[Multimodal treatment of malignant mixed Müllerian tumor]. / Malignus kevert Müller-cso-eredetu tumor komplex kezelése.

INTRODUCTION AND AIM: The aim of our study was to evaluate the prognostic factors and treatment options of a very rare and highly aggressive type of uterine neoplasms, the malignant mixed Müllerian tumor, known as carcinosarcoma. METHOD: Between 2009 and 2017, 29 patients were treated with malignant mixed Müllerian tumor. At stage I, surgery and postoperative radiotherapy were performed. At stages II-IV, trimodal treatment (surgery, chemotherapy and radiotherapy) was administered. RESULTS: The average age of patients was 68.51 (49-90) years, mean body mass index was 30.22 (20.90-37.22). We have experienced recurrence of disease after complete resection in 6 cases (4 of 6 patients did not accept radiation therapy). Local recurrence has occurred after an average 15.52 (6-36) months, distant metastasis with an average 19.2 (8-32) months. Overall survival was 11.92 (1-75) months. Six patients are free of tumours at the moment. CONCLUSIONS: As overall survival has not increased in recent decades by using combined chemotherapy, there is no congruent consensus associated with the optimal treatment. The standard surgical treatment is total abdominal hysterectomy with bilateral oophorectomy, although due to high rates of recurrence and metastases, the necessity of lymphadenectomy and postoperative treatment is in the focus of recent studies. Though postoperative irradiation improves local control, the beneficial effect on overall survival is still not proven. Adjuvant chemotherapy decreases the rate of both pelvic and extrapelvic recurrence at the same time, although there is no recommendation for the optimal chemoterapeutic agent. Multimodal therapy should lead to better outcomes. Recently there are many ongoing studies with biologic and target therapies to improve efficiency, however, the relevant results will be disclosed in many years only, due to the small number of patients. Orv Hetil. 2018; 159(19): 741-7747.

Cervical Mullerian adenosarcoma with heterologous sarcomatous overgrowth: a fourth case and review of literature.

BACKGROUND: Uterine sarcomas are relatively rare tumors that account for approximately 1-3% of female genital tract malignancies and between 4-9% of uterine cancers. Less than 8% of all cases are Mullerian adenosarcoma, a distinctive uterine neoplasm characterized by a benign, but occasionally atypical, epithelial and a malignant, usually low-grade, stromal component, both of which should be integral and neoplastic constituents of the tumor. Mullerian adenosarcoma with sarcomatous overgrowth (MASO) is a very aggressive variant, associated with post-operative recurrence, metastases, even when diagnosed in early stage. CASE PRESENTATION: We present a fourth MASO case derived from uterine cervix in a 72-year-old woman with metrorrhagia and a polypoid mass protruding through the cervical ostium. Total abdominal hysterectomy, bilateral salpingo-oophorectomy, systematic pelvic lymph node dissection, omental biopsy and appendectomy were performed. Surgery treatment was associated with adjuvant whole-pelvis radiation (45 Gy) and adjuvant chemotherapy (cisplatin/ifosfamide). After nine months of follow up, the patient was free of tumor. CONCLUSIONS: The rarity of MASO of the cervix involves a management difficult. Most authors recommend total abdominal hysterectomy, usually accompanied by bilateral salpingo-oophorectomy. There is no common agreement on staging by lymphadenectomy during primary surgery and adjuvant chemo-radio therapy.

Determining predominating histologic component in malignant mixed müllerian tumors: is it worth it?

Malignant mixed müllerian tumors (MMMT) are highly aggressive tumors, usually diagnosed in advanced stage. Cases of MMMT derive from either ovary or uterus. In our study, we investigated the role of carcinomatous and sarcomatous component on response to chemotherapy and disease outcome. We retrospectively analyzed 25 patients with MMMT who were treated in our outpatient clinic from 1998 to 2003. All the paraffin specimens were reevaluated according to the histopathologic features (primary site and percentages of carcinomatous and sarcomatous component) and the effect of predominant histologic type on response to treatment. Primary tumor sites were ovary and endometrium in 36% and 64% of patients, respectively. Ten of 25 patients (40%) were treated with a combination chemotherapy regimen of cisplatin-ifosfamide (PI) and 7 patients (28%) were treated with paclitaxel-carboplatin (PC) protocol. Despite chemotherapy, 17.6% of patients had progressive disease. The remaining 13 patients (54.2%) responded to chemotherapy. Response rates of patients treated with PC (100%) were remarkably higher than the response rates of patients treated with PI (66.6%). Moreover, patients with predominating carcinomatous component had a higher response rate (87.5%) than patients with predominating sarcomatous component (66.6%). MMMT are highly chemoresponsive tumors, irrespective of primary site. One of the best predictors to response is the histologic pattern. Predominating histopathologic feature (carcinoma or sarcoma) should be taken into consideration in predicting the response and planning the chemotherapy regimen.

Combined adjuvant cisplatin and ifosfamide chemotherapy and radiotherapy for malignant mixed müllerian tumors of the uterus.

The role of adjuvant therapy for malignant mixed müllerian tumors of the uterus has not been established. Our aim was to review our experience with sequential adjuvant therapy using cisplatin and ifosfamide chemotherapy and radiotherapy after surgical staging. A retrospective study of 43 patients from 1995 to 2004 was undertaken. Survival was calculated using the Kaplan-Meier method and compared by the log-rank test. The Cox proportional hazard regression model was used to assess the effect of treatment on survival after adjustment for age and stage. Twenty-eight patients received adjuvant chemotherapy and 28 patients had adjuvant radiotherapy. Twenty-one patients underwent sequential adjuvant chemotherapy and radiotherapy. Tumor recurrence occurred in 14 patients at a median duration of 10 months. The overall 2- and 5-year survival was 64% and 60%, respectively. The 2- and 5-year survival for stage I and II diseases was both 95%, while the 2-year survival for stage III and IV diseases was 25%. Patients who underwent sequential adjuvant therapy had an improved survival compared with patients who did not follow the protocol (P= 0.024). Our results with sequential adjuvant therapy are encouraging and justify future randomized trials.

Malignant mixed Mullerian tumors.

Malignant mixed Mullerian tumours (MMMTs) are rare neoplasms, highly aggressive and with an extremely poor prognosis, usually arising in elderly postmenopausal women and presenting at an advanced stage. MMMTs derive from the mullerian mesodermus that differentiates in epithelial and stromal elements, both malignant elements. The clinic pathological features of 3 uterine MMMTs are reported here. The patients ranged in age from 25 to 69 years. The initial manifestations were mainly bloody discharge, abdominal pain and increase of the volume of the uterus. Treatment in 2 patients was hysterectomy with double ooforectomy, and resection of the pelvic mass was the treatment in the third case. Adjuvant radio chemotherapy was administrated in 2 of the 3 cases. Follow-up revealed recurrent pelvic tumour in 1 patient at 59 months, and breast metastases at 20 months in the second one. Because of the high incidence of recurrence and poor prognosis of these tumours, they should be studied and managed by a multidisciplinary team composed by surgeons, oncologists, radiotherapists and pathologists.

On the apparent failure of adjuvant pelvic radiotherapy to improve survival for women with uterine sarcomas confined to the uterus.

Despite numerous studies documenting reduction of pelvic relapses after adjuvant pelvic radiotherapy stage I and II uterine sarcomas, improved survival remains unproven. This retrospective report analyzes patterns of failure, survival, and toxicity in 42 women with stage I and 7 patients with stage II uterine sarcomas treated from 1972 through 1998 to identify patients likely to benefit from pelvic or abdominal radiotherapy and chemotherapy. Four of these patients also received adjuvant chemotherapy. There were 20 leiomyosarcomas, 18 homologous mixed mullerian tumors, and 11 heterologous mixed mullerian tumors. Disease-free survivals for mixed mullerian tumors were 65% at 5 years and 61% at 15 years. Disease-free survivals for leiomyosarcomas were 40% at 5 years and 40% at 15 years. There were 14 distant only, 5 distant and abdominal, 1 abdominal, 1 distant and pelvic, and 2 unknown initial sites of failure. Acute toxicity was acceptable as measured by a median 1-kg weight loss from radiotherapy and a 2% rate of failure to complete therapy. Chronic toxicity consisted of 3 small bowel obstructions and 1 sigmoid colon obstruction. In conclusion, the efficacy of adjuvant pelvic radiation is demonstrated by the absence of any isolated pelvic failures. Although the frequent occurrence of peritoneal failures suggests a role for prophylactic abdominal radiation for mixed mullerian tumors, more effective systemic therapy is necessary to substantially increase the chance of cure for women with early-stage uterine sarcomas.

Limitations of adjuvant radiotherapy for uterine sarcomas spread beyond the uterus.

OBJECTIVE: The present review analyzes patients with advanced uterine sarcomas with the goal of identifying patients likely to benefit from larger volumes and higher dosages of radiotherapy. METHODS: A retrospective review was performed of medical records of all patients receiving adjuvant radiotherapy for advanced uterine sarcomas from 1978 to 1997 at the University of Minnesota. RESULTS: Nineteen women with advanced uterine sarcomas received adjuvant radiotherapy. Seven also received adjuvant chemotherapy. Three patients had FIGO stage IIIA, 1 stage IIIB, 5 stage IIIC, and 12 stage IVB. Patients with mixed mullerian tumors had overall and disease-free survivals of 31% at 1 year and 23% at 5 years. For leiomyosarcomas, overall survival was 67% at 1 year and 33% at 5 years, but relapse-free survival was 33% at 1 and 5 years. First sites of failure were three pelvic and abdominal, one abdominal only, one abdominal and distant, two pelvic and distant, one pelvic, abdominal, and distant, five distant only, and one unknown. No Grade 3 or 4 toxicity occurred. CONCLUSION: Ongoing technical advancements in radiotherapy offer more precise radiation delivery, particularly to the peritoneal cavity. Although abdominal failures are common in women with mixed mullerian tumors, translation of higher radiation dosage to cure is unproven, and the majority of failures have a distant component. Until effective systemic therapy is developed, the prognosis of uterine sarcomas with any spread beyond the uterus will remain poor.

Malignant mixed Müllerian tumors of the uterus: analysis of patterns of failure, prognostic factors, and treatment outcome.

PURPOSE: To determine the survival outcomes, prognostic factors, and patterns of failure in patients with malignant mixed Müllerian tumor (MMMT) of the uterus. METHODS AND MATERIALS: Between 1954 and 1998, 300 patients with clinical Stage I-III MMMT of the uterus were treated with curative intent at The University of Texas M. D. Anderson Cancer Center. Their hospital records were reviewed to obtain patient and tumor characteristics; details of surgery, radiotherapy (RT), and chemotherapy; and long-term outcome. Surviving patients were followed for a median of 109 months (range 15-138). Survival rates were calculated using the Kaplan-Meier method, with differences assessed by log-rank tests. RESULTS: Of the 300 patients, 113 (38%) were treated with surgery alone, 160 (53%) with surgery plus adjuvant EBRT or ICRT, and 27 (9%) with RT alone. Forty-eight patients received adjuvant chemotherapy. At 5 years, the overall rates of survival and cause-specific survival were 31% and 33%, respectively. Women who were postmenopausal or had a history of prior pelvic RT, pain at presentation, clinical Stage II-III disease, uterine enlargement (>/=12 weeks), or an abnormal Papanicolaou smear finding had a significantly poorer prognosis than the other patients in the series. Of the 273 patients who underwent surgery, those who had positive abdominal washings, uterine length >10 cm, or extrauterine spread of disease to the cervix, adnexa, or peritoneum had a significantly worse prognosis than the other patients. Factors found on multivariate analysis to have an independent adverse influence on cause-specific survival included postmenopausal status (p = 0.0007, relative risk [RR] 3.3), uterine length >10 cm (p = 0.0001, RR 2.2), cervical involvement (p = 0.002, RR 1.8), and peritoneal involvement (p = 0.0001, RR 4.3). At 5 years, the rates of pelvic and distant disease recurrence for the entire group of 300 patients were 38% and 57%, respectively. The most common site of distant recurrence was the peritoneal cavity. Patients treated with pelvic RT had a lower rate of pelvic recurrence than patients treated with surgery alone (28% vs. 48%, p = 0.0002), but the overall survival rates (36% vs. 27%, p = 0.10) and distant metastasis rates (57% vs. 54%, p = 0.96) were not significantly different. However, patients treated with pelvic RT had a longer mean time to any distant relapse (17.3 vs. 7.0 months, p = 0.001) than patients treated with surgery alone. The use of adjuvant chemotherapy did not correlate with the survival rate or rate of distant metastasis. CONCLUSION: Adjuvant pelvic RT decreased the risk of pelvic recurrence and may delay the appearance of distant metastases after hysterectomy for MMMT. However, the survival rates remain poor because of a high rate of distant recurrence. As more effective systemic chemotherapy is developed to control microscopic distant disease, the role of RT in controlling locoregional disease in the pelvis and abdomen may become more important. Future research should consider programs that integrate surgery, RT, and chemotherapy to maximize the probability of cure.

Uterine sarcoma: twenty-seven years of experience.

PURPOSE: A correlation of treatment for uterine sarcoma with outcome, prognostic importance of pathology, and clinical parameters. PATIENTS AND METHODS: One hundred forty-one patients (median age: 56 years, range: 19-85 years) with a histologically verified uterine sarcoma were identified from a database compiled at the Royal Marsden Hospital and the University of Florence between 1974 and 2001. Seventy-two patients had leiomyosarcoma, 42 had mixed müllerian tumors, 22 had endometrial stromal sarcoma, 1 hemangiopericytoma, 1 rhabdomyosarcoma, and 3 patients had unspecified sarcoma. According to FIGO classification, Stage I, II, III, and IV tumors were identified in 71, 13, 31, and 26 patients, respectively. RESULTS: At the time of analysis, 73.7% of patients were dead, and 26.3% were alive with a median survival of 2 years from initial diagnosis. Univariate analysis for cause-specific survival demonstrated statistical significance for histology (p = 0.02), grade (p = 0.003), stage (p = 0.007), and age (p = 0.02). Multivariate analysis demonstrated significant prognostic values for stage (p = 0.02) and histology (p = 0.05) only. Postoperative radiotherapy with a total dose higher than 50 Gy seems to be significant (p = 0.001) in reducing local recurrence. CONCLUSIONS: Our data favor treatment for Stages I, II, and III of uterine sarcoma with radical surgery plus radical dose irradiation comprising both external beam radiotherapy and brachytherapy.

Tumor mulleriano mixto maligno de endometrio con componente rabdomiosarcoma / Malignant mixed mullerian tumour of the endometrium with a rhabdomyosarcomatous component

Presentamos dos casos de tumor mulleriano mixto maligno de endometrio con componente heterólogo rabdomiosarcomatoso. Este tipo de tumores, más conocidos como carcinosarcomas, tienen epitelio y estroma malignos. Los componentes estromales se han dividido en homólogos y heterólogos. Los estudios immunohistoquímicos basados en la coloración positiva de los anticuerpos de las muestras del tumor son muy útiles para realizar el diagnóstico (AU)

Malignant mixed Müllerian tumour of the cervix treated with concurrent chemoradiation.

Malignant mixed Müllerian tumours of the cervix are very uncommon. Of the 26 cases reported in the literature only 8 consist of homologous sarcoma with squamous cell carcinoma. Historically, treatment has been with radiation or surgery or a combination of both. We describe a locally advanced case treated with concurrent chemoradiation.

Multimodality therapy for patients with clinical Stage I and II malignant mixed Müllerian tumors of the uterus.

BACKGROUND: The role of adjuvant therapy in the management of patients with malignant mixed Müllerian tumors (MMMT) of the uterus has not been defined. The outcome of planned multimodality therapy for patients with apparent early stage disease was assessed. METHODS: A pilot study was performed on 38 patients with clinical Stage I or II MMMTs of the uterus who were offered treatment according to a standard protocol. The protocol consisted of removal of the uterus, fallopian tubes, and ovaries and surgical staging followed by tailored radiation therapy and chemotherapy, consisting of cisplatin and epirubicin. RESULTS: The overall survival was 74% (28 of 38 patients), with a mean duration of follow-up for survivors of 55 months (range, 17-121 months). The mean time to death from disease was 26 months (range, 7-87 months). The survival rate for those patients who completed treatment according to the multimodality protocol was 95% (20 of 21 patients), with a disease free survival rate of 90% (19 of 21 patients). The overall survival of patients who did not receive the recommended treatment protocol for various reasons was 47% (8 of 17 patients). An analysis of survival curves demonstrated that there was a significant survival advantage for those patients who completed the treatment according to the multimodality protocol (P = 0.01). CONCLUSIONS: In this pilot study, patients with clinical Stage I or II MMMTs who underwent surgical staging and aggressive adjuvant radiation and chemotherapy had an excellent survival rate. The results justify a randomized prospective study of this approach.

The role of chemotherapy in malignant mixed mullerian tumors of the female genital tract.

Thirteen patients with malignant mixed mullerian tumor of the female genital tract, treated and followed in our clinic from 1989 to 1999 were retrospectively evaluated. Seven patients (53.8%) with advanced disease or postoperative residual tumor were treated with adjuvant chemotherapy. The median age at diagnosis was 64 years (range: 26-79). All patients underwent primary surgical cytoreduction. Tumors were localized to the endometrium in five (62.5%), to the ovaries in two (25%) and to the fallopian tube in one (12.5%) patient. One patient with endometrial carcinosarcoma had a simultaneous second primary ovarian epithelial carcinoma. Two patients (25%) had a heterologous sarcomatous component. Myometrial involvement included less than half the thickness in one patient, while there was no myometrial invasion encountered in two patients. Five patients (38.5%) had more than 50% of the myometrium invaded. Two patients received additional radiotherapy. Six patients received cisplatinum-based chemotherapy (4 had doxorubicin including combinations), while one patient was treated with a doxorubicin+ifosphamide combination. Five patients (71.4%) had a complete response (CR) to chemotherapy. Response duration in patients with a CR was +13, +67, +10, +14 and +2 months, respectively. After a median follow-up period of 20 months (3-115 months), six patients have died, five are being followed-up with no evidence of disease, one is alive with metastatic disease and one patient is under treatment. Malignant mixed mullerian tumor of the female genital tract is highly responsive to multimodality treatment strategies. Further prospective studies are required to identify distinct prognostic groups that may benefit from various treatment modalities.

Mullerian adenosarcoma of the uterus: case report and review of literature.

Mullerian adenosarcoma--a variant of mullerian mixed mesodermal tumor of the uterus--is typically composed of benign but sometimes mildly atypical glandular epithelial elements admixed with malignant sarcomatous stroma. This rare tumor, which accounts for only about 8% of all uterine sarcomas, usually originates in the endometrium and grows as a polypoid mass within the endometrial cavity. The most prevailing presenting symptom is abnormal vaginal bleeding and the most common finding is a polypoid mass protruding through a dilated cervical canal. The case of a woman, who at age 62 presented with symptoms and signs of acute pelvic inflammatory disease and on vaginal examination an infected mullerian adenosarcoma protruding through a dilated cervical canal was discovered, is reported. Treatment consisted of extensive antibiotic treatment and surgery comprised of total abdominal hysterectomy and bilateral salpingo-oophorectomy followed by postoperative adjuvant pelvic radiotherapy. One year later, the patient is alive with no evidence of disease.

Cancer-associated retinopathy.

Patients with systemic cancer may have a variety of ocular complaints. Most commonly these are metastases or adverse effects of therapy. Paraneoplastic syndromes, like cancer-associated retinopathy, rarely cause ophthalmic symptoms. We describe a patient with a malignant mixed mullerian tumor and cancer-associated retinopathy who had circulating serum antibodies to recoverin and cells positive for recoverin in the tumor. We discuss the typical clinical symptoms as well as the pathophysiology of this uncommon disorder.

Results of primary and adjuvant radiotherapy in the treatment of mixed Müllerian tumors of the corpus uteri.

OBJECTIVE: The benefit of primary or adjuvant irradiation in the treatment of mixed Müllerian tumors is still not clear. METHODS: During 1981-1997 63 patients were referred for primary (n = 13) or postoperative (n = 50) radiotherapy. Analysis of outcome of primarily and postoperatively irradiated patients was performed separately because of different staging systems. Of 50 patients treated after surgery 29 presented in histopathologic stage I, 4 in stage II, 14 in stage III, and 3 in stage IV. Clinical stage distribution for primary treatment was stage I: n = 9, stage II: n = 1, stage III: n = 3. Forty-four patients in the postoperatively treated group and 6 in the primarily treated group received radiotherapy with a curative intent; external beam therapy was given up to 56 Gy to the pelvis combined with intravaginal or intracavitary brachytherapy. RESULTS: Five-year actuarial overall survival, disease-specific survival, local control, and distant control for 50 patients receiving adjuvant irradiation was 52.9, 57. 5, 83.4, and 70.8%, in stage I: 68.4, 76.1, 95.2, and 81.7%, in stage II: 50.0, 50.0, 75.0, and 66.7%, and in stage III: 31.3, 34.1%, 70.4, and 47.6%, respectively. Four of 13 patients treated with primary irradiation achieved long-term local control. CONCLUSION: These data suggest that adjuvant radiotherapy improves local control and disease specific survival in the treatment of mixed Müllerian tumors compared to data in the literature concerning treatment by surgery alone.

Impact of radiotherapy on local control and survival in uterine sarcomas: a retrospective study from the Grup Oncologic Català-Occità.

PURPOSE: In order to provide more information for the clinician and to analyze the impact of radiation therapy on the loco-regional disease-free interval (LRFI), disease-free interval (DFI) and specific overall survival (OS), a multicentric retrospective study of uterine sarcomas has been undertaken using cases reported to the Grup Oncològic Català-Occità (GOCO). PATIENTS AND METHODS: One hundred three patients were selected for this study with a median follow-up period of 49 months. Patients were restaged using the FIGO classification for endometrial adenocarcinoma. Radiotherapy was administered postoperatively to the entire pelvis in 52% of cases (54/103) and was combined with brachytherapy in 24 patients. Mean given dose was 48 Gy, with a 95% confidence interval of 45 to 50 Gy. Variables have been tested for homogeneity between hospitals. Univariate and multivariate analyses have also been carried out. RESULTS: Mean age of the selected patients was 59 years (range 35-84). Stages were distributed as follows: 66 patients (64%) in Stage I; 16 in Stage II (15.5%); 12 in Stage III (11.5%); 9 patients in Stage IVa (9%). Pathological distribution was 41.5% leiomyosarcoma, 39% mixed Mullerian tumours, 16.5% stromal sarcomas, and 2.9% of a miscellaneous group. Overall survival for the entire group was 63.7% and 56% at 2 and 5 years, respectively. Probability of LRFI reached 59.8% at 2 years and 57.4 at 5 years. The DFI at 2 and 5 years were 52.9 % and 48.7%, respectively. The LRFI probability was 41% and 36% at 2 and 5 years, respectively, without radiotherapy and reached 76% at 2 and 5 years among those patients treated with radiotherapy. There was also an increase in DFI probability because of the effect of radiotherapy, from 35% to 68.5% and from 33% to 53% at 2 and 5 years, respectively. The overall survival probability for patients treated with radiotherapy was 76% and 73% at 2 and 5 years, respectively and 51% at 2 years and 37% at 5 years without radiotherapy. Multivariate analysis demonstrated that radiotherapy improved LRFI, DFI, and overall survival. CONCLUSION: We conclude that postoperative radiotherapy in our series of patients diagnosed with uterine sarcoma has an impact on loco-regional and disease-free progression intervals and survival.

Postoperative pelvic irradiation in early stage uterine mixed mullerian tumors.

PURPOSE OF INVESTIGATION: To review our management experience with uterine mixed mullerian tumors (MMTs) in order to evaluate potential prognostic indicators, and assess the efficacy of various treatment modalities. METHODS: A retrospective, clinicopathologic evaluation of 43 patients presenting for treatment of uterine MMTs between 1982 and 1992 was conducted. Diagnostic criteria for inclusion was the presence of both a malignant glandular or squamous epithelial component, and a homologous or heterologous stromal component. RESULTS: Overall 2- and 5-year cancer related Kaplan-Meier survival estimates with 95% confidence intervals were 44 (.28, .59) and 26% [.12, .39], respectively. Survivals were 83 [.62, .99] and 58% [.31, .85] when disease was confined to the uterus, and 22 [.03, .41] and 7% [.01, .20] when disease extended beyond the uterus. Clinical staging was often inaccurate, with 29% of clinical stage I or II disease being upstaged at laparotomy. A significant survival advantage was found in patients with stage I or II disease treated with surgery plus pelvic irradiation (p = 0.001), as compared to those treated with surgery alone. The prognosis after disease recurrence was poor, irrespective of secondary therapy, with a median survival of 11 months. CONCLUSIONS: A therapeutic advantage may be gained from postoperative pelvic irradiation in the treatment of surgical stage I or II uterine MMT.