The term ‘mixed Müllerian tumour’ applies to uterine tumours composed of epithelial and mesenchymal elements of Müllerian origin. These neoplasms are classified into adenomyomas, adenofibromas, adenosarcomas, and carcinosarcomas (malignant Müllerian mixed tumours) based on whether the epithelial and stromal elements are benign or malignant. The rare atypical polypoid adenomyoma usually involves the lower uterine segment and, on curettings, may be confused with invasive adenocarcinoma. Adenosarcomas are low-grade neoplasms classified halfway along the spectrum of mixed Müllerian tumours, with adenofibromas at one end and carcinosarcomas (malignant Müllerian mixed tumours) at the other. Some tumours currently classified as ‘adenofibromas’ on the basis of their low mitotic count and lack of nuclear atypia are, in fact, well differentiated adenosarcomas. Carcinosarcoma is composed of admixed but distinctive carcinomatous and sarcomatous elements. On the basis of the clonal origin of both tumour components, carcinosarcomas are currently thought to be metaplastic carcinomas rather than uterine sarcomas.
Introduction
Mixed Müllerian tumours contain epithelial and mesenchymal elements, both of which participate in the neoplastic process. The body of the uterus, along with the fallopian tubes, the cervix, and the upper part of the vagina, develop from the Müllerian ducts, which in turn are derived from the mesenchyme of the urogenital ridge and the celomic lining epithelium. This anlage gives rise to all the elements of which the uterus is eventually composed: myometrial smooth muscle, endometrial stroma, and endometrial glands. The term ‘mixed Müllerian tumour’ is applied to the group of uterine tumours (rarely, they may also arise in the ovary, fallopian tube or cervix) composed of both epithelial and mesenchymal elements of Müllerian origin. These mixed neoplasms are more common in the uterus than elsewhere, probably because the epithelium and mesenchyme in this site have a common embryologic origin. In fact, within the primitive uterus, duct epithelium and mesenchyme merge imperceptibly and distinguishing the precursors of the endometrium and myometrium is not possible. These tumours are classified into adenomyomas, adenofibromas, adenosarcomas, and carcinosarcomas (malignant Müllerian mixed tumours [MMMTs]) based on whether the epithelial and mesenchymal elements are benign or malignant. The capacity of uterine tumours to form heterologous mesenchymal elements, such as striated muscle or cartilage, reflects the potentiality of the Müllerian duct. Recently, carcinosarcoma has been reclassified as a dedifferentiated or metaplastic form of endometrial carcinoma. Despite this, and probably because it behaves more aggressively than the ordinary endometrial carcinoma, carcinosarcoma is still included in most retrospective studies of uterine sarcomas, as well as in the 2003 World Health Organization classification.
Müllerian adenofibroma
Adenofibroma is a biphasic tumour composed of benign epithelial and mesenchymal elements that typically occurs in the endometrium, although it may occasionally arise in the cervix or an extrauterine location. The existence of this tumour has been recently questioned, as some investigators consider adenofibroma as an exceedingly well-differentiated adenosarcoma that yet may behave aggressively. These women often have a history of ‘recurrent polyps’.
Clinical features
The tumours occur mainly in peri- or post-menopausal women. The median age is around 68 years. Nevertheless, it may develop in women of all ages, from 19 years to over 80 years. The most common presenting symptom is abnormal vaginal bleeding. Less frequently, women have abdominal pain, abdominal enlargement, or a polypoid tumour projecting from the cervix. Occasional cases have been associated with tamoxifen treatment.
Pathological features
Grossly, adenofibromas are polypoid tumours ranging from 2–20 cm (median 7 cm) in maximum diameter that arise anywhere in the uterus or in the cervix. Of a series of 10 adenofibromas, only one arose in the cervix. Tumours vary from soft to firm, to rubbery, and appear tan-brown with foci of haemorrhage. On cut surface, they may show small cysts, which give the tumour a spongy or mucoid appearance. Large adenofibromas may fill the endometrial cavity and enlarge the uterus; most tumours are superficial and do not invade the underlying stroma.
Microscopically, adenofibromas are composed of a mixture of bland glandular epithelium and hypocellular stroma ( Fig. 1 ). Broad papillary or polypoid stromal fronds, which appear relatively acellular and covered by epithelium, project from the surface of the tumour or extend into cystic spaces within it. Columnar, flattened, or cuboidal epithelium, not significantly proliferative and most often of endometrioid type, lines cysts and cleft-like spaces. A mixture of various types of epithelium, including endocervical, tubal, and squamous, is often present in the same tumour. The mesenchymal component is usually fibrous, and consists of fibroblasts and collagen with small uniform and bland nuclei. More rarely, endometrial stroma, smooth muscle, skeletal muscle, or adipose tissue have been reported and tumours designated as lipoadenofibroma or adenomyofibroma. The stroma, which may be cellular or fibrous, appears cytologically bland without nuclear pleomorphism. There is no periglandular condensation of stromal cells. Mitotic activity is usually absent and should not exceed 1 mitosis per 10 high power field (HPF) in the most active areas. Adenofibromas are confined to the endometrium or cervical mucosa, and do not invade the myometrium or the cervical stroma. Two ‘adenofibromas’ that invaded the myometrium and, in one case, the myometrial, veins have been reported.
Differential diagnosis
It may be difficult to distinguish an adenofibroma from a benign endometrial or endocervical polyp. A benign polyp, however, does not require further treatment. The stromal component of a typical polyp tends to be more hyaline than that of the adenofibroma. A papillary surface and a cellular ‘phyllodes-like’ stroma favours adenofibroma.
The main differential diagnosis is adenosarcoma, and the two tumours have a somewhat similar appearance at low magnification. Distinction usually requires hysterectomy for examining the entire tumour and to rule out the presence of adenosarcomatous areas. In contrast to adenosarcoma, adenofibroma lacks the stromal cellularity with condensation around glands; the stromal cells have bland nuclei and little or no mitotic activity, and have more intervening collagen. Mitotic activity greater than 1 per 10 HPFs warrants a diagnosis of adenosarcoma, which is also much more common than adenofibroma. A practical approach is to classify as adenosarcoma any biphasic tumour with atypical hypercellular stroma, periglandular stromal cuffing, and one or more mitosis per 10 HPFs. Using these criteria, the diagnosis of adenofibroma is made only rarely, comprising only about 5% of one large study of adenofibromas and adenosarcomas.
Clinical behaviour and treatment
Adenofibromas are benign, and no tumour-related deaths have been reported. Both of the previously mentioned women with myoinvasive adenofibromas were alive and well after hysterectomy. When hysterectomy is not the first choice of treatment, such as in young women in whom conservation of fertility is an important consideration, local excision is usually curative but the tumour may recur if it is incompletely curetted or excised. Recurrence may occur even in the absence of mitotic activity. Hysterectomy, which ensures complete removal, is the most appropriate treatment. It also permits the thorough sampling needed to exclude adenosarcoma.
Müllerian adenofibroma
Adenofibroma is a biphasic tumour composed of benign epithelial and mesenchymal elements that typically occurs in the endometrium, although it may occasionally arise in the cervix or an extrauterine location. The existence of this tumour has been recently questioned, as some investigators consider adenofibroma as an exceedingly well-differentiated adenosarcoma that yet may behave aggressively. These women often have a history of ‘recurrent polyps’.
Clinical features
The tumours occur mainly in peri- or post-menopausal women. The median age is around 68 years. Nevertheless, it may develop in women of all ages, from 19 years to over 80 years. The most common presenting symptom is abnormal vaginal bleeding. Less frequently, women have abdominal pain, abdominal enlargement, or a polypoid tumour projecting from the cervix. Occasional cases have been associated with tamoxifen treatment.
Pathological features
Grossly, adenofibromas are polypoid tumours ranging from 2–20 cm (median 7 cm) in maximum diameter that arise anywhere in the uterus or in the cervix. Of a series of 10 adenofibromas, only one arose in the cervix. Tumours vary from soft to firm, to rubbery, and appear tan-brown with foci of haemorrhage. On cut surface, they may show small cysts, which give the tumour a spongy or mucoid appearance. Large adenofibromas may fill the endometrial cavity and enlarge the uterus; most tumours are superficial and do not invade the underlying stroma.
Microscopically, adenofibromas are composed of a mixture of bland glandular epithelium and hypocellular stroma ( Fig. 1 ). Broad papillary or polypoid stromal fronds, which appear relatively acellular and covered by epithelium, project from the surface of the tumour or extend into cystic spaces within it. Columnar, flattened, or cuboidal epithelium, not significantly proliferative and most often of endometrioid type, lines cysts and cleft-like spaces. A mixture of various types of epithelium, including endocervical, tubal, and squamous, is often present in the same tumour. The mesenchymal component is usually fibrous, and consists of fibroblasts and collagen with small uniform and bland nuclei. More rarely, endometrial stroma, smooth muscle, skeletal muscle, or adipose tissue have been reported and tumours designated as lipoadenofibroma or adenomyofibroma. The stroma, which may be cellular or fibrous, appears cytologically bland without nuclear pleomorphism. There is no periglandular condensation of stromal cells. Mitotic activity is usually absent and should not exceed 1 mitosis per 10 high power field (HPF) in the most active areas. Adenofibromas are confined to the endometrium or cervical mucosa, and do not invade the myometrium or the cervical stroma. Two ‘adenofibromas’ that invaded the myometrium and, in one case, the myometrial, veins have been reported.
Differential diagnosis
It may be difficult to distinguish an adenofibroma from a benign endometrial or endocervical polyp. A benign polyp, however, does not require further treatment. The stromal component of a typical polyp tends to be more hyaline than that of the adenofibroma. A papillary surface and a cellular ‘phyllodes-like’ stroma favours adenofibroma.
The main differential diagnosis is adenosarcoma, and the two tumours have a somewhat similar appearance at low magnification. Distinction usually requires hysterectomy for examining the entire tumour and to rule out the presence of adenosarcomatous areas. In contrast to adenosarcoma, adenofibroma lacks the stromal cellularity with condensation around glands; the stromal cells have bland nuclei and little or no mitotic activity, and have more intervening collagen. Mitotic activity greater than 1 per 10 HPFs warrants a diagnosis of adenosarcoma, which is also much more common than adenofibroma. A practical approach is to classify as adenosarcoma any biphasic tumour with atypical hypercellular stroma, periglandular stromal cuffing, and one or more mitosis per 10 HPFs. Using these criteria, the diagnosis of adenofibroma is made only rarely, comprising only about 5% of one large study of adenofibromas and adenosarcomas.
Clinical behaviour and treatment
Adenofibromas are benign, and no tumour-related deaths have been reported. Both of the previously mentioned women with myoinvasive adenofibromas were alive and well after hysterectomy. When hysterectomy is not the first choice of treatment, such as in young women in whom conservation of fertility is an important consideration, local excision is usually curative but the tumour may recur if it is incompletely curetted or excised. Recurrence may occur even in the absence of mitotic activity. Hysterectomy, which ensures complete removal, is the most appropriate treatment. It also permits the thorough sampling needed to exclude adenosarcoma.
Müllerian adenosarcoma
Adenosarcoma is a mixed Müllerian tumour composed of benign-appearing but neoplastic glandular elements and a sarcomatous stroma, which is usually low grade.
Clinical features
Adenosarcoma occurs mainly in the uterus of postmenopausal women but also in adolescents and young women, and in extrauterine locations, such as the fallopian tube, ovary, paraovarian tissues, or even the intestinal serosa. Rarely, synchronous tumours occur in the uterus and an extrauterine site, such as the ovary. The most common presenting symptom is abnormal vaginal bleeding, but some women present with pelvic pain, palpable pelvic mass, non-specific urinary symptoms, vaginal discharge, a tumour mass protruding from the cervix, or both. Some women have received tamoxifen treatment for breast cancer or have a history of radiation therapy. Most adenosarcomas arise from the endometrium, including the lower uterine segment, but rare tumours develop in the endocervix (5–10% of cases), and within the myometrium, probably from adenomyosis. At the time of diagnosis, most tumours are confined to the uterus (stage I).
Pathological features
The uterine cavity is typically filled and distended by a polypoid tumour of about 5–6 cm in maximum diameter, which may protrude through the cervical os. It can be either soft or firm. The cut surface is tan brown or grey, and often has a spongy appearance with variably sized cysts or clefts. Focal haemorrhage and necrosis are often present. The tumour margin is usually well circumscribed.
Microscopically, the adenosarcoma shows an intimate admixture of apparently benign glandular epithelium that often resembles inactive or proliferative endometrium and low-grade sarcoma, usually of endometrial stromal type ( Fig. 2 ). Other types of epithelia, such as secretory, squamous, mucinous, and clear cell, may also be found in adenosarcoma. In one-third of cases, the glandular epithelium is atypical but, in contrast to carcinosarcoma, carcinomatous epithelium is absent. Rarely, an adenocarcinoma arises from an adenosarcoma resulting in a carcinosarcoma. Typically, the glands of adenosarcoma are cystic and the stroma concentrates around them forming periglandular cuffs ( Fig. 2 ). The stromal component is usually a low-grade homologous sarcoma, such as endometrial stromal sarcoma, leiomyosarcoma, fibroblastic or myofibloblastic sarcoma, or combinations thereof. The sarcomatous component is typically more cellular around the glands, often forming intraluminal polypoid projections. The histologic picture is reminiscent of a phyllodes tumour of the breast. Elsewhere, the stroma is usually less cellular and fibrotic, giving a deceptively benign appearance. The mean mitotic rate is generally 2–4 mitotic figures per 10 HPF or more ; however, in practice, a biphasic tumour with hypercellular and atypical stroma which appears condensed around the glands, is diagnosed as an adenosarcoma in the absence of mitotic figures. Heterologous mesenchymal elements (usually rhabdomyosarcoma, but also cartilage, fat, and other elements ) are found in 20–25% of cases. About 15% of adenosarcomas invade the myometrium with a border that may be well-defined or clearly infiltrative; deep invasion occurs in less than 5% of cases. Sarcomatous overgrowth, defined as the presence of pure sarcoma, usually high grade without a glandular component, and occupying at least 25% of the tumour, has been reported in 10–50% of adenosarcomas. Heterologous elements, particularly rhabdomyosarcoma, may occur and be limited to the sarcomatous overgrowth area.
Immunohistochemistry
The glandular epithelium of adenosarcoma immunoreacts for cytokeratins, oestrogen and progesterone receptors. In most adenosarcomas without sarcomatous overgrowth, the immunophenotype of the stromal component resembles that of an endometrial stromal sarcoma (i.e. typically shows cytoplasmic reactivity for CD10 and nuclear reactivity for oestrogen and progesterone receptors and the WT1 gene). In cases with sarcomatous overgrowth, the mesenchymal component produces stronger nuclear immunoreaction for proliferation marker Ki-67 (MIB-1) and p53. On the other hand, loss of expression of ER, PR, and CD10 usually takes place. The immunophenotype is similar to that of a high-grade uterine sarcoma, and DNA is aneuploid.
Adenosarcoma versus adenofibroma
Adenosarcomas are low-grade sarcomas classified halfway along the spectrum of mixed Müllerian tumours, with adenofibromas at one end and carcinosarcomas (MMMTs) at the other. Although the histologic diagnosis of the latter is usually straightforward, distinction between adenosarcoma and its rarer benign counterpart, the adenofibroma, may be difficult. A recent study has shown that some clinically malignant tumours without sarcomatous overgrowth may produce only moderate stromal cellularity with focal periglandular cuffs, low mitotic count (<2 MFs/10 HPF) and only mild nuclear atypia. The finding of such cases raises the question of whether or not adenofibroma exists as a tumour entity. In this study, immunoreaction for several markers of cell proliferation (Ki67, p53, and EGFR) and differentiation (CD10, ER, and PR) was similar in typical adenosarcomas and adenofibromas associated with favourable outcome. Thus, it was suggested that some of the mixed Müllerian tumours currently classified as ‘adenofibromas’ on the basis of their low mitotic count and lack of significant nuclear atypia, are, in fact, well-differentiated adenosarcomas. A confident diagnosis of adenofibroma cannot be made on a biopsy or curetted tissue as adenosarcoma cannot be ruled out unless the entire tumour is available for microscopic examination. Therefore, a hysterectomy is required to ensure adequate sampling.
Treatment and prognosis
The treatment of choice is total abdominal hysterectomy with bilateral salpingo-oophorectomy; however, a few young women have been treated by local excision of tumour. The role of postoperative pelvic radiation and chemotherapy is unclear.
Except when associated with myometrial invasion or sarcomatous overgrowth, the prognosis of adenosarcoma is far more favourable than that of carcinosarcoma; however, it recurs in 25–30% of women, and about 25% of women with adenosarcoma ultimately die of their disease. Recurrence usually occurs in the vagina, pelvis, or abdomen, but distant metastases develop in 5% of women. Interval between treatment and recurrence ranges from 3.5–5 years; thus, long-term follow up is needed. Local recurrences and distant metastases are almost always composed of pure sarcoma (70%). Pathologic features of the primary uterine tumour that are associated with a higher risk of recurrence or metastasis are deep myometrial invasion, lymphovascular space invasion, and sarcomatous overgrowth, especially when it contains rhabdomyosarcoma. In a study from Norway, which included 23 adenosarcomas, tumour-cell necrosis was the strongest prognostic factor ( P = 0.006). Metastasis to lymph nodes is rare, although occasionally, some women whose tumours show sarcomatous overgrowth have pelvic lymph-node metastases.
Carcinosarcoma or malignant Müllerian mixed tumour
Carcinosarcoma, also referred to as MMMT, is a biphasic neoplasm composed of distinctive and separate, but admixed, carcinomatous and sarcomatous elements ( Fig. 3 ). The former may be of different Müllerian types, usually serous or endometrioid carcinoma, whereas the latter component may be homologous (tissue types native to the Müllerian tract, such as endometrial stroma, fibrous tissue or smooth muscle) or heterologous (foreign tissue, such as skeletal muscle, cartilage, bone or adipose tissue). Any of these components may be limited to small foci or widespread.
Recent immunohistochemical and molecular genetic studies support the clonal origin of both tumour components (epithelial and mesenchymal-like elements). Accordingly, carcinosarcomas are currently thought to be ‘undifferentiated’ or ‘metaplastic’ carcinomas rather than uterine sarcomas. Nonetheless, carcinosarcomas have distinctive clinical and pathologic features that warrant their separation from endometrial carcinomas.
Clinical features
Carcinosarcoma (MMMT) accounts for 2–5% of all malignancies of the uterine corpus and almost half of all uterine sarcomas. Although they occur typically in postmenopausal women (from sixth to eighth decades), a small number of cases has been reported in women younger than40 years of age. Most women present with abnormal vaginal bleeding, abdominal pain and uterine enlargement. The serum level of CA125 is elevated in most cases. Gastrointestinal or urinary tract symptoms suggest extrauterine spread. At presentation, extrauterine spread (stage III-IV) is found in up to one-third of cases. Up to 37% of women with carcinosarcomas have a history of pelvic irradiation for treatment of benign conditions, such as abnormal uterine bleeding or cervical cancer. These tumours tend to occur in younger women, often contain heterologous elements, and are found at advanced stage. The time interval between radiation therapy and development of the carcinosarcoma is usually between 10 and 20 years.
Uterine carcinosarcoma shares risk factors with endometrial carcinoma. Both tumours may occur after long-term treatment with tamoxifen treatment for breast cancer, and both may be associated with obesity, nulliparity, and exogenous oestrogen use.
Pathological features
Carcinosarcomas are typically large, bulky polypoid masses, filling the uterine cavity and prolapsing through the cervical os. The cut surface is usually fleshy, and often shows areas of haemorrhage, necrosis, and cystic change. Occasionally, bone or cartilage can be present. Myometrial invasion is frequently seen. Rare tumours may arise in the uterine cervix.
On microscopic examination, carcinosarcoma is composed of distinctive and admixed malignant-appearing epithelial and mesenchymal elements ( Fig. 3 ). The two elements, however, should not merge with one another. This definition essentially excludes from consideration monophasic tumours such as sarcomatoid carcinomas or undifferentiated sarcomas. Occasionally, however, carcinosarcomas show either sarcoma or carcinoma almost exclusively. The carcinomatous component is usually serous (two-thirds of cases) or endometrioid (one-third) but, rarely, it may be clear cell, mucinous, or squamous cell carcinoma. In a recent study, 10% of the carcinomatous components were International Federation of Gynecology and Obstetrics grade 1, 10% grade 2, and 80% grade 3. About half of the tumours with endometrioid differentiation are associated with endometrial hyperplasia. Cervical MMMTs may contain non-glandular carcinomatous elements composed exclusively or predominantly of squamous, basaloid, or adenoid cystic carcinoma. In such cases, the overlying squamous epithelium may show intraepithelial neoplasia.
The sarcomatous components are also heterogeneous and may be either homologous or heterologous (50% of cases). They usually contain hypercellular sheets of small, hyperchromatic, round to spindle-shaped cells with a high mitotic rate and lacking apparent differentiation. In the homologous type, the sarcoma-like component resembles fibrosarcoma, malignant fibrous histiocytoma, high-grade endometrial stromal sarcoma, leiomyosarcoma, undifferentiated sarcoma or combination thereof. The heterologous tumour most often contains malignant skeletal muscle or cartilage resembling either pleomorphic rhabdomyosarcoma or embryonal rhabdomyosarcoma. Rarely, osteosarcoma or liposarcoma are present. Glial, neuronal, melanocytic, yolk sac, angiomatoid, and trophoblastic differentiation may be encountered. Presence of eosinophilic hyaline globules, which are immunoreactive for alpha-1-antitrypsin, is a common feature. Often, extensive necrosis, myometrial invasion, and cervical involvement are present.
Immunohistochemistry
The immunophenotype parallels that of the individual elements. For example, the serous components should express cytokeratins, epithelial membrane antigen and p53, whereas the rhabdomyoblastic elements should express desmin, myoglobin, myogenin, MyoD1 and CD34. Sarcomatous components, however, can express cytokeratins (as in leiomyosarcomas) and epithelial component are immunoreactive for vimentin (as in endometrial carcinomas). Such findings reflect the common mesodermal origin of these tumours. Nevertheless, differential immunoreactivity with cytokeratin and vimentin is a helpful method for enhancing the biphasic pattern of carcinosarcomas and distinguishing sarcomatoid or spindle cell carcinoma from the sarcomatous component of carcinosarcoma. The sarcomatous homologous component can also express CD10 (a marker used initially for the diagnosis of endometrial stromal tumours) and CD34. Both carcinomatous and sarcomatous components may show immunoreactivity for neuroendocrine markers, including synaptophysin and neuron-specific enolase. In most cases, immunohistochemistry is not needed for diagnosis, and should only be used to confirm the presence of heterologous elements, particularly rhabdomyoblasts.
Histogenesis
The histogenesis of uterine carcinosarcomas has long been a matter of debate. Four main theories have been proposed at various times: (1) the ‘collision’ theory, in which two independent tumours, a carcinoma and a sarcoma, collide and appear distinct rather than admixed, seems an unlikely explanation for most cases; (2) the ‘combination’ theory in which a common pluripotential cell gives rise to both epithelial and mesenchymal components has been the most popular theory over the years; (3) the ‘composition’ theory characterised by malignant transformation of both glandular epithelial cells and mesenchymal stromal cells in a single tissue or organ that is impossible to prove or disprove; and (4) the ‘conversion’ theory proposing that the sarcomatous components evolves from the carcinomatous components by a metaplastic process of dedifferentiation. This theory supports the dominant role of the epithelial elements and suggests that the sarcoma evolves from the carcinoma as a secondary phenomenon.
On the basis of the conversion theory, it is now accepted that carcinosarcomas most likely represent metaplastic carcinomas, with the sarcomatous component being a manifestation of their increased aggressiveness. Findings that support this hypothesis include (1) frequent association of carcinosarcomas with otherwise typical endometrial adenocarcinomas within the same hysterectomy specimen; (2) frequent recurrence of carcinosarcomas as pure adenocarcinomas; (3) occasional recurrence of apparently pure endometrial adenocarcinomas as carcinosarcomas; and (4) similar metastatic pattern of carcinosarcomas and endometrial adenocarcinomas.
Nevertheless, from a managerial viewpoint, it should be emphasise that carcinosarcomas have distinctive clinical and pathological features that warrant their separation from endometrial carcinomas (i.e. they are extraordinarily heterogeneous and highly aggressive tumours, fatal in most cases). Unlike metaplastic carcinomas in other sites, the two components of carcinosarcomas do not merge at either histological or ultrastructural levels and heterologous mesenchymal elements are common.
Molecular features
The epithelial and stromal components of carcinosarcomas show identical patterns of X chromosome inactivation, indicating that both elements derive from a single stem cell clone.
Recently, it has been shown that the malignant epithelial cells transdifferentiate to malignant mesenchymal cells by progressive loss of E-cadherin expression coupled with the expression of non-epithelial cadherins (N-cadherin and cadherin-11) and acquisition of mesenchymal markers (vimentin, fibronectin, and others). This epithelial-mesenchymal transition (EMT) promotes the interaction of tumour cells with the stroma, thus facilitating invasion and metastasis. An important finding is the down-regulation of the miR-200 family of miRNAs (key regulator of EMT) in the mesenchymal cells of carcinosarcomas. Inhibition of miR-200 reduces E-cadherin expression by allowing an increase in their transcriptional repressors ZEB1 and ZEB2 . Interestingly, miR-214, which is involved in muscle cell differentiation by modulating Hedgehog signalling, is over-expressed in the mesenchymal component of carcinosarcoma, thus correlating with rhabdomyoblastic differentiation. Also, down-regulation of stemness-inhibiting miR-203 could explain the ability of carcinosarcomas to undergo epithelial and mesenchymal (biphenotypic) differentiation while some of their cells maintain stem-like properties.
Differential diagnosis
Although monophasic uterine sarcomas are easily distinguishable from carcinosarcomas, some investigators believe that pleomorphic uterine rhabdomyosarcomas may represent carcinosarcomas in which the epithelial component has not been adequately sampled or has been overgrown by sarcoma.
A biphasic endometrial tumour that mimics carcinosarcoma is the endometrioid adenocarcinoma with spindle cell elements; however, these carcinomas are composed of low-grade glandular elements (FIGO 2 at most) and are far less aggressive than typical carcinosarcomas or even high-grade carcinomas. Furthermore, the endometrioid glands frequently show squamous metaplasia and merge almost imperceptibly with spindle cell elements that are never histologically high grade. In contrast, carcinosarcoma shows easily distinguishable high-grade epithelial and mesenchymal elements.
‘Dedifferentiated’ endometrial carcinoma is a recently described variant that includes a well- or moderately differentiated endometrioid adenocarcinoma juxtaposed with an undifferentiated carcinoma. In contrast to carcinosarcoma, the endometrioid component is usually well differentiated; the undifferentiated component is made of sheets of small rounded cells of uniform size instead of spindle shaped or obviously pleomorphic cells. Glandular, nested or trabecular cell arrangements are not encountered in the undifferentiated component. Squamous, mucinous and neuroendocrine differentiation is also lacking. The undifferentiated cells frequently have a rhabdoid phenotype, and the intervening stroma appears myxoid. The undifferentiated component may resemble lymphoma, plasmacytoma, myxoid chondrosarcoma, small-cell carcinoma, or even metastatic lobular carcinoma of the breast. These cells fail to express muscle-specific markers, including markers of skeletal muscle differentiation. The undifferentiated component shows only focal keratin expression, but there is strong epithelial membrane antigen and cytokeratin 18 immunoreactivity in a minority of cells in nearly every case. These tumours are even more aggressive than carcinosarcomas, as recurrence and death occur in almost every patient. Recent investigations have shown that, unlike carcinosarcoma, de-differentiated carcinomas frequently have an abnormal DNA mismatch repair gene expression profile, which places some of them within the spectrum of tumours encountered among individuals with Lynch syndrome or hereditary non-polyposis colorectal carcinoma syndrome.
Prognosis and treatment
Carcinosarcomas are highly aggressive tumours, far more aggressive than usual endometrial carcinomas. The overall 5-year survival for individuals with carcinosarcomas is around 30% and for those with stage I (confined to the corpus) about 50%. This is in contrast to high-grade endometrial cancers for which the 5-year survival in stage I disease is about 80% or better. Surgical stage and, particularly, depth of myometrial invasion are the most important prognostic indicators. Other important prognostic factors include advanced age (over 70 years), and amount of residual tumour. Myometrial invasion beyond the inner third is seen in 80% of tumours, and 40% show deep myometrial invasion. Confinement to an endometrial polyp in absence of myometrial invasion, however, does not preclude extrauterine spread. Lymphatic and blood-vessel invasion are found in most cases. Metastatic and recurrent tumours may be exclusively carcinomatous, sarcomatous, or mixed, but they are often predominantly carcinomatous. The overall recurrence rate is 55%, and the most common metastatic sites include ovaries, fallopian tubes and omentum. As in endometrial carcinomas, lung metastases can occur late in the course of the disease. Tumours containing serous and clear-cell carcinoma are thought to be associated with higher frequency of metastases, deep myometrial invasion, lymphatic or vascular space invasion, and cervical involvement. In common with older research, a recent study has found that the presence of heterologous elements is a statistically significant poor prognostic factor in stage I patients. Rhabdomyosarcomatous component has the worse prognosis of all, and chondrosarcoma is thought to confer a more favourable outcome.
Appropriate treatment includes total abdominal hysterectomy with bilateral salpingo-oophorectomy. Removal of pelvic and aortic lymph nodes, omentectomy, and peritoneal cytology are often carried out because of the propensity for abdominal dissemination. The role of adjuvant radiotherapy and chemotherapy is uncertain, but some studies have shown the advantage of radiotherapy for disease-specific survival in early stage tumours as well as local control in advanced-stage tumours. Taxanes and cisplatin-based chemotherapy, ifosphamide, along with whole pelvic irradiation, may lead to increased survival in people with metastatic carcinosarcomas. Nonetheless, the survival rates remain poor because of a high rate of distant metastasis, even in cases lacking myometrial invasion.
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