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Leiomyosarcoma of the uterus
GYNECOLOGY
Leiomyosarcoma TUNG J.
VAN
DONALD
Baltimorr,
DINH,
of the uterus
M.D.
WOODRUFF,
M.D.
Maryland
A series of 43 cases of uterine leiomyosarcoma was reviewed. Forty-one of the 43 patients were followed up 2 or more years. The overall 5-year survival was 73%. Favorable prognostic features included the premenopausal status of the patient, the confinement of the tumor within a myoma, the low mitotic count (less than four mitotic figures in any one high-power field or less than four mitotic figures per 10 high-power fields), the absence of necrosis, and the presence of hyalinization in the adjacent tissue suggesting confinement. Special cases such as those in which only myomectomy was performed and those receiving adjunctive chemotherapy are discussed. The differential in survival between patients with primary myosarcoma and those with lesions arising in a leiomyoma stressed. (AM. J. OBSTET. GYNECOL. 144:817, 1982.)
UTERINE LEIoMYosARcoh4As are rare mesenchymal tumors, the incidence generally quoted as approximately 0.67/100,000 women.’ Historically, much attention has been directed toward the identification of the specific malignant criteria. Nelrertheless, at the present moment, conflicting opinions still exist as to the precise histopathologic features necessary to justify the diagnosis of leiomyosarcoma, such as the number of mitotic figures per unit of tissue, containment of the tumor within the uterus, and age of the patient. This study of 43 uterine leiomyosarcomas attempts to elucidate some of these conrro\rersial features.
Material and methods Between the years 1965 and 1980, 43 cases diagnosed as uterine leiom\,osarcomas were found in the
is
files of the Gynecologic Pathology Department of The Johns Hopkins Hospital. Either the sections were referred for consultation or the patients were treated at The Johns Hopkins Hospital. The slides, stained only with hematoxylin and eosin, were examined independently by both authors. The number of slides available for review in each case varied from three to 18. The following histologic characteristics were studied: number of mitotic figures in the most anaplastic high-power field, mitoses per 10 randomly selected high-power fields, degree of pleomorphism (none, low, high), presence of hyalinization, necrosis, or vascular invasion, and margins of the tumor (infiltrating, pushing). Additionally, the routine clinical data, operating findings, gross pathologic findings, and follow-up data were recorded.
Results From the Departrnrrrt Hopkins Hospital.
of Gynecologic
Rereizled for publication
December
Pathology,
The Johns
8, 1981.
Revised June 4, 19X2. Accepted July
12, 1982.
Reprint requests: J. Donald Woodruff, M.D., 709 A Pathology, The Johns Hopkins Hospital, 600 N. Wolfe St., Baltz’more, Ma,;vland 21205. 000%9378/82/230817+07$00.70/O
0 1982 The C.V.MosbyCo.
Age, race, and parity. The youngest patient was 19 and the oldest, 71, with a mean of age 43. Of the 43 cases, 29 patients were in the third, fourth, or fifth decade of life and 14 were in the sixth, seventh, or eighth decade of life (Table 1). There were 17 (40%~) postmenopausal and 26 (60%) premenopausal patients. Eleven (28%) were black and 32 (74%) were white. Among the 37 patients of known parity, seven 817
818
I. Age of 43 patients leiomyosarcoma Table
Table
December Am. J. Obstet.
Van Dinh and Woodruff
II.
Table
with uterine No.
<20 21-30 31-40 41-50 51-60 >60
1 5 13 10 10 4
treatment
after diagnosis
2 3 5 *Excluding
TAH TAH and BSO TVH and BSO or US0 TAH, BSO, and omentectomy Myomectomy only Myomectomy followed by TAH and BSO Radical hysterectomy
1 No.
6 23 2 2 6 3 1*
in leiomyosarcomas NO.
NO.
of patients
oj’ death.!
41* 35
3 7 x
3ot
of‘ the uterus Sunk& ( %I
92 HO 73
one postoperative death and one case of leio-
myosarcoma of the uterus associated with papillary adenocarcinoma of the ovary. The patient died of the latter disease 1 year and 6 months after operation. Cause of death confirmed by autopsy.
*Including 10 patients alive 5 to IO years and five patients alive 10 to 15 years.
of 43 leiomyosarcomas
Treatment
1
%
14 53 5 5 14 7 2
TAH, Total abdominal hysterectomy; TVH, total vaginal hysterectomy; USO, unilateral salpingo-oophorectomy; BSO, bilateral salpingo-oophorectomy. *Patient had microinvasive carcinoma of cervix. Died postoperatively of pulmonary embolism. (19%) were nulligravid, 28 (75%) were gravida 1 to 5, and two (6%) had had six or more pregnancies. None of the patients had had previous pelvic irradiation. Symptomatology and diagnosis. Abnormal uterine bleeding and pelvic discomfort were the most common presenting complaints. In five instances the patient was being treated for infertility, and a myomectomy had been performed. Five patients were asymptomatic, the uterine enlargement being discovered on a routine pelvic examination. In most cases, the preoperative diagnosis was uterine myoma or an adnexal mass. The diagnosis of leiomyosarcoma was made on curettage in two instances, once for postmenopausal bleeding and the other for postpartum bleeding, and in both the lesion was submucous. Finally, in two cases the tumor was asymptomatic and found in the uterus after removal for other indications, once for carcinoma of the cervix and the other for sterilization following failure of tubal ligation. Pathologic
Survival
Years
Age (~9
Primary
III.
1. 1982 Gynecol.
findings.
Gross. The largest tumor measured 19 by 15 by 7.5 cm and weighed 695 gm. The lesions were described as whitish gray or pale pink with cystic, hemorrhagic, or necrotic soft areas. A solitary tumor was described in 20 cases (45%); there were multiple myomas in 18 (42%), and in five instances a gross lesion was not recognized. The tumor was submucous in five cases, intramural in 27, and retroperitoneal in one. Both submucous and
intramural myomas were involved in one case. In eight instances there was no definable tumor; thus, the myometrium de novo was considered the site of origin. The poor prognosis in the latter cases is stressed. Microscopic. The diagnosis of leiomyosarcoma has usually been made made on the basis of hypercellularity, cellular atypia, pleomorphism, and mitoscs. In this series, at least two mitotic figures per any high-power field were necessary to validate the diagnosis of leiomyosarcoma. The highest number of mitork figures in any one high-power field was nine and the highest number of mitotic figures per 10 high-power fields was 28. Pleomorphism was characterized by bizarre cells (including giant cells) and was recorded as either less or more than 10 per high-power field. The differenriation of the latter from abnormal mitoses was often difficult. Pleomorphism was not found in 18 cases (42%): there was low pleomorphism in 15 cases (35%) and high pleomorphism in 10 cases (23%)). The presence of histologically well-defined borders between the benign and malignant elements was ltiund in 20 tumors. Hyaline change adjacent to the tumor was noted in 19 instances. Vascular invasion was seen in six, and there was necrosis in 14 cases. There were two lesions diagnosed as epithelioid leiomyosarcoma characterized by r-ound or polygonal cells with eosinophilic cytoplasm as contrasted to the elongated cell of the classic leiomyosarcoma. Treatment. Total hysterectom) with or without salpingo-oophorectomy was performed in 37 (86%) cases. Myomectomy only was performed in the remaining six cases (14%~) (Table II). Adjunctive radiation and/or chemotherapy was used when there was extension of the tumor beyond the uterus or for recurrent disease. Radiotherapy alone was used in one instance; chemotherapy, in two; and radiation with chemotherapy, in an additional three cases. Results of treatment. With the exclusion of one op-
Volume
144
Number
7
Table
IV. Survival
Leiomyosarcoma
related
to most mitoses in any high-power
No. *
of
2-3 4-5 6-7 8-9
14 19t 3 5
Toral
41
Survival (%)
0 1 0 2
V. Survival
related
No. of
patients
No. of deaths
Sun:ival (%J
100
11
0
100
95 100 60
13t 3 3
4 2 2
69 33 33
30
*Number of mitotic figures in most anaplastic high-power tone patient living with recurrence. Table
5 Years after diagnosis
No. of death
patdents
819
field
2 Years after diagnosis 90. of mitoses per high-powerjie.!d
of uterus
to number
field
of mitoses per 10 high-power
fields
2 Years after diagnosis ,Vo. of mitoses per 10 high-power fields
No. of patients
I-4 5-9 210
12 22’ 7
Total
41
5 Years aftir Survival 03
NO.
of deaths 0 2 1
diagnosis
No. of patients
NO.
Survival
of deaths
(%)
9* 16 5
0 4 4
100 75 20
100 91 86
30
*One patient living with recurrence. Table
VI. Survival
related
I Menopausal
statw
Premenopausal Postmenopausal Total
I
to menopausal
status
2 Years after diagnosis
No.
of patients
I
5 Years after diagnosis
NO.
of deaths
I
Survival (%)
No. of patients
25
1
96
16*
16* 41
1
93
14
NO.
I
of deaths
:
Suroiual (%) 93 50
30
*One patient living with recurrence. erative non-tumor-related death and one patient who died of an associated papillary adenocarcinoma of the ovary, 11 patients have been followed up 2 years, and 30, for 5 years or more. 7‘he overall 5-year survival for these 41 patients was 73% (Table III). There were eight patients (19.5%) who died of metastatic disease in the abdomen, liver, and lungs from 6 months to 3 years after initial therapy. Three patients (7.5%) are alive with recurrences from 2 to 6 years. of leiomyosarcoma In this series. the diagnosis necessitated the finding of at least two mitoses in any high-power field. Tumors with one mitosis in any high-power field were clinically benign as noted in a prior publication, regardless of the number of mitoses found in many fields.’ When survival is related to number of mitoses per one or 10 high-power fields (Tables IV and V), there were no tumor-related deaths in patients with two or three mitoses in any high-power
field or one to four mitoses in 10 high-power fields; however, one is alive with recurrence in the latter category. This patient had a leiomyosarcoma in a myoma with four mitotic figures in 10 high-power fields and is alive with liver and abdominal metastases 6 years after myomectomy, four years after total abdominal hysterectomy and bilateral salpingo-oophorectomy, and 2 years after liver resection (see Table VII). Pleomorphism did not influence with prognosis. The 5-year survival was equal for the tumors without and with high degrees of pleomorphism (77%). Histologic grade was not a useful prognostic feature in this series.% On the contrary, the presence of hyalinization around the tumor was associated with increased survival. The latter microscopic feature was noted by Kurman and Norris“ in a study of epithelioid leiomyosarcomas. Absence of necrosis was also a good prognostic feature. The borders of the tumor (infiltrating or pushing)
820
Van Dinh
Table
VII.
Analysis
No. Patients
of eight deaths and three patients
Age (~7) dying
December Am. J. Obstet.
and Woodruff
Race
living
1, 1982 Gynecol.
with recurrence Location
Initial
operation
TAH TAH TAH
and BSO and BSO and BSO
Myometrium Myometrium Intramural
TAH
and BSO
Myometrium Myometrium Myometrium Intramural
Mitoses
of tumor
per high-power
field
of disease:
2 3
68 43 53
White White White
4 5 6 7 8
55 69 61 52 54
White White White Black White
1
TAH and BSO TAH TAH TAH
and BSO and BSO and BSO
and sigmoid
9 8 4
myoma and vagina
myoma
Submucous and intramural myomas
Patients 1
with recurrence: 63
White
2 3
57 36
White White
*0
Table Case No.
living
= Operation;
VIII. Age (Yd
R = radiation;
Leiomyosarcomas Mitoses per high-powmjeld
-1 9 4
Myometrium and abdomen Intramural myoma Intramural myoma
TAH and BSO TAH and BSO Myomectomy
C = chemotherapy.
discovered Mitoses per 10 high-power fields
after myomectomy
in infertile
Subsequent management
Follow-up
TAH and BSO TAH and BSO TAH None
1 2 3
35 25 19
3 4 8
4 9 15
4 5 6 7
31 22 29 33
3 2 4 7
6 4 5 9
8
24
4
6
None
9
32
4
4
None
*No
evidence
None
None None
patients results
NED,* NED, NED, NED, NED,
6 yr 2 yr 1 yr 2 yr 3 yr; 1 delivery 2 yr after myomectomy
NED,
5 yr
NED, 6 yr; 2 successive pregnancies terminated by suction curettage NED, 13 yr; 3 successive pregnancies delivered by cesarean section Recurrence in uterus and abdomen 2 yr later (TAH and BSO) and in liver 4 yr later (resection). Alive 6 yr after initial operation with liver and abdominal metastases
of disease.
and vascular invasion by malignant cells in this series did not affect survival. Among six cases with vascular invasion, only two patients are dead, one of intercurrent disease without tumor and one of tumor 5 years after operation. This is in contradistinction to Gallup and Cordray’s results and Vardi and ToveIl’s series. A large tumor is not always a poor prognostic indicator. Among 20 cases of tumors with known size followed up for 5 years or more, the best survival was in patients with tumors ranging from 6 to 10 cm. On the contrary, the localization of the tumor is possibly the most important prognostic feature. Whereas the 5-year survival is similar for the submucous (80%), the intramural (88%), and the one subserous tumor (loo%), it is dismal for tumors occurring de novo in the myometrium (25%) and those having extended beyond the uterus (33%) at the initial operation. Of the eight tumor-related deaths, there was extension beyond the
confines of the uterus in two cases, and in three instances the malignancy arose in the myometrium without a definable tumor. The latter is possibly the most significant prognostic feature and has not been emphasized adequately in previous series. Montague and associates’ pointed out a correlation in survival between the premenopausal and postmenopausal patient. Silverberg confirmed this impression, and our series reaffirmed it. Premenopausal patients had a j-year survival of 93% (Table VI). In contrast, only eight of 16 postmenopausal patients (50%) survived 5 years. Among the eight deaths in this series, only one of 25 premenopausal patients died of disease. Operation consisting of total hysterectomy and bilateral salpingo-oophorectomy was the initial treatment for leiomyosarcoma. An analysis of eight deaths and three patients living with recurrences in this series (Table VII) reveals that recurrences and/or metastases
Volume Number
144 7
Leiomyosarcoma
Mitoses per 10 high-powerfields 28 9 5
Vasculur
invasion
0 0 0
5
0
10
0
11 7 15
0 0 +
6
0
16
0 0
4
Metustases
Subsequent
treatment*
of uterus
Length
of survival
Abdomen Lung, abdomen Liver, lung, hip, face Liver Liver Vagina, buttocks Abdomen Lung, abdomen
None C R,C
6 mo
R.C, 0 None 0 R
3 3 3 4 4
Abdomen Abdomen Liver, abdomen
None W.3 QC
Alive 2 yr Alive 4 yr Alive 6 yr
developed only in tumors with at least four mitoses in the most anaplastic high-power field or four mitoses in 10 high-power fields. Furthermore, the deaths occurred and the recurrences developed in the first 4 years after therapy, as suggested by Silverberg and Hannigan and Gomez.8 Once recurrence and/or metastases developed (often in the abdomen, liver, or lungs), palliative operation, radiation, and chemotherapy did not control the disease. The finding of leiomyosarcoma removed in the performance of a myomectomy in infertile patients places the clinician with a most difficult therapeutic dilemma. Obviously, the patient and family must be made aware of the problem and must be involved in the final decision. Summary of our experience in the management of such cases can be seen in Table VIII. The safest procedure is, without doubt, total hysterectomy with or without salpingo-oophorectomy. However, preserving the uterus after myomectomy, in case the patient strongly desires pregnancy, is also a viable alternative if the patient understands and accepts the risk. In this series, myomectomy alone was performed in six cases with one recurrence (Fig. 1). The role of adjunctiv-e chemotherapy with the two most promising agents, Adriamycin and dacarbazine, is still unclear. Some authors”, S, g propose systemic chemotherapy in the presence of leiomyosarcomas with a high mitotic count (greater than eight mitoses per high-power held or greater than 10 mitoses per 10 high-power fields) or with extension of tumor beyond the confines of the uterus. In the current series, one such patient, a 50-year-old white woman, was treated by total abdominal hysterectomy with bilateral salpingooophorectomy for intramural leiomyoma of uterus. Microscopic study revealed a leiomyosarcoma with
821
1 y’ 2 yr
yr yr yr Yr yr
eight mitoses in the most anaplastic high-po\ver field and 14 mitoses per 10 high-power fields with no necrosis or hyaline degeneration around the tumor. Intraperitoneal P32, Adriamycin, and dacarbazine were administered. The patient is alive 6 years and 3 months after operation without evidence of disease (Fig. 2). One case does not make a series but, nevertheless, is suggestive evidence that adjunctive therapy may play a role in the postoperative treatment of the patient with the more aggressive disease, especially with extrauterine extension. In this series of 43 leiomyosarcomas of the uterus, there were two cases diagnosed as sm epithelioid leiomyosarcomas. These lesions were considered more malignant by Kurman and Norris’ and Hendrikson and Kempson. i” The two cases of epithelioid leiomyosarcoma in this series with four mitoses per high-power field and six mitoses per 10 high-power fields each have been followed up only 2 to 3 years and recurrences have not been reported to date (Fig. 3).
Comment Criteria for separating leiomyomas from leiomyosarcomas differ from author to author. Taylor and Norris” considered all lesions with fewer than 10 mitoses per 10 high-power fields as benign. Hart and Billman” accepted as malignant those tumors containing six or more mitoses per 10 high-power fields, whereas Hendrikson and Kempson*o considered as “smooth muscle tumors of uncertain malignant potential” those which have five to nine mitoses per 10 high-power helds and well-differentiated spindle smooth muscle cells without atypia, anaplasia, or pleomorphism. Counting mitoses, which has been the fundamental criterion for determining the malignancy of the tumor,
822
Van Dinh
and Woodruff
December
I. 1982
Am. 1. Obrtrt.
Cyne~~l.
Fig. 1. Leiom)osarcoma with seven mitoses per high-poker field and nine mitoses per 10 high-power fields and high pleomorphism. Myomectomy was performed. .4live 6 years with IWO pregnancies. Note bidarrc pleomorphic figures in center. (Case 7, Table VIII.)
Fig. 2. Leiomyosarcoma with eight mitoses per high-power tield and 14 mitoses per 10 high-power fields. Six-year surviwl with adjunctive chemotherapy.
can differ
from
one
pathologist
Silverberg.”
Consequently,
single
most
anaplastic
more
accurate
and
to another, counting
high-power easier
sailor” seem
as Hendrikson wiser
is done
for
to high-grade clear that mitoses (Fig.
the
increases, 1)
and
to depend most
mitoses
Kempson’” most and
aggressive then
to be
add
as agreed
by most
authors’,
uterine
anaplastic for
leiomyosarcoma
is operation. alters survival. high-power
diagnosis
as
equal
to four
high-power it is of
“3 5. Ii. 8, lo
mitoses fields.
is rare.
field
is accepted
of leiomyosarcoma,
per
Factors
The
There is no evidence that If at least two miroses in
suwival in this series is 73%. tases may occur with mitotic
low-grade
divide by 2. Nevertheless, decreases as the number
most
criterion
it. It would focus,
basic “therapy” adnexectomy the
observer
per 10 highof a drunken put
In conclusion.
by
in the
seemed from
of mitoses randomness
on the
malignancies, areas and survival
field
to reproduce
to observer than the counting power fields, even with “the
as noted
the
Fig. 4. LAomyosarcoma with mne mitoses per high-power field and 16 mitoses per 10 high-power fields. .4livr with recurrence 1 years after operation (Case 2).
as the
the
overall
Recurrences and metascounts higher than 01
high-power indicating
field a good
or
per
are: premenopausal status of the patient, localization the tumor in a myoma, low mitotic count, presence hyalinization sis.
Histologic
around grade
the of
tumor. the
and and/or
10
prognosis
absence
of necro-
tumor,
pleomor-
of of
Volume Number
144 7
phism,
Leiomyosarcoma
infiltrating
borders,
vascular
invasion
significant
prognostic
features
in this
tomy
adjunctive
systemic
chemotherapy
and
indicated
in patients
with
extension
of the tumor
currently
there
thesis.
Most
high
beyond is insufficient
significant,
mitotic
series.
not
may
counts
the uterus, evidence to
it is important
were Hysterecor
that arising
be with
although prove this
nosis
regardless
of
de novo than
that
histopathologic
in the myometrium lesion
developing
of uterus
features
the
has a poorer in a leiomyoma.
823
tumor progCon-
versely, those lesions confined to the uterus, regardless of histopathologic characteristics, are associated with an excellent
survival.
to appreciate
REFERENCES
1. Christopherson. W. M., Williamson, E. O., and Gray, L. A.: Leiomyosarcoma of the uterus, Cancer 29:1512, 1972. A. C. W., Swartz, D. P., and Woodruff, j. D.: 2. Montague, Sarcoma arising in a leiomyoma of the uterus, AM. J. OBSTLT. GYNECOL. 92:-f21, 1965. 3. Hart, W. R., and Billman, J. K.: A reassessment of uterine neoplasms originally diagnosed as leiomyosarcomas, Cancer 41:1902, 1978. 4. Kurman, R. J., and Norris, H. J.: Mesenchymal tumors of the uterus. VI. Epithelioid smooth muscle tumors including leiomyoblastoma and clear cell leiomyoma. A clinical and pathological study, Cancer 37: 1853, 1976. 5. Gallup, D. G., and Cordray, D. R.: Leiomyosarcoma of the uterus: Case reports and a review, Obstet. Gynecol. Surv. 34:300, 1979. 6. Vardi. J. R., and Tovell, H. M. M.: Leiomyosarcoma of the uterus: Clinicopathologic study, Obstet. Gynecol. 56:428, 1980.
Silverberg, S. G.: Leiomyosarcoma of the uterus. A clinicopathologic study, Obstet. Gynecol. 38:613, 1971. Hannigan, E. V., and Gomez, L. G.: Uterine leiomyosarcoma. A review of prognostic and pathologic features, AM. J. OBSTET. GYNECOL. 134:557,1979. Azizi, F., Bitran, J., Jahevari, G., and Herbst, A. L.: Remission of uterine leiomyosarcomas treated with vincristin&, Adriamycin, and dimethyl-triazeno-imidazole carboximide, AM. J. OBSTET. GYNECOL. 133:379, 1979. 10. Hendrikson, M. R., and Kempson, R. L.: Smooth muscle neoplasms, in Surgical Pathology of the Uterus, Philadelphia, 1980, W. B. Saunders Company, pp. 468-529. 11. Taylor, H. B., and Norris, H. J.; Mesenchymal tumors of the uterus. IV. Diagnosis and prognosis of leiomyosarcomas, Arch. Pathol. 82:40, 1966. 12. Silverberg, S. G.: Reproducibility of the mitosis count in the histologic diagnosis of smooth muscle tumors of the uterus, Hum. Pathol. 7:451, 1976.
Leiomyosarcoma TUNG J.
VAN
DONALD
Baltimorr,
DINH,
of the uterus
M.D.
WOODRUFF,
M.D.
Maryland
A series of 43 cases of uterine leiomyosarcoma was reviewed. Forty-one of the 43 patients were followed up 2 or more years. The overall 5-year survival was 73%. Favorable prognostic features included the premenopausal status of the patient, the confinement of the tumor within a myoma, the low mitotic count (less than four mitotic figures in any one high-power field or less than four mitotic figures per 10 high-power fields), the absence of necrosis, and the presence of hyalinization in the adjacent tissue suggesting confinement. Special cases such as those in which only myomectomy was performed and those receiving adjunctive chemotherapy are discussed. The differential in survival between patients with primary myosarcoma and those with lesions arising in a leiomyoma stressed. (AM. J. OBSTET. GYNECOL. 144:817, 1982.)
UTERINE LEIoMYosARcoh4As are rare mesenchymal tumors, the incidence generally quoted as approximately 0.67/100,000 women.’ Historically, much attention has been directed toward the identification of the specific malignant criteria. Nelrertheless, at the present moment, conflicting opinions still exist as to the precise histopathologic features necessary to justify the diagnosis of leiomyosarcoma, such as the number of mitotic figures per unit of tissue, containment of the tumor within the uterus, and age of the patient. This study of 43 uterine leiomyosarcomas attempts to elucidate some of these conrro\rersial features.
Material and methods Between the years 1965 and 1980, 43 cases diagnosed as uterine leiom\,osarcomas were found in the
is
files of the Gynecologic Pathology Department of The Johns Hopkins Hospital. Either the sections were referred for consultation or the patients were treated at The Johns Hopkins Hospital. The slides, stained only with hematoxylin and eosin, were examined independently by both authors. The number of slides available for review in each case varied from three to 18. The following histologic characteristics were studied: number of mitotic figures in the most anaplastic high-power field, mitoses per 10 randomly selected high-power fields, degree of pleomorphism (none, low, high), presence of hyalinization, necrosis, or vascular invasion, and margins of the tumor (infiltrating, pushing). Additionally, the routine clinical data, operating findings, gross pathologic findings, and follow-up data were recorded.
Results From the Departrnrrrt Hopkins Hospital.
of Gynecologic
Rereizled for publication
December
Pathology,
The Johns
8, 1981.
Revised June 4, 19X2. Accepted July
12, 1982.
Reprint requests: J. Donald Woodruff, M.D., 709 A Pathology, The Johns Hopkins Hospital, 600 N. Wolfe St., Baltz’more, Ma,;vland 21205. 000%9378/82/230817+07$00.70/O
0 1982 The C.V.MosbyCo.
Age, race, and parity. The youngest patient was 19 and the oldest, 71, with a mean of age 43. Of the 43 cases, 29 patients were in the third, fourth, or fifth decade of life and 14 were in the sixth, seventh, or eighth decade of life (Table 1). There were 17 (40%~) postmenopausal and 26 (60%) premenopausal patients. Eleven (28%) were black and 32 (74%) were white. Among the 37 patients of known parity, seven 817
818
I. Age of 43 patients leiomyosarcoma Table
Table
December Am. J. Obstet.
Van Dinh and Woodruff
II.
Table
with uterine No.
<20 21-30 31-40 41-50 51-60 >60
1 5 13 10 10 4
treatment
after diagnosis
2 3 5 *Excluding
TAH TAH and BSO TVH and BSO or US0 TAH, BSO, and omentectomy Myomectomy only Myomectomy followed by TAH and BSO Radical hysterectomy
1 No.
6 23 2 2 6 3 1*
in leiomyosarcomas NO.
NO.
of patients
oj’ death.!
41* 35
3 7 x
3ot
of‘ the uterus Sunk& ( %I
92 HO 73
one postoperative death and one case of leio-
myosarcoma of the uterus associated with papillary adenocarcinoma of the ovary. The patient died of the latter disease 1 year and 6 months after operation. Cause of death confirmed by autopsy.
*Including 10 patients alive 5 to IO years and five patients alive 10 to 15 years.
of 43 leiomyosarcomas
Treatment
1
%
14 53 5 5 14 7 2
TAH, Total abdominal hysterectomy; TVH, total vaginal hysterectomy; USO, unilateral salpingo-oophorectomy; BSO, bilateral salpingo-oophorectomy. *Patient had microinvasive carcinoma of cervix. Died postoperatively of pulmonary embolism. (19%) were nulligravid, 28 (75%) were gravida 1 to 5, and two (6%) had had six or more pregnancies. None of the patients had had previous pelvic irradiation. Symptomatology and diagnosis. Abnormal uterine bleeding and pelvic discomfort were the most common presenting complaints. In five instances the patient was being treated for infertility, and a myomectomy had been performed. Five patients were asymptomatic, the uterine enlargement being discovered on a routine pelvic examination. In most cases, the preoperative diagnosis was uterine myoma or an adnexal mass. The diagnosis of leiomyosarcoma was made on curettage in two instances, once for postmenopausal bleeding and the other for postpartum bleeding, and in both the lesion was submucous. Finally, in two cases the tumor was asymptomatic and found in the uterus after removal for other indications, once for carcinoma of the cervix and the other for sterilization following failure of tubal ligation. Pathologic
Survival
Years
Age (~9
Primary
III.
1. 1982 Gynecol.
findings.
Gross. The largest tumor measured 19 by 15 by 7.5 cm and weighed 695 gm. The lesions were described as whitish gray or pale pink with cystic, hemorrhagic, or necrotic soft areas. A solitary tumor was described in 20 cases (45%); there were multiple myomas in 18 (42%), and in five instances a gross lesion was not recognized. The tumor was submucous in five cases, intramural in 27, and retroperitoneal in one. Both submucous and
intramural myomas were involved in one case. In eight instances there was no definable tumor; thus, the myometrium de novo was considered the site of origin. The poor prognosis in the latter cases is stressed. Microscopic. The diagnosis of leiomyosarcoma has usually been made made on the basis of hypercellularity, cellular atypia, pleomorphism, and mitoscs. In this series, at least two mitotic figures per any high-power field were necessary to validate the diagnosis of leiomyosarcoma. The highest number of mitork figures in any one high-power field was nine and the highest number of mitotic figures per 10 high-power fields was 28. Pleomorphism was characterized by bizarre cells (including giant cells) and was recorded as either less or more than 10 per high-power field. The differenriation of the latter from abnormal mitoses was often difficult. Pleomorphism was not found in 18 cases (42%): there was low pleomorphism in 15 cases (35%) and high pleomorphism in 10 cases (23%)). The presence of histologically well-defined borders between the benign and malignant elements was ltiund in 20 tumors. Hyaline change adjacent to the tumor was noted in 19 instances. Vascular invasion was seen in six, and there was necrosis in 14 cases. There were two lesions diagnosed as epithelioid leiomyosarcoma characterized by r-ound or polygonal cells with eosinophilic cytoplasm as contrasted to the elongated cell of the classic leiomyosarcoma. Treatment. Total hysterectom) with or without salpingo-oophorectomy was performed in 37 (86%) cases. Myomectomy only was performed in the remaining six cases (14%~) (Table II). Adjunctive radiation and/or chemotherapy was used when there was extension of the tumor beyond the uterus or for recurrent disease. Radiotherapy alone was used in one instance; chemotherapy, in two; and radiation with chemotherapy, in an additional three cases. Results of treatment. With the exclusion of one op-
Volume
144
Number
7
Table
IV. Survival
Leiomyosarcoma
related
to most mitoses in any high-power
No. *
of
2-3 4-5 6-7 8-9
14 19t 3 5
Toral
41
Survival (%)
0 1 0 2
V. Survival
related
No. of
patients
No. of deaths
Sun:ival (%J
100
11
0
100
95 100 60
13t 3 3
4 2 2
69 33 33
30
*Number of mitotic figures in most anaplastic high-power tone patient living with recurrence. Table
5 Years after diagnosis
No. of death
patdents
819
field
2 Years after diagnosis 90. of mitoses per high-powerjie.!d
of uterus
to number
field
of mitoses per 10 high-power
fields
2 Years after diagnosis ,Vo. of mitoses per 10 high-power fields
No. of patients
I-4 5-9 210
12 22’ 7
Total
41
5 Years aftir Survival 03
NO.
of deaths 0 2 1
diagnosis
No. of patients
NO.
Survival
of deaths
(%)
9* 16 5
0 4 4
100 75 20
100 91 86
30
*One patient living with recurrence. Table
VI. Survival
related
I Menopausal
statw
Premenopausal Postmenopausal Total
I
to menopausal
status
2 Years after diagnosis
No.
of patients
I
5 Years after diagnosis
NO.
of deaths
I
Survival (%)
No. of patients
25
1
96
16*
16* 41
1
93
14
NO.
I
of deaths
:
Suroiual (%) 93 50
30
*One patient living with recurrence. erative non-tumor-related death and one patient who died of an associated papillary adenocarcinoma of the ovary, 11 patients have been followed up 2 years, and 30, for 5 years or more. 7‘he overall 5-year survival for these 41 patients was 73% (Table III). There were eight patients (19.5%) who died of metastatic disease in the abdomen, liver, and lungs from 6 months to 3 years after initial therapy. Three patients (7.5%) are alive with recurrences from 2 to 6 years. of leiomyosarcoma In this series. the diagnosis necessitated the finding of at least two mitoses in any high-power field. Tumors with one mitosis in any high-power field were clinically benign as noted in a prior publication, regardless of the number of mitoses found in many fields.’ When survival is related to number of mitoses per one or 10 high-power fields (Tables IV and V), there were no tumor-related deaths in patients with two or three mitoses in any high-power
field or one to four mitoses in 10 high-power fields; however, one is alive with recurrence in the latter category. This patient had a leiomyosarcoma in a myoma with four mitotic figures in 10 high-power fields and is alive with liver and abdominal metastases 6 years after myomectomy, four years after total abdominal hysterectomy and bilateral salpingo-oophorectomy, and 2 years after liver resection (see Table VII). Pleomorphism did not influence with prognosis. The 5-year survival was equal for the tumors without and with high degrees of pleomorphism (77%). Histologic grade was not a useful prognostic feature in this series.% On the contrary, the presence of hyalinization around the tumor was associated with increased survival. The latter microscopic feature was noted by Kurman and Norris“ in a study of epithelioid leiomyosarcomas. Absence of necrosis was also a good prognostic feature. The borders of the tumor (infiltrating or pushing)
820
Van Dinh
Table
VII.
Analysis
No. Patients
of eight deaths and three patients
Age (~7) dying
December Am. J. Obstet.
and Woodruff
Race
living
1, 1982 Gynecol.
with recurrence Location
Initial
operation
TAH TAH TAH
and BSO and BSO and BSO
Myometrium Myometrium Intramural
TAH
and BSO
Myometrium Myometrium Myometrium Intramural
Mitoses
of tumor
per high-power
field
of disease:
2 3
68 43 53
White White White
4 5 6 7 8
55 69 61 52 54
White White White Black White
1
TAH and BSO TAH TAH TAH
and BSO and BSO and BSO
and sigmoid
9 8 4
myoma and vagina
myoma
Submucous and intramural myomas
Patients 1
with recurrence: 63
White
2 3
57 36
White White
*0
Table Case No.
living
= Operation;
VIII. Age (Yd
R = radiation;
Leiomyosarcomas Mitoses per high-powmjeld
-1 9 4
Myometrium and abdomen Intramural myoma Intramural myoma
TAH and BSO TAH and BSO Myomectomy
C = chemotherapy.
discovered Mitoses per 10 high-power fields
after myomectomy
in infertile
Subsequent management
Follow-up
TAH and BSO TAH and BSO TAH None
1 2 3
35 25 19
3 4 8
4 9 15
4 5 6 7
31 22 29 33
3 2 4 7
6 4 5 9
8
24
4
6
None
9
32
4
4
None
*No
evidence
None
None None
patients results
NED,* NED, NED, NED, NED,
6 yr 2 yr 1 yr 2 yr 3 yr; 1 delivery 2 yr after myomectomy
NED,
5 yr
NED, 6 yr; 2 successive pregnancies terminated by suction curettage NED, 13 yr; 3 successive pregnancies delivered by cesarean section Recurrence in uterus and abdomen 2 yr later (TAH and BSO) and in liver 4 yr later (resection). Alive 6 yr after initial operation with liver and abdominal metastases
of disease.
and vascular invasion by malignant cells in this series did not affect survival. Among six cases with vascular invasion, only two patients are dead, one of intercurrent disease without tumor and one of tumor 5 years after operation. This is in contradistinction to Gallup and Cordray’s results and Vardi and ToveIl’s series. A large tumor is not always a poor prognostic indicator. Among 20 cases of tumors with known size followed up for 5 years or more, the best survival was in patients with tumors ranging from 6 to 10 cm. On the contrary, the localization of the tumor is possibly the most important prognostic feature. Whereas the 5-year survival is similar for the submucous (80%), the intramural (88%), and the one subserous tumor (loo%), it is dismal for tumors occurring de novo in the myometrium (25%) and those having extended beyond the uterus (33%) at the initial operation. Of the eight tumor-related deaths, there was extension beyond the
confines of the uterus in two cases, and in three instances the malignancy arose in the myometrium without a definable tumor. The latter is possibly the most significant prognostic feature and has not been emphasized adequately in previous series. Montague and associates’ pointed out a correlation in survival between the premenopausal and postmenopausal patient. Silverberg confirmed this impression, and our series reaffirmed it. Premenopausal patients had a j-year survival of 93% (Table VI). In contrast, only eight of 16 postmenopausal patients (50%) survived 5 years. Among the eight deaths in this series, only one of 25 premenopausal patients died of disease. Operation consisting of total hysterectomy and bilateral salpingo-oophorectomy was the initial treatment for leiomyosarcoma. An analysis of eight deaths and three patients living with recurrences in this series (Table VII) reveals that recurrences and/or metastases
Volume Number
144 7
Leiomyosarcoma
Mitoses per 10 high-powerfields 28 9 5
Vasculur
invasion
0 0 0
5
0
10
0
11 7 15
0 0 +
6
0
16
0 0
4
Metustases
Subsequent
treatment*
of uterus
Length
of survival
Abdomen Lung, abdomen Liver, lung, hip, face Liver Liver Vagina, buttocks Abdomen Lung, abdomen
None C R,C
6 mo
R.C, 0 None 0 R
3 3 3 4 4
Abdomen Abdomen Liver, abdomen
None W.3 QC
Alive 2 yr Alive 4 yr Alive 6 yr
developed only in tumors with at least four mitoses in the most anaplastic high-power field or four mitoses in 10 high-power fields. Furthermore, the deaths occurred and the recurrences developed in the first 4 years after therapy, as suggested by Silverberg and Hannigan and Gomez.8 Once recurrence and/or metastases developed (often in the abdomen, liver, or lungs), palliative operation, radiation, and chemotherapy did not control the disease. The finding of leiomyosarcoma removed in the performance of a myomectomy in infertile patients places the clinician with a most difficult therapeutic dilemma. Obviously, the patient and family must be made aware of the problem and must be involved in the final decision. Summary of our experience in the management of such cases can be seen in Table VIII. The safest procedure is, without doubt, total hysterectomy with or without salpingo-oophorectomy. However, preserving the uterus after myomectomy, in case the patient strongly desires pregnancy, is also a viable alternative if the patient understands and accepts the risk. In this series, myomectomy alone was performed in six cases with one recurrence (Fig. 1). The role of adjunctiv-e chemotherapy with the two most promising agents, Adriamycin and dacarbazine, is still unclear. Some authors”, S, g propose systemic chemotherapy in the presence of leiomyosarcomas with a high mitotic count (greater than eight mitoses per high-power held or greater than 10 mitoses per 10 high-power fields) or with extension of tumor beyond the confines of the uterus. In the current series, one such patient, a 50-year-old white woman, was treated by total abdominal hysterectomy with bilateral salpingooophorectomy for intramural leiomyoma of uterus. Microscopic study revealed a leiomyosarcoma with
821
1 y’ 2 yr
yr yr yr Yr yr
eight mitoses in the most anaplastic high-po\ver field and 14 mitoses per 10 high-power fields with no necrosis or hyaline degeneration around the tumor. Intraperitoneal P32, Adriamycin, and dacarbazine were administered. The patient is alive 6 years and 3 months after operation without evidence of disease (Fig. 2). One case does not make a series but, nevertheless, is suggestive evidence that adjunctive therapy may play a role in the postoperative treatment of the patient with the more aggressive disease, especially with extrauterine extension. In this series of 43 leiomyosarcomas of the uterus, there were two cases diagnosed as sm epithelioid leiomyosarcomas. These lesions were considered more malignant by Kurman and Norris’ and Hendrikson and Kempson. i” The two cases of epithelioid leiomyosarcoma in this series with four mitoses per high-power field and six mitoses per 10 high-power fields each have been followed up only 2 to 3 years and recurrences have not been reported to date (Fig. 3).
Comment Criteria for separating leiomyomas from leiomyosarcomas differ from author to author. Taylor and Norris” considered all lesions with fewer than 10 mitoses per 10 high-power fields as benign. Hart and Billman” accepted as malignant those tumors containing six or more mitoses per 10 high-power fields, whereas Hendrikson and Kempson*o considered as “smooth muscle tumors of uncertain malignant potential” those which have five to nine mitoses per 10 high-power helds and well-differentiated spindle smooth muscle cells without atypia, anaplasia, or pleomorphism. Counting mitoses, which has been the fundamental criterion for determining the malignancy of the tumor,
822
Van Dinh
and Woodruff
December
I. 1982
Am. 1. Obrtrt.
Cyne~~l.
Fig. 1. Leiom)osarcoma with seven mitoses per high-poker field and nine mitoses per 10 high-power fields and high pleomorphism. Myomectomy was performed. .4live 6 years with IWO pregnancies. Note bidarrc pleomorphic figures in center. (Case 7, Table VIII.)
Fig. 2. Leiomyosarcoma with eight mitoses per high-power tield and 14 mitoses per 10 high-power fields. Six-year surviwl with adjunctive chemotherapy.
can differ
from
one
pathologist
Silverberg.”
Consequently,
single
most
anaplastic
more
accurate
and
to another, counting
high-power easier
sailor” seem
as Hendrikson wiser
is done
for
to high-grade clear that mitoses (Fig.
the
increases, 1)
and
to depend most
mitoses
Kempson’” most and
aggressive then
to be
add
as agreed
by most
authors’,
uterine
anaplastic for
leiomyosarcoma
is operation. alters survival. high-power
diagnosis
as
equal
to four
high-power it is of
“3 5. Ii. 8, lo
mitoses fields.
is rare.
field
is accepted
of leiomyosarcoma,
per
Factors
The
There is no evidence that If at least two miroses in
suwival in this series is 73%. tases may occur with mitotic
low-grade
divide by 2. Nevertheless, decreases as the number
most
criterion
it. It would focus,
basic “therapy” adnexectomy the
observer
per 10 highof a drunken put
In conclusion.
by
in the
seemed from
of mitoses randomness
on the
malignancies, areas and survival
field
to reproduce
to observer than the counting power fields, even with “the
as noted
the
Fig. 4. LAomyosarcoma with mne mitoses per high-power field and 16 mitoses per 10 high-power fields. .4livr with recurrence 1 years after operation (Case 2).
as the
the
overall
Recurrences and metascounts higher than 01
high-power indicating
field a good
or
per
are: premenopausal status of the patient, localization the tumor in a myoma, low mitotic count, presence hyalinization sis.
Histologic
around grade
the of
tumor. the
and and/or
10
prognosis
absence
of necro-
tumor,
pleomor-
of of
Volume Number
144 7
phism,
Leiomyosarcoma
infiltrating
borders,
vascular
invasion
significant
prognostic
features
in this
tomy
adjunctive
systemic
chemotherapy
and
indicated
in patients
with
extension
of the tumor
currently
there
thesis.
Most
high
beyond is insufficient
significant,
mitotic
series.
not
may
counts
the uterus, evidence to
it is important
were Hysterecor
that arising
be with
although prove this
nosis
regardless
of
de novo than
that
histopathologic
in the myometrium lesion
developing
of uterus
features
the
has a poorer in a leiomyoma.
823
tumor progCon-
versely, those lesions confined to the uterus, regardless of histopathologic characteristics, are associated with an excellent
survival.
to appreciate
REFERENCES
1. Christopherson. W. M., Williamson, E. O., and Gray, L. A.: Leiomyosarcoma of the uterus, Cancer 29:1512, 1972. A. C. W., Swartz, D. P., and Woodruff, j. D.: 2. Montague, Sarcoma arising in a leiomyoma of the uterus, AM. J. OBSTLT. GYNECOL. 92:-f21, 1965. 3. Hart, W. R., and Billman, J. K.: A reassessment of uterine neoplasms originally diagnosed as leiomyosarcomas, Cancer 41:1902, 1978. 4. Kurman, R. J., and Norris, H. J.: Mesenchymal tumors of the uterus. VI. Epithelioid smooth muscle tumors including leiomyoblastoma and clear cell leiomyoma. A clinical and pathological study, Cancer 37: 1853, 1976. 5. Gallup, D. G., and Cordray, D. R.: Leiomyosarcoma of the uterus: Case reports and a review, Obstet. Gynecol. Surv. 34:300, 1979. 6. Vardi. J. R., and Tovell, H. M. M.: Leiomyosarcoma of the uterus: Clinicopathologic study, Obstet. Gynecol. 56:428, 1980.
Silverberg, S. G.: Leiomyosarcoma of the uterus. A clinicopathologic study, Obstet. Gynecol. 38:613, 1971. Hannigan, E. V., and Gomez, L. G.: Uterine leiomyosarcoma. A review of prognostic and pathologic features, AM. J. OBSTET. GYNECOL. 134:557,1979. Azizi, F., Bitran, J., Jahevari, G., and Herbst, A. L.: Remission of uterine leiomyosarcomas treated with vincristin&, Adriamycin, and dimethyl-triazeno-imidazole carboximide, AM. J. OBSTET. GYNECOL. 133:379, 1979. 10. Hendrikson, M. R., and Kempson, R. L.: Smooth muscle neoplasms, in Surgical Pathology of the Uterus, Philadelphia, 1980, W. B. Saunders Company, pp. 468-529. 11. Taylor, H. B., and Norris, H. J.; Mesenchymal tumors of the uterus. IV. Diagnosis and prognosis of leiomyosarcomas, Arch. Pathol. 82:40, 1966. 12. Silverberg, S. G.: Reproducibility of the mitosis count in the histologic diagnosis of smooth muscle tumors of the uterus, Hum. Pathol. 7:451, 1976.