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A clinical-pathologic study of mixed mullerian tumors of the uterus over a 16-year period—The Medical College of Georgia experience
Pregnancy after liver transplant
Volume 161 Number 3
man organ transplant recipient survival rate has been improved by use of the immunosuppressive agent cyclosporine. Cyclosporine is lipid soluble, widely distributed in the body, and highly metabolized. Cyclosporine has been detected in cord blood, placenta, amniotic fluid, and breast milk. The toxicity of cyclosporine metabolites is unknown. Cyclosporine did not produce any chromosomal abnormalities in animals exposed to chronic therapy. Further follow-up is necessary to evaluate the possible effects on the fetus exposed to chronic cyclosporine immunosuppression in utero. The care of the organ transplant recipient during pregnancy requires a team approach. Not only are the immediate concerns of the pregnancy important, but
long-term follow-up of the mother and her infant will be relevant to fully evaluate the extent of possible complications. REFERENCES 1. Walcott WO, Derick DE, Jolley JJ, Snyder DL. Successful pregnancy in a liver transplant patient. AM J OBSTET GvNECOL 1978;132:340. 2. Myers RL, Schmid R, Newton JJ. Childbirth after liver transplantation. Transplantation 1980;29:432. 3. Newton ER, Turksay N, Kaplan M, Reinhold R. Pregnancy and liver transplantation. Obstet Gynecol 1988; 71:499. 4. Venkataramanan R. Koneru B. Wang CC. Burckart GJ. Caritis S, Starzl TE. Cydosporine and its metabolites in mother and baby. Transplantation 1988;46:468.
A clinical-pathologic study of mixed miillerian tumors of the uterus over a 16-year period-The Medical College of Georgia experience Donald G. Gallup, MD, Donna S. Gable, MD, O. Eduardo Talledo, MD, and Luther. B. Otken, Jr., MD Augusta, Georgia From 1972 through 1987, 40 patients at the Medical College of Georgia were assessed with a diagnosis of mixed mOlierian tumors which constituted 3.5% of all female genital tract malignanCies. The mean patient age was 65.3 years; 60% of the patients had stage I disease. Of those patients with clinical stage I disease, more advanced disease was found at celiotomy in 33%. Retroperitoneal nodes were positive for malignancy in 35% of 20 patients who underwent node sampling. Cell washings were positive in 12%, and 9% had omental metastases. Forty-seven percent had homologous tumors; 53% of tumors were heterologous. Relatively poor prognosis was associated with large tumor volume, vascular invaSion, nodal metastases, and disease outside the uterus. The overall survival rate was 32%; 14 of 24 patients with stage I disease are dead of disease. Of patients dead of disease, 92.5% had distant metastases. Adjuvant therapy with a combination of VP-16, cisplatin, and irradiation was beneficial in four high-risk patients. (AM J OasTET GVNECOL 1989;161 :533-9.)
Key words: Mixed miillerian tumors, uterus, cancer Mixed miillerian tumors of the uterus have been traditionally associated with a relatively poor prognosis. Controversies about some prognostic factors continue. From the Departments of Obstetrics and Gynecology and Pathology, Medical College of Georgia. Presented as Official Guest at the Fifty-Jirst Annual Meeting of the South Atlantic Association of Obstetriczans and Gynecologists, Hot Springj, Virgtnia, January 29-February 1,1989. Repnnt requests: Donald G. Gallup, MD, Medical College of Georgia, Department of Obstetrics and Gynecology, Section of Gynecologic Oncology, Augusta, GA 30912. 616112993
Mixed tumors with homologous patterns (tissue elements entirely indigenous to the uterus) have been thought to be associated with a better survival than mixed tumors with heterologous elements (tissue with cells foreign to the uterus). If the heterologous element present is other than chondrosarcoma (i.e., striated muscle), survival has been relatively poor. 1• 2 The mixed miillerian tumors are highly aggressive neoplasms that spread early to regional nodes and adjacent tissues. Nodal involvement is usually associated with deep myometrial invasion. In an earlier report, DiSaia et aI.'
533
534 Gallup et al.
September 1989 Am J Obstet Gynecol
Table II. International Federation of Gynecology and Obstetrics clinical stage and survival
Table I. Status of retroperitoneal nodes in 20 patients with stage I or II mixed miillerian tumors Positive nodes
Pelvic Paraaortic Pelvic and paraaortic Total
No. of patients 4 1
2
"7
% 20 5 10 35
Stage
*1 *II
III IV
Total noted pelvic node metastases in one third of the patients who had operations. The single most important factor signaling poor prognosis at diagnosis is extrauterine extension of disease. Hematogenous spread of both homologous and heterologous tumors is not uncommon!-8 Controversy regarding the role of primary surgical staging versus preoperative pelvic irradiation continues. The role of presently available chemotherapy as an adjuvant in primary treatment is also unsettled. This article is a retrospective review of the patients assessed with a diagnosis of mixed miillerian tumor who were managed at one institution during a 16-year period. Material and methods
The clinical records of all patients assessed with a diagnosis of mixed miillerian tumor of the uterus at the Medical College of Georgia from Jan. 1, 1972, to Dec. 31, 1987, were reviewed. Follow-up information was obtained from tumor records, and when necessary by telephone and correspondence. Histopathologic material was reviewed with two pathologists (D. S. G. and L. B. 0.). Re-cuts and special stains were obtained and reviewed when necessary. The patients were retrospectively staged based on the 1971 International Federal of Gynecology and Obstetrics criteria for adenocarcinoma of the uterine corpus. In addition to the clinical stage, patients who underwent celiotomy were also staged on a surgicalpathologic basis. Results
During the study, 49 patients were assessed with a diagnosis of mixed miillerian tumor of the uterus. Nine patients were removed from the study group because of inadequate material to make the diagnosis (5 patients), or because of misdiagnosis after the slides were reviewed; thus 40 patients qualified for the study group. These cases constituted approximately 3.5% of all female genital tract malignancies managed at the Medical College of Georgia during the same period. The mean age was 65.3 years, with a range from 47 to 89 years. Only one patient was <50 years old, and
No. of patients
Dead of disease n
24 8
14t
7 40
7 27
1
5
1
l
% 58.3 62.5 100 100 67.5
*Three in stage I and two in stage II are alive with disease. tOne patient lost to follow-up and presumed dead.
26.2% were <60. All but three women were postmenopausal. The mean parity was 2.9, but 14.3% of the patients were nulliparous. One third of the patients were white; 67% were black. Thirty-three percent had diabetes mellitus. The most frequent initial primary symptom was abnormal vaginal bleeding, which occurred in 95% of patients. Of the two patients who had no bleeding, one had passage of tissue, and the other, who had prior irradiation treatment, had ascites. Other symptoms noted in addition to bleeding were pain (17%), increased girth (11 %), and weight loss (5%). Exogenous estrogen was used from 5 to 25 years by 10% of the patients. Of those with symptoms, 9.5% of patients gave a symptom history of <1 month; 48%, <3 months, and 90%, <6 months. Only 7.5% had a history of prior pelvic irradiation treatment for cervical cancer. Additionally, one patient had prior breast cancer and one had chronic lymphocytic leukemia. Twenty-five percent of the patients weighed >20% of their ideal body weight. Results of cervical cytologic testing, available in 25 patients, were suspicious for malignancy in 44% and inflammatory in 12%. When International Federal of Gynecology and Obstetrics criteria for staging were applied to the study cases, 60% had clinical stage I disease; 20% had clinical stage II disease; 2.5% had clinical stage III tumors, and 17.5% had clinical stage IV disease. Six women with clinical stage I and II disease did not undergo hysterectomy. Thirty-three percent of women undergoing surgery were restaged from clinical stage I to more advanced disease. Four of five patients with clinical stage II disease had more advanced disease at celiotomy. Retroperitoneal nodes were positive for tumor in 35% of 20 patients who underwent node sampling (Table I). Nine percent of patients undergoing celiotomy with hysterectomy and removal of the ovaries had omental metastases, regardless of whether nodes were sampled. Cul-de-sac washings were positive in 12%. All living patients have been followed up at least 9 months. When survival was correlated with clinical
Mixed mOlierian tumors of uterus
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535
Fig. 1. Chondrosarcoma. Elements of cartilage are noted with a heterologous tumor in a 72-yearold woman who died within 6 months of surgery.
International Federal of Gynecology and Obstetrics stage, 58.3% with stage I were dead of disease (Table II). In one of the patients with stage I who was considered dead of disease, death was treatment-related. She developed pelvic recurrence with an obstructed ur ~ter and was treated with methotrexate, actinomycin D, and cyclophosphamide. After the second chemotherapy course she died of toxicity manifested by thrombocytopenia, leukopenia, and eventual disseminated intravascular coagulation. Three patients with clinical stage I are living with disease at 9, 13, and 29 months. Two patients with clinical stage II disease are living with disease at 12 and 13 months. Of patients dead of disease, 39% died within a 6-month period; 50% died in a period of 7 to 12 months; and 11 % died after a period of 13 months. One of these latter three died 36 months after diagnosis. Seventy-four percent of the 27 black patients are dead of disease, compared with 46% of the 13 white patients. Of 11 patients with clinical stage I or II disease who underwent surgery and were found to have extrauterine spread, 6 are dead and 5 are living and are presumed to have disease. Of the 15 patients with disease confined to the uterus who underwent surgery, 46.7% are dead of disease. If patients with stage III and IV are added to the group with extrauterine spread, there are no survivors without evidence of disease. Nineteen patients (47.5%) had homologous mixed mullerian tumors, and 63% are dead of disease, whereas 67% of the 21 patients with heterologous mixed mullerian tumors are dead of disease. The various elements of the sarcoma (Le., chondrosarcoma) did not appear to affect survival (Fig. 1). Tumor volume was obtained from pathology reports in 26 patients. Of 18 patients with
tumor size ;:::5 em, 55% are dead of disease. Eight patients had tumors <5 em in size, and only 25% are dead from disease. Tumor volume was not always related to depth of myometrial invasion. Five patients with tumor >5 em who are dead of disease had only superficial invasion. Vascular invasion was identified in 14 patients; 64.2% are dead of disease, compared with 12 patients without identifiable vascular invasion, only 25% of whom are dead of disease. In patients with vascular invasion, 43% had sarcoma in the vessels and 28% had carcinoma (Fig. 2). The remaining patients had a mixture of the elements in vascular spaces. The presence of vascular invasion as a poor prognostic factor is illustrated by the case of a 67-year-old woman with a stage IB heterologous mixed mullerian tumor. She had only superficial myometrial invasion of a polypoid lesion that filled the cavity. Paraaortic and pelvic nodes removed contained no tumor. Cell washings were negative, and an omental biopsy revealed no tumor. Because of tumor in vascular spaces, she was offered adjuvant chemotherapy but refused. Four months after surgery, she died of massive liver and lung metastases. Mitotic activity did not playa significant role in survival. Regardless of outcome, almost all patients had high counts (> 10 mitoses per 10 high-power fields in the sarcomatous element. The carcinoma/ sarcoma ratio also did not affect survival. The overall mortality in this series was 67.5%. In patients dying of disease, the location of tumor was assessed by physical examination, x-ray studies, or postmortem examination. Two patients died with local recurrence only, whereas 92.5% had distant metastases, either alone or combined with local recurrence (Fig.
536
Gallup et al.
September 1989 Am J Obstet Gynecol
Fig. 2. Metastatic carcinoma in a vascular-lymphatic space in the uterus of a patient who died 9 months after treatment.
Table III. Role of radiation therapy in stage I and II disease*
20 III
C
Dead
Q)
Q...
....Q)
10
.0
E :J
Z
o OM Alone
OM + Local
Local Alone
Fig. 3. Location of disease at time of death. DM, Distant metastases.
3) . The most common sites of metastatic disease were lung (17 cases) and liver (7 cases). Other extrapelvic sites of disease included the upper abdomen, supraclavicular nodes, mediastinum, and bone. Treatment for patients with operable disease was variable. The addition of radiation therapy did not significantly contribute to survival (Table III). Only two patients had postoperative external beam irradiation without chemotherapy; both are long-term survivors. Although nodes were not sampled in these two patients, these nodes were not suspicious at the time of operation. Four patients were treated with two courses of VP16 and cisplatin followed by whole pelvis irradiation. Two of these also had 4500 cGy radiation treatment to the paraaortic nodes. None of the four patients has clinical evidence of disease, but all are considered to be
of
Treatment
N(}. of patzents
disease
Preoperative irradiation No irradiation Postoperative irradiationt
7 15 2
57.1 60
n3
(%)
o
*Doses = 4000 to 4500 cGy external beam with average 5000 mg hr of cesium. tDoses = 4500 to 5000 cGy; does not include patients treated with cisplatin and VP-16.
alive with disease because of the short follow-up period. One additional patient was treated with six courses of VP-16 and cisplatin (Table IV) .
Comment Although this study population had a relatively high incidence (3.5%) of mixed mullerian tumor in all female genital tract tumors, the past reported incidence is relatively rare:' 6. 9.10 Any increase in incidence of this tumor is probably associated with increased recognition of the neoplasm. These tumors most often occur in women in the last menopausal years. The mean age of our patients (65.3 years) is consistent with other reports, with a mean age of 63 to 70 years in studies reported from European countries and the United States:' 6.10·12 Of 45,342 female patients admitted to the Medical College of Georgia Hospital in a recent 4-year period, 49.6% were black. Two third of the patients in this
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537
Table IV. Role of VP-16 and cisplatin Origtnal clznical stage
IB II II IB III
Adjuvant radzatzon therapy
Paraaortic whole pelvis Whole pelvis Paraaortic whole pelvis Whole pelvis
No
Reason for treatment
Positive pelvic and paraaortic nodes Positive pelvic nodes Positive pelvic and paraaortic nodes Positive pelvic nodes Tumor of ovaries and in vessels
series with mixed mullerian tumor were black. More black patients died from disease in this report than whites. Macasaet et ai." have suggested that mixed miillerian tumors in black women may have a different biologic origin since black women in their series tended to have more advanced disease at diagnosis. Seven percent of the patients reported herein had a history of prior pelvic irradiation. Most series report that approximately 15% of patients have a history of prior pelvic irradiation, but individual series may vary from none to 29%.3. 4. 6-9. 11. " Others have also reported nulliparity to occur in from none of the patients to 32%'" 7-9.12 Obesity has been noted in from 20% to 31 % to two other reports. 7. 9 Patients who have appropriate staging laparotomies have almost a 35% chance of having positive retroperitoneal nodes, as reported in our series and other current reports 3. 14 (Table V). Earlier reports on mixed miilIerian tumors suggested that there may be a somewhat better outcome in patients with homologous elements only. 1.2 However, we and other recent investigators" 7-9. 12. 14 found no difference in outcome between homologous and heterologous tumors. The survival (32% reported herein) continues to be dismal. Survival rates reported by others, when. all stages of mixed miillerian tumor are evaluated, range from 14% to 41 %.* A group of patients at high risk for failure was identified in our study and included those with vascular or lymphatic space involvement, extrauterine spread noted at the time of operative procedure, large (>5 cm) tumor bulk, and nodal metastases. How might survival be improved? Although the number of patients in our study is small, we found no significant impact on survival when perioperative irradiation was added to surgery. Vongtama et al. 17 noted that radiation therapy was of adjunctive value to surgery in terms of decreasing pelvic recurrences and increasing survival. Salazar et al. 18 and Spanos et al. 19 also noted that adjuvant irradiation significantly improved disease controlability in the pelvis. However, other recent studies indicate no significant added benefit of adjuvant pelvic irradiation."' 11. 14. 15 *References 2, 4, 5, 8, 9, 11, 13, 15, 16.
Months after treatment
State of disease
Alive Alive Alive Alive Dead
with disease with disease with disease with disease of disease
15 12 12 9 18
Table V. Incidence of positive retroperitoneal nodes in patients with mixed miillerian tumors Posztive nodes Authors
DiSaia et aU Peters et al. 14 Present series Total
Total No. of patients
28
13 20 61
n
I
%
10 4 7
35.7 31 35
21
34.4
Preoperative irradiation could be detrimental to survival. These tumors tend to be blood-borne neoplasms. Macasaet et aU strongly advocated a primary surgical approach because 55% of women with clinical stage I were found to have widespread disease at surgery; this incidence is more common than the 33% of patients in our series with clinical stage I who had extrauterine spread. Other investigators have also noted an upgrading of clinical stage I or II to more advanced disease in from 23% to 29% of patients.'" 14 As in our series, others have reported that extrauterine spread was associated with a poor prognosis with survival rates from 0 to 28%.5. R. II. 13. 19 Eighty-nine percent of our patients dead of mixed miillerian tumor died within 12 months. Spanos et al. 19 and Salazar et al. 18 noted that 90% of local and distant failures were apparent within 2 years. Shaw l l reported that 53% of his patients died within 12 months of diagnosis. Others have also reported that when distant metastases occurred, the lungs were often involved. 6. 9.15 Response rates, partial or complete, are below 15% in patients with advanced or recurrent mixed mullerian tumor treated with Adriamycin alone or Adriamycin plus cyclophosphamide or dimethyl triazeno imidazole carboxamide. 2o. 21 Recently Seltzer et al. 22 reported a 50% response rate in six patients treated with a combination of cisplatin and Adriamycin, with duration of response from 9 to 11 months. Gershenson et al. 23 reported a 42% response rate in patients with disseminated mixed miillerian tumor treated with cisplatin alone. Cisplatin seems to have moderate activity in this neoplasm. Kohorn et al. 13 reported an 80% survival rate
538
Gallup et al.
in patients who received adjuvant radiation therapy and combination chemotherapy. All of our high-risk patients treated with irradiation plus VP-16 and cisplatin are alive from 9 to 18 months after diagnosis and surgery. These patients have no apparent progression of tumor. However, the follow-up period is too short and the number of patients too small to draw any conclusions about these adjuvant modalities. In summary, the survival in our series and others has not been improved by use of adjunctive radiation alone. High-risk factors can be identified, but only if a primary surgical approach is used to delineate the extent of disease and these risk factors. A pilot study is warranted with cisplatin-based combination chemotherapy, with or without irradiation, in these high-risk patients. All treatment modalities should be considered in women with mixed miillerian tumors of the uterus. REFERENCES 1. Kempson RL, Bari W. Uterine sarcomas: classification, diagnosis, and prognosis. Hum PathoI1970;1:331-49. 2. Norris H]. Roth E, Taylor HB. Mesenchymal tumors of the uterus II. A clinical and pathologic study of 31 mixed mesodermal tumors. Obstet Gynecol 1966;28:57-63. 3. DiSaia P], Morrow CP, Boronow R, Creasman W, Mittelstaedt L. Endometrial sarcoma: lymphatic spread pattern. AM] OBSTET GYNECOL 1978;103:104-5. 4. Chaung ]T, Velden V, Graham ]B. Carcinosarcoma and mixed mesodermal tumor of the uterine corpus. Obstet Gynecol 1970;35:769-80. 5. Mortel R, Koss LG, Lewis ]L, D'Urso ]R. Mesodermal mixed tumors of the uterine corpus. Obstet Gynecol 1974;43:248-52. 6. Marchese M], Liskow AS, Crum CP, McCaffrey RM, Frick HC. Uterine sarcomas: a clinicopathologic study, 19651981. Gynecol Oncol 1984;18:229-312. 7. Macasaet MA, Waxman M, Fruchter RG, et al. Prognostic factors in malignant mesodermal (Mullerian) mixed tumors of the uterus. Gynecol Oncol 1985;20:32-42. 8. Lotocki R, Rosenshein NB, Grumbine F, Dillon M, Parmley T, Woodruff ]D. Mixed Mullerian tumors of the uterus: clinical and pathologic correlations. lnt] Gynaecol Obstet 1982;20:237-43. 9. Williamson EO, Christopherson WM. Malignant mixed Mullerian tumors of the uterus. Cancer 1972;29:585-92. 10. George M, Pejovic MH, Kramar M. Uterine sarcomas: prognostic factors and treatment modalities-study on 209 patients. Gynecol Oncol 1986;24:58-67. 11. Shaw RW. Mullerian mixed tumour of the uterine corpus: a clinical histopathological review of28 patients. Br] Obstet Gynaecol 1983;90:562-9. 12. Barwick KW, LiVolsi VA. Malignant mixed Mullerian tumors of the uterus. A clinicopathologic assessment of 39 cases. Am] Surg Pathol 1979;3: 125-35. 13. Kohorn EI, Schwartz PE, Chambers]T, Peschel FE, Kapp DS, Merino M. Adjuvant therapy in mixed Mullerian tumors of the uterus. Gynecol Oncol 1986;23:212-21. 14. Peters WA III, Kumar NB, Fleming WP, Morley Gw. Progostic features of sarcomas and mixed tumors of the endometrium. Obstet Gynecol 1984;63:550-6. 15. Rachmaninoff N, Climie ARW. Mixed mesodermal tumors of the uterus. Cancer 1966;19:1705-10. 16. Tanga R, Delgado G. Uterine sarcoma. Int Surg 1982; 67:339-44. 17. Vongtama V, Karlen]R, Piver MS, Tsukaoa Y, Moore RH. Treatment results and prognostic factors in stage I and
September 1989 Am J Obstet Gynecol
18. 19. 20.
21.
22. 23.
II sarcomas of the corpus uteri. Am] Roentgenol Rad Ther NucI Med 1976;126:139-47. Salazar OM, Bonfiglio TA, Patten SF, et al. Uterine sarcomas. Natural history, treatment and prognosis. Cancer 1978;42: 1152-60. Spanos W], Wharton]T, Gomez L, Fletcher GH, Oswald MJ. Malignant mixed mullerian tumors of the uterus. Cancer 1984;53:311-6. Omura GA, Major R], Blessing ]A, et al. A randomized trial of Adriamycin with and without dimethyl triazeno imidazole carboxamide in advanced uterine sarcomas. Cancer 1983;52:40-6. Muss HB, Bundy B, DiSaia P], et al. Treatment of recurrent or advanced uterine sarcoma: a randomized trial of doxorubicin versus doxorubicin and cyclophosphamide (a phase III trial of the Gynecologic Oncology Group). Cancer 1985;55:1648-53. Seltzer V, Kaplan B, Vogi S, Spitzer M. Doxorubicin and cisplatin in the treatment of advanced mixed mesodermal uterine sarcoma. Cancer Treat Rep 1984;68:1389-90. Gershenson DM, kavanagh]], Copeland]T, Edwards CL, Shinger CA, Wharton]T. Cisplatin therapy for disseminated mixed mesodermal sarcoma of the uterus. ] Clin OncoI1987;5:618-21.
Editors' note: This manuscript was revised after these
discussions were presented.
Discussion DR. R. HENRY TEMPLE, Wilmington, North Carolina, (Official Guest). In the 16-year time span of this study, the records of 41 patients with mixed miillerian tumors of the uterus were analyzed. This is a very large series of these rare and deadly tumors. They represented 3.5% of the female genital tract tumors at the Medical College of Georgia. This is an unusually high incidence of these unusual tumors and represents a fourfold increase over what one would normally expect. Other views of the subject quote mixed miillerian tumors as representing 3% to 6% of uterine cancers. When International Federal of Gynecology and Obstetrics criteria were applied, 61 % had stage I disease. 19.5% had stage II, 2.5% had stage III, and 17% had stage IV disease. The deadly nature and dismal prognosis for this disease is reflected in the fact that there were no cures in patients with stage III or IV disease and only 12.5% of patients with stage II and 28% of patients with stage I disease were free of disease after treatment. The demographic data presented by Dr. Gallup were generally in agreement with other large series. The mean patient age was 65.3 years, and the mean parity was 2.9. Two thirds of the patients were black; one third had diabetes. Seven percent had previous pelvic irradiation, and 9.5% had a history of previous use of exogenous estrogen. One of the few criticisms I have of this review and, indeed, of the oncologic literature in general is the failure to define the population from which the study patients are drawn. Figures that show a third of patients with diabetes mellitus or two third being black have little meaning if the prevalence of diabetes or the racial makeup of the community at large from which these patients are drawn is also unknown.
Volume 161 Number 3
From his data, Dr. Gallup clearly delineates some very important truisms regarding mixed miilerian tumors of the uterus. They are: 1. The single most important factor signaling poor prognosis is extra uterine extension of disease. There were no survivors free of disease in the group with cancer outside the uterus. 2. In patients with disease confined to the uterus, poor prognostic factors were increasing depth of myometrial invasion, vascular or lymphatic space involvement, and large tumor bulk (>5 cm) even without myometrial invasion. The correlation between bulk of tumor and prognosis is one not appreciated in most other reviews of the subject. 3. Finally. surgery is the mainstay of treatment. Only surgery seems to make any difference incure rates. Neither adjuvant radiation nor chemotherapy significantly increased cure rates. Furthermore, their effect on length of survival is uncertain. Somewhat as an addendum, the paper describes five patients treated with cisplatin and VP-16. One patients with stage III disease was dead of disease 18 months after treatment. The other four (two patients with stage IB and two with stage II disease) were described as alive with disease 9 to 15 months after treatment. On the basis of these results, the paper calls for a pilot study using cisplatin-based combination chemotherapy for high-risk patients. In closing, I would like to pose some questions. Although there have been several previous studies point-
Mixed mOllerian tumors of uterus
539
ing out cisplatin's possible activity in mixed mullerian tumors, the role of VP-16 has not been reported. How was this agent chosen? Was there a control group for the group treated with cisplatin and VP-16? What might be the expected natural course of the disease in similarly matched stage IB and II patients not treated with chemotherapy? DR. GALLUP (Closing). I appreciate Dr. Temple's kind comments. I again apologize for the slight change in the numbers. After review of re-cut slides on one patient, she was dropped from the study group; this left 40 patients for analysis. He is correct in his criticism about our failure to more clearly define the overall population makeup of our study group. We presented a group of patients who underwent running midline incision closures at the annual clinical meeting in May last year. Of those Medical College of Georgia patients, 54% were black and one third had diabetes mellitus. Why did we choose VP-16 and cisplatin as chemotherapeutic agents? We have treated a group of about 15 patients with ovarian carcinoma and failed treatment with cisplatin-based chemotherapy, with secondline VP-16 and cisplatin. We have had significant longterm responses, some of which were complete, in this group. One of these long-term responders had a pri~ mary mixed mesodermal sarcoma of the ovary. We did not have a matched control group, but no patients with clinical stage I or II disease who had positive nodes and did not receive VP-16 and platinum are survivors. I agree with Dr. Underwood that we should try to give chemotherapy as soon after surgery as possible.
Volume 161 Number 3
man organ transplant recipient survival rate has been improved by use of the immunosuppressive agent cyclosporine. Cyclosporine is lipid soluble, widely distributed in the body, and highly metabolized. Cyclosporine has been detected in cord blood, placenta, amniotic fluid, and breast milk. The toxicity of cyclosporine metabolites is unknown. Cyclosporine did not produce any chromosomal abnormalities in animals exposed to chronic therapy. Further follow-up is necessary to evaluate the possible effects on the fetus exposed to chronic cyclosporine immunosuppression in utero. The care of the organ transplant recipient during pregnancy requires a team approach. Not only are the immediate concerns of the pregnancy important, but
long-term follow-up of the mother and her infant will be relevant to fully evaluate the extent of possible complications. REFERENCES 1. Walcott WO, Derick DE, Jolley JJ, Snyder DL. Successful pregnancy in a liver transplant patient. AM J OBSTET GvNECOL 1978;132:340. 2. Myers RL, Schmid R, Newton JJ. Childbirth after liver transplantation. Transplantation 1980;29:432. 3. Newton ER, Turksay N, Kaplan M, Reinhold R. Pregnancy and liver transplantation. Obstet Gynecol 1988; 71:499. 4. Venkataramanan R. Koneru B. Wang CC. Burckart GJ. Caritis S, Starzl TE. Cydosporine and its metabolites in mother and baby. Transplantation 1988;46:468.
A clinical-pathologic study of mixed miillerian tumors of the uterus over a 16-year period-The Medical College of Georgia experience Donald G. Gallup, MD, Donna S. Gable, MD, O. Eduardo Talledo, MD, and Luther. B. Otken, Jr., MD Augusta, Georgia From 1972 through 1987, 40 patients at the Medical College of Georgia were assessed with a diagnosis of mixed mOlierian tumors which constituted 3.5% of all female genital tract malignanCies. The mean patient age was 65.3 years; 60% of the patients had stage I disease. Of those patients with clinical stage I disease, more advanced disease was found at celiotomy in 33%. Retroperitoneal nodes were positive for malignancy in 35% of 20 patients who underwent node sampling. Cell washings were positive in 12%, and 9% had omental metastases. Forty-seven percent had homologous tumors; 53% of tumors were heterologous. Relatively poor prognosis was associated with large tumor volume, vascular invaSion, nodal metastases, and disease outside the uterus. The overall survival rate was 32%; 14 of 24 patients with stage I disease are dead of disease. Of patients dead of disease, 92.5% had distant metastases. Adjuvant therapy with a combination of VP-16, cisplatin, and irradiation was beneficial in four high-risk patients. (AM J OasTET GVNECOL 1989;161 :533-9.)
Key words: Mixed miillerian tumors, uterus, cancer Mixed miillerian tumors of the uterus have been traditionally associated with a relatively poor prognosis. Controversies about some prognostic factors continue. From the Departments of Obstetrics and Gynecology and Pathology, Medical College of Georgia. Presented as Official Guest at the Fifty-Jirst Annual Meeting of the South Atlantic Association of Obstetriczans and Gynecologists, Hot Springj, Virgtnia, January 29-February 1,1989. Repnnt requests: Donald G. Gallup, MD, Medical College of Georgia, Department of Obstetrics and Gynecology, Section of Gynecologic Oncology, Augusta, GA 30912. 616112993
Mixed tumors with homologous patterns (tissue elements entirely indigenous to the uterus) have been thought to be associated with a better survival than mixed tumors with heterologous elements (tissue with cells foreign to the uterus). If the heterologous element present is other than chondrosarcoma (i.e., striated muscle), survival has been relatively poor. 1• 2 The mixed miillerian tumors are highly aggressive neoplasms that spread early to regional nodes and adjacent tissues. Nodal involvement is usually associated with deep myometrial invasion. In an earlier report, DiSaia et aI.'
533
534 Gallup et al.
September 1989 Am J Obstet Gynecol
Table II. International Federation of Gynecology and Obstetrics clinical stage and survival
Table I. Status of retroperitoneal nodes in 20 patients with stage I or II mixed miillerian tumors Positive nodes
Pelvic Paraaortic Pelvic and paraaortic Total
No. of patients 4 1
2
"7
% 20 5 10 35
Stage
*1 *II
III IV
Total noted pelvic node metastases in one third of the patients who had operations. The single most important factor signaling poor prognosis at diagnosis is extrauterine extension of disease. Hematogenous spread of both homologous and heterologous tumors is not uncommon!-8 Controversy regarding the role of primary surgical staging versus preoperative pelvic irradiation continues. The role of presently available chemotherapy as an adjuvant in primary treatment is also unsettled. This article is a retrospective review of the patients assessed with a diagnosis of mixed miillerian tumor who were managed at one institution during a 16-year period. Material and methods
The clinical records of all patients assessed with a diagnosis of mixed miillerian tumor of the uterus at the Medical College of Georgia from Jan. 1, 1972, to Dec. 31, 1987, were reviewed. Follow-up information was obtained from tumor records, and when necessary by telephone and correspondence. Histopathologic material was reviewed with two pathologists (D. S. G. and L. B. 0.). Re-cuts and special stains were obtained and reviewed when necessary. The patients were retrospectively staged based on the 1971 International Federal of Gynecology and Obstetrics criteria for adenocarcinoma of the uterine corpus. In addition to the clinical stage, patients who underwent celiotomy were also staged on a surgicalpathologic basis. Results
During the study, 49 patients were assessed with a diagnosis of mixed miillerian tumor of the uterus. Nine patients were removed from the study group because of inadequate material to make the diagnosis (5 patients), or because of misdiagnosis after the slides were reviewed; thus 40 patients qualified for the study group. These cases constituted approximately 3.5% of all female genital tract malignancies managed at the Medical College of Georgia during the same period. The mean age was 65.3 years, with a range from 47 to 89 years. Only one patient was <50 years old, and
No. of patients
Dead of disease n
24 8
14t
7 40
7 27
1
5
1
l
% 58.3 62.5 100 100 67.5
*Three in stage I and two in stage II are alive with disease. tOne patient lost to follow-up and presumed dead.
26.2% were <60. All but three women were postmenopausal. The mean parity was 2.9, but 14.3% of the patients were nulliparous. One third of the patients were white; 67% were black. Thirty-three percent had diabetes mellitus. The most frequent initial primary symptom was abnormal vaginal bleeding, which occurred in 95% of patients. Of the two patients who had no bleeding, one had passage of tissue, and the other, who had prior irradiation treatment, had ascites. Other symptoms noted in addition to bleeding were pain (17%), increased girth (11 %), and weight loss (5%). Exogenous estrogen was used from 5 to 25 years by 10% of the patients. Of those with symptoms, 9.5% of patients gave a symptom history of <1 month; 48%, <3 months, and 90%, <6 months. Only 7.5% had a history of prior pelvic irradiation treatment for cervical cancer. Additionally, one patient had prior breast cancer and one had chronic lymphocytic leukemia. Twenty-five percent of the patients weighed >20% of their ideal body weight. Results of cervical cytologic testing, available in 25 patients, were suspicious for malignancy in 44% and inflammatory in 12%. When International Federal of Gynecology and Obstetrics criteria for staging were applied to the study cases, 60% had clinical stage I disease; 20% had clinical stage II disease; 2.5% had clinical stage III tumors, and 17.5% had clinical stage IV disease. Six women with clinical stage I and II disease did not undergo hysterectomy. Thirty-three percent of women undergoing surgery were restaged from clinical stage I to more advanced disease. Four of five patients with clinical stage II disease had more advanced disease at celiotomy. Retroperitoneal nodes were positive for tumor in 35% of 20 patients who underwent node sampling (Table I). Nine percent of patients undergoing celiotomy with hysterectomy and removal of the ovaries had omental metastases, regardless of whether nodes were sampled. Cul-de-sac washings were positive in 12%. All living patients have been followed up at least 9 months. When survival was correlated with clinical
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Fig. 1. Chondrosarcoma. Elements of cartilage are noted with a heterologous tumor in a 72-yearold woman who died within 6 months of surgery.
International Federal of Gynecology and Obstetrics stage, 58.3% with stage I were dead of disease (Table II). In one of the patients with stage I who was considered dead of disease, death was treatment-related. She developed pelvic recurrence with an obstructed ur ~ter and was treated with methotrexate, actinomycin D, and cyclophosphamide. After the second chemotherapy course she died of toxicity manifested by thrombocytopenia, leukopenia, and eventual disseminated intravascular coagulation. Three patients with clinical stage I are living with disease at 9, 13, and 29 months. Two patients with clinical stage II disease are living with disease at 12 and 13 months. Of patients dead of disease, 39% died within a 6-month period; 50% died in a period of 7 to 12 months; and 11 % died after a period of 13 months. One of these latter three died 36 months after diagnosis. Seventy-four percent of the 27 black patients are dead of disease, compared with 46% of the 13 white patients. Of 11 patients with clinical stage I or II disease who underwent surgery and were found to have extrauterine spread, 6 are dead and 5 are living and are presumed to have disease. Of the 15 patients with disease confined to the uterus who underwent surgery, 46.7% are dead of disease. If patients with stage III and IV are added to the group with extrauterine spread, there are no survivors without evidence of disease. Nineteen patients (47.5%) had homologous mixed mullerian tumors, and 63% are dead of disease, whereas 67% of the 21 patients with heterologous mixed mullerian tumors are dead of disease. The various elements of the sarcoma (Le., chondrosarcoma) did not appear to affect survival (Fig. 1). Tumor volume was obtained from pathology reports in 26 patients. Of 18 patients with
tumor size ;:::5 em, 55% are dead of disease. Eight patients had tumors <5 em in size, and only 25% are dead from disease. Tumor volume was not always related to depth of myometrial invasion. Five patients with tumor >5 em who are dead of disease had only superficial invasion. Vascular invasion was identified in 14 patients; 64.2% are dead of disease, compared with 12 patients without identifiable vascular invasion, only 25% of whom are dead of disease. In patients with vascular invasion, 43% had sarcoma in the vessels and 28% had carcinoma (Fig. 2). The remaining patients had a mixture of the elements in vascular spaces. The presence of vascular invasion as a poor prognostic factor is illustrated by the case of a 67-year-old woman with a stage IB heterologous mixed mullerian tumor. She had only superficial myometrial invasion of a polypoid lesion that filled the cavity. Paraaortic and pelvic nodes removed contained no tumor. Cell washings were negative, and an omental biopsy revealed no tumor. Because of tumor in vascular spaces, she was offered adjuvant chemotherapy but refused. Four months after surgery, she died of massive liver and lung metastases. Mitotic activity did not playa significant role in survival. Regardless of outcome, almost all patients had high counts (> 10 mitoses per 10 high-power fields in the sarcomatous element. The carcinoma/ sarcoma ratio also did not affect survival. The overall mortality in this series was 67.5%. In patients dying of disease, the location of tumor was assessed by physical examination, x-ray studies, or postmortem examination. Two patients died with local recurrence only, whereas 92.5% had distant metastases, either alone or combined with local recurrence (Fig.
536
Gallup et al.
September 1989 Am J Obstet Gynecol
Fig. 2. Metastatic carcinoma in a vascular-lymphatic space in the uterus of a patient who died 9 months after treatment.
Table III. Role of radiation therapy in stage I and II disease*
20 III
C
Dead
Q)
Q...
....Q)
10
.0
E :J
Z
o OM Alone
OM + Local
Local Alone
Fig. 3. Location of disease at time of death. DM, Distant metastases.
3) . The most common sites of metastatic disease were lung (17 cases) and liver (7 cases). Other extrapelvic sites of disease included the upper abdomen, supraclavicular nodes, mediastinum, and bone. Treatment for patients with operable disease was variable. The addition of radiation therapy did not significantly contribute to survival (Table III). Only two patients had postoperative external beam irradiation without chemotherapy; both are long-term survivors. Although nodes were not sampled in these two patients, these nodes were not suspicious at the time of operation. Four patients were treated with two courses of VP16 and cisplatin followed by whole pelvis irradiation. Two of these also had 4500 cGy radiation treatment to the paraaortic nodes. None of the four patients has clinical evidence of disease, but all are considered to be
of
Treatment
N(}. of patzents
disease
Preoperative irradiation No irradiation Postoperative irradiationt
7 15 2
57.1 60
n3
(%)
o
*Doses = 4000 to 4500 cGy external beam with average 5000 mg hr of cesium. tDoses = 4500 to 5000 cGy; does not include patients treated with cisplatin and VP-16.
alive with disease because of the short follow-up period. One additional patient was treated with six courses of VP-16 and cisplatin (Table IV) .
Comment Although this study population had a relatively high incidence (3.5%) of mixed mullerian tumor in all female genital tract tumors, the past reported incidence is relatively rare:' 6. 9.10 Any increase in incidence of this tumor is probably associated with increased recognition of the neoplasm. These tumors most often occur in women in the last menopausal years. The mean age of our patients (65.3 years) is consistent with other reports, with a mean age of 63 to 70 years in studies reported from European countries and the United States:' 6.10·12 Of 45,342 female patients admitted to the Medical College of Georgia Hospital in a recent 4-year period, 49.6% were black. Two third of the patients in this
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Table IV. Role of VP-16 and cisplatin Origtnal clznical stage
IB II II IB III
Adjuvant radzatzon therapy
Paraaortic whole pelvis Whole pelvis Paraaortic whole pelvis Whole pelvis
No
Reason for treatment
Positive pelvic and paraaortic nodes Positive pelvic nodes Positive pelvic and paraaortic nodes Positive pelvic nodes Tumor of ovaries and in vessels
series with mixed mullerian tumor were black. More black patients died from disease in this report than whites. Macasaet et ai." have suggested that mixed miillerian tumors in black women may have a different biologic origin since black women in their series tended to have more advanced disease at diagnosis. Seven percent of the patients reported herein had a history of prior pelvic irradiation. Most series report that approximately 15% of patients have a history of prior pelvic irradiation, but individual series may vary from none to 29%.3. 4. 6-9. 11. " Others have also reported nulliparity to occur in from none of the patients to 32%'" 7-9.12 Obesity has been noted in from 20% to 31 % to two other reports. 7. 9 Patients who have appropriate staging laparotomies have almost a 35% chance of having positive retroperitoneal nodes, as reported in our series and other current reports 3. 14 (Table V). Earlier reports on mixed miilIerian tumors suggested that there may be a somewhat better outcome in patients with homologous elements only. 1.2 However, we and other recent investigators" 7-9. 12. 14 found no difference in outcome between homologous and heterologous tumors. The survival (32% reported herein) continues to be dismal. Survival rates reported by others, when. all stages of mixed miillerian tumor are evaluated, range from 14% to 41 %.* A group of patients at high risk for failure was identified in our study and included those with vascular or lymphatic space involvement, extrauterine spread noted at the time of operative procedure, large (>5 cm) tumor bulk, and nodal metastases. How might survival be improved? Although the number of patients in our study is small, we found no significant impact on survival when perioperative irradiation was added to surgery. Vongtama et al. 17 noted that radiation therapy was of adjunctive value to surgery in terms of decreasing pelvic recurrences and increasing survival. Salazar et al. 18 and Spanos et al. 19 also noted that adjuvant irradiation significantly improved disease controlability in the pelvis. However, other recent studies indicate no significant added benefit of adjuvant pelvic irradiation."' 11. 14. 15 *References 2, 4, 5, 8, 9, 11, 13, 15, 16.
Months after treatment
State of disease
Alive Alive Alive Alive Dead
with disease with disease with disease with disease of disease
15 12 12 9 18
Table V. Incidence of positive retroperitoneal nodes in patients with mixed miillerian tumors Posztive nodes Authors
DiSaia et aU Peters et al. 14 Present series Total
Total No. of patients
28
13 20 61
n
I
%
10 4 7
35.7 31 35
21
34.4
Preoperative irradiation could be detrimental to survival. These tumors tend to be blood-borne neoplasms. Macasaet et aU strongly advocated a primary surgical approach because 55% of women with clinical stage I were found to have widespread disease at surgery; this incidence is more common than the 33% of patients in our series with clinical stage I who had extrauterine spread. Other investigators have also noted an upgrading of clinical stage I or II to more advanced disease in from 23% to 29% of patients.'" 14 As in our series, others have reported that extrauterine spread was associated with a poor prognosis with survival rates from 0 to 28%.5. R. II. 13. 19 Eighty-nine percent of our patients dead of mixed miillerian tumor died within 12 months. Spanos et al. 19 and Salazar et al. 18 noted that 90% of local and distant failures were apparent within 2 years. Shaw l l reported that 53% of his patients died within 12 months of diagnosis. Others have also reported that when distant metastases occurred, the lungs were often involved. 6. 9.15 Response rates, partial or complete, are below 15% in patients with advanced or recurrent mixed mullerian tumor treated with Adriamycin alone or Adriamycin plus cyclophosphamide or dimethyl triazeno imidazole carboxamide. 2o. 21 Recently Seltzer et al. 22 reported a 50% response rate in six patients treated with a combination of cisplatin and Adriamycin, with duration of response from 9 to 11 months. Gershenson et al. 23 reported a 42% response rate in patients with disseminated mixed miillerian tumor treated with cisplatin alone. Cisplatin seems to have moderate activity in this neoplasm. Kohorn et al. 13 reported an 80% survival rate
538
Gallup et al.
in patients who received adjuvant radiation therapy and combination chemotherapy. All of our high-risk patients treated with irradiation plus VP-16 and cisplatin are alive from 9 to 18 months after diagnosis and surgery. These patients have no apparent progression of tumor. However, the follow-up period is too short and the number of patients too small to draw any conclusions about these adjuvant modalities. In summary, the survival in our series and others has not been improved by use of adjunctive radiation alone. High-risk factors can be identified, but only if a primary surgical approach is used to delineate the extent of disease and these risk factors. A pilot study is warranted with cisplatin-based combination chemotherapy, with or without irradiation, in these high-risk patients. All treatment modalities should be considered in women with mixed miillerian tumors of the uterus. REFERENCES 1. Kempson RL, Bari W. Uterine sarcomas: classification, diagnosis, and prognosis. Hum PathoI1970;1:331-49. 2. Norris H]. Roth E, Taylor HB. Mesenchymal tumors of the uterus II. A clinical and pathologic study of 31 mixed mesodermal tumors. Obstet Gynecol 1966;28:57-63. 3. DiSaia P], Morrow CP, Boronow R, Creasman W, Mittelstaedt L. Endometrial sarcoma: lymphatic spread pattern. AM] OBSTET GYNECOL 1978;103:104-5. 4. Chaung ]T, Velden V, Graham ]B. Carcinosarcoma and mixed mesodermal tumor of the uterine corpus. Obstet Gynecol 1970;35:769-80. 5. Mortel R, Koss LG, Lewis ]L, D'Urso ]R. Mesodermal mixed tumors of the uterine corpus. Obstet Gynecol 1974;43:248-52. 6. Marchese M], Liskow AS, Crum CP, McCaffrey RM, Frick HC. Uterine sarcomas: a clinicopathologic study, 19651981. Gynecol Oncol 1984;18:229-312. 7. Macasaet MA, Waxman M, Fruchter RG, et al. Prognostic factors in malignant mesodermal (Mullerian) mixed tumors of the uterus. Gynecol Oncol 1985;20:32-42. 8. Lotocki R, Rosenshein NB, Grumbine F, Dillon M, Parmley T, Woodruff ]D. Mixed Mullerian tumors of the uterus: clinical and pathologic correlations. lnt] Gynaecol Obstet 1982;20:237-43. 9. Williamson EO, Christopherson WM. Malignant mixed Mullerian tumors of the uterus. Cancer 1972;29:585-92. 10. George M, Pejovic MH, Kramar M. Uterine sarcomas: prognostic factors and treatment modalities-study on 209 patients. Gynecol Oncol 1986;24:58-67. 11. Shaw RW. Mullerian mixed tumour of the uterine corpus: a clinical histopathological review of28 patients. Br] Obstet Gynaecol 1983;90:562-9. 12. Barwick KW, LiVolsi VA. Malignant mixed Mullerian tumors of the uterus. A clinicopathologic assessment of 39 cases. Am] Surg Pathol 1979;3: 125-35. 13. Kohorn EI, Schwartz PE, Chambers]T, Peschel FE, Kapp DS, Merino M. Adjuvant therapy in mixed Mullerian tumors of the uterus. Gynecol Oncol 1986;23:212-21. 14. Peters WA III, Kumar NB, Fleming WP, Morley Gw. Progostic features of sarcomas and mixed tumors of the endometrium. Obstet Gynecol 1984;63:550-6. 15. Rachmaninoff N, Climie ARW. Mixed mesodermal tumors of the uterus. Cancer 1966;19:1705-10. 16. Tanga R, Delgado G. Uterine sarcoma. Int Surg 1982; 67:339-44. 17. Vongtama V, Karlen]R, Piver MS, Tsukaoa Y, Moore RH. Treatment results and prognostic factors in stage I and
September 1989 Am J Obstet Gynecol
18. 19. 20.
21.
22. 23.
II sarcomas of the corpus uteri. Am] Roentgenol Rad Ther NucI Med 1976;126:139-47. Salazar OM, Bonfiglio TA, Patten SF, et al. Uterine sarcomas. Natural history, treatment and prognosis. Cancer 1978;42: 1152-60. Spanos W], Wharton]T, Gomez L, Fletcher GH, Oswald MJ. Malignant mixed mullerian tumors of the uterus. Cancer 1984;53:311-6. Omura GA, Major R], Blessing ]A, et al. A randomized trial of Adriamycin with and without dimethyl triazeno imidazole carboxamide in advanced uterine sarcomas. Cancer 1983;52:40-6. Muss HB, Bundy B, DiSaia P], et al. Treatment of recurrent or advanced uterine sarcoma: a randomized trial of doxorubicin versus doxorubicin and cyclophosphamide (a phase III trial of the Gynecologic Oncology Group). Cancer 1985;55:1648-53. Seltzer V, Kaplan B, Vogi S, Spitzer M. Doxorubicin and cisplatin in the treatment of advanced mixed mesodermal uterine sarcoma. Cancer Treat Rep 1984;68:1389-90. Gershenson DM, kavanagh]], Copeland]T, Edwards CL, Shinger CA, Wharton]T. Cisplatin therapy for disseminated mixed mesodermal sarcoma of the uterus. ] Clin OncoI1987;5:618-21.
Editors' note: This manuscript was revised after these
discussions were presented.
Discussion DR. R. HENRY TEMPLE, Wilmington, North Carolina, (Official Guest). In the 16-year time span of this study, the records of 41 patients with mixed miillerian tumors of the uterus were analyzed. This is a very large series of these rare and deadly tumors. They represented 3.5% of the female genital tract tumors at the Medical College of Georgia. This is an unusually high incidence of these unusual tumors and represents a fourfold increase over what one would normally expect. Other views of the subject quote mixed miillerian tumors as representing 3% to 6% of uterine cancers. When International Federal of Gynecology and Obstetrics criteria were applied, 61 % had stage I disease. 19.5% had stage II, 2.5% had stage III, and 17% had stage IV disease. The deadly nature and dismal prognosis for this disease is reflected in the fact that there were no cures in patients with stage III or IV disease and only 12.5% of patients with stage II and 28% of patients with stage I disease were free of disease after treatment. The demographic data presented by Dr. Gallup were generally in agreement with other large series. The mean patient age was 65.3 years, and the mean parity was 2.9. Two thirds of the patients were black; one third had diabetes. Seven percent had previous pelvic irradiation, and 9.5% had a history of previous use of exogenous estrogen. One of the few criticisms I have of this review and, indeed, of the oncologic literature in general is the failure to define the population from which the study patients are drawn. Figures that show a third of patients with diabetes mellitus or two third being black have little meaning if the prevalence of diabetes or the racial makeup of the community at large from which these patients are drawn is also unknown.
Volume 161 Number 3
From his data, Dr. Gallup clearly delineates some very important truisms regarding mixed miilerian tumors of the uterus. They are: 1. The single most important factor signaling poor prognosis is extra uterine extension of disease. There were no survivors free of disease in the group with cancer outside the uterus. 2. In patients with disease confined to the uterus, poor prognostic factors were increasing depth of myometrial invasion, vascular or lymphatic space involvement, and large tumor bulk (>5 cm) even without myometrial invasion. The correlation between bulk of tumor and prognosis is one not appreciated in most other reviews of the subject. 3. Finally. surgery is the mainstay of treatment. Only surgery seems to make any difference incure rates. Neither adjuvant radiation nor chemotherapy significantly increased cure rates. Furthermore, their effect on length of survival is uncertain. Somewhat as an addendum, the paper describes five patients treated with cisplatin and VP-16. One patients with stage III disease was dead of disease 18 months after treatment. The other four (two patients with stage IB and two with stage II disease) were described as alive with disease 9 to 15 months after treatment. On the basis of these results, the paper calls for a pilot study using cisplatin-based combination chemotherapy for high-risk patients. In closing, I would like to pose some questions. Although there have been several previous studies point-
Mixed mOllerian tumors of uterus
539
ing out cisplatin's possible activity in mixed mullerian tumors, the role of VP-16 has not been reported. How was this agent chosen? Was there a control group for the group treated with cisplatin and VP-16? What might be the expected natural course of the disease in similarly matched stage IB and II patients not treated with chemotherapy? DR. GALLUP (Closing). I appreciate Dr. Temple's kind comments. I again apologize for the slight change in the numbers. After review of re-cut slides on one patient, she was dropped from the study group; this left 40 patients for analysis. He is correct in his criticism about our failure to more clearly define the overall population makeup of our study group. We presented a group of patients who underwent running midline incision closures at the annual clinical meeting in May last year. Of those Medical College of Georgia patients, 54% were black and one third had diabetes mellitus. Why did we choose VP-16 and cisplatin as chemotherapeutic agents? We have treated a group of about 15 patients with ovarian carcinoma and failed treatment with cisplatin-based chemotherapy, with secondline VP-16 and cisplatin. We have had significant longterm responses, some of which were complete, in this group. One of these long-term responders had a pri~ mary mixed mesodermal sarcoma of the ovary. We did not have a matched control group, but no patients with clinical stage I or II disease who had positive nodes and did not receive VP-16 and platinum are survivors. I agree with Dr. Underwood that we should try to give chemotherapy as soon after surgery as possible.