Introduction
Leiomyosarcoma (LMS) is a type of spindle-cell tumor characterized by smooth muscle
markers that does not produce an osteoid matrix and behaves like a malignant tumor.
Leiomyosarcomas usually occur at the retroperitoneum and gastrointestinal tract, and[1]
[2]
[3] the presentation in bone is rare. Information regarding intraosseous LMS is scarce
in the literature, mostly consisting of case reports.[1]
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14] We present the case of a female patient with a primary bone LMS at the left distal
femur submitted to surgical treatment and chemotherapy who later presented a metastatic
lesion at the clavicle with a pathological fracture, which was managed with surgical
resection.
Case Description
A 28-year-old female patient complaining of pain in the right knee and functional
limitation for 2.5 months, predominantly at night and with limb support. On physical
examination, she presented mild pain with limb support and during knee mobilization,
with no other important findings and no limitation to knee mobility.
A radiograph of the right knee showed a lytic lesion at the distal femoral metaphysis,
with no cortical compromise. Magnetic resonance imaging (MRI) and computed tomography
(CT) scans of the knee revealed findings consistent with giant cell tumor due to a
lytic lesion at the distal femur, with a potential differential diagnosis of telangiectatic
osteosarcoma. Bone scintigraphy showed marked uptake at the distal femur, with no
other bone lesions ([figures 1]-[3]).
Fig. 1 Anteroposterior and lateral right-knee radiographs showing a lytic lesion in the
distal metaphysis of the femur.
Fig. 2 Comparative knee computed tomography scan. Note the lytic lesion within the right
femur.
Fig. 3 Right-knee magnetic resonance imaging scan showing extensive involvement of the distal
femoral metaphysis, with no extraosseous compromise.
An open biopsy of the distal femur was performed at the operating room. Pathology
reported the presence of spindle cells with blunt ends, pink cytoplasm with vacuolated
areas organized in fascicles, moderately pleomorphic tumoral nuclei, variable mitotic
activity ranging from 0 to 5, and 5% of necrotic areas. Immunohistochemistry revealed
a strong, diffuse positivity for muscle actin, h-caldesmon and myosin. The Ki67 proliferation
index was of 60%. There was no positivity for cytokeratin AE1/Ae3, desmin, protein
S-100, monoclonal antibiody HMB458, cluster of differentiation 99 (CD99), or for estrogen
receptors, resulting in a diagnosis of well-differentiated bone LMS. The treatment
started with 3 cycles of preoperative neoadjuvant chemotherapy with ifosfamide 1,000 mg/m2 from days 1 to 3, and doxorubicin 70 mg/m2.
A second surgery was carried out for extended tumor resection and limb salvage with
a knee endoprosthesis ([figure 4]), with no complications. Pathology confirmed the diagnosis of a well-differentiated
primary bone LMS with negative margins and 20% of necrosis ([figures 5] and [6]). Next, the patient received adjuvant chemotherapy, with 4 cycles of gemcitabine
1,000 mg/m2 between days 1 to 8, and docetaxel 70 mg/m2 on day 1.
Fig. 4 Postsurgical follow-up right-knee radiograph.
Fig. 5 Gross appearance of the pathology specimen.
Fig. 6 (A) Elongated tumor cells with atypia and mitosis. Hematoxylin-eosin staining, 20x magnification.
(B) Positive tumor (brown stain) for h-caldesmon. Immunohistochemical technique, 20x
magnification. (C) Desmin-positive tumor (brown stain). Special immunohistochemical technique, 20x
magnification. (D) Study of Ki67 proliferation index at 30%. Immunohistochemical technique, 20X magnification.
Note: This marker indicates the percentage of dividing cells within a tumor.
During the postoperative follow-up, the patient presented adequate clinical evolution,
with good rehabilitation and recovery of the mobility and functionality of the right
knee. Two months after the surgery, the patient complained of pain in the right clavicle.
A radiograph revealed a fracture in the middle third of the clavicle with pathological
characteristics ([figure 7]). A positron emission tomography (PET) scan was requested, and it showed a lesion
in the middle third of the right clavicle consistent with a pathological lesion. A
biopsy was taken, and it revealed a metastatic bone LMS lesion, which was surgically
resected. Eighteen months after the surgery, the patient was evaluated with a PET
scan, which showed no new metastasis ([figura 8]), no infection, and good general conditions. The rehabilitation was adequate, and
follow-up radiographs revealed no new lesions, but showed an osteoblastic reaction
in the femur and tibia due to the use of a cementless prosthesis.
Fig. 7 Right-clavicle radiograph revealing a pathological fracture in the middle third of
the bone.
Fig. 8 (A) Positron emission tomography (PET) scan revealing a metastatic lesion in the right
clavicle two months after salvage surgery. (B) Follow-up PET scan 18 months after the resection of the femoral lesion.
Discussion
Bone LMS was first described in 1965 by Evans and Sanerkin.[15] It has a wide presentation according to age and gender,[5]
[6]
[7]
[8]
[9],[14] but it is a very infrequent condition, accounting for less than 0.7% of all bone
tumors.[4],[5],[7],[9] It may be primary or metastatic in onset.[16] In recent years, this rate might have increased due to the improvement in immunohistochemical
diagnostic techniques.[3],[12] According to a 2009 review by Adelani et al.,[17] based on 107 cases reported in English, LMS is more frequent in 40-year-old males
(age range: 9 to 87 years); however, the present case report is that of a young female
patient.
There are several hypotheses on the origin of primary bone LMS, which probably arises
from smooth muscle vascular cells or from fibroblasts capable of differentiating into
smooth muscle.[4],[18] Some reports[19] have associated LMS with the Epstein-Barr virus (EBV) infection in the context of
severe immunosuppression (patients with acquired immunodeficiency syndrome [AIDS]
and those submitted to kidney, heart or liver transplantations).[19] Other known factors for the development of sarcomas, such as radiation therapy,
were not related to LMS. It occurs mainly in long bones, such as the distal femur
(42–45% of the cases), as in the present clinical case, the proximal tibia (25–38%
of the cases), and the proximal humerus (15% of the cases), predominantly at the epiphysial-metaphyseal
region. Although it is not very frequent, cases of LMS have been reported in the craniofacial
bones, the radius, the clavicle, the fibula, the pelvis, the phalanges, the metatarsals,
and the vertebrae.[1],[5],[8]
[9]
[10]
[11],[14] Symptoms are usually nonspecific and insidious, although some studies[5]
[8]
[11] have identified pain as the main symptom, which is consistent with the case herein
described.
Bone LMS has no pathognomonic radiographic appearance, and it can be similar to any
other primary or secondary disorder.[10] It is an osteolytic lesion with aggressive behavior, periosteal reaction, endosteal
erosion, a permeative pattern, poorly-defined borders, medullary and cortical compromise,
and no sclerosis.[7],[10],[11],[14] It presents with pathological fracture in 15% to 20% of the cases.[4],[14] In 20% of the cases, areas of calcification are identified, complicating its differentiation
with an osteosarcoma.[9] The MRI scans reveal low signal intensity on T1-weighted images, similar to that
of muscle, and a high signal intensity on T2-weighted images, usually with areas of
greater compromise compared to plain radiographs.[5],[7],[16] However, MRI enables the clear identification of the tumor and surrounding tissues,
which contributes to the correct evaluation of the adjacent structures.[14] Differential diagnoses are gastrointestinal-tract or soft-tissue LMS metastases,
low-grade intramedullary osteosarcoma, bone fibrosarcoma, dedifferentiated chondrosarcoma,
metastatic spindle-cell carcinoma, malignant hemangiopericytoma, epithelioid angiosarcoma,
epithelioid hemangioendothelioma, and osteomyelitis.[1]
[5]
[7]
[8]
[11]
The most common site of metastasis is the lung, followed by the lumbar spine and liver.[1],[16] Other common sites of metastasis include the adrenal glands, the kidney, the mediastinum,
the inguinal lymph nodes, and the supraclavicular lymph nodes;[14] herein, we report a distant bone metastasis located at the right clavicle.
Macroscopically, bone LMS is a grayish-white fleshy lesion with necrotic areas.[18] Histologically, it is characterized by the absence of chondral or osteoid matrices,
with trabecular-bone infiltration, areas of necrosis or hemorrhage, and the presence
of spindle cells, usually arranged in disorganized fascicles with intersections at
perpendicular angles, cellular atypia, nuclear pleomorphism with cigar-shaped nuclei,
abundant eosinophilic and fibrillar cytoplasm, in addition to an immunohistochemical
profile positive for actin, smooth muscle, and tumor markers, including actin, desmin,
alpha-smooth muscle actin, h-caldesmon, and vimentin.[1]
[2]
[5]
[6]
[9]
[10]
[11]
[12] Our patient presented spindle cells with blunt ends, pink cytoplasm with vacuolated
areas organized in fascicles, moderately pleomorphic tumor nuclei, variable mitotic
activity (ranging from 0 to 5), 5% of necrotic areas, and positivity for muscle actin,
h-caldesmon, and myosin, which is consistent with descriptions in the literature.[1]
[2]
[5]
[6]
[9]
[10]
[11]
[12]
Surgical excision with wide margins is considered the gold standard in LMS management,
ensuring curative treatment. Amputation must be reserved for cases with compromise
of the neurovascular bundle or extensive soft-tissue involvement.[1],[16] Although the role of preoperative and postoperative chemotherapy and radiation therapy
remains debatable, they were used as neoadjuvant therapy in our patient.[1]
[3]
[4]
[6]
[12]
The prognosis of LMS is difficult to determine because of the limited number of reports.[2]
[3]
[5]
[6]
[7]
[8]
[10]
[11]
[12]
[13]
[14]
[15]
[17] However, most studies report an aggressive behavior associated with an unfavorable
prognosis. The prognostic factors that have been related to a lower survival in bone
LMS include age > 40 years, size > 8 cm, the presence of a pathological fracture,
amputation, affected margins, the presence of metastasis, delay or absence of surgical
management, and poor response to preoperative chemotherapy.[3]
[20] In a study, Brewer et al.[16] showed that the prognosis is based on the stage at diagnosis. In cases with stages
1b or 2a on the Enneking classification, survival reached 100%; in stage 2b, the 5-year
survival was of 60% and the 10 and 15-year survivals were of 43%.[16] A multicenter study[3] in Japan with 48 patients with primary LMS showed an overall 5-year survival rate
of 78.3%, and a tumor-free survival of 44.9%. However, neoadjuvant chemotherapy was
used in 18 patients, with no clear benefits. The presence of metastases in the first
visit and the lack of definitive surgery were significantly correlated with a poor
overall survival, and the surgical margin was a significant prognostic factor for
disease-free survival.[3] In a case series[20] of 8 patients with bone LMS, all subjects developed metastases within 12 months
of the primary diagnosis, regardless of the tumor grade; in the patient herein described,
the metastasis appeared 2 months after the initial procedure.
Conclusions
Primary bone LMSs are rare, aggressive tumors that must be treated vigorously. Today,
radical surgical management with negative margins represents the only curative option;
adjuvant treatment with chemotherapy and radiation therapy have not been shown to
be effective. During follow-up, it is essential to evaluate the possibility of metastatic
lesions to treat them in a timely manner. Further studies with long-term case series
are required to establish treatment protocols and prognosis for this type of injury.
