carcinosarcoma present with abnormal vaginal bleeding. Other clinical presentations include pelvic or abdominal pain, bloody or watery discharge, and/or an abdominal mass.[15] A polypoid tumor may protrude through the external os.

Up to one third of patients may present with extrauterine spread; thus, gastrointestinal or genitourinary symptoms may be present.[1] Rare cervical carcinosarcomas manifest as vaginal bleeding, spotting, or an abnormal Papanicolaou test result.[14]

On MRI, carcinosarcoma cannot be distinguished from endometrial carcinoma, but a large uterine tumor with widened endometrial cavity and extensive myometrial invasion or intraperitoneal metastases should raise suspicion for carcinosarcoma.[16, 17]

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Gross Findings

These tumors are generally large, soft, broad-based, and polypoid, expanding the uterine cavity and, in some cases, protruding through the cervical os. In some cases, tumors arise from a normal-sized atrophic uterus[1] or a benign polyp.[18, 19] Grossly evident myometrial invasion into the outer half and extrauterine extension are common.

The cut surface is usually fleshy with extensive necrosis, hemorrhage, and cystic degeneration. Areas of cartilage and bone formation yield a gritty or hard consistency.

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Microscopic Findings

Carcinosarcomas comprise an admixture of histologically malignant epithelial and mesenchymal components, as depicted below. In general, both components are easily identifiable. However, the proportion of each component varies greatly, and the diagnosis may not be apparent until after hysterectomy.

Both components are typically high-grade, with marked anaplasia and atypical mitotic figures (as shown below). Low-grade neoplasms are less common but do occur. An estimated 16% of carcinosarcomas have a low-grade stromal component.[20]

The carcinoma component is usually high-grade endometrioid, serous, clear cell, or undifferentiated carcinoma. Rarely, mucinous differentiation or squamous cell carcinoma is seen.

Both epithelial and mesenchymal components of carc Both epithelial and mesenchymal components of carcinosarcoma show high-grade malignant cells. (H&E stain, X400)
Carcinosarcoma with both a high-grade carcinomatou Carcinosarcoma with both a high-grade carcinomatous and sarcomatous component. (H&E stain, X400)
A higher power view of carcinosarcoma. Note the nu A higher power view of carcinosarcoma. Note the numerous mitotic figures. (H&E stain, X1000)

The sarcomatous component may be either homologous or heterologous. Homologous elements (composed of cell types normally found in the uterus) are typically undifferentiated spindle cell sarcoma, pleomorphic sarcoma, or fibrosarcoma. Leiomyosarcoma may also be seen. The most common heterologous elements include rhabdomyosarcoma and chondrosarcoma. Rhabdomyoblasts, if well-differentiated, have cross-striations apparent on routine stains (see image below), although large "straplike" cells with round-to-oval atypical nuclei and abundant eosinophilic cytoplasm should raise suspicion (refer to image below). Rarer forms of heterologous elements include osteosarcoma and liposarcoma. Mature cartilage or osteoid or bone formation may also be seen. Intracellular and extracellular eosinophilic hyaline droplets are common, especially in the sarcomatous component.[21]

Some rhabdomyoblasts are well-differentiated and s Some rhabdomyoblasts are well-differentiated and show cross-striations. (H&E stain, x1000, oil)
Rhabdomyoblasts may be seen in carcinosarcoma and Rhabdomyoblasts may be seen in carcinosarcoma and have abundant eosinophilic or foamy cytopplasm and large vacuolated nuclei with prominent nucleoli. (H&E stain, x200)

In most cases, the carcinomatous and sarcomatous areas are sharply demarcated, but, in some forms, they appear to merge with transitional forms between the two elements, as shown below.[22] Some heterologous foci may appear intimately associated with the epithelial component with no intervening nonspecific sarcomatous component. In a minority of cases (13%), an associated adenosarcomalike component may be present;[20] 40% have deep myometrial invasion.[23]

Lymphatic and vascular space invasion is detected in many cases, with extrauterine spread and metastases at the time of presentation. In general, most metastatic deposits and foci of lymphatic and vascular space invasion are composed of the carcinomatous element, with sarcomatous metastases being rare.[24, 2, 25, 26] However, some studies have found biphasic metastases to be the most common type.[27]

Carcinosarcomas have been reported in otherwise benign endometrial polyps.[18, 19] Others have described carcinosarcoma with a rhabdoid phenotype,[28] a malignant neuroectodermal component,[29] and melanocytic differentiation.[30] A uterine carcinosarcoma of mesonephric origin has been described,[31] as well as a carcinosarcoma with a yolk sac component and elevated serum alpha fetoprotein levels.[32]

Rare cervical carcinosarcomas have been reported. The epithelial component is typically a basaloid carcinoma, squamous cell carcinoma, or adenocarcinoma (endometrioid type). Mesonephric type has also been reported.[68] Some cases may resemble adenoid cystic carcinoma. The mesenchymal component may be fibrosarcoma or endometrial stromal sarcoma, some with myxoid change.[14]

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Immunohistochemistry

Immunohistochemistry is typically not required to establish the diagnosis of this entity, although it may be required to distinguish it from a sarcomatoid carcinoma. The epithelial component is usually immunoreactive with cytokeratins, epithelial membrane antigen (EMA), and vimentin. The mesenchymal component usually stains for vimentin, smooth muscle actin, desmin, and focal cytokeratin.[23] Both the sarcomatous and carcinomatous components often coexpress epithelial markers and vimentin to varying degrees.[33, 34, 35, 36] } Myogenic differentiation 1 (MyoD1) and myogenin may help to highlight a rhabdomyosarcomatous component.

The cartilaginous elements usually stain with S-100. TP53 expression typically shows concordance between epithelial and mesenchymal components, supporting a monoclonal origin.[37, 38] Estrogen receptor and progesterone receptor expression have been reported in some cases.[39] Variable expression of epidermal growth factor receptor, HER-2/neu,[40] and c-kit[41] has also been reported.

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Molecular/Genetics

By convention, the WHO classifies carcinosarcoma as a "mixed’ epithelial and mesenchymal tumor. However, it is generally accepted that most of these biphasic neoplasms are monoclonal, metaplastic, or sarcomatoid carcinomas in which the mesenchymal component retains some epithelial features. This is supported by much of the clinical, histopathological, and immunohistochemical features described above and by recent tissue culture and molecular genetic studies.

Cell lines from carcinosarcoma have supported the theory of a single cell origin.[42, 43] TP53 and KRAS mutations, along with a pattern of chromosome X-inactivation, confirm that most carcinosarcomas are monoclonal.[44] Another study using 3 different methods of determining clonality demonstrated 3 cases of carcinosarcoma were monoclonal.[45] Additional studies examining TP53 mutations[46] and p53 expression[37, 38] have shown concordance between epithelial and mesenchymal elements. Loss of heterozygosity studies also support a monoclonal origin.[47]

Finally, recent cytogenetic studies show shared allelic losses and gains in separate carcinomatous and sarcomatous foci within each tumor.[48] Overrepresentation of 8q has been reported in these neoplasms.[49, 50] DNA mismatch repair and TP53 defects may be early events in tumorigenesis.[51]

While most carcinosarcomas appear to be monoclonal, a subset of carcinosarcomas are truly “biphasic,” as demonstrated by molecular studies[44] and supported by cases demonstrating gross and microscopic features of “collision” tumors and an adjacent adenosarcomalike component.[20] It is estimated that at least 8% of carcinosarcomas are biclonal and that up to 16% may belong to this subset of truly biphasic carcinosarcomas.[20] A recent gene expression profile study found carcinosarcomas were more similar to uterine sarcomas than endometrial carcinoma.[69]

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Tumor Spread and Staging

The pattern of tumor spread is similar to that of high-grade endometrial carcinoma: primarily via lymphatics with frequent intra-abdominal and retroperitoneal metastases.[4, 2, 24] This is distinct from uterine sarcomas, in which disease spreads hematogenously. Deep myometrial invasion and extrauterine spread are often seen at the time of presentation.

Mortality is associated with tumor growth within the pelvis and abdomen rather than metastatic disease,[4] although most such patients also have hematogenous spread, most commonly to the lungs, liver, bone, and brain.[23] Carcinosarcomas are staged similarly to endometrial carcinomas using the TNM and FIGO classification of nontrophoblastic tumors of the uterine corpus.[70, 71]

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Prognosis and Predictive Factors

Carcinosarcomas behave aggressively and have a poor overall prognosis, considerably worse than high-grade endometrial carcinoma, even after other important prognostic variables such as stage, depth of myometrial invasion, and lymphatic and vascular space invasion are taken into account.[27] Surgical stage is the most important prognostic factor, with deep myometrial invasion and extrauterine extension negatively affecting survival.[65, 52, 53, 54] Deep myometrial invasion is associated with metastatic disease.[2]

The 5-year survival ranges from 60%-75% for uterine-confined disease, 40%-60% for early-stage disease (I and II), and 15%-30% for late-stage disease with a median survival of less than 2 years.[55, 23, 72]

Some have found high-grade epithelial type (serous or clear cell carcinoma) to be associated with a poor prognosis,[53, 52, 72] while others have not.[26] Recent data have linked black/nonwhite race and advanced age with decreased survival.[72, 73]

In general, the presence of heterologous elements does not appear to have prognostic significance.[2, 27, 26]

Another study of 83 patients demonstrated multiparity (≥3 children) to be an independent prognostic factor in improving survival likelihood.[57] Disease confined to a polyp is thought to have a better prognosis.[18, 19, 74] It should be noted that, although tumor stage is the most significant prognostic indicator, even cases lacking myometrial invasion may have subsequent recurrences.

A small subset of carcinosarcomas are true “collision”’ tumors, which may have a better prognosis than similarly staged “metaplastic” carcinosarcoma in some cases.[58] Of the rare cases of cervical carcinosarcomas that have been reported, they are generally confined to the uterus at presentation and may have a better prognosis.[14]

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Contributor Information and Disclosures
Author

Peggy S Sullivan, MD Assistant Professor, Department of Pathology and Lab Medicine, University of California, Los Angeles, David Geffen School of Medicine

Peggy S Sullivan, MD is a member of the following medical societies: American Society for Clinical Pathology, American Society of Cytopathology, College of American Pathologists, United States and Canadian Academy of Pathology

Disclosure: Nothing to disclose.

Chief Editor

Ramya Masand, MD Assistant Professor, Department of Pathology and Immunology, Baylor College of Medicine

Ramya Masand, MD is a member of the following medical societies: American Society for Clinical Pathology, College of American Pathologists, United States and Canadian Academy of Pathology, International Society of Gynecological Pathologists

Disclosure: Nothing to disclose.

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Both epithelial and mesenchymal components of carcinosarcoma show high-grade malignant cells. (H&E stain, X400)
Carcinosarcoma with both a high-grade carcinomatous and sarcomatous component. (H&E stain, X400)
A higher power view of carcinosarcoma. Note the numerous mitotic figures. (H&E stain, X1000)
Rhabdomyoblasts may be seen in carcinosarcoma and have abundant eosinophilic or foamy cytopplasm and large vacuolated nuclei with prominent nucleoli. (H&E stain, x200)
Some rhabdomyoblasts are well-differentiated and show cross-striations. (H&E stain, x1000, oil)
 
 
 
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