Key words leiomyosarcoma - uterine neoplasms - lymphadenectomy - adjuvant therapy
Schlüsselwörter Leiomyosarkom - uterine Neoplasien - Lymphonodektomie - adjuvante Therapie
Introduction
Uterine leiomyosarcomas (LMS) are rare uterine neoplasms, which account for 1 % of
all uterine malignancies and approximately one third of all uterine sarcomas [1 ]. Uterine LMS carry a poor prognosis with five-year survival rates ranging between
4 and 75 % for all stages of disease, and five-year recurrence rates ranging between
45 and 73 % [2 ], [3 ], [4 ]. The histologic diagnosis of uterine LMS relies on the presence of mitotic activity,
necrosis and atypia. Nevertheless, in some cases, in the absence of cytogenetic and
molecular characterization, leiomyoma variants (uterine lesions with a benign clinical
course or having low malignant potential) are misdiagnosed as uterine LMS [5 ], [6 ].
Symptoms of uterine LMS are commonly reported as abdominal pain, the presence of a
pelvic mass and abnormal bleeding [7 ]. The absence of pathognomonic features on imaging techniques like ultrasonography,
CT and MRI makes a reliable preoperative diagnosis of uterine LMS difficult [8 ], [9 ]. Thus, the diagnosis of LMS is often unexpected and discovered incidentally following
surgery for uterine leiomyomas [10 ], [11 ].
Surgery is the most important element in the therapy of uterine LMS; total hysterectomy
with or without bilateral salpingo-oophorectomy (BSO) represent the initial standard
management for LMS [12 ]. Furthermore, primary surgery, complete cytoreduction and secondary cytoreductive
surgery can help to achieve favorable prognoses in patients with uterine LMS [3 ], [13 ], [14 ].
However, the role of adjuvant therapy after surgery for LMS continues to be undefined
[4 ], [15 ]. Two randomized controlled trials, both including only a total of 151 patients with
uterine LMS, have addressed the potential benefit of adjuvant therapy [16 ], [17 ]. Neither the administration of adjuvant chemotherapy with doxorubicin nor adjuvant
radiation therapy did improve survival of patients with LMS [16 ], [17 ].
Due to the rareness of the disease and lack of prospective RCTs, guidelines of therapeutic
management for uterine LMS have low levels of evidence. Hence, there is a continued
need for review of past and current practice. The present study reviews the experience
over a 27-year period of the Department of Obstetrics and Gynecology, University of
Tuebingen, Germany, in the management of uterine LMS for insight into surgical practice,
adjuvant therapy and clinical outcome.
Material and Methods
This was a retrospective study conducted at the Department of Obstetrics and Gynecology,
University of Tuebingen. Using institutional databases from the clinical cancer registry
of the Comprehensive Cancer Centre Tuebingen, we identified all women who were included
in the registry with uterine LMS as final diagnosis between January 1st, 1983 and
January 31st, 2010.
Diagnoses of the identified uterine LMS cases were manually compared with the pathology
reports; the sources agreed in 32 out of 33 (97 %) of cases. Only histologically confirmed
cases were analyzed. One case was excluded because histology revealed a diagnosis
of benign metastasizing leiomyoma. Thus, the study group comprised 32 patients with
a diagnosis of uterine LMS.
A retrospective medical record review of both inpatient and ambulatory records (Department
of Obstetrics and Gynecology, University of Tuebingen) was performed to ascertain
sociodemographic and anthropometric variables, as well as to confirm intraoperative
and pathologic findings. Furthermore, adjuvant therapy data were recorded. The clinical
cancer registry of the Comprehensive Cancer Centre Tuebingen provided follow-up and
survival data. Time to disease recurrence and death or last contact was calculated.
Premenopausal status was defined as occurrence of at least one menstrual period within
12 months before surgery. Adjuvant treatment was performed in selected patients at
the discretion of the tumor board. We assessed the disease stage retrospectively for
every patient using the new 2009 International Federation of Gynecology and Obstetrics
(FIGO) staging system, used specifically for uterine sarcomas [18 ]. We grouped the study sample in
patients with “disease limited to the uterus” (FIGO stages IA and IB) and patients
with “extrauterine disease” (FIGO stages IIA – IVB) to analyze the influence of disease
stage on survival.
Data was coded and entered into an Excel spreadsheet version 2007 (Microsoft, Redmond,
Washington DC, USA). Statistical analysis was carried out using JMP for Windows version
8.0 (SAS Institute Cary, NC, USA) and Prism 5 (GraphPad Software, La Jolla, CA, USA).
Means, standard deviations (SD) and medians are reported for continuous variables
and frequency counts and percentages for categorical variables. Survival curves were
generated using the Kaplan-Meier method and compared using the long-rank test. Calculation
of disease free survival (DFS): 7 patients were lost to follow-up, 11 patients were
censored having no disease recurrence at last follow-up and 14 patients had disease
recurrence. Calculation of overall survival: 5 patients were lost to follow-up, 12
patients were censored being alive at last follow-up and 15 patients died of uterine
LMS. p-values < 0.05 were considered statistically significant in all statistical
analyses.
Results
The study sample comprised 32 patients with uterine LMS that underwent treatment at
our institution. Between January, 1st 1983 and December, 31st 1999 a total of 12 cases
were identified, between January, 1st 2000 and January, 31st 2010 we identified 20
women that underwent treatment for uterine LMS. The median follow-up for survivors
was 87.5 months. Patient characteristics are summarized in [Table 1 ]. The mean age was 56.0 years (range 34–81). At the time of primary surgical treatment,
69 % of the patients were postmenopausal. A pelvic mass was the most common presenting
symptom and was reported by 44 % of the patients; abdominal pain was reported by 38 %
of the patients, abnormal bleeding was reported by 34 % of the patients and 13 % of
the patients reported both abdominal pain and abnormal bleeding as presenting symptoms
([Table 1 ]).
Table 1 Characteristics of 32 patients with leiomyosarcoma of the uterus.
Characteristics
Value
* The sum of numbers for each variable exceeds the total number of patients because
some patients had multiple conditions that apply.
Mean
Age at diagnosis (range), years
56,0 (34–81)
Size uterine lesion (± SD), cm
10,2 (± 4,2)
Uterine/composite compound weight (± SD), g
766,2 (± 623,3)
Preoperative symptoms*
No. (%)
Pelvic mass
14 (44)
Abdominal pain
12 (38)
Abnormal bleeding
11 (34)
Abdominal pain and abnormal bleeding
4 (13)
FIGO Stage
I
23 (72)
II
3 (9)
III
2 (6)
IV
4 (13)
Grade
I
6 (19)
II
8 (25)
III
18 (56)
Mitosis < 10/10 HPF
14 out of 27 (52)
Mitosis ≥ 10/10 HPF
13 out of 27 (48)
Bilateral Salpingo-oophorectomy
27 (84)
Lymphadenectomy
Pelvic
17 (53)
Para-aortic
5 (16)
Adjuvant chemotherapy
8 (25)
Adjuvant radiation therapy
5 (14)
Combined adjuvant therapy
4 (13)
Tumor markers were evaluated in 22 women and were elevated in 10 women (45 %). CA
125 was elevated in 9 patients, CEA in 3 patients and CA 15-3 in 1 patient (data not
shown). The mean size of the uterine lesions was 10.2 ± 4.2 cm (SD; range 4–40 cm)
([Table 1 ]).
There were 23 patients (72 %) with FIGO stage I, 3 patients (9 %) with stage II, 2
patients (6 %) with stage III and 4 patients (13 %) with stage IV disease. Distribution
by grade revealed 6 patients (19 %) with grade 1 disease, 8 patients (25 %) with grade
2 disease and 18 patients (56 %) with grade 3 disease. The median mitotic count of
all patients was 9 (range 5/10 high-power fields [HPF] – 50/10 HPF). Fourteen women
had a low mitotic count (< 10/10 HPF), whereas 13 women had a higher mitotic count
(≥ 10/10 HPF) ([Table 1 ]).
Primary surgical treatment consisted of total abdominal hysterectomy in 28 patients
(88 %) and laparoscopic total hysterectomy in 4 patients (12 %). Six women (19 %)
underwent surgery for presumed symptomatic leiomyoma recurrence. BSO was performed
in 84 % of the patients (27/32), 8 out of 10 premenopausal patients underwent BSO.
Lymph nodes were evaluated in 17 women (53 %), 12 women underwent pelvic lymphadenectomy
and 5 women underwent pelvic and para-aortic lymphadenectomy ([Table 1 ]). Positive pelvic lymph nodes were present in 1 patient (6 %) with extrauterine
disease; there were no reported positive para-aortic lymph nodes.
A total of 17 patients (53 %) received adjuvant therapy ([Table 1 ]). Among those, 5 patients received adjuvant radiation therapy. Adjuvant chemotherapy
was administered to 8 patients and 4 patients received combined adjuvant radiation
therapy and chemotherapy ([Table 1 ]). Chemotherapy consisted of doxorubicin in 2 patients (one patient also received
radiation therapy), doxorubicin and ifosfamide in 3 patients, non-pegylated liposomal
doxorubicin and carboplatin in 2 patients and epirubicin and ifosfamide in 1 patient.
The administered chemotherapy regimen was unknown in 4 patients.
There were a total of 19 (59 %) disease recurrences in our study group. Five women
had pelvic recurrence, 12 women had distant recurrence and 2 patients had both pelvic
and distant recurrence ([Table 2 ]). The sites of distant recurrence included lungs (10 patients), bone (3 patients),
and brain (1 patient) ([Table 2 ]).
Table 2 Sites of local and distant recurrence in 32 patients with uterine leiomyosarcoma.
Site
No. of cases (%)
Vagina
2 (6)
Pelvis
3 (9)
Lung
8 (28)
Bone
3 (9)
Brain
1 (3)
Lung and pelvis
2 (6)
DFS and OS of patients with LMS are shown in [Figs. 1 ] and [2 ]. Median follow-up for DFS was 35.6 months and median DFS was 27.0 months for all
patients ([Fig. 1 ]). By log-rank test DFS was not significantly related to menopausal status (p = 0.52),
mitosis rate (p = 0.27) and age (< 50 years vs. ≥ 50 years; p = 0.83).
Fig. 1 Kaplan-Meier analysis of disease free survival (DFS) of patients with leiomyosarcoma
of the uterus.
Fig. 2 Kaplan-Meier analysis of overall survival (OS) of patients with leiomyosarcoma of
the uterus.
The median follow-up for OS was 51.3 months and the median OS was 28.0 months for
our study group ([Fig. 2 ]). The 5-year survival rate was 30 % ([Fig. 2 ]). OS was not significantly related to menopausal status (p = 0.40), mitosis rate
(p = 0.69) and age (< 50 years vs. ≥ 50 years; p = 0.86). There was no significant
difference in DFS (p = 0.76) and OS (p = 0.51) between patients who did or did not
receive adjuvant therapy. Furthermore, the clinical stage of uterine LMS, “disease
limited to uterus” (FIGO stage I, OS54.0 months) vs. “extrauterine disease” (FIGO
stages II–IV, OS17.0 months), also was not statistically significant in determining
survival (data not shown).
Discussion
Uterine LMS are a rare and aggressive subtype of uterine malignancies. Due to the
rareness of the disease high-level evidence guidelines of therapeutic management are
nonexistent. Hence, there is a need for individual centers to report data of surgical
management, adjuvant treatment and clinical outcome in patients with this disease.
The present study reviewed the experience over a 27-year period in our department
in the management of uterine LMS.
Menopausal status and patient age at diagnosis have been identified in several studies
as independent prognostic factors for survival in women with uterine LMS [19 ], [20 ], [21 ]. Postmenopausal patients with uterine LMS have been described to have a poor prognosis
compared to premenopausal patients with LMS [22 ], [23 ]. Our results, however, are in accordance with the results of Barter et al. and Mayerhofer
et al. indicating that menopausal status has no prognostic significance on survival
in patients with LMS [7 ], [24 ]. Additionally, younger women with uterine LMS have been reported to have better
outcomes [3 ], [4 ], [19 ], [25 ], [26 ]. Conversely, in our
series of patients age (< 50 years vs. ≥ 50 years) did not have any significant effect
on survival, in concordance with previous published data [23 ], [24 ].
Five-year survival rates for uterine LMS range between 4 % and 75 % for all stages
of disease. Kapp et al. interpreted this wide variation as being a result of multiple
factors: small sample sizes, failure to use standardized histopathologic criteria,
various proportions of low- and high-stage patients and inclusion of patients with
various treatment approaches [3 ]. We observed a five-year OS rate of 30 % in accordance with several other studies:
Hannigan et al. observed a 5-year OS rate of 29 %, Blom et al. reported a five-year
OS rate of 33 % and Loizzi et al. reported a five-year OS of 32 % [23 ], [27 ], [28 ]. It is clear that early stage disease has an influence on the 5-year overall survival
in patients with uterine LMS, since dismal results have been noted in nearly all series
for patients with advanced-stage disease [3 ].
However, in contrast to the majority of studies on uterine LMS, in which tumor stage
was strongly correlated with prognosis, we did not observe any correlation between
this variable and survival [9 ], [12 ], [29 ]. We found only one other study that also failed to show a prognostic value of tumor
stage in patients with uterine LMS [24 ]. A possible explanation for this discrepancy to previously published data might
be the small sample size of our study.
Another controversial issue regarding prognostic factors in women with uterine LMS
is the mitosis rate. We did not observe any correlation between mitosis rate and DFS
and OS consistent with several other studies [28 ], [30 ]. Other studies, on the contrary, found a significant association between mitosis
rate and survival at least in subgroups of patients with uterine LMS [7 ], [22 ], [31 ].
Surgery is the most important treatment-element in patients with uterine LMS; the
absence of primary surgery and/or incomplete cytoreduction have been shown to be independent
prognostic factors for survival [12 ]. Many investigators recommend total hysterectomy with bilateral salpingo-oophorectomy
(BSO) and lymphadenectomy as the standard treatment for patients with operable uterine
LMS [3 ]. Nonetheless, evidence supporting both BSO and lymphadenectomy for uterine LMS is
sparse and controversial.
Eight out of 10 premenopausal patients in our study underwent BSO at primary surgery.
Several studies addressed the issue of preservation of ovaries in premenopausal women
with uterine LMS and that ovarian preservation did not adversely affect outcome [22 ], [26 ], [32 ]. Giuntoli et al. unexpectedly found in univariate analysis a significant association
between ovarian preservation and improved survival in a series of 208 patients with
uterine LMS [4 ]. However, the presumed correlation of ovarian preservation and improved survival
in patients with LMS of the uterus was no longer significant as this specific subgroup
of patients was further analyzed in a case-control study [4 ]. Moreover, a study of 1396 women with uterine LMS revealed no survival difference
between women with ovarian preservation and women that underwent BSO [3 ]. Thus, ovarian preservation in premenopausal women in the absence of hormone-sensitive
uterine LMS does not compromise the oncologic outcome.
The role of lymphadenectomy in patients with uterine LMS is likewise unclear, since
the literature on lymph node metastases associated with LMS is limited mainly consisting
of small, retrospective case series. In agreement with our series demonstrating an
incidence of lymph node metastases of 6 % (1 of 17 patients), the incidence of lymph
node metastases in patients with uterine LMS is described in several other studies
as being low, varying between 7 and 9 % [3 ], [33 ], [34 ]. Additionally, involvement of lymph nodes in patients with uterine LMS is mostly
associated with advanced stage disease or with macroscopically visible enlargement
of the lymph nodes in early stage disease. In a series of 1396 patients, lymphadenectomy
failed to be an independent prognostic factor for survival [3 ]. As a result, lymph node dissection for uterine LMS should be reserved for patients
with clinically suspicious nodes [33 ].
In our series of patients 19 of 32 women with uterine LMS developed disease recurrence.
Consistent with other studies, the majority of recurrences involved distant spread
outside the pelvis [7 ], [26 ], [35 ]. Hence, the use of adjuvant therapy to reduce local and distant relapses could be
an attractive option in patients with LMS but evidence on the role of adjuvant therapy
in uterine LMS is limited [12 ]. Although the effect of adjuvant therapy cannot be determined reliably in an analysis
of a disease with mixed stages and grades, in agreement with previous reports we found
no significant difference in DFS and OS between women that received adjuvant therapy
and those who did not [4 ], [26 ], [36 ]. Adjuvant radiation therapy does not appear to have a survival benefit in LMS, although
it may
reduce local recurrences in women with FIGO stage II–IV disease [21 ], [37 ]. Regarding adjuvant chemotherapy, only one prospective phase II study and one retrospective
study demonstrated benefit on DFS of adjuvant chemotherapy in patients with uterine
LMS [38 ], [39 ]. Thus, women with uterine LMS and higher risk of local recurrence might benefit
from adjuvant radiation therapy, but the routine use of adjuvant chemotherapy in uterine
LMS is not recommended outside of clinical trials.
Major limitations of this study are its retrospective design and the small number
of patients with uterine LMS included. However, the long follow-up augments the assessment
of clinical characteristics. Prospective studies with larger cohorts including new
prognostic factors would be important to be able to predict the prognosis of patients
with uterine LMS and to gain insight in the pathogenesis of this rare disease in a
better way. Additionally, future prospective studies should address the role of adjuvant
therapy, patient selection criteria, and optimal adjuvant therapy regimes for uterine
LMS.
Conclusions for Practice
Uterine LMS are rare and aggressive uterine neoplasms with high recurrence rates and
metastatic potential. Surgery consisting of total hysterectomy with or without BSO
is the most important treatment-element in patients with uterine LMS. Lymphadenectomy
should be reserved for patients with clinically suspicious nodes. Women with uterine
LMS and higher risk of local recurrence might benefit from adjuvant radiation therapy,
but the routine use of adjuvant chemotherapy in uterine LMS is not advocated outside
of clinical trials.
Acknowledgements
We acknowledge the assistance of Brigit Trilling in obtaining patient follow-up data.
