Malignant mixed Müllerian tumors of the uterus

International Journal of Gynecology & Obstetrics 47 (1994) 39-44

Article

Malignant mixed Miillerian tumors of the uterus W.W.K. To*, H.Y.S. Ngan Department

of Obstetrics and Gynecology,

University of Hong Kong, Queen Mary Hospital, Pokjiilam, Hong Kong

Received 29 March 1994; revision received 25 May 1994; accepted 3 June 1994

Abstract Objective: To review the prognostic factors of Chinese women with mixed Miillerian tumors of the uterus. Method: review of 21 cases of malignant mixed Miillerian tumors of the uterus treated during the IO-year period from 1980 to 1990. Results: All patients except one were postmenopausal. The incidence of previous pelvic irradiation

A retrospective

was 9.5%. The most common presenting symptom was abnormal vaginal bleeding. One-third of patients yielded an abnormal cervical smear. Treatment included surgery, chemotherapy and radiotherapy in the majority of patients. Prognosis was poor with only three long-term survivors, all with stage-I homologous tumors with superficial myometrial invasion. The survival rate for stage-I and -II disease at 2 years was 50% and for more advanced disease extending beyond the uterus was 0%. The survival rate for all stages at 5 years was 14.3% and the cumulative probability of survival at 5 years was 0.165. Conclusion: The most important prognostic factors appear to be the extent of tumor

involvement at the time of diagnosis and the depth of myometrial invasion. Keywords: Malignant mixed Miillerian tumors; Uterus; Prognosis

1. Introduction

The Miillerian ducts from which the uterus arises are formed by the mesenchyme of the urogenital ridge and are lined by epithelium derived from the coelomic surface. This biphasic ancestry is present during normal endometrial development in the menstrual cycle, when both epithelial and stromal elements proliferate. Malignant mixed Miillerian tumors (MMMT) of the uterus are composed of both epithelial and mesenchymal eleCorresponding author, Fax: (852) 8175374.

??

0 1994 International 0020-7292/94/$07.00 SSDI 0020-7292(94)02168-X

ments. This pairing of the two cell lines has been well documented by tissue culture studies [l] and electron microscopy findings [2]. The immediate precursors of MMMT are believed to be the least differentiated pluripotential stromal cells of the endometrium. It has been reported that mesenchymal elements within these tumors stained also for epithelial tumor markers, indicating a possible common cellular ancestry [3]. The possibility of a different origin of the epithelial and stromal components from different primordial cells has, however, also been raised [4]. The precise histogenesis remains elusive.

Federation of Gynecology and Obstetrics

40

W. W.K. To. H. Y.S. Ngan / ht. J. Gynecol. Obstet. 47 (1994) 39-44

While MMMT is well known for its very aggressive course, uncertainty still exists in the literature as to the significance of various prognostic indicators, such as histological variations, tumor size, previous irradiation history, clinical and operative staging, and extent of the disease at diagnosis [5-71. Not less controversial is the response of MMMT to the various treatment modalities, and in particular the role of adjuvant radiotherapy and chemotherapy [8,9]. This review aims to verify some of these parameters in the group of patients under study. 2. Materials and methods All patients with MMMT of the uterus treated in the Department of Obstetrics and Gynecology, University of Hong Kong, between 1980 and 1990 were reviewed. A total of 21 patients with primary evaluation and treatment in our unit were included for study, the rest being referred after initial treatment with or without tumor recurrence. No patient presented with distant metastasis, and none of the reviewed patients were lost to follow-up. All patients were Chinese. All histopathological slides were reviewed by a specialist hospital pathologist. The histories and clinical details were extracted from medical records. The patients were staged according to the International Federation of Gynecology and Obstetrics 1988 staging for carcinoma of the corpus. The total follow-up time of these patients ranged from 3 to 14 years. 3. Results The average age of this group of patients was 62.9 years, with a range of 54-78 years. All patients were postmenopausal except one, who had regular menses at the time of presentation at age 55. Five patients were discovered to have the diagnosis within 10 years after the menopause, a further 13 were diagnosed more than 10 years after the menopause. The average time from menopause to the development of the tumor in these 18 patients was 14.8 years. Two patients had a history of carcinoma of the cervix and received pelvic irradiation (external irradiation and intracavitary

radium insertion) 9 and 24 years prior to the diagnosis of MMMT, giving an incidence of previous pelvic irradiation of 9.5% in this series. No patients had a history of exogenous estrogen intake after the menopause. One patient was single, five had involuntary primary infertility, and the other 15 were parous with an average parity of five and a range of l-l 1. Seven (33.3%) patients had chronic hypertension requiring drug treatment, three (14.3%) had diabetes mellitus, and five (23.8%) were obese with a body weight over 150% of their ideal weight for height and age. Vaginal bleeding was reported in 15 (71.4%) patients and was the most common presenting symptom. Six (28.6%) had a self-detectable abdominal mass. Vaginal discharge and pelvic pain were the chief complaint in three (14.3%) and two (9.5%) patients, respectively. The most common physical sign at presentation was an abdominal or pelvic mass, which was present in 14 (66.7%) patients. A vaginal mass was present in five (23.8%). An abnormal cervical cytology smear was documented in 10 (47.6%) of these patients, seven of which were reported as adenocarcinoma, two as squamous cell carcinoma and one as malignant cells of unknown origin. A diagnostic dilatation and curettage was performed in 10 patients and a definitive diagnosis of MMMT was made in six cases from histology of the curettings. The other four were variously reported as squamous carcinoma, adenocarcinoma and suspected stromal sarcoma. A conclusive histological diagnosis of MMMT was only possible after histological examination of the hysterectomy specimen in these cases. The operative staging of the 21 patients was as follows: six in stage I (28.6%), six in stage II (28.6%), four in stage III (19%) and five in stage IV (23.8%). Amongst stage-1 patients, the tumor size ranged from a 3-cm polyp to a 16-week gravid-size uterus. One patient had a tumor polyp with involvement limited to the endometrium, two had myometrial invasion less than half thickness, and the other three had deep myometrial invasion. Five had a total hysterectomy and bilateral salpingooophorectomy (THBSO). One patient who had previous pelvic irradiation for carcinoma of the

W. W.K. To, H. Y.S. Ngan 111~. J. Gynecol. Obster. 47 (1994) 39-44

41

Table 1 Summary of treatment of MMMT THBSO

Other hysterectomy

No hysterectomy

Radiotherapy

Chemotherapy

Stage I (n = 6)

5

1 (subtotal)

0

5

6

Stage II (n = 6)

5

1

0

5

5

Stage III (n = 4)

2

(Wertheim) 0

2

1

I

Stage IV (n = 5)

4

0

I

3

4

cervix had a subtotal hysterectomy. All five patients without previous irradiation were given external pelvic irradiation and vault radium insertion, and all six had adjuvant chemotherapy, two with doxorubicin and four with the vincristine, doxorubicin and cyclophosphamide (VDC) regime (Table 1). There were three longterm survivors in this group, all with superficial myometrial invasion, now free of disease for 10, 13 and 15 years, respectively. One patient died of sepsis during chemotherapy, and the other two died of intraperitoneal metastasis within 2 years following initial treatment. Of the 15 patients in stages II-IV, 11 had a THBSO with/without debulking of the extrauterine pelvic tumor. One had a Wertheim hysterectomy, and a positive metastatic tumor was discovered in the iliac lymph nodes grossly and on histology. One patient with stage-II disease with a history of previous pelvic irradiation for carcinoma of the cervix was not further irradiated, but nine others were given external pelvic irradiation and seven were given radium insertion

postoperatively. A total of 10 patients were given chemotherapy, four with doxorubicin and six with the VDC regime. Two patients in stage III with widespread intraperitoneal metastasis involving the omentum and colon were deemed inoperable at laparotomy. One patient with metastasis to the bladder died of acute obstructive renal failure before commencement of active treatment (Table 1). One patient in stage IV had a suburethral metastasis at presentation, but further metastasis or tumor recurrence was documented in this patient as well as in the other 11 actively treated cases within 15 months after diagnosis. The most common sites of metastasis or recurrence included intraperitoneal (9/12), bone (2/12), hepatic (3/12), pulmonary (3/12) and vaginal (2112). A substantial proportion of patients had multiple sites of metastasis. Three patients with stage-II disease survived more than 2 years but all died of the disease within 3 years. All other patients in stages II and IV succumbed within the 1st year after diagnosis. The survival rate for stage-I and -II disease

Table 2 Life table estimates of survival (all stages) Interval

1 2 3 4 5

No. at risk

21 6 4 3 3

No. of terminations Deaths

Censored

15 2 1 0 0

0 0 0 0 0

Cumulative probability of survival 0.33 0.22 0.165 0.165 0.165

42

W. W.K. To, H. Y.S. Ngan /hr.

at 2 years was 50%, and for more advanced disease extending beyond the uterus was 0%. The survival rate for all stages taken together was 14.3% at 5 years. The cumulative probability of survival at 5 years of all stages taken together was 0.165 (Table 2). Gross examination of the 18 hysterectomy specimens available showed the tumor ranging from a 3-cm polypoid growth (the only tumor confined to the endometrium) to a huge necrotic infiltrative mass measuring 32 cm at its greatest diameter. Histopathological reports of these tumors showed nine homologous tumors and 11 heterologous tumors; one remained undefined due to the very extensive necrosis in the biopsy specimen. Of the homologous tumors, eight had adenocarcinoma as the main epithelial element, while one had clear cell carcinoma. Sarcomatous pattern was the most common stromal element, but two had leiomyosarcoma, two had fibrosarcoma and one had a liposarcoma. Of the heterologous elements present, five had rhabdomyoblasts, five had chondrosarcoma and three had osteosarcomatous elements. Several elements were present together in some of these tumors. 4. Discussion Mixed mesodermal tumors contain both epithelial and mesenchymal elements as active participants in the neoplastic process. There is a gradation of malignant potential in both the epithelium and stroma, ranging from adenofibroma at the benign end, through adenosarcoma and carcinotibroma to mixed Miillerian tumor when both elements are malignant. The poor prognosis demonstrated in this series is consistent with that reported in the literature. In a pathological review of this condition, Spanos et al. [8] showed a survival rate of only 38% at 5 years despite a high proportion (59%) of patients with stage-I disease. However, over 90% of the recurrences and 800/oof the metastasis occurred within the first 2 years, which is similar to our series. In another study, Dinh et al. [9] showed that despite 68% of patients in stage I at diagnosis, the 5-year survival was again a meager 35%. The low 5-year survival rate of 14.3% reported in this study is

J. Gynecol. Obstet. 47 (1994) 39-44

probably due to the higher proportion of tumors presenting at more advanced stages. The high incidence of abnormal cervical cytology smears reported in this series showed that cervical cytology may be a useful step in alerting the clinician to the diagnosis of MMMT in the presence of abnormal vaginal bleeding. Costa et al. [lo] found that 61% patients with MMMT had abnormal cervical smears, though the diagnosis of MMMT was only occasionally arrived at on smear cytology evidence alone. Moreover, while a smear positive for cancer was associated with a high stage of disease at presentation or with recurrent disease, there was no association with the depth of myometrial invasion size, grade or histological type of the tumor. The importance of consultative cytology reporting in these difficult cases was emphasized, and appropriate recommendations for further action, including curettage or endometrial biopsies should therefore be encouraged. While there is often a difference in clinical and operative staging of these tumors [8], the pathological extent of tumor spread has been consistently reported in the literature as a crucial prognostic indicator [6,8,11,12]. In those tumors confined to the uterus, the depth of myometrial invasion becomes an issue of paramount importance. Both Dinh et al. [9] and King and Kramer [12] reported that the best correlation with survival was the depth of uterine invasion, while tumors restricted to a polyp have been consistently reported to bear the best prognosis, usually with long-term survival [9,13,14]. These points are well illustrated in our series, as the three long-term survivors all had superficial myometrial invasion, which in one case was confined to a polyp. Reports of the behavior of MMMT in Asian populations have been sparse, if at all, in the world literature. Macasaet et al. [6] showed that homologous tumors were more common in white than in black women (67 vs. 30%). Our series of Chinese women showed that homologous and heterologous tumors occurred with roughly equal incidence in females of this ethnic group. The high proportion of nulliparous women in our series is consistent with the hypothesis that nulliparity may predispose to the development of MMMT. Less remarkable is the incidence of concurrent chronic

W. W. K. To, H. Y.S. Ngan /ht.

medical problems, such as diabetes mellitus or obesity, which is probably average for women of this age group in our population. The small numbers involved, however, preclude any reasonable attempt at case-controlled comparison. The presence or absence of stromal heterologous elements, the types of such elements when present, the degree of atypia and the extent of mitotic activity of the stromal component have all been claimed to be significantly associated with metastatic ability and the outcome of these tumors by various authors. In a large series of 203 cases with detailed histological analysis, Silverberg et al. [S] stated definitively that none of these factors bears any relationship whatsoever to the metastatic risk or progression of these tumors. On the other hand, similar to endometrial carcinoma, the degree of myometrial invasion, vascular permeation, cervical involvement and lymph node metastasis, all appeared to be directly related to one another. While the long-term survivors in our series all have homologous tumors, it is our impression that the stage of the disease and degree of myometrial invasion are of primary importance in determining the outcome in these patients. DiSaia et al. [ 151 casted doubt on any correlation between previous irradiation and MMMT of the uterus. Other studies, however, have suggested an extremely poor prognosis in this postirradiated group [7,9,12,16]. Our experience with the irradiated patients in this series is consistent with the hypothesis of a poor prognosis in this group. This compromised prognosis may in part be related to the suboptimal treatment options encountered, including difficult or inadequate surgical treatment and the inability to further irradiate these patients. There is no doubt that surgery remains the mainstay of treatment of MMMT. The role of adjuvant radiotherapy and chemotherapy still remains to be defined. While Kohorn et al. [ 171have reported an 80% survival of 3-5 years in five patients treated by a combination of surgery, radiation and chemotherapy, other larger studies [ 18,191have reported no beneficial effect on survival by radiotherapy. Recent reports, however, indicate that there may be a role for adjuvant chemotherapy. Van Le et al. [20] showed that pa-

J. Gynecol. Obster. 47 (1994) 39-44

43

tients receiving adjuvant chemotherapy survived longer than those undergoing surgery alone. The beneficial effects were evident, particularly in patients without residual disease after surgery, where recurrences were delayed and survival was prolonged. Resnik et al. [21] reported favorable experiences with etoposide, doxorubicin and cisplatin and pointed out that the regime was particularly active in early-stage disease and in those tumors with an adenocarcinoma component of the papillary serous variety. While chemotherapy and radiotherapy were liberally employed in our series in all patients who were fit to receive active treatment, the possible beneficial effects in terms of prolonging disease-free survival cannot be discerned. The optimal treatment for this rare but very aggressive tumor remains to be established. References 111lschiwata I, Ischiwata C, Nazoyama T, Ishikawa H: Histogenesis culture of human uterine carcinosarcoma. Cancer Res 41: 1978, 1981. 121Hall-Craggs M, Token C, Nedwich A: Carcinosarcoma of the uterine cervix: a light and electron microscopic study. Cancer 48: 161, 1981. 131 Silverberg SG: Malignant mixed mesodermal tumour of the uterus: an ultrastructural study. Am J Obstet Gynecol 110: 702, 1971. 141 Waxman M, Boyce JG, Macasaet MM, Lu T: Concurrence of malignant and benign heterologous mixed tumors of the uterus. Am J Clin Pathol 77: 631, 1982. PI Silverberg SG, Major FJ, Blessing JA, Fetter B, Askin FB, Liao SY, Miller A: Carcinosarcoma (malignant mixed mesodermal tumour) of the uterus a Gynecologic Oncology Group pathologic study of 203 cases. Int J Gynecol Pathol 9(l): 1, 1990. 161 Macasaet MM, Wasman M, Fruchta RG: Prognostic factors in malignant mesodermal (Miillerian) mixed tumors of the uterus. Gynecol Oncol 20: 32, 1985. [71 Peters WA III, Kuman NB, Flemimh WP, Morley GW: Prognostic features of sarcoma and mixed Miillerian tumors of the endometrium. Obstet Gynecol 63: 550, 1984. 181 Spanos WJ, Wharton JT, Gomez L, Fletcher GH, Oswald MJ: Malignant mixed Miillerian tumors of the uterus. Cancer 53: 311, 1984. [91 Dinh TV, Slavin RE, Bhagavan BS, Hannigan EV, Tiamson EM, Yandell RB: Mixed Miillerian tumors of the uterus: a clinicopathological study. Obstet Gynecol 74: 388, 1989. ilO1 Costa MJ, Tidd C, Willis D: Cervicovaginal cytology in carcinosarcoma of the uterus. Diagn Cytopathol 8(l): 33, 1992.

44

W. W. K. To, H. Y.S. Ngan /ht.

[11] Wheelock JB, Krebs HB, Schneider V, Goplerud DR: Uterine sarcoma: analysis of prognostic variables in 71 cases. Am J Obstet Gynecol 151: 1016, 1985. [12] King ME, Kramer EE: Malignant mixed Miillerian tumors of the uterus. A study of 21 cases. Cancer 45: 188, 1980. [I31 Barwick KW, LiVolsi VA: Heterologous mixed Miillerian tumour confined to an endometrial polyp. Obstet Ciynecol 53: 512, 1979. [14] Kahner S, Frerenzy A, Richart RM: Homologous mixed Miillerian tumors (carcinosarcoma) confined to endometrial polyps. Am J Obstet Gynecol f21: 278, 1975. [15] DiSaia PJ, Cartro JR, Rutledge FN: Mixed mesodermal sarcoma of the uterus. Am J Roentgen01 Radium Ther Nucl Med 117: 632, 1972. [16] Duran JV, Nochomovitz LE, Prem KA, Dehner LP: Postirradiation mixed Mtillerian tumors of the uterus. A comparative clinicopathologic study. Cancer 45: 1625, 1980.

J. Gynecol. Obstet. 47 (1994)

39-44

[17] Kohom EI, Schwartz PE, Chambers JT, Peschel RE, Kapp DS, Merino M: Adjuvant therapy in mixed Miillerian tumors of the uterus. Gynecol Oncol23: 212, 1986. [18] George M, Pejoric MH, Kramar A: Uterine sarcomas. Prognostic factors and treatment modalities. Study on 209 patients. Gynecol Oncol 24: 58, 1986. [I91 Chuang JT, Van Velden DJJ, Graham JB: Carcinoma and mixed mesodermal tumour of the uterine corpus. Obstet Gynecol 35: 769, 1970. [20] Van Le L, O’Meara AT, Moore AH, DeMars LR, Waltin LA, Dotters J, Fowler WC: Adjuvant chemotherapy for advanced uterine sarcomas. Gynecol Oncol 52 (Abstr. 120): 132, 1994. 1211 Resnik E, Chambers SK, Kohom EL Schwartz PE, Chambers JT: Phase II study of etoposide, adriamycin, cisplatin (EPA) in mixed Miillerian tumors of the uterus. Gynecol Oncol 52 (Abstr. 132): 135, 1994.