1. Introduction
Leiomyosarcoma (LMS) is a rare malignant tumor
caused by smooth muscle cells, accounting for ~5-10% of all soft
tissue sarcomas (STS) (1,2). They are commonly originating in the
uterus, retroperitoneum, gastrointestinal and genitourinary tract
(3,4). LMS are known for aggressive behavior
and high tendency towards metastasis, with ~30-40% of patients
experiencing metastatic progression within the first 5 years after
diagnosis (5). The typical
metastatic sites for LMS include the lungs, liver and
retroperitoneum (3). Cutaneous
metastases are exceptionally rare, occurring in 1-2.6% of all cases
(6,7), and can often signify advanced disease
with poor prognosis.
The presentation of LMS with metastasis to the skin
poses unique diagnostic and therapeutic challenges. Unlike primary
cutaneous malignancies, skin metastases are secondary
manifestations of systemic spread, reflecting the tumor's
aggressive nature. These lesions often present as firm, painless
nodules or plaques and may mimic benign dermatological conditions,
leading to diagnostic delays (8).
Early recognition of cutaneous metastases is crucial as it
frequently indicates widespread disease and necessitates prompt
systemic management.
The present review aims to provide a comprehensive
analysis of retroperitoneal LMS (RPLMS) with metastasis to the
skin, encompassing its pathophysiology, clinical presentation,
diagnostic strategies and treatment options. Additionally, it
highlights emerging therapeutic approaches and the prognostic
implications of cutaneous involvement. By synthesizing existing
knowledge, the present review seeks to enhance the understanding of
this rare phenomenon and improve clinical outcomes for affected
patients.
2. Epidemiology and clinical features
STS accounts for <1% of all cancers (9), of which ~40% are located in the
abdomen or retroperitoneum (10).
The most common abdominal and retroperitoneal STS are
gastrointestinal stromal tumors (GIST), LMS and liposarcoma (LS)
(11).
LMS is the second most common retroperitoneal
sarcoma, with an incidence rate of about 20%, second only to LS
(12). In the retroperitoneum, LMS
is more commonly found in the vena cava and occasionally in the
iliac vein or renal vein (13). In
a prospective cohort study on abdominal and retroperitoneal sarcoma
in Denmark, 11% of tumors were LMS (9).
RPLMS are also known for aggressive behavior and
high tendency towards metastasis, with ~30-40% of patients
experiencing metastatic progression within the first 5 years after
diagnosis (5). The most common
metastatic sites of RPLMS are the lungs, liver and vascular
regions. Skin is a less common site of metastasis, with an
incidence rate of only 1-2.6% (6,7).
This type of metastasis may occur months or years after the
diagnosis of the primary tumor and usually means advance stage and
a poor prognosis (12).
Previously, in the largest review of the reported cases at present,
Wang et al (12) reported
65 patients with sarcoma with skin metastases, of which 43% were
from LMS (12). LMS commonly
affects individuals between the fifth and seventh decades of life,
and while LMS overall shows a slight female predominance due to its
association with uterine LMS, advanced LMS with skin metastases
affects both sexes equally (12).
RPLMS lacks specific clinical manifestations. Most
patients are asymptomatic, and the tumor is discovered
incidentally. Symptoms such as upper abdominal pain or sore back
pain can be more apparent when the tumor becomes big enough to
invade surrounding tissues. According to Clark et al
(14), the most common finding at
diagnosis is a painless, gradually enlarging mass. Some patients
primarily present with weight loss and abdominal pain, other with
intestinal obstruction and dysphagia.
Cutaneous metastases are also usually asymptomatic.
They are usually presented as painless firm, nodular lesions on the
trunk, extremities, or scalp corresponding to areas of rich
vascularization (8,15). Usually, the presence of cutaneous
metastases is frequently accompanied by other systemic symptoms,
due to late stage of the disease.
3. Imaging features
While preoperative diagnosis is very difficult, and
most patients are diagnosed by intra-operative exploration and
postoperative pathology, imaging plays a critical role in
evaluating LMS with skin metastasis. Ultrasound is effective for
superficial lesion characterization. On Ultrasound, the mass may
appear as hypo echoic nodules with irregular borders. Computed
tomography (CT) scan and magnetic resonance imaging (MRI) provide
detailed insights into lesion extent and systemic involvement. The
National Comprehensive Cancer Network guidelines for intraabdominal
and retroperitoneal STS, recommends CT of the chest, abdomen and
pelvis with intravenous contrast for diagnosis, occasionally
supplemented by MRI of lesions in the pelvis or abdomen. On the CT
scan, skin metastases appear as soft tissue nodules within dermis
or subcutaneous tissue and may show enhancement after contrast
administration (16). MRI is
useful for evaluating the extent of skin and soft tissue
involvement. Positron emission tomography is invaluable for
detecting and monitoring metastatic disease. A multi-modal imaging
approach, integrated with clinical and histopathological findings,
ensures accurate diagnosis and optimal management of this rare
metastatic presentation.
4. Pathophysiology
Histopathology is the gold standard for diagnosing
LMS and confirming skin metastases. The histopathological
examination provides insights into the tumor's morphology,
immunohistochemical profile, and differentiation from other
malignancies. According to the European Society for Medical
Oncology-European Reference Network for rare adult solid cancers
report on soft tissue and visceral sarcomas from 2018, all
retroperitoneal tumors should be biopsied. The risk of needle track
seeding is minimal, if the biopsy is thoroughly planned, and not
performed trans-peritoneally (11).
LMS typically shows fascicles of spindle-shaped
tumor cells with blunt-ended nuclei and moderate to abundant,
brightly eosinophilic fibrillary cytoplasm (17). Useful immunohistochemical markers
for retroperitoneal sarcomas include smooth muscle actin (SMA),
Desmin, Myogenin, CD34, S100 protein, MDM2, CDK4, STAT6, ALK, CD99,
H3K27me3, NKX2.2, TLE1, SOX10, melanocytic markers, cyclin D1, and
epithelial markers.
In LMS, at least one myogenic marker (that is, SMA,
Desmin, or Caldesmon) is positive, with >70% of cases showing
positivity for more than one of these markers. Tumor cells are also
positive for cytokeratin and endomysial antibodies in ~40% of cases
(18). In a retrospective study of
29 consecutive cases of histologically proven soft tissue LMS by
Mestiri et al (19), they
found that tumor cells were positive for SMA (79.3%), desmin
(68.9%), and h-Caldesmon (58.6%). They were negative for PS100,
CD34 and c-Kit in all cases (19).
Mitotic count is also an important histological
factor in advance LMS (20). In a
recent study by Grimaudo et al (21), which analyzed 121 patients with LMS
between June 1999 to May 2022, it was found that mitotic count is
an important prognostic factor in early and advanced LMS. In a
previous study by Rodríguez-Lomba et al (22), in total of 17 LMS in 12 patients (5
men, 41%; 7 women, 59%), histology found a mean of 11 mitotic
figures per 10 high-power field (HPF) and Ki-67 protein expression
of 30% in cutaneous tumors; 7.5 mitotic figures per 10 HPF and
Ki-67 expression of 60% in subcutaneous forms; and 10.2 mitotic
figures per 10 HPF and Ki-67 expression of 48% in metastatic forms.
Immunohistochemical staining was positive for Vimentin (>25% of
cases), Desmin (>50%), HHF-35 (>75%) and SMA (>75%). S100
staining was focally positive in one cutaneous LMS. CD34 staining
was also positive in one cutaneous tumor.
It is vastly agreed that Desmin, SMA and Caldesmon
staining are positive in a vast majority of LMS cases. However, a
positive CD34 in patients with LMS remains uncommon, and its role
in prognosis of these patients remains controversial (23,24).
CD34 expression is more commonly associated in patients with LMS
originated from vascular areas. In the study of Rodríguez-Lomba
et al (22), only one
patient was CD34-positive in 17 patients with LMS. Sugiura et
al (25) studied the
prognostic value of CD34 expression status in 192 patients with
myxofibrosarcomas and undifferentiated pleomorphic sarcomas (UPS).
Of the 192 patients, 32 patients were positive for CD34. They found
that CD34-positive patients (n=32) had a significantly improved
overall and distant metastasis-free survival compared with
CD34-negative patients (n=160) (P<0.001 and P=0.027,
respectively), although local recurrence-free survival was not
significantly influenced by their CD34 status.
Histopathology remains to be challenging and may
overlap with other tumors, including dermatofibrosarcoma
protuberans (DFSP), vascular sarcoma and GIST. The key differential
diagnosis between LMS and DFSP includes spindle shaped arrangement
of spindle cells, but lack of SMA or histone positivity. In
vascular sarcoma, it shows vascular channels arranged by atypical
endothelial cells, with CD31 and CD34 positive but SMA negative.
Malignant melanoma may mimic LMS, but S-100 and HMB-45 are
positive, unlike LMS. In GIST, SMA and CD34 are positive, but CD117
and DOG1 are negative.
5. Treatment of RPLMS with skin
metastasis
Treatment of RPLMS with skin metastasis is often
challenging, as the presence of cutaneous lesions indicates
advanced, systemic disease (12).
The therapeutic approach focuses on systemic control of the primary
tumor and its metastases while addressing local skin lesions for
symptomatic relief or cosmetic reasons.
Chemotherapy is the first line for advanced LMS with
skin metastasis. Doxorubicin is the first-line chemotherapeutic
agent for advanced LMS (26).
Previously, Judson et al (27), compared the efficacy of monotherapy
with doxorubicin (A) and doxorubicin + ifosfamide (AI) regimen in
the treatment of patients with advanced STS. The results showed
that the objective response rate (ORR) of the AI group was markedly
higher than that of monotherapy A group (26% vs. 14%, P<0.006),
and the median progression-free survival (mPFS) was also higher
than that of monotherapy A group (7.4 months vs. 4.6 months,
P=0.003), but the difference in overall survival (OS) between the
two groups was not statistically significant (14.3 months vs. 12.8
months, P=0.076). Stratified analysis showed that except for the
UPS subgroup which showed significant OS benefits, no other
subtypes showed significant OS benefits, and the incidence of
adverse reactions was higher with combination therapy.
Similarly, in a retrospective study by D'Ambrosio
et al (28), which
evaluated the efficacy of first-line treatment with doxorubicin +
dacarbazine (AD), doxorubicin + ifosfamide (AI), and doxorubicin
(A) for advanced metastatic LMS. In their study, 117 patients (39%)
received AD treatment, 71 cases (23%) received AI treatment, and
115 cases (38%) received (A) treatment. Among the 205 patients
matched with a 2:1:2 propensity score, the mPFS of the three groups
were 9.2 months, 8.2 months, and 4.8 months, respectively, and the
ORRs were 30.9, 19.5 and 25.6%, respectively. The mPFS of the AD
group was significantly improved compared with that of the A group
(HR=0.72, 95% CI 0.52-0.99). The median OS of the three groups were
36.8, 21.9 and 30.3 months, respectively, with no significant
difference. In the population with propensity score matching,
doxorubicin + dacarbazine showed favorable efficacy in ORR and PFS
and is worthy of further evaluation in prospective trials.
In another randomized phase 2 study, the efficacy of
gemcitabine + dacarbazine and dacarbazine monotherapy was compared
in previously treated patients with STS. The results showed that
the median PFS of the gemcitabine + dacarbazine group was 4.2
months, while the dacarbazine monotherapy group was 2 months. The
median OS was 16.8 and 8.2 months, respectively, with ORRs of 49
and 25% (29).
Furthermore, in a phase 3 trial called GeDDiS, the
efficacy of gemcitabine + docetaxel versus doxorubicin as
first-line treatment was compared in advanced unresectable or
metastatic STS (including LMS). The results showed that the two
regimens were equally effective. For gemcitabine + docetaxel and
doxorubicin, the mPFS was 5.5 months and 5.3 months, the OS was
14.5 months and 16.3 months, and the ORR was 20 and 19%,
respectively (30).
In a multicenter, open label, and efficacy
randomized phase III clinical trial from January 18, 2017 to March
21, 2019, Pautier et al (31), included 150 patients with
metastatic or recurrent unresectable LMS, among which were 67
uterine LMS, and 83 soft tissue LMS from 20 centers in the French
Sarcoma Group who had not previously received chemotherapy.
Randomly allocate (1:1) to receive doxorubicin (75
mg/m2) every 3 weeks for a maximum of 6 cycles; Or
doxorubicin (60 mg/m2) + qubetidine (1.1
mg/m2, d1), once every 3 weeks for a maximum of 6
cycles, followed by maintenance treatment with qubetidine alone.
There were 76 cases in the doxorubicin group and 74 cases in the
doxorubicin + qubetidine group. The results showed that the mPFS of
the doxorubicin + qubetidine group was significantly improved
compared with that of the doxorubicin group, at 12.2 and 6.2
months, respectively (HR=0.41; 95% CI: 0.29-0.58; P<0.0001). The
most common grade 3-4 adverse events were neutropenia, with
incidence rates of 12 and 20% in the two groups, respectively.
In terms of targeted therapy, pazopanib is a
multi-tyrosine kinase inhibitor that targets vascular endothelial
growth factor, platelet-derived growth factor, and c-kit pathways.
Pazopanib is approved for non-adipocytic STS, including LMS, and
helps stabilize the disease. In a randomized phase III study called
PALETTE, the median PFS of the pazopanib group was significantly
improved compared with that of the placebo group (4.6 vs. 1.6
months). However, there was no significant difference in OS between
the two groups (12.5 vs. 10.7 months), and only 6% of patients
experienced objective remission (32).
Anlotinib is another targeted therapy. In a
randomized controlled phase IB study (ALTER0203), compared with
placebo, anlotinib significantly prolonged PFS and reduced the risk
of disease progression (6.27 vs. 1.47 months; HR=0.33;
P<0.0001). Subgroup analysis showed that anlotinib significantly
prolonged the PFS of patients with various sub-types of LMS (5.83
vs. 1.43 months, P<0.0001) (33). In a retrospective analysis, the
ORRs of patients with advanced LMS receiving combination therapy
with anlotinib was 19%, the disease control rate (DCR) was 88%, and
the median PFS was 8.8 months. The ORR did not show significant
improvement, but the DCR and recent survival rate were satisfactory
(34).
Regorafenib is another targeted therapy that showed
positive results in treatment of advanced sarcomas. In the Phase II
REGOSARC clinical study, which included 182 patients with advanced
STS, grouped according to pathological types, and observed the
efficacy and safety of regorafenib in different pathological types,
the results demonstrated that for patients with STS who had
previously received anthracycline treatment, regorafenib
significantly improved PFS in subgroups of LMS, synovial sarcoma,
and other sarcomas (35).
In terms of immunotherapy, immunotherapy with immune
checkpoint inhibitors (ICIs) PD-1/PD-L1 antibodies has shown
effectiveness in various tumors and has also been attempted in STS.
However, currently, the efficacy of immunotherapy alone in LMS is
not significant (36-38).
In addition, DNA damage repair pathway inhibitors-related studies
have found that drugs targeting the DNA damage repair pathway may
become potential therapeutic targets.
Combination therapies such as combining
chemotherapy, targeted therapy and immunotherapy are promising. In
A single arm open phase II clinical trial (NCT04028063) of
doxorubicin combined with CTLA-4 inhibitor zalifrelimab and PD-1
inhibitor balstilimab in patients with advanced and metastatic STS,
patients with advanced and metastatic sarcoma who had not
previously received doxorubicin or ICIs were included. All patients
received up to 6 cycles of doxorubicin and received zalifrelimab +
balstilimab simultaneously. In the first stage, patients received
zalifrelimab + balstilimab treatment for one cycle, and doxorubicin
began in the second cycle. In the second stage, the patients used
doxorubicin + zalifrelimab + balstilimab simultaneously in the
first cycle. A total of 35 patients were enrolled. PFS 6 months was
~46.4%, and mPFS was 24.4 weeks. The ORR was 33.3%, and the DCR was
80.0%. The median duration of remission was 12.8 weeks. Therapeutic
effects have been observed in endometrial sarcoma, vascular
sarcoma, malignant peripheral nerve sheath tumor, LP, LMS,
endometrial stromal sarcoma, UPS and sclerosing epithelioid
fibrosarcoma. Compared with patients in the second stage, patients
in the first stage showed improved efficacy, including PFS 6 months
(56.3 vs. 25.0%), mPFS (31.7 vs. 25.3 weeks), ORR (56 vs. 8.3%) and
DCR (94 vs. 0.75%) (39).
Another NitraSarc trial explored the efficacy and
safety of Nivolumab and Tribetidine in advanced STS. The study
prospectively and non-randomly enrolled patients in Group A
(advanced LP, LMS; L-type tumor) and Group B (non-LP, non-LMS;
non-L-type tumor). Treatment was divided into late combination
cohort (LCC) and early combination cohort (ECC) based on the timing
of combination. All patients were first treated with 1.5
mg/m2 of tramadol, followed by 3 cycles of combined
treatment with 240 mg of nivolumab, known as LCC. Starting from the
second cycle, receiving combination therapy was called ECC. The
primary endpoint was PFS at 6 months. A total of 92 patients were
included, with 43 in Group A and 49 in Group B. After a median
follow-up of 16.6 months, the overall PFS at 6 months of Group A
was 47.6% (LCC was 60%, ECC was 36.4%), while the overall PFS at 6
months of Group B was 14.6%. The median PFS of group A was higher
than that of group B (5.5 vs. 2.3 months), and the LCC group was
longer than the ECC group (9.8 vs. 4.4 months). The median OS of
Group A was longer than that of Group B (18.7 vs. 5.6 months), and
LCC was longer than ECC (24.6 vs. 13.9 months) (40).
ImmunoSarc2 study, a first-line treatment of
advanced LMS with doxorubicin, dacarbazine, and nivolumumab - a
phase Ib clinical trial in Spanish sarcoma tissue (GEIS), included
adult patients with advanced and metastatic LMS who had an Eastern
Cooperative Oncology Group score of 0-1 and had not previously
received anthracycline treatment. A total of 20 subjects were
included. Among the 16 subjects with assessable efficacy, 9 (56.2%)
had partial response (PR), 6 patients (37.5%) had partial response
and 2 patients had tumor shrinkage greater than 20%, and 1 (6.3%)
had disease progression. The mPFS was 8.67 months, with a median
follow-up time of 8 months (41).
In term of surgical treatment, surgical treatment
and complete excision with clear margins is the ideal choice in
early stages, and surgical removal of isolated skin metastases is
only recommended for skin tumor that are causing pain, ulceration,
or functional impairment or for pathological reason.
6. Prognosis
In term of prognosis, advanced RPLMS have a bad
prognosis, with frequent metastasis and an overall 5-year survival
rate of 30-40% (5). LMS of
vascular origin have the worst prognosis with metastasis at the
time of diagnosis observed with half of patients (42). The presence of skin metastases
itself is a poor prognostic indicator and sign of advanced stage of
the disease, with median survival ranging from 14-17 months
(43). Age, location of tumor,
size, histological grade, clinical stage, surgical margins and
mitotic count are crucial prognostic factors in defining outcomes
of patients with LMS (19).
Guillou et al (44)
reported that tumors larger than 10 cm, deep-location and
high-grade tumors (G2, G3) were predictive of metastasis in
multivariate analysis.
In a study from the National Cancer Database, which
included more than 7,000 patients with LMS, age was identified as
an independent prognostic factor. The survival statistics improved
proportionally to the smaller age of the patient at the time of
diagnosis. The authors reported a 3% increase in mortality per
additional year of age (45).
However, the patient group was homogenous, and there was no
subgroup analysis of the effect of age on abdominal LMS
specifically.
In a retrospective review of 144 patients with
abdominal or retroperitoneal LMS from New York, the 5-year disease
free survival of patients was 67%, significantly lower than LMS at
other anatomical locations (46).
There was a recurrence rate of 51%, which also was higher than for
LMS located elsewhere. Distant recurrence was the most common
recurrence for LMS at all anatomical sites (53%), but local
recurrence was more common amongst patients with intraabdominal or
retroperitoneal tumors (30%), than at other anatomical locations
(46).
7. Future direction and conclusion
The present comprehensive review has summarized the
current knowledge and evidence on advance RPLMS with skin
metastases. To the best of our knowledge, this is the first review
on advanced LMS with skin metastases. Despite the current
biological understanding of advanced LMS has improved over years,
management of these patients remains challenging. The current
review has revealed a lack of high-quality evidence, and a lack of
randomized trials in treatment of advanced LMS. Therefore, there is
a great need for more substantial and high-quality research in this
area.
RPLMS is an uncommon tumor with aggressive nature,
therefore it requires special measures to obtain more evidence.
Larger studies, especially international multicenter randomized
trials with relevant clinical and patient reported outcomes are
highly needed. Treatment should be with multidisciplinary approach,
combining systemic therapies for disease control with local
interventions for symptom relief.
Acknowledgements
Not applicable.
Funding
Funding: No funding was received.
Availability of data and materials
Not applicable.
Authors' contributions
QB and XW drafted the manuscript. WL and JX
conducted literature review. BZ and ZM revised the manuscript. All
authors contributed to the article, read and approved the final
version of the manuscript. Data authentication is not
applicable.
Ethics approval and consent to
participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing
interests.
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