Uterine Malignant Mixed Müllerian Tumors Research Articles

Differential risk factors between uterine sarcomas and malignant mixed Müllerian tumors.

e23551 Background: Uterine sarcomas are malignant tumors of the smooth muscle or connective tissue of the uterus. Its main histological types are leiomyosarcomas and endometrial stromal sarcomas, with recent classifications considering malignant mixed müllerian tumors (MMMT) as a dedifferentiated endometrial carcinoma rather than a primary uterine sarcoma. We hypothesize there are different risk factors which predispose to MMMT as compared to uterine sarcomas. This study investigates these risk factors to determine if they contribute to the development of either disease. Methods: Under an IRB-approved protocol, we identified patients with uterine sarcomas and MMMT treated at Sylvester Comprehensive Cancer Center and University of Miami Hospital between 2010 and 2020 by Patient Atlas (clinical database tool; Miami, FL). We compared the risk factors known to be associated with endometrial carcinomas between uterine sarcomas and MMMT using independent sample t-test, Chi Square, Spearman Rho and Pearson correlation. Results: A total of 59 patients with MMMT and 115 cases of uterine sarcoma were identified in our database. In the sarcoma group, the most common histology was leiomyosarcoma (n = 76, 66%). Upon analysis of the characteristics of the sarcoma and MMMT cohorts respectively, 38 (33%) vs 16 (27%) were Hispanics, 18 (15%) vs 13 (22%) had diabetes, 26 (22%) vs 20 (34%) used contraception or hormonal replacement therapy (HRT), 35 (30%) vs 17 (28%) were alcohol users, 26 (22%) vs 15 (25%) were smokers, and 54 (47%) vs 31 (52%) had a positive family history of cancer, with no statistically significant differences found (p > 0.05). The sarcoma group had a significantly lower age at diagnosis (AAD) (53 vs. 65, P < 0.001) and a larger tumor size (11.3 vs. 7.3 cm, p < 0.0005). Use of contraception or HRT was not significantly different among the 2 groups (χ(1) = 0.699, p = 0.4). Similarly, no significant difference was found in the mean age of menarche/menopause, patient’s weight, median gravidity and parity (p > 0.05). The patient’s weight and BMI negatively correlated with the AAD in the MMMT group (ρ = - 0.279, p = 0.043 and r = -0.274, p = 0.041 respectively). Older age at menopause was associated with older AAD in the sarcoma group (ρ = 0.571, p = 0.0001). Patients with higher gravidity and parity had an older AAD among the 2 groups (p ≤ 0.05). Conclusions: The uterine sarcoma patients had significantly younger AAD than the MMMT group, with the age at menopause being positively correlated with the AAD. The use of contraception or HRT were not significantly different among the 2 cohorts, suggesting that there could be an overlap of the risk factors of MMMT and uterine sarcomas. Interestingly, higher gravidity and parity were associated with an older AAD. In the MMMT group, patient’s weight and BMI were inversely associated with the AAD. Larger studies are needed to investigate whether similarities or discrepancies in the studied risk factors truly exist.

Staging MRI of uterine malignant mixed Müllerian tumors versus endometrial carcinomas with emphasis on dynamic enhancement characteristics.

To determine whether staging pelvic magnetic resonance imaging (MRI) can distinguish malignant mixed Müllerian tumor (MMMT) from EC. Thirty-seven treatment-naïve patients with histologically proven uterine MMMT and 42 treatment-naïve patients with EC, treated at our institution, were included in our retrospective study. Staging pelvic MRI scans were reviewed for tumor size, prolapse through cervical os, and other features. Time-intensity curves for tumor and surrounding myometrium regions of interest were generated, and positive enhancement integral (PEI), maximum slope of increase (MSI), and signal enhancement ratio (SER) were measured. The Fisher's exact test or Wilcoxon rank-sum test was used to compare characteristics between disease groups. Multivariate and univariate logistic regression models were used to distinguish MMMT from EC. Receiver operating characteristic analysis and the area under the curve (AUC) were used to evaluate prediction ability. MMMTs were larger than ECs with higher rate of tumor prolapse and more heterogeneous tumor enhancement compared to ECs. During the late phase of contrast enhancement, 100% of ECs, but only 84% of MMMTs, had lower signal intensity than the myometrium. Threshold PEI ratio ≥ 0.67 predict MMMT with 76% sensitivity, 84%, specificity and 0.83 AUC. Threshold SER ≤ 125 predict MMMT with 90% sensitivity, 50% specificity, and 0.72 AUC. MMMTs may show more frequent tumor prolapse, more heterogeneous enhancement, delayed iso- or hyper-enhancement, higher PEI ratios, and lower tumor SERs compared with EC. MRI can be used as a biomarker to distinguish MMMT from EC based on the enhancement pattern.

Keratin 17 is a Negative Prognostic Biomarker for Endometrial Carcinoma

BACKGROUNDKeratin 17 (K17) is a negative prognostic biomarker in cervical and ovarian cancers but has not previously been evaluated as a prognostic biomarker in endometrial adenocarcinoma. The association of K17 with decreased patient survival may be explained in part by the recent discovery that K17, unique among all keratins, drives tumor aggression by serving as a nuclear shuttle of p27, leading to cell cycle progression. Analysis of gene expression data from The Cancer Genome Atlas (TCGA) demonstrated that high K17 mRNA expression is prognostic for decreased overall survival in patients with endometrial carcinoma (n=228), prompting to test in the current study the hypothesis that immunohistochemical (IHC) staining for K17 correlates with survival of patients with endometrial cancer.METHODSCases of endometrial carcinoma were selected from Stony Brook Medicine Cancer Registry and UMass Memorial Cancer Registry. Histologic subtypes included endometrioid carcinoma (n=81), serous carcinoma (n=44), clear cell carcinoma (n=37), and malignant mixed Müllerian tumor (MMMT) (n=48). K17 was detected in sections of formalin‐fixed, paraffin‐embedded tissue blocks by indirect immunoperoxidase methods. Staining was scored based on the proportion of tumor cells that showed strong staining for K17 (PathSQ Score). Cases with “high‐K17” were defined as those with PathSQ score ≥10% and “low‐K17” cases were those with PathSQ <10% of tumor cells. Survival analyses were determined using the Kaplan‐Meier method and Mantel‐Haenszel method.RESULTS AND DISCUSSIONHigh‐K17 was detected in 31/210 cases of endometrial carcinoma, including 18/81 endometrioid carcinomas, 5/37 clear cell carcinomas, 6/44 serous carcinomas, and 17/48 MMMTs. Staining was localized to the malignant epithelial component in each case and was not detected in benign stromal cells, myometrium, or sarcomatous elements of MMMTs. Overall, High‐K17 correlated with decreased patient survival (HR: 4.8, n=210, p=0.0002). This trend was also found in clear cell carcinoma, serous carcinoma, and MMMT subtypes. K17 expression was also independently prognostic for both cases with localized (HR: 6.8, p=0.0009) and metastatic disease (HR: 2.4, p=0.0625), as well as for high‐grade tumors (HR: 2.3, p=0.0142), across all histologic subtypes of endometrial carcinoma.Prognostic biomarkers for endometrial adenocarcinoma have the potential to identify patients that are most likely to benefit from aggressive surgical intervention, including complete staging at the time of primary resection. The results of this study support the hypothesis that K17 is a powerful negative prognostic biomarker for not only high‐grade endometrioid adenocarcinomas, but also for other high‐grade histologic types of uterine carcinoma and MMMT, including cases limited to the uterus and those with advanced stage disease. Further studies are indicated to address the potential role of K17 as prognostic biomarker, to inform patient treatment decisions.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Eight cases of malignant mixed müllerian tumor (carcinosarcoma) of the uterus: Findings in surepath™ cervical cytology

Malignant mixed Müllerian tumor (MMMT)/carcinosarcoma is a rare neoplasm of the female genital tract characterized by a mixture of epithelial and mesenchymal components. There are published reports of conventional cervical smear findings in uterine MMMT, but to the best of our knowledge the cytomorphology of MMMT in SurePath™ liquid-based cytology samples has not been described. We present a series of eight cases of uterine MMMT in SurePath™ cervical samples. The mean age of the women was 65.5 years (range, 60-82 years) and the most common presenting symptom was postmenopausal bleeding. Three out of the eight cases had both epithelial and sarcomatous elements in highly cellular cervical samples. In two cases, abnormal glandular cell clusters were closely associated with the mesenchymal component. The glandular component was usually represented by three-dimensional clusters of malignant glandular cells and a dispersed population of large, round to oval malignant epithelial cells with single prominent nucleoli. Necrosis or tumor diathesis was not seen in any cases. Six out of the eight cases were initially reported as adenocarcinoma, endometrial type, and two cases as normal. Five cases had an atrophic background and tiny atypical glandular clusters that could easily be overlooked. Although cervical sample is not the method of choice for primary uterine carcinosarcoma screening, the possibility of the same should be kept in mind, when reporting a cervical sample from a woman with postmenopausal vaginal bleeding.

Malignant mixed Müllerian tumors of the uterus: sonographic spectrum

To describe the sonographic findings for malignant mixed Müllerian tumors (MMMTs) of the uterus with particular emphasis on their features on saline contrast sonohysterography (SCSH) and color Doppler sonography, and to determine how they relate to pathological findings. The SCSH and color Doppler findings in 29 histologically proven cases of uterine MMMT were reviewed retrospectively and their relationship to gross and histological findings were investigated. Of the 29 uterine tumors, 16 were located only in the corpus, nine only in the fundus and four in both the corpus and fundus. Mean tumor size was 5.4 cm. The most common appearance was a polypoid mass projecting into the endometrial cavity, found in 23 cases. Twenty-eight tumors had an irregular surface, which was papillary in 20 cases and lobulated in eight. Most appeared heterogeneously isoechoic (n = 16) or hypoechoic (n = 12), occasionally with a trabecular appearance, and they often had clefts or fissure-like cystic areas (n = 10), necrosis (n = 4) or hemorrhagic areas (n = 7). Myometrial invasion was present in 27 cases and dilatation of the endometrial cavity was seen in 11. Color Doppler sonography showed moderate to marked vascularity in 20 out of the 24 cases in which it was performed, with a mean resistance index of 0.41, and appeared as feeding (n = 15) or randomly dispersed (n = 9) vessels. Uterine MMMTs have distinct sonographic features that are related to pathological findings. Knowledge of the sonographic appearance of MMMTs may facilitate diagnosis.

Concurrent Diagnosis of Pulmonary Metastasis of Malignant Mixed Müllerian Tumor and Small Cell Lung Cancer

A patient who has multiple lung masses with a history of malignancy in organs other than the lung is more likely to be diagnosed with metastatic rather than primary lung cancer. Rarely, metastatic cancer can coexist with primary. We experienced a case of concurrent diagnosis of primary small cell lung cancer and pulmonary metastasis of uterine malignant mixed Müllerian tumor (MMMT). The patient was a 52-year-old female with femur fracture and multiple lung masses with a history of an operation for uterine MMMT. The small cell lung cancer was diagnosed by bronchoscopic biopsy. The central lung mass decreased after chemotherapy for small cell lung cancer but multiple peripheral masses increased. A percutaneous biopsy for one of peripheral masses revealed metastatic uterine MMMT. We suggest that we have to consider the possible presence of concomitant malignancies of different origins in one organ especially with patients who had a history of malignancy in another organ.

Primary Malignant Mixed Müllerian Tumor of the Uterus: Findings on Sonography, CT, and Gadolinium-Enhanced MRI

The purpose of our study was to evaluate the sonographic, contrast-enhanced CT, and gadolinium-enhanced MRI findings of primary malignant mixed müllerian tumors (MMMTs) of the uterus. Uterine MMMT most commonly presents as an intracavitary mass with coexistent dilatation of the endometrial canal. Tumors tend to appear hyperechoic on sonography, heterogeneously hypodense and ill defined on contrast-enhanced CT, and heterogeneously hyperintense on T2-weighted MR images with signal abnormalities indicating subacute hemorrhage on T1-weighted MR images. Myometrial invasion is common and has a predilection for the uterine fundus.

Loss of p16 in recurrent malignant mixed mullerian tumors of the uterus

Uterine malignant mixed müllerian tumors (MMMTs) are rare and highly aggressive malignancies with poor clinical prognoses. We examined for differences in the oncoprotein profiles of primary versus recurrent MMMTs. Five cases of recurrent uterine MMMT were examined by paraffin immunohistochemistry for the expression of p53, p16, P-cadherin, and Cerb-B2. P16, p53, and P-cadherin were each expressed in 100%, 80%, and 60% of the primary cases, respectively. Three cases expressed all three oncoproteins. All five cases were negative for Cerb-B2. No difference in antigen expression was seen in the epithelial versus sarcomatous components. Primary and recurrent tumors were concordant for p53, P-cadherin, and Cerb-B2. However, three cases of recurrent tumors were negative for p16 expression. P53, p16, and P-cadherin are common tumor suppressor genes expressed in uterine MMMT. Interestingly, p16 protein expression was lost in some cases of MMMTs when they recurred. This suggests that the oncoprotein and possibly genetic profile of p16 changes over time. We did not observe any difference in antigen expression between areas of epithelial or sarcomatous differentiation, which would support a single pluripotential malignant clone in the histogenesis of these tumors.

Loss of p16 in recurrent malignant mixed müllerian tumors of the uterus

Uterine malignant mixed müllerian tumors (MMMTs) are rare and highly aggressive malignancies with poor clinical prognoses. We examined for differences in the oncoprotein profiles of primary versus recurrent MMMTs. Five cases of recurrent uterine MMMT were examined by paraffin immunohistochemistry for the expression of p53, p16, P-cadherin, and Cerb-B2. P16, p53, and P-cadherin were each expressed in 100%, 80%, and 60% of the primary cases, respectively. Three cases expressed all three oncoproteins. All five cases were negative for Cerb-B2. No difference in antigen expression was seen in the epithelial versus sarcomatous components. Primary and recurrent tumors were concordant for p53, P-cadherin, and Cerb-B2. However, three cases of recurrent tumors were negative for p16 expression. P53, p16, and P-cadherin are common tumor suppressor genes expressed in uterine MMMT. Interestingly, p16 protein expression was lost in some cases of MMMTs when they recurred. This suggests that the oncoprotein and possibly genetic profile of p16 changes over time. We did not observe any difference in antigen expression between areas of epithelial or sarcomatous differentiation, which would support a single pluripotential malignant clone in the histogenesis of these tumors.

Response of recurrent uterine high-grade malignant mixed mullerian tumor to letrozole

Uterine malignant mixed müllerian tumor (MMMT) is a rare malignancy occurring most often in postmenopausal women. Despite the use of multimodality treatments including surgery, chemotherapy, and radiotherapy, prognosis is still poor in most cases. We report the case of a 69-year-old woman with recurrent metastatic high-grade MMMT that responded to letrozole, an aromatase inhibitor. At the initial diagnosis of high-grade uterine MMMT in February 2001, the patient underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, and postoperative pelvic radiotherapy. Two years later, an asymptomatic retroperitoneal mass was discovered on surveillance abdominal computed tomography scanning. The 3.5- x 3.0-cm mass was considered inoperable owing to its location near the aorta at the level of the renal vessels. The patient declined radiation or chemotherapy. Treatment with letrozole was begun at 2.5 mg daily. Serial computed tomography scans demonstrated marked tumor shrinkage; after 11 months of letrozole therapy, the tumor had shrunk to less than 25% of its original volume. Further study of letrozole for high-grade uterine MMMT is warranted.

A phase II trial of cisplatin, ifosfamide, and mesna in patients with advanced or recurrent uterine malignant mixed müllerian tumors with evaluation of potential molecular targets

Objective The aim of this study was to determine the efficacy of cisplatin, ifosfamide, and mesna in uterine malignant mixed müllerian tumor (MMMT) and to evaluate the expression of clinically relevant molecular markers. Methods Women with advanced or recurrent MMMT were treated every 28 days with cisplatin (75 mg/m 2), ifosfamide (1.2 gm/m 2), and mesna (240 mg/m 2). Treatment continued until disease progression or for six courses in the case of nonmeasurable disease. Immunohistochemical analysis for estrogen receptor (ER), progesterone receptor (PR), HER-2/neu, C-kit, Abl, and PDGFR-β expression were performed. Results Sixteen patients received 1–10 cycles; 2 died of disease progression after 1 cycle; 3 stopped after 1 cycle because of toxicity. Of 6 with measurable disease, 2 had a partial response, 1 had stable disease (SD), and 3 had progression (RR 33%). Partial response durations were 6 and 9 months; SD duration was 6 months. Of 5 patients without measurable disease, 4 received 6 cycles; 1 received 4 cycles. Four died of recurrent disease and 1 was without disease 6.5 years after treatment. Thirty-six percent experienced at least one neutropenic G3 or G4 event. All experienced G1 gastrointestinal toxicity. Four required dose reductions. At 7.5 months, only 1 with measurable disease was still living. Immunohistochemical analyses revealed that 24% expressed ER or PR, 19% expressed HER-2/neu, and none expressed C-kit. However, 45% expressed Abl and 100% expressed PDGFR-β. Conclusions Although the combination of cisplatin, ifosfamide, and mesna in patients with MMMT had moderate activity, the high toxicity and short response duration in this uncommon, aggressive malignancy suggest that this regiment continues to be a disappointing treatment choice for uterine MMMT. HER-2/Neu, Abl, or PDGFR-β expression may be of value in order to investigate novel multimodality treatment strategies.

Analysis of clinicopathologic factors in malignant mixed Müllerian tumors of the uterine corpus.

The aim of this study was to retrospectively analyze the clinical and pathologic data of a series of patients presenting to our unit with uterine malignant mixed Müllerian tumors (MMMT) to attempt to identify prognostic factors and relate them to survival. Thirty-seven patients diagnosed with MMMT of the uterus from 1988 through 2000 were identified from the gynecological tumor registry. Data was abstracted and analyzed. The effect of a variety of clinical, histopathologic, and surgical variables on recurrence and survival were analyzed by univariate and multivariate analyses. Patients tended to be postmenopausal, overweight, hypertensive, and presented with abnormal bleeding. Preoperatively 28 (76%) were thought to have clinical stage I-II disease. Nine (32%) were upstaged based on surgical data. Five (56%) of these patients were found to have gross extrauterine disease and four (44%) were found subsequently to have microscopic extrauterine disease. Twenty (54%) patients underwent lymph node dissection and positive nodes were found in seven (35%) patients. Nine patients underwent omentectomy and disease was found in three (33%). Peritoneal washings were positive in three of 16 patients (19%). At the completion of primary surgery, 27 (75%) patients had no residual disease. Twelve (44%) of these patients had recurrence of disease. Median disease-free interval prior to first recurrence was 15 months. Median overall survival was 30 months. Log-rank analysis performed on multiple variables, including stage, age, residual disease, and depth of myometrial invasion showed a statistically significant association with overall survival probability. Only stage remained a significant independent variable predictive of overall survival (P = 0.034). We found that stage was an independent prognostic factor for overall survival in patients with uterine MMMT. Age, depth of myometrial invasion, and residual tumor were significant prognostic factors on univariate analysis. These factors may be a guide in order to select a group of high risk patients that may benefit from adjuvant therapy.

P53 Protein Overexpression and Gene Mutation in Mixed Mullerian Tumors of the Uterus

Alteration of the p53 tumor suppressor gene is associated with poor prognosis in many human cancer types. We examined the incidence and prognostic significance of p53 gene alterations in a series of uterine malignant mixed Müllerian tumors (MMT). Nuclear overexpression of p53 protein detected by immunohistochemistry (IHC) with the DO-7 antibody was observed in 12 of 24 (50%) tumors. Mutation of the p53 gene detected by single-strand conformation polymorphism (SSCP) of exons 5 to 8 was found in 11 of 24 (46%) tumors. The incidence of p53 alteration in uterine MMT was significantly higher than in several common epithelial tumor cell types previously investigated in our laboratory using identical techniques. However, unlike these tumors alteration of the p53 gene does not appear to be of prognostic importance in uterine MMT.

Malignant Mixed Müllerian Tumor of the Uterus. Features Favoring its Origin from a Common Cell Clone and an Epithelial-to-Mesenchymal Transformation Mechanism of Histogenesis

Various histogenetic mechanisms have been postulated to explain the biphasic carcinomatous-sarcomatous appearance of malignant mixed mullerian tumors (MMMTs), but the nature of these uncommon neoplasms is still unclear. Some evidence would suggest that MMMT displays similarities with sarcomatoid carcinoma, a tumor arising in extragenital sites that also features a mixed appearance. To gain further insight into the histogenesis of this tumor, we have studied by immunohistochemistry a case of uterine MMMT showing an extensive rhabdomyosarcomatous component. A panel of antibodies including reactivity for p53, cytokeratin, vimentin, desmin, muscle actin, epithelial membrane antigen (EMA), myoglobin, type IV collagen, laminin, and tenascin was applied to paraffin tumor sections by means of the avidin-biotin complex technique. p53 immunoreactivity was observed in approximately the same number of cells in carcinomatous and sarcomatous tissue. The former stained for vimentin, cytokeratin and EMA, while the latter, in addition to expressing vimentin, desmin, muscle actin and myoglobin, also exhibited immunoreactivity for epithelial markers such as cytokeratin and EMA. At the borders between carcinoma and sarcoma the basement membrane pattern, as seen by staining for type IV collagen and laminin, showed interruptions in correspondence with areas of transition between the two tissues. Antibody to tenascin strongly labeled the sarcomatous tissue immediately around carcinomatous elements. A similar immunoreactivity for p53 in both carcinomatous and sarcomatous components, expression of epithelial markers in the sarcomatous cells, and disruption of the basement membrane profile in areas of transition between carcinomatous and sarcomatous tissue, would all suggest, as has been postulated for extragenital sarcomatoid carcinomas, an origin from a common epithelial clone and an epithelial-to-mesenchymal transformation-based mechanism of development for this MMMT. In addition, these findings provide further analogies between these categories of tumors, supporting a unifying nosological concept for MMMTs and sarcomatoid carcinomas of non-genital tract origin.

Establishment and Characterization of Cell Lines Derived from Uterine Malignant Mixed Müllerian Tumor

Objective.We report the establishment and characterization of three new cell lines derived from uterine malignant mixed müllerian tumor (MMMT).Methods.Three uterine MMMT cell lines from primary tumors of Korean patients were cultured and the involved cell morphology, growth properties, DNA profiles, immunohistochemical properties, tumor-associated antigen secretion, and genetic alterations of related oncogenes and tumor suppressor genes were studied as well.Results.Three MMMT cell lines were successfully established including one homologous tumor SNU-539 and two heterologous tumors SNU-685 and SNU-1077. All lines showed substrate adherence and high viability and were proven by DNA fingerprinting analysis to be unique. Contamination by mycoplasma and bacteria was excluded. SNU-539 and SNU-1077 cells stained positively for both epithelial and mesenchymal antigens, while SNU-685 cells only stained positively for mesenchymal antigens. The level of secretion of tumor-associated antigens, CA125 and CEA, was shown to be undetectable in all three lines. One missense mutation from AAC to GAC at codon 239 of exon 7 in the p53 gene was identified in SNU-539.Conclusions.These newly established and characterized permanent uterine MMMT cell lines might be regarded as valuable resources for a multitude ofin vitroinvestigations, which should be used for clarifying the obscure histogenetic origin and understanding the biological behavior of this aggressive tumor.

Characteristics of cloned cells of mixed müllerian tumor of the human uterus carcinoma cells showing myogenic differentiation in vitro

To elucidate the relationship between the epithelial and mesenchymal elements of malignant mixed Müllerian tumors (MMMT), the authors examined the biologic properties of two clones of different cell types (designated as FU-MMT-2-C1 and FU-MMT-2-S1) established from a uterine MMMT cell line (FU-MMT-2), which they previously have reported. By morphologic and immunocytochemical analyses, FU-MMT-2-C1 exhibited features of adenocarcinoma cells, whereas FU-MMT-2-S1 showed characteristics of sarcoma cells with myogenic differentiation. Some FU-MMT-2-C1 cells at confluence differentiated spontaneously into myogenic mesenchymal cells in vitro. In addition, transitional-type cells between epithelial cells and sarcomatous cells were observed in the areas of mesenchymal differentiation in FU-MMT-2-C1 by light and electron microscopic study. Ultrastructurally, the transitional-type cells represented biphasic morphologic characteristics consisting of epithelial and myogenic features, which proved to coexpress epithelial, mesenchymal, and muscle markers by double immunoenzymatic staining. However, no epithelial differentiations were apparent in the sarcoma clone FU-MMT-2-S1. FU-MMT-2-C1 produced tumor in nude mice, the histologic study of which showed a mixture of adenocarcinoma and myogenic sarcomatous elements that resembled the original tumor. Cytogenetic studies demonstrated that these two clones were monoclonal in origin because of the presence of common karyotypic abnormalities in both cells. In addition, the amplified (approximately fourfold to eightfold) c-myc oncogene was found in the cloned cells and the original tumor cells. The current results strongly support the theory of single cell origin in uterine MMMT and suggest that the mesenchymal elements originated from primitive Müllerian epithelial cells capable of differentiating into epithelial, mesenchymal, or both elements.

Malignant mixed Müllerian tumors of the uterus. An immunohistochemical study.

Malignant mixed müllerian tumors (MMMT) of the uterus have been subdivided into two types: those with heterologous sarcomatous elements (e.g., rhabdomyosarcoma, and chondrosarcoma) and those with only homologous elements (e.g., stromal sarcoma). The distinction, which may have prognostic significance, was based on the identification by light microscopy of cells that exhibited definite cross-striations, cartilage, or osteoid production. We studied 32 cases of uterine MMMT to assess the value of immunohistochemical markers in delineating the sarcomatous and epithelial components. Of 32 cases, 11 showed heterologous sarcoma (6, rhabdomyosarcoma, and 5, chondrosarcoma), and the remaining 21 were homologous MMMT. Six antigens--desmin, myoglobin, S-100, alpha 1-antichymotrypsin (ACT), epithelial membrane antigen (EMA), and monoclonal cytokeratin (AE1 and AE3), (to test for possible myogenic, chondroid, fibrohistiocytic, and carcinomatous differentiation)--were analyzed by the avidin-biotin-peroxidase method. EMA was found in neoplastic cells in all cases; 31 of 32 cases showed keratin. Desmin reactivity was detected in 14 of 32 cases, whereas myoglobin was present in 10 of 32. Three cases exhibited S-100 positivity (two in areas of chondrosarcoma, and one in some stromal sarcoma cells). Twenty-two cases (69%) exhibited ACT reactivity. Several cases displayed a malignant fibrous histiocytoma pattern. These demonstrated ACT positivity in both the neoplastic spindle and giant cells. We conclude that immunohistochemical staining for the above mentioned antigens is a useful diagnostic aid in delineating the sarcomatous and carcinomatous elements in MMMT.