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Leiomyosarcoma of the uterus: Clinicopathologic study of 21 cases
GYNECOLOGIC
ONCOLOGY
21, 220-227 (1985)
Leiomyosarcoma of the Uterus: Clinicopathologic Study of 21 Cases F. BARTER, M.D.,* ELLEN BLAIR SMITH, M.D.,* CHERYL A. SZPAK, M.D. ,t WANDA HINSHAW, M.S. ,$ DANIEL L. CLARKE-PEARSON, M.D. ,* AND WILLIAM T. CREASMAN, M.D.*,]
JAMES
*Division
of Gynecologic Oncology; tDepartment of Pathology; and *Duke Comprehensive Cancer Center Data Base, Duke University Medical Center, Durham, North Carolina 27710
Received May 21, 1984 A detailed clinicopathologic study of 21 patients with uterine leiomyosarcoma was undertaken. The diagnosis of leiomyosarcoma was made for those uterine smooth muscle tumors showing cellular atypia and 5-9 mitoses per 10 high-powered fields (M/IO HPF) and those with 10 or more M/10 HPF. Using these strict pathologic criteria to define leiomyosarcoma, menopausal status, margin type (pushing vs infiltrating), tumor size, grade, location, and the presence of vascular invasion and/or hemorrhage were not associated with prognosis. The S-year survival rate was 25%. Survival rates were not improved by the use of adjuvant chemotherapy in those patients rendered free of gross disease by initial surgery. 0 1985 Academic Press, Inc.
Leiomyosarcoma (LMS) represents I .3% of all uterine malignancies and about 25% of uterine sarcomas [l]. Christopherson [2] estimated that the yearly incidence of LMS was 0.67 per 100,000 women age 20 years or older. Discussion of LMS is confused by the lack of universally accepted pathologic criteria for diagnosis. Diagnostic criteria have centered on the grade of tumor and on mitotic count. Spiro and Koss [4] and Silverberg [5] suggest the diagnosis should be based on the degree of cellular atypia. In 1920, Evans [6] quantitated the number of mitoses in the uterine smooth muscle tumors and demonstrated a poorer outcome with increased mitoses. Taylor and Norris [7], Kempson and Bari [8], and Christopherson and associates [2] found very poor outcomes for those patients with 2 10 mitoses per 10high-powered fields (M/ IOHPF). The 5-year survival rate in Christopherson’s study was 21%. Kempson and Bari [8] found no survivors among patients with 5-9 M/IO HPF who also showed cytologic atypia. More recently, Zaloudek and Norris [93 and Hendrickson and Kempson [lo] have proposed definitions of uterine smooth muscle tumors that consider both mitotic rate and nuclear atypia. Tumors with 5-9 M/10 HPF and nuclear atypia are included as LMS. The present study presents the results of treatment of patients with uterine LMS at Duke University Medical Center. ’ To whom reprint requests should be addressed.
220 0090-8258/85 $1.50 Copyright All rights
Q 1985 by Academic Press, Inc. of reproduction in any form reserved.
LEIOMYOSARCOMA
OF THE UTERUS
221
METHODS AND MATERIALS Hospital charts of all patients admitted between January 1968and August 1981, with the diagnosis of uterine leiomyosarcoma were reviewed. Histologic sections of specimens taken from these patients were independently reviewed. Four sets of 10 HPFs in the area of greatest mitotic activity were analyzed for number of mitoses. The set with the highest number of mitotic figures was taken to determine the mitotic count of the tumors. Cytologic atypia was judged present or absent as was vascular invasion, hemorrhage, necrosis, nuclear inclusions, strap cells, and giant cells. In addition, all tumors were graded as to degree of differentiation as defined by Spiro and Koss [4] and Silverberg [5]. The location of the primary tumor in the myometrium was assessed and the nature of tumor margins characterized. The criteria of Hendrickson and Kempson were used to assign pathologic diagnosis of leiomyosarcoma [ 101. Kaplan-Meier [ 1l] product limit estimates of survival time and time to recurrence for those patients free of disease after surgery were calculated. The log-rank test [12] was used to compare survival curves. The lack of power of these tests due to small sample size must be considered in the interpretation of the results. Statistical significance was assigned at the 5% probability level. RESULTS Thirty-six patients with a discharge diagnosis of uterine LMS were identified. Pathology review of original pathologic slides, using the Hendrickson-Kempson criteria, identified 21 patients with LMS. Two tumors were reclassified as cellular leiomyoma, two as bizarre leiomyoma, one as benign metastasizing leiomyoma, and four as smooth muscle tumors of uncertain malignant potential. Six patients were excluded from analysis because the original tumor sections were either lost or unsuitable for diagnosis. Data from the 21 patients with LMS are analyzed in this study. Clinical Data Median age at diagnosis was 51 years (range 35-69). Only one patient was nulligravid. Eleven (52%) were postmenopausal, one (5%) was perimenopausal, and nine (43%) were premenopausal. The most frequent presenting symptoms were abnormal uterine bleeding in 67% of patients and abdominal pain in 43%. The average interval between onset of symptoms and diagnosis was 5.2 months. Ten patients (48%) were followed by their physician for “enlarging fibroids” prior to the diagnosis of LMS. Fourteen percent of the patients had diabetes, and 33% had hypertension. No patient had a prior or concurrent malignancy, and none had a history of prior pelvic irradiation or exogenous estrogen usage. Uterine size varied from normal to 40 (gestational) weeks size with median size of 13 (gestational) weeks. Five patients (24%) presented with a mass in the cervical OS. No patient had symptoms of metastatic disease at diagnosis, but two (10%) were found to have pulmonary metastases on initial chest X ray. Ten patients underwent sampling of the uterine contents; in 6 it was diagnostic. In the remainder of patients, diagnosis was made only after hysterectomy. Pap
222
BARTER ET AL.
smears of the cervix were obtained on 11 patients; in only 1 were cells seen consistent with leiomyosarcoma. Eighteen patients clinically had disease limited to the uterine corpus (Stage I). Two patients had lung metastases at diagnosis (Stage IV). One patient’s abdominal mass filled the abdomen and extended to the right pelvis sidewall (Stage III). Surgical Data
All patients underwent hysterectomy. Intraperitoneal tumor extension or metastasis was found in three patients with clinical Stage I disease. One of the patients with pulmonary metastases was found to have multiple intraperitoneal metastases. Selective lymphadenectomy (pelvic and/or paraaortic) was performed in seven cases; no lymph node metastases were found. Pelvic washings for cytologic evaluation were obtained from six patients; none showed malignant cells. Washings in two instances were taken from patients with histologically confirmed intraperitoneal spread. Pathology
Review
Ten (59%) of LMS were associated with leiomyomas, 7 (41%) were not, and the information was not given in 4 cases. There were no documented cases of LMS arising from a leiomyoma. The median tumor diameter was 6 cm (mean 6.5 cm) with a range of 2 to 10 cm. In one patient, the exact size of the tumor was not recorded. Ten (50%) of the tumors were primarily located submucosally, 9 (45%) intramural, 1 (5%) subserosally. In one case, this information was not available. The range and frequency of mitotic counts is shown in Fig. 1. There
5-9
lo-19 20-29 30-39 40-49 50-59 60-69 No. Mitoses/lO
FIG. 1.
HPF
Range and frequency of mitotic counts.
LEIOMYOSARCOMA OF THE UTERUS
223
were no grade 1 lesions, 8 grade 2 lesions, 12 grade 3 lesions, and 1 grade 4. The tumor margins were pushing in 10 cases, infiltrating in 7, and no assessment could be made in 4. Vessel invasion was present in 6 tumors. Hemorrhage and/ or necrosis was present in 16. Additional
Therapy
Eleven patients received adjunctive therapy following surgical removal of all gross tumor. Three patients received external pelvic radiotherapy as well as three 5-day courses of methotrexate, actinomycin D, and cyclophosphamide. Eight patients received only adjunctive chemotherapy. Various regimens were used including Adriamycin 50 mg/m’ body surface area given repetitively every 21 days, Adriamycin (50 mg/m*) with additional, concurrent cyclophosphamide, and vincristine as repetitively given single-agent therapy. Two patients were given three 5-day cycles of vincristine, actinomycin D, and cyclophosphamide. Five patients received no adjuvant therapy. Median mitotic count of the tumors of patients who received adjunctive therapy was 23 M/IO HPF (range 9-45). For patients who received no adjunctive therapy, median number of mitoses was 28 M/10 HPF (range 11-61). The five patients with residual disease after hysterectomy were treated with a variety of chemotherapeutic regimens. Median mitotic count for those tumors that were either metastatic or had gross residual after surgery was 21 M/10 HPF (range 10-41). Outcome
The overall Kaplan-Meier product limit survival curve is shown in Fig. 2. The S-year survival rate is 25%. Only two patients (with 25 and 9 M/10 HPF and cellular atypia, respectively) survive without evidence of recurrence. Two patients (45 and 41 M/10 HPF) survive with disease at 28 and 91 months. Menopausal status had no bearing on outcome. Clinical stage also was not statistically significant in determining survival. Review of histologic criteria previously reported to be related to prognosis did not reveal any association with recurrence or survival (Table 1). While mitotic
z 0.2a z i= 2 0
FIG. 2.
I
01 Iti I I 81 60 80 loo 120 SURVIVAL IN MONTHS
20
Kaplan-Meier
I
40
estimated probability of survival.
224
BARTER
ET AL.
TABLE 1 FEATURES NOT PATHOLOGIC SIGNIFICANCE
OF PROGNOSTIC FOR SURVIVAL
Infiltrating vs pushing margins Intramural vs submucosal location Intravascular invasion Hemorrhage and/or necrosis Grade of tumor Tumor size
count was used to establish whether the tumor was LMS or other uterine smooth muscle tumor, within those tumors judged leiomyosarcomas, the number of mitoses per 10 high-power fields was not prognostic. There was a trend toward increased survival with lower mitotic counts, but it failed to reach statistical significance. Smaller uterine size was prognostic of longer survival (P < 0.5), but when tumor size within the uterus was analyzed, there was no significant difference in survival with smaller tumors. While patients received a variety of treatments, adjunctive therapy appears to be of no benefit (Table 2). Median time from diagnosis to recurrence for patients with adjunctive therapy was 17.6 months; it was 18.8 months for those with no adjuvant treatment. This difference is not statistically significant. Three patients developed metastatic disease during the administration of adjuvant chemotherapy. The treatment and time to death of those patients with residual disease after hysterectomy is shown in Table 3. The initial recurrence for those grossly free of disease postoperatively was confined to the vaginal apex or pelvis in 33% of the cases. Forty-six percent of recurrences were distant only, and 23% were local and distant. Of those with distant metastases, all but one had lung involvement. All patients received some TABLE 2 OUTCOME OF PATIENTS
Adjuvant treatment regimen Pelvic radiotherapy + MAC” MAC Adriamycin Adriamycin + cyclophosphamide VAC” Vincristine None
RENDERED MACROSCOPICALLY
DISEASE FREE BY INITIAL
SURGERY
Number of patients
Recurrence
Time to recurrence (months)
Number of survivors
3 1 3
2 1 2
12.5, 18.5 60 3,9.5
1’ 0 1’
1 2 1 5
I 2 1 5
8 28,40 5.5 4,19,19,22,78
0 1” 0 0
’ MAC: Methotrexate, actinomycin D, chlorambucil. ’ VAC: Vincristine, actinomycin D, cyclophosphamide. ’ Alive without evidence of disease. d Alive with disease.
225
LEIOMYOSARCOMA OF THE UTERUS TABLE 3 TREATMENT
OF PATIENTS
WITH RESIDUAL
LMS
AFTER SURGERY
Number of patients
Time to death
Pelvic radiotherapy MAC” VACb
1 1 1
10.5 45 ‘
Adriamycin
2
7,14
Initial treatment
’ MAC: Methotrexate, actinomycin D, chlorambucil. b VAC: Vincristine, actinomycin D, cyclophosphamide. ’ One patient survives 91 months after diagnosis and after initial treatment with VAC. After initial response to VAC, pulmonary metastases enlarged and adriamycin was begun. After a period of stable disease, pulmonary metastases again enlarged and a perianal recurrence was excised. Cisplatin chemotherapy failed to halt tumor growth and cyclophosphamide chemotherapy was begun. She continues today under treatment with cyclophosphamide and tamoxifen, and her metastatic disease is slowly progressive.
form of chemotherapy as treatment of recurrent disease. No regimen appeared superior. DISCUSSION
Lack of standard pathologic criteria for the diagnosis of LMS hampers discussion about this neoplasm and evaluation of treatment results. In our review, 25% of patients initially diagnosed and treated as having LMS, when reviewed using strict histologic criteria, had tumors of lesser malignant potential (only one of these patients succumbed to metastatic disease). Hart and Billman [13] reviewed 28 tumors initially diagnosed as leiomyosarcoma and revised the diagnosis to cellular or pleomorphic leiomyoma in 13 (46%). Others have documented sampling deficiencies upon review of original materials [4]. Sections for histologic review must be taken at l-cm intervals through suspicious tumors in order to adequately identify the most malignant portions of the tumor [lo]. Strict adherence to criteria of nuclear and cellular morphology and mitotic counts will reduce the inclusion of patients with rarely fatal lesions in series of LMS. Clinical factors have been associated with treatment outcome in LMS. While clinically determined uterine size appears to have statistically significant prognostic importance in this series, tumor size as determined from hysterectomy specimen did not. Salazar and associates [I71 found clinical stage to be prognostic when Stage I was contrasted to more advanced stages. In our series, clinical stage was not found to be a statistically significant prognostic factor. Our finding was influenced by the small number of patients with advanced stage disease and by the fact that one patient with Stage IV disease is a 5-year survivor. Notably, both patients in this report who survive without evidence of recurrence had tumor clinically limited to the uterine corpus. In this series, as in others [2,7,13], menopausal status did not influence prognosis. This finding is contested [4,5], and the conflict remains unresolved. Pathologic criteria found by others to be prognostic did not appear significant in this series. Silverberg [14] suggests that the grade of the tumor is predictive
226
BARTER ET AL.
of outcome. He and others [lo] have suggestedthe absence of invasion is favorable. Silverberg [I41 suggests that pushing rather than infiltrating margins portend a better outcome. None of the pathologic factors evaluated in this series were found to have prognostic significance. Further, mitotic count did not influence survival for patients with tumors judged leiomyosarcoma when rigid criteria were used to make that diagnosis. The problem encountered in the treatment of uterine sarcoma, including leiomyosarcoma, has been their propensity for widespread metastases. As such, we and others [1,16] have advocated the administration of systemic chemotherapy in an attempt to eradicate distant and local occult metastases. We add our findings to those of Hannigan and co-workers [17-191 and Omura et al. [20]. While costly and morbid, the administration of adjuvant chemotherapy fails to affect patient survival. Survival after leiomyosarcoma has not changed since an earlier report from this institution [21]. These poor survival rates demand further investigation into ways to control this aggressive disease, but we advise caution in the administration of therapeutic regimens of unproven efficacy. REFERENCES 1. Norris, H. J., and Zaloudek, C. J. Mesenchymal tumors of the uterus, in Pathology of the female genital tract (A. Blaustein, Ed.), Springer Verlag, 2nd ed., pp. 352-392 (1982). 2. Christopherson, W. M., Williamson, E. O., and Gray, L. A. Leiomyosarcoma of the uterus, Cancer 29, 1512-1517 (1972). 3. Bartisch, E. G., Bowe, E. T., and Moore, S. G. Leiomyosarcoma of the uterus, Obstet. Gynecol. 32, 101-106 (1968). 4. Spiro, R. H., and Koss, G. Myosarcoma of the uterus: A clinicopathologic study, Cancer 18, 571-588 (1965). 5. Silverberg, S. G. Leiomyosarcoma of the uterus. A clinicopathologic study, Obster. Gynecol. 38, 613-628 (1971). 6. Evans, N. Malignant myomata and related tumors of the uterus, Surg. Gynecol. Obstet. 30, 255-239 (1920). 7. Taylor, H. B., and Norris, H. J. Mesenchymal tumors of the uterus. IV. Diagnosis and prognosis of leiomyosarcomas, Arch. Pathol. 82, 40-44 (1966). 8. Kempson, R. L., and Bari, W. Uterine sarcomas: Classification, diagnosis, and prognosis, Hum. Pathol. 14, 331-350 (1970). 9. Zaloudek, C. J., and Norris, H. J. Mesenchymal tumors of the uterus, in Progress in surgical pathology (C. M. Fenoglio, M. Wolff, Eds.), Masson, New York, Vol. III, pp. 1-35 (1981). 10. Hendrickson, M. R., and Kempson, R. L. Surgical pathology of the uterine corpus, in Major problems in pathology, (J. L. Bennington, Ed.), Saunders, Philadelphia, Vol. 12, pp. 468-529 (1980). Il. Kaplan, E. L., and Meier, P. Nonparametric estimation from incomplete observations, J. Amer. Stat. Assoc. 53, 457 (1958). 12. Kalbfleisch, J. D., and Prentice, J. D. The srarisrical analysis offailure rime da&, Wiley, New York (1980). 13. Hart, W. R., and Billman, J. K. A reassessment of uterine neoplasms originally diagnosed as leiomyosarcoma, Cancer 41, 1902-1910 (1978). 14. Silverberg, S. G. Reproducibility of the mitosis count in the histologic diagnosis of smooth muscle tumors of the uterus, Hum. Parhol. 7, 451-454 (1976). 15. Salazar, 0. M., Bonfiglio, T. A., Patten, S. F., Keller, B. E., Feldstein, M., Dunne, M. E., and Rudolph, J. Uterine sarcomas: Analysis of failures with special emphasis on the use of adjuvant radiation therapy, Cancer 42, 1161-l 170 (1978).
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OF THE UTERUS
227
16. Buchsbaum, H. J., Lifshitz, S., and Blythe, J. G. Prophylactic chemotherapy in stage I and II uterine sarcoma, Gynecol. Oncol. 8, 346-348 (1979). 17. Hannigan, E. V., Freedman, R. S., and Rutledge, F. N. Adjuvant chemotherapy in early uterine sarcoma, Gynecol. Oncol. 15, 56-64 (1983). 18. Hannigan, E. V., Freedman, R. S., Elder, K. W., and Rutledge, F. N. Treatment of advanced uterine sarcoma with vincristine, actinomycin D, and cyclophosphamide, Gynecol. Oncol. 15, 224-229 (1983). 19. Hannigan, E. V., Freedman, R. S., Elder, K. W., and Rutledge, F. N. Treatment of advanced uterine sarcoma with adriamycin, Gynecol. Oncol. 16, 101-104 (1983). 20. Omura, G. A., Blessing, J. A., Major, F. J., and Silverberg, S. A randomized trial of adriamycin vs. no adjuvant chemotherapy in stage I and II uterine sarcoma. hoc. Amer. Sot. Clin. Oncol. 2, C580 (1983). 21. White, T. H., Glover, J. S., Peete, C. H., and Parker, R. T. A 34-year clinical study of uterine sarcoma, including experience with chemotherapy, Obsret. Gynecol. 25, 657 (1965).
ONCOLOGY
21, 220-227 (1985)
Leiomyosarcoma of the Uterus: Clinicopathologic Study of 21 Cases F. BARTER, M.D.,* ELLEN BLAIR SMITH, M.D.,* CHERYL A. SZPAK, M.D. ,t WANDA HINSHAW, M.S. ,$ DANIEL L. CLARKE-PEARSON, M.D. ,* AND WILLIAM T. CREASMAN, M.D.*,]
JAMES
*Division
of Gynecologic Oncology; tDepartment of Pathology; and *Duke Comprehensive Cancer Center Data Base, Duke University Medical Center, Durham, North Carolina 27710
Received May 21, 1984 A detailed clinicopathologic study of 21 patients with uterine leiomyosarcoma was undertaken. The diagnosis of leiomyosarcoma was made for those uterine smooth muscle tumors showing cellular atypia and 5-9 mitoses per 10 high-powered fields (M/IO HPF) and those with 10 or more M/10 HPF. Using these strict pathologic criteria to define leiomyosarcoma, menopausal status, margin type (pushing vs infiltrating), tumor size, grade, location, and the presence of vascular invasion and/or hemorrhage were not associated with prognosis. The S-year survival rate was 25%. Survival rates were not improved by the use of adjuvant chemotherapy in those patients rendered free of gross disease by initial surgery. 0 1985 Academic Press, Inc.
Leiomyosarcoma (LMS) represents I .3% of all uterine malignancies and about 25% of uterine sarcomas [l]. Christopherson [2] estimated that the yearly incidence of LMS was 0.67 per 100,000 women age 20 years or older. Discussion of LMS is confused by the lack of universally accepted pathologic criteria for diagnosis. Diagnostic criteria have centered on the grade of tumor and on mitotic count. Spiro and Koss [4] and Silverberg [5] suggest the diagnosis should be based on the degree of cellular atypia. In 1920, Evans [6] quantitated the number of mitoses in the uterine smooth muscle tumors and demonstrated a poorer outcome with increased mitoses. Taylor and Norris [7], Kempson and Bari [8], and Christopherson and associates [2] found very poor outcomes for those patients with 2 10 mitoses per 10high-powered fields (M/ IOHPF). The 5-year survival rate in Christopherson’s study was 21%. Kempson and Bari [8] found no survivors among patients with 5-9 M/IO HPF who also showed cytologic atypia. More recently, Zaloudek and Norris [93 and Hendrickson and Kempson [lo] have proposed definitions of uterine smooth muscle tumors that consider both mitotic rate and nuclear atypia. Tumors with 5-9 M/10 HPF and nuclear atypia are included as LMS. The present study presents the results of treatment of patients with uterine LMS at Duke University Medical Center. ’ To whom reprint requests should be addressed.
220 0090-8258/85 $1.50 Copyright All rights
Q 1985 by Academic Press, Inc. of reproduction in any form reserved.
LEIOMYOSARCOMA
OF THE UTERUS
221
METHODS AND MATERIALS Hospital charts of all patients admitted between January 1968and August 1981, with the diagnosis of uterine leiomyosarcoma were reviewed. Histologic sections of specimens taken from these patients were independently reviewed. Four sets of 10 HPFs in the area of greatest mitotic activity were analyzed for number of mitoses. The set with the highest number of mitotic figures was taken to determine the mitotic count of the tumors. Cytologic atypia was judged present or absent as was vascular invasion, hemorrhage, necrosis, nuclear inclusions, strap cells, and giant cells. In addition, all tumors were graded as to degree of differentiation as defined by Spiro and Koss [4] and Silverberg [5]. The location of the primary tumor in the myometrium was assessed and the nature of tumor margins characterized. The criteria of Hendrickson and Kempson were used to assign pathologic diagnosis of leiomyosarcoma [ 101. Kaplan-Meier [ 1l] product limit estimates of survival time and time to recurrence for those patients free of disease after surgery were calculated. The log-rank test [12] was used to compare survival curves. The lack of power of these tests due to small sample size must be considered in the interpretation of the results. Statistical significance was assigned at the 5% probability level. RESULTS Thirty-six patients with a discharge diagnosis of uterine LMS were identified. Pathology review of original pathologic slides, using the Hendrickson-Kempson criteria, identified 21 patients with LMS. Two tumors were reclassified as cellular leiomyoma, two as bizarre leiomyoma, one as benign metastasizing leiomyoma, and four as smooth muscle tumors of uncertain malignant potential. Six patients were excluded from analysis because the original tumor sections were either lost or unsuitable for diagnosis. Data from the 21 patients with LMS are analyzed in this study. Clinical Data Median age at diagnosis was 51 years (range 35-69). Only one patient was nulligravid. Eleven (52%) were postmenopausal, one (5%) was perimenopausal, and nine (43%) were premenopausal. The most frequent presenting symptoms were abnormal uterine bleeding in 67% of patients and abdominal pain in 43%. The average interval between onset of symptoms and diagnosis was 5.2 months. Ten patients (48%) were followed by their physician for “enlarging fibroids” prior to the diagnosis of LMS. Fourteen percent of the patients had diabetes, and 33% had hypertension. No patient had a prior or concurrent malignancy, and none had a history of prior pelvic irradiation or exogenous estrogen usage. Uterine size varied from normal to 40 (gestational) weeks size with median size of 13 (gestational) weeks. Five patients (24%) presented with a mass in the cervical OS. No patient had symptoms of metastatic disease at diagnosis, but two (10%) were found to have pulmonary metastases on initial chest X ray. Ten patients underwent sampling of the uterine contents; in 6 it was diagnostic. In the remainder of patients, diagnosis was made only after hysterectomy. Pap
222
BARTER ET AL.
smears of the cervix were obtained on 11 patients; in only 1 were cells seen consistent with leiomyosarcoma. Eighteen patients clinically had disease limited to the uterine corpus (Stage I). Two patients had lung metastases at diagnosis (Stage IV). One patient’s abdominal mass filled the abdomen and extended to the right pelvis sidewall (Stage III). Surgical Data
All patients underwent hysterectomy. Intraperitoneal tumor extension or metastasis was found in three patients with clinical Stage I disease. One of the patients with pulmonary metastases was found to have multiple intraperitoneal metastases. Selective lymphadenectomy (pelvic and/or paraaortic) was performed in seven cases; no lymph node metastases were found. Pelvic washings for cytologic evaluation were obtained from six patients; none showed malignant cells. Washings in two instances were taken from patients with histologically confirmed intraperitoneal spread. Pathology
Review
Ten (59%) of LMS were associated with leiomyomas, 7 (41%) were not, and the information was not given in 4 cases. There were no documented cases of LMS arising from a leiomyoma. The median tumor diameter was 6 cm (mean 6.5 cm) with a range of 2 to 10 cm. In one patient, the exact size of the tumor was not recorded. Ten (50%) of the tumors were primarily located submucosally, 9 (45%) intramural, 1 (5%) subserosally. In one case, this information was not available. The range and frequency of mitotic counts is shown in Fig. 1. There
5-9
lo-19 20-29 30-39 40-49 50-59 60-69 No. Mitoses/lO
FIG. 1.
HPF
Range and frequency of mitotic counts.
LEIOMYOSARCOMA OF THE UTERUS
223
were no grade 1 lesions, 8 grade 2 lesions, 12 grade 3 lesions, and 1 grade 4. The tumor margins were pushing in 10 cases, infiltrating in 7, and no assessment could be made in 4. Vessel invasion was present in 6 tumors. Hemorrhage and/ or necrosis was present in 16. Additional
Therapy
Eleven patients received adjunctive therapy following surgical removal of all gross tumor. Three patients received external pelvic radiotherapy as well as three 5-day courses of methotrexate, actinomycin D, and cyclophosphamide. Eight patients received only adjunctive chemotherapy. Various regimens were used including Adriamycin 50 mg/m’ body surface area given repetitively every 21 days, Adriamycin (50 mg/m*) with additional, concurrent cyclophosphamide, and vincristine as repetitively given single-agent therapy. Two patients were given three 5-day cycles of vincristine, actinomycin D, and cyclophosphamide. Five patients received no adjuvant therapy. Median mitotic count of the tumors of patients who received adjunctive therapy was 23 M/IO HPF (range 9-45). For patients who received no adjunctive therapy, median number of mitoses was 28 M/10 HPF (range 11-61). The five patients with residual disease after hysterectomy were treated with a variety of chemotherapeutic regimens. Median mitotic count for those tumors that were either metastatic or had gross residual after surgery was 21 M/10 HPF (range 10-41). Outcome
The overall Kaplan-Meier product limit survival curve is shown in Fig. 2. The S-year survival rate is 25%. Only two patients (with 25 and 9 M/10 HPF and cellular atypia, respectively) survive without evidence of recurrence. Two patients (45 and 41 M/10 HPF) survive with disease at 28 and 91 months. Menopausal status had no bearing on outcome. Clinical stage also was not statistically significant in determining survival. Review of histologic criteria previously reported to be related to prognosis did not reveal any association with recurrence or survival (Table 1). While mitotic
z 0.2a z i= 2 0
FIG. 2.
I
01 Iti I I 81 60 80 loo 120 SURVIVAL IN MONTHS
20
Kaplan-Meier
I
40
estimated probability of survival.
224
BARTER
ET AL.
TABLE 1 FEATURES NOT PATHOLOGIC SIGNIFICANCE
OF PROGNOSTIC FOR SURVIVAL
Infiltrating vs pushing margins Intramural vs submucosal location Intravascular invasion Hemorrhage and/or necrosis Grade of tumor Tumor size
count was used to establish whether the tumor was LMS or other uterine smooth muscle tumor, within those tumors judged leiomyosarcomas, the number of mitoses per 10 high-power fields was not prognostic. There was a trend toward increased survival with lower mitotic counts, but it failed to reach statistical significance. Smaller uterine size was prognostic of longer survival (P < 0.5), but when tumor size within the uterus was analyzed, there was no significant difference in survival with smaller tumors. While patients received a variety of treatments, adjunctive therapy appears to be of no benefit (Table 2). Median time from diagnosis to recurrence for patients with adjunctive therapy was 17.6 months; it was 18.8 months for those with no adjuvant treatment. This difference is not statistically significant. Three patients developed metastatic disease during the administration of adjuvant chemotherapy. The treatment and time to death of those patients with residual disease after hysterectomy is shown in Table 3. The initial recurrence for those grossly free of disease postoperatively was confined to the vaginal apex or pelvis in 33% of the cases. Forty-six percent of recurrences were distant only, and 23% were local and distant. Of those with distant metastases, all but one had lung involvement. All patients received some TABLE 2 OUTCOME OF PATIENTS
Adjuvant treatment regimen Pelvic radiotherapy + MAC” MAC Adriamycin Adriamycin + cyclophosphamide VAC” Vincristine None
RENDERED MACROSCOPICALLY
DISEASE FREE BY INITIAL
SURGERY
Number of patients
Recurrence
Time to recurrence (months)
Number of survivors
3 1 3
2 1 2
12.5, 18.5 60 3,9.5
1’ 0 1’
1 2 1 5
I 2 1 5
8 28,40 5.5 4,19,19,22,78
0 1” 0 0
’ MAC: Methotrexate, actinomycin D, chlorambucil. ’ VAC: Vincristine, actinomycin D, cyclophosphamide. ’ Alive without evidence of disease. d Alive with disease.
225
LEIOMYOSARCOMA OF THE UTERUS TABLE 3 TREATMENT
OF PATIENTS
WITH RESIDUAL
LMS
AFTER SURGERY
Number of patients
Time to death
Pelvic radiotherapy MAC” VACb
1 1 1
10.5 45 ‘
Adriamycin
2
7,14
Initial treatment
’ MAC: Methotrexate, actinomycin D, chlorambucil. b VAC: Vincristine, actinomycin D, cyclophosphamide. ’ One patient survives 91 months after diagnosis and after initial treatment with VAC. After initial response to VAC, pulmonary metastases enlarged and adriamycin was begun. After a period of stable disease, pulmonary metastases again enlarged and a perianal recurrence was excised. Cisplatin chemotherapy failed to halt tumor growth and cyclophosphamide chemotherapy was begun. She continues today under treatment with cyclophosphamide and tamoxifen, and her metastatic disease is slowly progressive.
form of chemotherapy as treatment of recurrent disease. No regimen appeared superior. DISCUSSION
Lack of standard pathologic criteria for the diagnosis of LMS hampers discussion about this neoplasm and evaluation of treatment results. In our review, 25% of patients initially diagnosed and treated as having LMS, when reviewed using strict histologic criteria, had tumors of lesser malignant potential (only one of these patients succumbed to metastatic disease). Hart and Billman [13] reviewed 28 tumors initially diagnosed as leiomyosarcoma and revised the diagnosis to cellular or pleomorphic leiomyoma in 13 (46%). Others have documented sampling deficiencies upon review of original materials [4]. Sections for histologic review must be taken at l-cm intervals through suspicious tumors in order to adequately identify the most malignant portions of the tumor [lo]. Strict adherence to criteria of nuclear and cellular morphology and mitotic counts will reduce the inclusion of patients with rarely fatal lesions in series of LMS. Clinical factors have been associated with treatment outcome in LMS. While clinically determined uterine size appears to have statistically significant prognostic importance in this series, tumor size as determined from hysterectomy specimen did not. Salazar and associates [I71 found clinical stage to be prognostic when Stage I was contrasted to more advanced stages. In our series, clinical stage was not found to be a statistically significant prognostic factor. Our finding was influenced by the small number of patients with advanced stage disease and by the fact that one patient with Stage IV disease is a 5-year survivor. Notably, both patients in this report who survive without evidence of recurrence had tumor clinically limited to the uterine corpus. In this series, as in others [2,7,13], menopausal status did not influence prognosis. This finding is contested [4,5], and the conflict remains unresolved. Pathologic criteria found by others to be prognostic did not appear significant in this series. Silverberg [14] suggests that the grade of the tumor is predictive
226
BARTER ET AL.
of outcome. He and others [lo] have suggestedthe absence of invasion is favorable. Silverberg [I41 suggests that pushing rather than infiltrating margins portend a better outcome. None of the pathologic factors evaluated in this series were found to have prognostic significance. Further, mitotic count did not influence survival for patients with tumors judged leiomyosarcoma when rigid criteria were used to make that diagnosis. The problem encountered in the treatment of uterine sarcoma, including leiomyosarcoma, has been their propensity for widespread metastases. As such, we and others [1,16] have advocated the administration of systemic chemotherapy in an attempt to eradicate distant and local occult metastases. We add our findings to those of Hannigan and co-workers [17-191 and Omura et al. [20]. While costly and morbid, the administration of adjuvant chemotherapy fails to affect patient survival. Survival after leiomyosarcoma has not changed since an earlier report from this institution [21]. These poor survival rates demand further investigation into ways to control this aggressive disease, but we advise caution in the administration of therapeutic regimens of unproven efficacy. REFERENCES 1. Norris, H. J., and Zaloudek, C. J. Mesenchymal tumors of the uterus, in Pathology of the female genital tract (A. Blaustein, Ed.), Springer Verlag, 2nd ed., pp. 352-392 (1982). 2. Christopherson, W. M., Williamson, E. O., and Gray, L. A. Leiomyosarcoma of the uterus, Cancer 29, 1512-1517 (1972). 3. Bartisch, E. G., Bowe, E. T., and Moore, S. G. Leiomyosarcoma of the uterus, Obstet. Gynecol. 32, 101-106 (1968). 4. Spiro, R. H., and Koss, G. Myosarcoma of the uterus: A clinicopathologic study, Cancer 18, 571-588 (1965). 5. Silverberg, S. G. Leiomyosarcoma of the uterus. A clinicopathologic study, Obster. Gynecol. 38, 613-628 (1971). 6. Evans, N. Malignant myomata and related tumors of the uterus, Surg. Gynecol. Obstet. 30, 255-239 (1920). 7. Taylor, H. B., and Norris, H. J. Mesenchymal tumors of the uterus. IV. Diagnosis and prognosis of leiomyosarcomas, Arch. Pathol. 82, 40-44 (1966). 8. Kempson, R. L., and Bari, W. Uterine sarcomas: Classification, diagnosis, and prognosis, Hum. Pathol. 14, 331-350 (1970). 9. Zaloudek, C. J., and Norris, H. J. Mesenchymal tumors of the uterus, in Progress in surgical pathology (C. M. Fenoglio, M. Wolff, Eds.), Masson, New York, Vol. III, pp. 1-35 (1981). 10. Hendrickson, M. R., and Kempson, R. L. Surgical pathology of the uterine corpus, in Major problems in pathology, (J. L. Bennington, Ed.), Saunders, Philadelphia, Vol. 12, pp. 468-529 (1980). Il. Kaplan, E. L., and Meier, P. Nonparametric estimation from incomplete observations, J. Amer. Stat. Assoc. 53, 457 (1958). 12. Kalbfleisch, J. D., and Prentice, J. D. The srarisrical analysis offailure rime da&, Wiley, New York (1980). 13. Hart, W. R., and Billman, J. K. A reassessment of uterine neoplasms originally diagnosed as leiomyosarcoma, Cancer 41, 1902-1910 (1978). 14. Silverberg, S. G. Reproducibility of the mitosis count in the histologic diagnosis of smooth muscle tumors of the uterus, Hum. Parhol. 7, 451-454 (1976). 15. Salazar, 0. M., Bonfiglio, T. A., Patten, S. F., Keller, B. E., Feldstein, M., Dunne, M. E., and Rudolph, J. Uterine sarcomas: Analysis of failures with special emphasis on the use of adjuvant radiation therapy, Cancer 42, 1161-l 170 (1978).
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