Keywords
epidemiology - early detection of cancer - metastasis - neoplasm - bone tissue - prognostic
factors - soft tissue sarcoma
Introduction
Musculoskeletal sarcomas are rare diseases of mesenchymal origin that may appear at
any age and that may develop anywhere in the body. These neoplasms are classified
as soft tissue sarcomas (STS) or bone sarcomas.
In 2013, the World Health Organization (OMS) described more than 50 types of soft
tissue sarcomas and about 30 types of bone sarcomas.[1] Sarcomas are a heterogeneous group of more than 100 tumors.[2]
Epidemiology
Despite this great variety, musculoskeletal sarcomas account for less than 1% of adult
malignant tumors and around 15% of pediatric malignant tumors[1]
[3]
[4]
[5]; therefore, STS account for less than 1% if all malignant tumors. Bone sarcomas
are even more rare and account for around 0.2%.[1]
[6] Therefore, STS occur 4 to 5 times more often than bone sarcomas. The worldwide incidence
rate of STS varies from 1.8 to 5.0 per 100,000 persons/year.[7] They may appear at any age, although over 65% of these sarcomas occur in patients
over the age of 65.[5] According to the Scandinavian Sarcoma Group (SSG) from 1987 to 2011, 6.027 cases
of soft tissue sarcoma were registered, that is, a rate of 1.5 to 2.0 per 100.000
inhabitants/year.[8] In Japan, the Bone and Soft Tissue Tumor Registry (BSTT), the specific cancer registration
body throughout the country for bone and soft tissue tumors registered, from 2006
to 2012, 44,709 patients with benign and malignant musculoskeletal tumors. Out of
these cases, 2,773 were of malignant bone tumors and 8,228 were of malignant soft
tissue tumors.[9]
[10] In 2004, around 8,700 new STS cases were diagnosed in the US and 1,500 in the United
Kingdom.[5] In Europe, the incidence of sarcomas in general is 6 cases per 100,000, with 28,000
cases per year. In 2008, STS accounted for almost 87% of all sarcomas.[11] The American Cancer Society estimates that in 2019 there will be approximately 1,762,450
new cases of cancer diagnosed in the US, leading to 606,880 deaths.[4] Out of these cases, around 3,500 will affect bones and joints and 1,660 will lead
to death; the incidence of soft tissue tumors will be 12,750 cases, with approximately
5,270 deaths.[4]
A general orthopedic surgeon will find during his or her career at least one osteosarcoma
or Ewing sarcoma.[12] Because there is a higher prevalence of STS, a general orthopedist will probably
see four or more of these neoplasms.
Clinical Aspects
Musculoskeletal sarcomas are a heterogeneous group of tumors with different clinical
manifestations, locations, evolutions and managements. Approximately 75% of STS are
located in the extremities and girdles. The thigh is the most commonly affected location.[1] About 10% of the cases affect the trunk and retroperitoneum.[1]
The most frequent malignant soft tissue tumors in children and adolescents are rhabdomyosarcoma
and synovial sarcoma.[13] The most frequent STS in adults are the undifferentiated pleomorphic sarcoma, liposarcoma,
leiomyosarcoma, myxofibrosarcoma and synovial sarcoma.[1]
[6] Metastatic disease is the major cause of death related to sarcomas. Metastasis of
soft tissue sarcomas and high grade bone sarcomas disseminate to the lungs through
the blood.[14] As around three quarters of STS are histologically classified as having a high grade
of malignancy,[1] during the diagnosis investigation and staging, it is expected that 10% of patients
will have metastasis, predominantly to the lungs.[1] During the follow up period, about 50% of STS patients develop distant metastasis
with an average global survival of 12 to 18 months. From the patients with metastasis,
less than 20% will be alive in two years.[15] In addition to the presence of metastases, the surgical margins of these sarcomas
have a great impact on the prognosis.[16]
[17]
Although less frequent in the pediatric group, STS may affect this age range. Approximately
50% of the cases of STS in the pediatric group are rhabdomyosarcomas, of which the
subtypes embrionary (head, neck and genitourinary tract) and alveolar (thorax and
extremities) are the most common. Rhabdomyosarcoma botryoid and other subtypes are
less frequent.[18] The main characteristic of embrionary rhabdomyosarcoma is its bimodal presentation,
that is, it has its peaks of incidence in patients with ages 2 to 6 and 15 to 19.[18]
[19] The alveolar subtype is the most common in adolescents.[18]
The greatest problems related to the approach to STS result from mistaken concepts
that are still part of clinical medical practice. One of them is that malignant soft
tissue tumors should be painful, grow rapidly and be deep. Actually, they may grow
slowly, be painless and located on the surface.[20] For this reason, the clinical condition may go on for a long time and, even in developed
countries, referral to reference services may take from 6 to 14 months.[21]
Diagnosis and staging
In oncology centers of reference, patients are cared by different teams of highly
specialized professionals. The same service will carry out tests for local and distant
staging. For this, magnetic resonance imaging (MRI) is mandatory. Most patients still
need a biopsy. However, biopsies cannot be performed in soft tissue tumors that show
clearly fatty content on MRI. In 2018, the 8th edition of the Cancer Manual Staging
of the American Joint Committee on Cancer (AJCC) updated the staging system for evaluation
of soft tissue tumors (TNM system). This system considers the histologic grade of
the tumor, its extent, the presence of lymph nodes and the presence of metastases.
There is no longer any differentiation between superficial and deep tumors. The extent
(T) has four levels (T1 to T4): the tumor is smaller than 5 cm (T1), the tumor is
larger than 5 cm but not more than 10 cm (T2), the tumor is larger than 10 cm but
not more than 15 cm (T3) and the tumor is larger than 15 cm (T4), the spread to nearby
lymph nodes (N) and the spread to distant sites (M). In sarcomas, the involvement
of lymph nodes is defined as systemic involvement by the neoplasm and has the same
importance as a distant metastasis. Therefore, N0 and M0 means no systemic involvement,
but N1 or M1 is considered systemic involvement. Patients are classified in 4 stages,
from I to IV, with some subdivisions. Tumors that present N1 or M1 are classified
in stage IV, the most advanced.[22]
The Birmingham group described a criterion that estimates the probability of malignancy
in soft tissue tumors: the tumor is larger than 4.3 cm (the size of a golf ball),
progressively increases in size, is located under the fascia and is painful.
The two first of these criteria are the most important.[23] If three or four criteria are positive, there is a possibility of more than 80%
of the soft tissue lesion's being malignant.[24]
The imaging test of choice to evaluate a soft tissue lesion is the MRI of the affected
segment after a gadolinium contrast injection. The MRI enables us to evaluate the
features of the tumor, its extent and define the best location to carry out the biopsy.
The main characteristics to be considered in an MRI are: whether the tumor is solid
and if there is fat tissue. Therefore, any soft tissue lesion that is not cystic and
does not show any sign of homogeneous fat in the MRI should be potentially treated
as a sarcoma ([Figure 1]). The surgeon must plan the surgical approach and biopsy technique to allow for
resection of the entire tract in block, together with the tumor. Consequently, procedures
with transversal incision techniques or following lines of force should be avoided
when performing biopsies on extremities. The biopsy incision must follow the line
of the muscle fibers and violate the smallest possible number of compartments ([Figure 2]). Currently, many biopsies are performed with needles and guided by ultrasound or
computerized tomography (TC) imaging. This demands a rapport between the surgeon and
interventionist radiologist to guarantee that the procedure be performed through the
proper access.
Fig. 1 Knee magnetic resonance imaging cuts. ((A)) coronal sequence T1, ((B)) Sagital SPAIR
T2, ((C)) axial T1 post GD. Note that the lesion is solid, relatively small, size
close to that of a golf or table tennis ball. This is a high-grade soft tissue sarcoma.
Fig. 2 Photo of the same patient in [Figure 1]. Posterior region of the right knee of a patient submitted to an open biopsy with
inadequate access route. It's possible to observe a transverse scar that will need
to be completely resected. Skin closure may be compromised.
Staging must be conducted before resection of the tumor, and the physician must request
at least a thoracic computerized tomography to track any lung metastasis.[25] Several services of reference in oncology offer PET-CT scans using 18F-fluorodeoxyglucose
(18F-FDG) for staging. The PET-CT scan evaluates the glucose metabolism and the more
aggressive the tumor the more glucose it will absorb. Because it evaluates the entire
body, in addition to the lungs, the PET-CT scan changes the staging grade when it
detects metastases of doubtful diagnosis inside or outside the lungs. In addition,
the standard uptake value (SUV max) showed in the PET-CT may predict not only the
biological activity but also the grade of the tumor. This has become a useful prognostic
factor in reviewing the survival rate of patients with STS. The PET-CT scan also plays
an important role in the evaluation of the response to chemotherapy and in planning
the amount of radiotherapy. Because it allows for early evaluation of the aggressiveness
of the tumor, the PET-CT scan may indicate more aggressive resections with proper
margins while at the same time avoiding unnecessary biopsies.[3]
[11]
[26]
Despite the attempts to avoid unnecessary biopsies, this procedure is still indicated
for the vast majority of patients. The material for anatomopathological examination
must be evaluated by a pathologist with experience in musculoskeletal tumors. Currently,
pathologists supplement their histopathology analysis with a panel of immunohistochemical
markers. Molecular tests have been used to supplement the diagnosis. Regardless of
the need to molecular testing to support certain diagnoses, the detailed genetic analysis
of the tumor tissue of a patient may have important implications in the therapy.[27] Techniques such as Fluorescent In Situ Hybridization (FISH) and Next Generation
Sequencing (NGS ) are slowly showing the existence, within the same diagnosis, of
different subtypes of tumor, with patterns which are often similar and which will
probably need target therapies for their treatment, probably generating a positive
impact on survival.[2]
[27]
Treatment
Treatment of STS depends essentially on histological grading, tumor's location and
its extent. Protocols use neoadjuvant (preoperative) or adjuvant chemotherapy and
combine surgical treatment with radiotherapy before or after surgery. Resection of
soft tissue sarcomas seeks to achieve microscopic surgical margins, free of tumor
cells.[16] The resection margins of sarcomas are currently defined as R0 (negative microscopic
margin) , R1 (positive microscopic margin), R2 positive macroscopic positive margin,
that is, evident residual tumor remaining). The extent of the R0 margin is not important
provided that there is no residual tumor,[16] that is, there is no difference between a slim margin and three-centimeter margin.
Despite the incessant search to preserve the extremity with STS, amputation is still
indicated in cases where the free microscopic surgical margins (R0) cannot be reached
without the resection of the tumor affecting critical structures such as the large
neurovascular bundles. As mentioned before, patients submitted to unplanned resection
of a STS using transversal access have greater possibility of having to undergo amputation.
It is essential to expand the surgical margins in patients submitted to unplanned
resections of sarcomas. This second procedure will bring the survival prognosis of
patients submitted to unplanned procedures close to that of patients submitted to
a planned treatment.[28]
Patients with rhabdomyosarcoma frequently have metastasis when diagnosed, and for
such reason need neoadjuvant systemic treatment. Polychemotherapy is the foundation
for treatment of rhabdomyosarcoma and should be used in all patients. Normally, STS
respond well (80–90%) to chemotherapy and radiotherapy. As a consequence, resection
becomes a more conservative procedure and the radiotherapy doses are reduced to limit
the risk of sequellae.[13]
Prognosis
Benign soft tissue tumors, such as lipomas, are 100 times more frequent that soft
tissue sarcomas.[23] Because they are rare, many physicians and patients do not recognize STS, which
contributes to delays in the investigation and diagnosis. This leads to an increase
in the extent of the lesions. Tumors of less than 5 cm and depth are bad prognostic
factors.[29] In addition, the greater incidence of benign soft tissue tumors frequently leads
to unplanned resections of sarcomas, which leave residual tumor. Hanasilo et al. report
that services of reference receive up to 50% of new cases of patients with STS who
were submitted to unplanned resections, and 90% of these patients have a residual
tumor.[28] After an unplanned resection, there is a greater risk of complications and an amputation
may be needed to obtain a margin free of tumor cells.[23]
[30]
[31]
Global survival of patients with musculoskeletal tumors depends on several factors,
such as the tumor's histological subtype, degree of malignancy, age of the patient,
location, extent, surgical margins achieved, the presence of metastasis, adjuvant/neoadjuvant
chemotherapy and radiotherapy.
Baptista et al.[32] report that in patients diagnosed with non-metastatic synovial sarcoma the prognostic
factors unfavorable to survival were the high histological grade, location (tumors
close to the knee or elbow) and spontaneous necrosis of the tumor greater than 25%.
Local relapse had no influence on survival rates. Zumarraga et al.[33] reported that in patients with myxofibrosarcoma a worse global survival prognosis
was related to the histological grade of the tumors, compromised margins, local relapse
and distant metastasis. Wu et al.[34] report that myxoid liposarcomas age (over 30), male sex, tumor grade (high grade)
and size of the tumor (greater than 10 cm) were independent prognostic factors for
global survival and in the specific disease in patients with STS in the extremities.
Tsuda et al.[35] reported that in patients aged 65 and over negative surgical margins were related
to a greater survival rate. Nakamura et al.[36] reported that the presence of a systemic inflammation is associated with a worse
prognosis. Increase in the levels of C-Reactive Protein (CRP), hypoalbuminemia and
anemia reflect the tumor's aggressive behavior. The first two serum markers may be
useful to predict the survival of patients with metastatic disease at the time of
diagnosis. Ishihara et al. reported that the histological grade of malignancy (high
grade), the extent of the tumor (greater than 10 cm) and metastases change the prognosis.
Local relapse is not actually related to the occurrence of metastases, extent of the
tumor, histological grade and death.[37]
Patients with rhabdomyosarcoma have, in general, a global survival of 70% in 5 years.
In several pediatric series, patients older than 10 years of age were reported as
having a worse prognosis than that of younger children.[13] In bone tumors (osteosarcoma and Ewing sarcoma), metastatic disease reduced global
survival rate to between 20% and 30%. About 15 to 20% of the patients with osteosarcomas
and 15% to 35% of the patients with Ewing sarcoma already had macroscopic evidence
of metastasis when diagnosed.[38]
[39]
[40]
[41]
[42] Literature shows that soft tissue tumors are tumors with a high metastatic potential
and great chance of local relapse if not properly resected.[16]
[17] Approximately 10% of the patients present metastasis when diagnosed and about 50%
of the patients with STS will develop them. Less than 20% of these patients will be
alive in 2 years. Therefore, as most STS occur in the extremities, orthopedists are
likely to the first professionals to approach these lesions.
Final Considerations
In conclusion, it is important that any soft tissue tumor be submitted to proper imaging
evaluation and, in the tumor is solid and non-fatty, it must be biopsied with a proper
technique before undergoing a resection without planning, which may compromise the
patient's treatment and prognosis.
