mixed mullerian tumors of the uterine corpus: a review

Int ] Gynecol Cancer 1993, 3, 1-11

Mixed Mullerian tumors of the S. ALI* & M. WELLS~

uterine corpus:

REVIEW

a review

*Department of Obstetrics and Gynaecology, Clarendon Wing, Leeds General Infirmary, and tAcademic Unit of Pathology, University of Leeds, and Honorary Consultant, United Leeds Teaching Hospitals NHS Trust, Leeds, UK

Abstract. Ali S, Wells M. Mixed Mullerian tumors of the uterine corpus: a review. Int J Gynecol Cancer 1993; 3: 1-11.

The literature relating to mixed Mullerian tumors of the uterine corpus has been reviewed. A critical account of the clinico-pathologic features of these tumors, their prognosis and treatment is presented.

KEYWORDS: carcinosarcoma, corpus uteri, mixed Mullerian tumors.

Mixed Mullerian tumors of the uterus are neoplasms composed histologically of neoplastic epithelial components and mesodermal elements either or both of which may show a spectrum of change varying from mild atypia to frank malignancy. This variation in the histologic picture is reflected in their biologic behavior. The continuing reports concerning these tumors attest to the active pathologic interest they en- gender and the clinical frustration associated with their management. These tumors are still sufficiently uncommon that data must be pooled from various sources to arrive at reasonable conclusions regarding their nature and course.

H i s t o r y a n d c l a s s i f i c a t i o n

The first report of mixed Mullerian tumor of the uterus, as we recognize the lesion today took place, according to Shaw, in 1870 (1) . Over the subsequent de- cades a confusing variety of terminologies was applied to the tumor depending on the site of origin, naked eye appearances and histologic structure including mixed mesodermal tumors carcinosarcoma, car- cinosarcomatoides, sarcoma botryoides and mesenchymal sarcoma. In an extensive review of the literature, McFarland (2) found 119 different names used to refer to the same type of neoplasia from a list of 516 references.

Malignant mixed mesodermal tumor has been the term usually used to describe a neoplasm when heterologous elements such as skeletal muscle, bone and cartilage can be found, i.e. elements that have no benign counterpart in the uterus. The term carcinosar-

Address for correspondence: Dr M. Wells, Senior Lecturer and Honorary Consultant, Academic Unit of Pathology, The Univer- sity of Leeds, Leeds LS2 9JT, UK.

coma has been reserved for a homologous mixture of carcinomatous and sarcomatous elements which are derived from tissues which are normal components of the Mullerian system.

Some investigators have suggested that malignant mixed mesodermal tumors and carcinosarcomas should be classified as separate entities and believe that carcinosarcoma has a better prognosis (3'4). Others have suggested an identical origin, clinical features, gross appearance and prognosis for these lesions, and hold the view that since the distinction between the two tumor groups is based on the presence of heterotopic elements, (the recognition of which de- pends on many variable factors), the subclassification seems unhelpful (5'6). The World Health Organisation (WHO), in 1975, recommended the term 'Malignant Mixed Mullerian Tumor' (MMMT) to include both tumor subgroups (7). However, the new WHO ter- minology (8), as well as the one recommended by the International Society of Gynecological Pathologists (9) is carcinosarcoma, this including all highly malignant entities containing both epithelial and mesenchymal components.

Although the great majority of reported cases of mixed Mullerian tumors of the uterus have both carcinomatous and sarcomatous elements, tumors in which the stromal component is malignant but the epithelial elements benign have also been reported (1°). These tumors have been called 'Mullerian adenosarcoma' and are characterized by low-grade malignancy manifested often by local recurrence and exceptionally by metastasis. Similarly, a variant of mixed Mullerian tumors characterized by malignant epithelium and benign but neoplastic stroma has also been reported for which the authors coined the term 'carcinofibroma '(n). The malignant potential of carcinofibroma

2 S. Ali & M . Wells

has been described as intermediate between low- grade adenosarcoma and the more malignant carcinosarcoma. Benign (adenofibroma) and other low grade variants of mixed Mullerian tumors have also been described (~2), but they are rarer than carcinosarcoma.

Table 1. Classification of mixed Mullerian tumors modified from Fortune & Oster (n)

Epithelial component Stromal component Tumor

Benign Benign Adenofibroma Benign Mal ignant Adenosarcoma Malignant B e n i g n Carcinofibroma Malignant Mal ignant Carcinosarcoma

A classification of mixed Mullerian tumors proposed by Fortune & Oster (13) is based on the recognition that these tumors form a spectrum, the components of which range from benign to low grade to frankly malignant merging imperceptibly from one to another (Table 1).

Histogenesis The histogenesis of these tumors has been considered by many workers and various theories of origin have been proposed to explain the coexistence of carcinoma and sarcoma. Speculation has centred mainly on whether these tumors represent 'collision tumors' (a mixture of two histogenetically distinct populations of malignant cells), 'combination tumors' (representing origin of both elements from a common stem cell), or 'composition tumors' (pure carcinomas with reactive atypical but benign stromal elements).

Many authors believe that carcinosarcomas are combination tumors, arising from a primitive multipotential Mullerian stromal cell which differentiates along various sarcomatous and carcinomatous Mullerian lines (5'14-17). This theory is attractive since it explains the plethora of histologic patterns within one tumor and yet assumes monoclonal proliferation. Tissue culture and heterotransplantation studies (ls-2°) have shown that in in vitro culture of carcinosarcoma two morphologically distinct cell lines, carcinoma and sarcoma, can be identified and that metastases showing both histological elements can be produced in ani- mals. Furthermore, a change from carcinomatous to sarcomatous phenotype was demonstrated. The authors of these studies suggest that their findings support the 'combination theory' rather than a composition tumor with reactive atypical stromal hyperplasia. Similarly, ultrastructural and immunohistochemical analysis of carcinosarcoma (21"22) have demonstrated

the distinctive nature of the malignant epithelial and stromal cell populations.

Other investigators (23-25), whilst agreeing with the combination tumor theory, have noted that in some cases of carcinosarcoma, there were areas of pure endometrial adenocarcinoma developing directly from the epithelium and separate from the main tumor mass. These authors suggest that in some carcinosarcomas the endometrial glands are an integral part of the tumor supporting the view that these tumors represent the simultaneous transformation of endometrial glands to carcinoma and of endometrial stroma to sarcoma in response to common oncogenic factors. This view supposes a biclonal nature to the tumor.

The 'composition theory' proposes that in carcinosarcoma, the presence of one neoplastic component can excite proliferation of the other. Rare cases suggesting such a sequence of events have been described (26). The 'collision tumor theory' proposes that carcinosarcoma orginate from a collision of two histogenetically different neoplasms, one arising from epithelium and the other from stroma. Collision tumors are not true carcinosarcomas but the two lesions have been confused in the past (s'27). Carcinosar- comas, however, are solitary tumors with diffusely in- termixed carcinomatous and sarcomatous elements rather than being two tumors whose elements are largely separated with intermingling at the point of collision(15,1s).

In their recent study, Silverberg and his col- leagues (2s) noted that carcinosarcomas, whether of homologous or heterologous type, behaved like poorly differentiated endometrial adenocarcinoma, and they proposed that carcinomas might in reality represent 'metaplastic carcinomas' comparable to tumors of other organs like the breast which might exhibit exactly the same histologic features, often including the presence of heterologous elements.

Adenosarcoma and carcinofibroma

Controversy continues to surround the histogenesis of these variants of mixed Mullerian tumors. Some authors suggest that both components of the lesion are neoplastic in nature and originate from a multipotential stem cell (29'3°). Others have found it difficult to believe that such multipotential cells could give rise to two tumor lines, one benign and one malignant and postulate that the proliferation in these tumors must be at least biclonal (31'32). There have been suggestions that carcinofibroma involves a benign fibroblastic stromal reaction to the carcinoma (33). Conversely, others have proposed that in adenosarcoma, benign

Mixed Mullerian tumors of the uterine corpus 3

epithelial elements might be entrapped in the malignant stromal proliferation (34).

Adenoflbroma

Some believe that these tumors are derived from a primitive mesenchymal cell which differentiates into various benign mesenchymal cell lines (23). Other authors consider benign mixed Mullerian tumors as hamartomatous tumor-like malformations related to adenomyosis (34'35). Whether a benign mesenchymal uterine tumor can undergo malignant change remains uncertain (23). Ostor & Fortune (n) reported on 11 cases of benign and low-grade variants of mixed Mullerian tumors of the uterus in which the epithelial and the stromal elements ranged from completely benign through to frankly malignant and interpreted their findings as lending support to the concept that these neoplasms are a variant of mixed Mullerian tumors.

Epidemiology

It is difficult to define the true incidence of carcinosarcomas because the classification of these tumors as well as the histologic criteria under which cases are accepted or excluded by various authors have been so variable. Some studies quote an incidence of carcinosarcoma between 2 and 5% of all malignancies of the uter ine corpus (25'36-38). In one report (4) one carcinosarcoma was found for every 143 endometrial carcinomas. In a second report along the same lines (39) one such tumor was found for every 14 endometrial carcinomas, while in a third study (4°) one carcinosarcoma was found for every 8 with adenocarcinoma of the uterine corpus and the authors concluded that these tumors are not as rare as previously thought par- ticularly when endometrial malignancies are submit- ted to critical histopathologic review.

The great majority of patients with carcinosarcoma have been postmenopausal in their 5th, 6th or 7th de- cade of life, although examples of much younger and much older women have been reported in the literature (3'25'36'38'41-45). The median interval from

menopause to presentation appears to be between 15 and 17 years (5'25'42).

There is no convincing evidence that carcinosarcomas of the uterus are prone to occur more frequently in nuUigravid than gravid women(3'15'25"40'43'46), although some series have reported that 30 to 50% of patients were nulliparous (41'47'48).

Similarly, there is no clear ethnic influence in the epidemiology of these tumors. Some studies have reported a predominance of carcinosarcomas among

white women (3'36'46), whilst others have shown a higher relative frequency in black women (25'32'39'4s'49). In one study (42) the ratio of black to white women with mixed Mullerian tumors was 2.5:1 in contrast to endometrial carcinoma where the ratio was 0.8:1. In the latter study the authors noted that the white women were significantly older than the black patients. In spite of this the black women tended to have more advanced disease at presentation. Furthermore, they noted that white women had significantly more homologous than heterologous carcinosarcomas and questioned whether this variation between the 2 groups reflected two biologically different tumor types. Dinh et al. (s°) also noted that homologous carcinosarcoma was significantly more common amongst white women. The constitutional factors associated with endometrial carcinoma, i.e. hypertension, diab- etes and obesity are found in comparable proportions among patients with carcinosarcomas (3"6"25'42'49'51-53).

Some authors (44's4) have suggested a possible role for estrogenic stimulation in their genesis.

The role of pelvic irradiation in the genesis of uterine neoplasia remains uncertain and controversial. Some reports have implicated prior pelvic irradiation as a causal factor in uterine carcinosarcomas, the incidence quoted ranging between 7%and 37% (3'4'25'36'40-42"47"55-61). On the other hand, other series have reported no history or prior pelvic irradiation (5'43'49'62). In one study (46) the authors compared nine cases of carcinosarcoma associated with prior pelvic irradiation with eight unassociated with prior irradiation. Patients with a history of irradiation presented at a younger age and with much more extensive disease. The prognosis did not significantly differ and was poor in both groups. In the latter study it was noted that a greater proportion of tumors that developed after radiotherapy were heterologous (67%) in comparison with 25% in the absence of such history. Simi- lar observations have been made by others (s7). Since pelvic irradiation for benign uterine bleeding has been considered inappropriate for over 30 years, the associ- ation between irradiation and carcinosarcoma would be expected to decline significantly. However, a de- creasing incidence of mixed Mullerian tumors has not yet been reported (43).

Pathology

Gross features

Carcinosarcomas of the uterine corpus do not seem to have a characteristic appearance. The size of the uterus may range from small and atrophic to enlarged

4 S. All & M. Wells

with fusion to all other pelvic organs as a large mass (63). In some cases the pelvic organs are not readily identifi- able being replaced by a large friable mass (47).

In one series (42), the weight of the uterus ranged be tween 85 and 4050 g wi th a mean of 1157 g and a median of 500 g. The length of the uterus ranged from 9 to 30 cm. The mean diameter was 8.5 ranging from 3 to 20 cm in comparison with another series where it was 5.6 cm but with a similar range (3). In another s tudy the max imum tumor diameter for 27 cases ranged from 1.4 to 16 cm, with a mean of 7.8 cm (64).

The tumor is usually polypoid with areas of necrosis, hemorrhage and cystic change. The color and consistency of the tumor are variable due to areas of necrosis and hemorrhage. Gritty or hard areas may indicate bone or cartilage. The tumor mass frequently fills and distends the endometrial cavity but is often at- tached by a definite base at one or m o r e s i t e s (37'65). The endometr ial tumor surface is smooth and lobulated and sometimes the tumor projects through the external cervical os to the vagina w h e n it can be mistaken for a prolapsed fibroid polyp.

The presence of myometrial invasion at the time of surgery is the rule but carcinosarcomas have been reported which were confined to an endometrial polyp(28,37,66).

Histopathology

In carcinosarcoma both epithelial and stromal components are malignant and microscopically there is a be- wildering variety of tissue patterns involving a diffuse admixture of the two neoplastic elements.

The differentiation of the epithelial element is usually glandular, endometr ioid adenocarcinoma being the most common epithelial element. However, clear cell, mucinous, serous or anaplastic patterns may be seen. Squamous carcinomatous elements occur not in- frequently in carcinosarcomas and can be extensive T M . The residual endomet r ium is usually atrophic but may be proliferative or replaced by adenocarcinoma adjoining the polypoid area of the mixed tumor (4°'65).

The stromal component of homologous carcinosarcomas typically resembles endometrial stromal sarcoma but may be leiomyosarcoma, fibrosarcoma, undifferent iated sarcoma or any combination there- of (67-69). In the heterologous variety of carcinosarcoma, rhabdomyosarcoma is the most common heterologous element but mature appearing cartilage, embryonic cartilage or chondrosarcoma, osteoid, bone or osteo- sarcoma, liposarcoma, and, rarely, neuroectodermal differentiation may be s e e n (13'41'69'110). Homologous

sarcomatous elements usually predominate even in heterologous tumors and are found with the same frequency as in the purely homologous tumors (13). Vel- lacott & S h a w (63) described four patterns for the relationship between the epithelial and sarcomatous elements in these tumors. The first pattern involves papillary differentiation where masses of sarcomatous tissues are surrounded by epithelial elements. In the second pattern malignant glands are surrounded by concentric layers of sarcomatous tissues. The two tissue elements in the third pattern are more intimately mixed with an increasing and apparently random mixture of carcinomatous and sarcomatous components . In the fourth pattern, pure carcinoma exists alongside typically malignant mixed Mullerian tumor.

Mitotic activity varies greatly with these tumors. In one s tudy (4°), the mitotic count ranged from I to 44 per 20 oil immersion fields and showed no correlation with clinical outcome. Similar observations in this re- gard have been made by other investigators (2s'36).

Tumor s p r e a d

FIGO staging of carcinosarcoma is the same as for endometrial carcinoma. Early local spread occurs by di- rect extension to the cervix and the vagina as well as to other pelvic organs including the bladder and rectum. Spread to local and regional lymph nodes seems to occur at an early stage of the disease. Gallup et al.(as) reported nodal involvement in 35% of FIGO stage I and II patients. Other studies similarly have showed about a third of the patients to have lymph node metastases at the time of diagnosis (7°'71). Haematogenous spread of these tumors is also c o m m o n (6'36'42'43'72), usually to lung, liver and bone.

In a recent review of 203 cases of stage I and II disease subjected to hysterectomy and staging laparotomy (2s), 40 cases (20%) had metastatic tumor foci. Thirty four of these involved pelvic or para-aortic lymph nodes with or without other metastatic deposits, whilst an additional six cases demonstra ted only vaginal, adnexal and/or omental metastases in the absence of lymph node involvement. This s tudy also revealed a recurrence rate of 25% at 31 months for stage I and II disease wi thout myometrial invasion and the authors suggested that these tumors may dissemi- nate or at least be multifocal fairly frequently even w h e n they appear to be limited to the endometr ium.

In a series of autopsied patients who died of tumor (15), local spread was found in all cases, lymph node involvement in 90% (40% pelvic, 40% abdominal aortic and 30% thoracic aortic) and peritoneal spread in 60%. Hematogenous spread was also common


(lung and pleura 50%, liver 30%, bone 20% and vagina 20%). Other studies have also reported on the generalized nature of tumor dissemination (36'4L73'74).

The histology of metastases is variable and different patterns may be seen in different secondary deposits in the same patient. They may be the same as the primary tumor or may consist entirely of carcinoma or sarcoma, or a mixture of the two with or without heterotopic elements (13"63). In a recent study (28) it was found that of 40 well documented cases with metastases, carcinoma was the sole element in 30, six showed carcinoma and sarcoma and four showed pure sarcoma on initial evaluation. Subsequent meticulous review of the latter four cases however, did not disclose a single well documented case in which metastases were composed of pure sarcoma. The authors of this s tudy suggest that the carcinomatous element may indeed be the 'driver' that influences the behaviour of these tumors and that the differentiation of the epithelial component into a stromal one is a relatively late event. In another recent study the authors share this view (m) .

Clincal features

The most common symptom of these tumors is abnormal vaginal bleeding occurring in 80-90% of the cases and presenting as a bloody discharge, intermenstrual bleeding, post-coital bleeding, menorrhagia or most commonly post-menopausal bleeding. Less frequent symptoms are vaginal discharge which may be watery or purulent, lower abdominal pain, passage of tissues per vaginum, weight loss, anorexia, weakness, uri- nary and gastrointestinal symptoms or the presence of an abdominal m a s s (13'40'41'50'61"63).

Physical examination usually reveals an enlarged uterus. Extrusion of the tumor through the cervical os is not uncommon and, indeed, was noted in up to 33% of cases by some authors (2s). These aggressive tumors have frequently already spread outside the uterus at the time of diagnosis and may be palpable in the parametrial and adnexal regions. Distant metastases, e.g. to the liver, lung or spine may be detected by various imaging techniques.

Cytological evaluation has not played a significant role in the diagnosis of these tumors. Cytology is negative in up to 45% of cases (7s). Shaw et al. (4°) performed cervical and/or vaginal cytology in 21 out of 28 patients. The smears were reported as positive with malignant cells of endometrial origin in nine, atypical glandular cells in six, atypical squamous cells in one and negative in five. Similarly, other investigators (42) noted that amongst the patients presenting with an

endometrial mass, only 40% showed abnormal cytology although biopsies of all masses were positive. It has been suggested that endometrial aspiration smears are more accurate in the diagnosis of carcinosarcomas than ordinary cervical smears (76).

Many authors have reported that a definitive histological diagnosis from curettings can be made only in 50-70% of cases(41'5°'77); the small amount of tissue obtained, the frequent necrosis and inflammation of the tumor surface being limiting factors. Also, uterine curettings can be misleading in that only one type of tissue may be obtained, i.e. adenocarcinoma of stromal sarcoma and the true biphasic nature of the tumor becomes apparent only when the entire speci- men is available for study 03'75).

Hysteroscopy and biopsies under visual control seem to offer an accurate and safe method for the diagnosis of intrauterine malignancy; the hysteroscopic findings of patients with carcinosarcoma have been reported to reflect the histology near the surface of the endometrium (78).

Prognosis

These tumors are among the most malignant neoplasms known to occur in the uterus (79). In a review by Piver & Lurain (75) of 19 studies including 610 patients, the average 5-year survival for all stages was 21%. Seventy to 90% of tumor-related deaths occur within 18 months of diagnosis 05'37'39). The relatively large proportion of cases (30-60%) in advanced stages at time of diagnosis reflect the aggressive nature of the tumor(75,80).

Most authorities agree that the most important prognostic factor is the extent of the tumor at the time of treatment03'37"42'48'5°'53'71"74'81"82); the prognosis being

very poor when the tumor has extended beyond the uterus, i.e. stage III and IV. DiSaia, Castro & Rut- ledge (49) in their study of 94 patients with malignant mixed Mullerian tumors found that patients with Stage I disease had a 53% 2-year survival, whereas survival dropped to 8.5% when the disease had extended to cervix, vagina or parametrium i.e. stage II and III, and there were no survivors in those cases with disease outside the pelvis (stage IV). In another study the 2-year survival for disease confined to the uterus was 76% compared with 16.5% for extrauterine disease (6). Other series report no survivors when the tumor has extended beyond the uterus (53'83'84).

The other important prognostic factor is the depth of myometrial invasion (6A3'28'43'65'68"71'75"81'83-85). The clini-

cal stage of the disease and the incidence of lymph node metastases seem directly related to the depth of

6 S. A l i & M . Wells

myometrial invasion (6s'7°). Some authors (42'5°'82'83), however, have shown no difference in survival with different levels of myometrial invasion. Some authorities have indicated that positive peritoneal washings are associated with a poor prognosis (6'86'87), reflecting the advanced stage of the disease.

A history of prior pelvic radiotherapy has been noted by some to have an adverse effect on prognosis (25'36"71'84), but others do not agree (46).

The histologic criteria which are of value in predicting the prognosis of other uterine sarcomas, e.g. mitotic activity, degree of cytologic atypia and infiltrating tumor margin are not helpful in predicting the outcome of carc inosarcomas (25"28'36'4°'48'64'71'81), neither is

the grading of glandular components as used for endometrial adenocarcinoma (13"37'64"81). Some authors, however, have noted a greater tendency for cases in which the primary carcinomatous elements were serous or clear cell to be associated with distant metastases and with grade 2 or 3 carcinoma (2s'37). Lymphatic and vascular space invasion were found by some authors to be significant predictors of metastatic disease (28'42), a view not shared by others (81).

Some workers have noted that patients with tumors containing heterologous components do worse than those whose tumors contain homologous elements (3'15'37'51'65'88). Other authors did not find statistically significant differences in survival between homologous and heterologous tumors and concluded that the prognosis of these tumors is essentially the same(6,13,25,28,32,41,42,46,50,65,68,74,81,82,84,85,89).

It has also been suggested that the presence of cartilage in carcinosarcoma is associated with a favorable prognosis (4'65'68), a claim not substantiated by other studies (25'28'36'45). Similarly some authors have suggested that the presence of rhabdomyosarcomat- ous elements are associated with a bad prognosis (3'48'68), whilst others have found that they do not influence the clinical o u t c o m e (25'28'36'37'65'82'84).

Schwizer et al. (64) noted that in some cases the tumors were 'sessile' with a broad base of attachment, whereas in other instances the tumor's attachment tapered to a narrow base (pedunculated). In this study which included 28 cases, patients with pedunculated tumors had statistically better survival rates than those with sessile tumors. The authors speculate that cases with pedunculated tumors tended to have smaller tumors, with less myometrial and/or vascular invasion. Tumor location might also correlate with metastatic disease since some authors have found isthmi- cally located tumors to be more likely to metastasize than those limited to the uterine fundus (28). Uterine and tumor size in early-stage disease did not affect sur-

vival in some studies (48'74), a finding at variance with reports by others (71's5'9°). Increasing age is associated with a worse prognosis (48'71) as is abdominal pain as a presenting symptom (4s) possibly because it is indica- tive of advanced disease.

T r e a t m e n t

Various therapeutic modalities have been employed in the management of these tumors ranging from pallia- tive treatment to exenterative procedures. A combination of surgery and radiotherapy (both external and in- ternal) in varying sequences and, more recently, chemotherapy have been used in the hope of improving survival. No form of treatment, as yet, has proved definitive in the treatment of carcinosarcoma and the extent of surgery and whether it is combined with adjuvant therapy has depended in most series on the individual preference of the clinician.

Early-stage disease (FIGO stage I & II)

Surgery in the form of abdominal hysterectomy and bilateral salpingo-oophorectomy has been the mainstay of treatment of carcinosarcomas (36'47'52'89'91). However, the poor survival of patients with carcinosarcoma, despite control of disease in the pelvis, indicates that micrometastases must be present at the time of operation in many who have been clinically staged as FIGO stage I and II. Indeed, various studies have shown the frequency with which these tumors are understaged. Spanos eta/. (74) reported that 16% of stage Ia, 42% of stage Ib, 42% of stage II and 50% of stage III patients were staged higher on surgical findings than on clinical staging. In a series of 49 patients reported on by Doss et al. (61), 25 patients under- went laparotomies and 14 of these (56%) had more extensive disease than could be determined by pelvic examination under anaesthesia. Other investigators have also noted that a large proportion of patients with early-stage disease had a higher surgical pathologic stage (42'45"59'71'81'90). For this reason, it has been suggested that aggressive surgical staging should include peritoneal cytology, hysterectomy, bilateral sapingo- oophorectomy, omentectomy, para-aortic and pelvic lymph node evaluation and when appropriate tumor debulking 03'71'81's6). This should allow more accurate individual prognostication of cases and subsequent additional therapy with irradiation or chemotherapy could be offered selectively to patients with residual disease or high probability of tumor recurrence. Un- fortunately, such additional treatments carry risks of significant morbidity and are of questionable value.

M i x e d Mul le r ian tumors of the uter ine corpus 7

The role of radiotherapy in the treatment of carcinosarcoma is still controversial. Many workers believe that radiotherapy offers very little in the control of this neoplasm (4A5'18'39'51'62'71"89). Nielson et al. (s~) in a

recent study of 60 cases showed no significant survival advantage for surgery plus radiation compared with surgery alone after stratification according to stage; progression-free survival after complete extirpation of macroscopic disease was not significantly different, stage for stage, between surgery alone and surgery plus radiation.

Other authors have suggested that radiotherapy adjuvant to surgery may be of value in improving control of pelvic disease but have shown no improvement in overall survival (6'36'53'74'83'90'92). Some studies, on the other hand, have shown that adjuvant radiotherapy led to a decrease in pelvic recurrence and also im- proved survival (85'93). Larson et al. (48), in their series of 147 patients, found that surgery and combined radiotherapy (intracavitary and external irradiation), gave for stage I disease a lower local failure rate and a statistically significant improvement in overall survival compared with surgery when combined with either intracavitary or external irradiation.

The need for effective systemic therapy in carcinosarcoma becomes obvious on examining the frequency and sites of recurrence, since these reflect therapeutic effectiveness and the need for treatment modification more accurately than do survival data. In carcinosarcoma, recurrences consist of or include systemic disease in 75-85% of cases despite initially localized disease and therapy with surgery and/or irradiation (3A5'52'83), suggesting that the disease (as already suggested above) is systemically disseminated at diagnosis in many patients, thus demonstrating the need for systemic chemotherapy. Presently, adjuvant chemotherapy remains largely unproven in carcinosarcoma. Patients with stage I disease treated with doxorubicin after surgery had no better survival than control cases undergoing surgery alone in a randomised prospective study conducted by the Gynecologic Oncology Group (94). Other investigators (81) have also shown no significant survival advantage for surgery plus chemotherapy compared with surgery alone.

Late-stage (FIGO stage III and IV), disseminated and recurrent disease

The results of all therapeutic modalities have been dismal in patients with advanced and recurrent disease. In some institutions such patients are not subjected to

extensive surgical procedures and are treated with radiotherapy with or without chemotherapy (83). Others have suggested that aggressive surgery in the form of pelvic exenteration is more suited to control some cases of stage IV disease than radiotherapy with limited surgery or chemotherapy (61). Yazigi et al. (95) advocated an aggressive combined surgical radiotherapeutic and chemotherapeutic regimen for stage III disease. Radiotherapy alone may be employed for inoperable patients, for patients who are poor surgical risks and in palliation of initial and/or recurrent disease.

Chemotherapy in advanced or recurrent disease may produce responses but they are rarely complete or of long duration. Gershenson et al. (96) treated 11 patients with metastatic carcinosarcoma with single- agent cisplatin and observed one complete response and four partial responses with a median progression- free interval of only 4.5 months. Jansen et al. (97) reported treating seven patients with cyclophos- phamide, hexamethylmelamine, adriamycin and cisplatin and achieved a response in five of six patients with evaluable disease; the progression free intervals ranged from 4 to 40 months. Grosh et a1.(98) used a comparable regimen and found no complete response, partial response in 33.3% and stable disease in 50% with a mean survival of 112 weeks for responders and 19 weeks for non-responders. Kohorn et al.(90) treated eight patients with persistent and recurrent disease using cisplatin adriamycin and DTIC; six patients showed a response for 4-24 months, none complete. Sutton et a1.(99) in a study of the Gynecologic Oncology Group treated patients with advanced and recurrent disease with ifosfamide and mesna and reported responses in 32.2% of cases; two of the 29 patients evaluable for toxicity developed neurotoxicity and one of these two patients died after 3 days of therapy. Other investigators have used etoposide (1°°) and doxorubicin (1°1) as single agents and both drugs proved ineffec- tive.

The literature is replete with reports addressing the dismal survival of patients with carcinosarcoma, suggesting the lack of effective primary therapy and the need for treatment modification. The high frequency of distant recurrences, the lack of therapeutic gains in patients with stage I and II disease treated with surgery and radiotherapy, as compared with treatment by surgery alone, and the inability to control or to prevent distant recurrences with current first line cytotoxic agents suggest that further improvement in patients prognosis must await the availability of effective therapeutic alternatives that afford more optimal systemic control. Earlier diagnosis and more effective

8 S. Ali & M. Wells

chemotherapy seem to offer the most promise for the future.

MuUerian adenosarcoma

This rare variant of mixed Mullerian tumor, first described by Clement & Scully in 1974 0°), is characterized by an admixture of benign, but sometimes atypical, glandular component and a sarcomatous stromal element 0°-12'29'31). Adenosarcoma may be mistaken histologically for benign Mullerian adenofibroma, carcinosarcoma or endometrial stromal sarcoma, especially in curettage specimens °°'~2'69).

The tumor usually forms a soft polypoid mass filling the uterine cavity and may project through the cervical os; occasionally these tumors are partially or completely intramural. The cut surface has been described as firm or spongy, with a whorled fibrous matrix in which are embedded numerous small cysts filled with watery or mucoid fluid 0°'13).

Microscopically, the tumor is biphasic and contains benign Mullerian epithelium set in a sarcomatous stroma. The stromal element usually exhibits a marked variation in its cellular density and is often ar- ranged in hypercellular periglandular cuffs envelop- ing an inactive glandular c o m p o n e n t (13'29'31'102'103). The stroma may be homologous or heterologous with elements such as striated muscle (1°'31'1°2), cartilage 0°4) and fat (1°). To designate the stromal component as malignant, some authorities (12'1°s) demand at least 4 mitotic figures per 10 HPF, pronounced stormal cellular atypia, heterologous malignant tissue constituents or myometrial invasion. Others (m3) demanded 1 to 2 mitoses per 10HPF or a cytologically malignant stroma.

There is usually a variety of histologically benign epithelial elements lining the glands and the endometrial surfaces. Most tumors contain as their major epithelial component, cells similar to those of proliferative or hyperplastic endometrium with occasional mitotic activity, and atypia manifested by focal cellular stratification and nuclear pleomorphism; squamous epithelium, mucinous epithelium of endocervical type and ciliated epithelium are also often encoun- tered(10,13).

Adenosarcoma, typically has low malignant potential compared with carcinosarcoma, manifest by local recurrence in about 25% of cases. Distant metastasis occurs in about 5% of cases (m'l°2A°5,l°6). Some authors (13) suggest that 40% of adenosarcomas recur or metastasize. The commonest sites for metastasis are the pelvis and vagina, but distant metastases have also been reported (1°'12'1°2).

The main finding reflecting malignant behavior of these tumors is deep myometrial invasion (1°'12'1°7). Some authors 0°2) state that a mitotic count of > 10 per HPF and the presence of heterologous elements are also associated with poor prognosis, an opinion not shared by others (13).

Mullerian adenosarcoma is found predominantly in postmenopausal women, but has been described in all age groups (1°3). The usual presenting symptoms are post-menopausal bleeding, vaginal discharge and abdominal pain. The treatment is usually pelvic clear- ance by total hysterectomy and bilateral salpingo- oophorectomy. Patients with poor prognostic indi- cators, e.g. deep myometrial invasion or a high mitotic count may benefit from adjuvant treatment with radiotherapy/chemotherapy. The value of such combined therapy remains to be evaluated. On the whole the outcome is more favourable than for carcinosarcoma through approximately 25% of patients still die of their disease.

Carcinofibroma

This very rare variant of mixed Mullerian tumor, first described by Ostor & Fortune in 1980 (11), is composed of both stromal and epithelial elements but only the epithelial component is malignant. In 1973, Vellios/1°8) had reported on a case of adenofibroma in which there was a focus of malignant epithelium but did not assign a name to this variant.

Thompson & Husemeyer (33) suggested that the presence of early myometrial invasion in two cases might indicate malignant potential intermediate between low-grade Mullerian adenosarcoma and carcinosarcoma. There is evidence of a tendency to regrowth (33), and recurrence In) but the tumor's metastatic potential is still rather unclear. The clinical features of this tumor are not distinctive and simple hysterectomy has been suggested as the treatment of choice for Mullerian carcinofibroma, the existing evidence is that it is curative (32).

Adenofibroma

In this variant of mixed Mullerian tumor, both epithelial and stromal components are benign. The tumor might be difficult to distinguish histologically from adenosarcoma. Tumors with 3 or fewer mitotic figures per 10 HPF have been designated as adenofibroma by some authors 02'1°9) whilst mitotic counts greater than 3 would allocate the tumor to the adenosarcoma categ-


ory. Adenofibromas have a benign clinical course°2'1°9); they may recur or persist after incomplete excision but do not metastasize 03). Hysterectomy is the preferred treatment for adenofibroma and will allow thorough examination and sampling to exclude adenosarcoma 01'a3). Local excision may be considered in young women wanting to preserve their fertility but periodic follow up with hysteroscopy and curettage is important.

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Accepted for publication 6 April 1992

mixed mullerian tumors of the uterine corpus: a review

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