Positron Emission Tomography.
Positron most soft tissue sarcomas, particularly
emission tomography
(PET) is a functional imaging modality that
measures tumor
uptake of the glucose analog [18F]
fluorodeoxyglucose (FDG).
PET imaging allows evaluation of the entire
body. Although
PET/CT may be useful in specific
circumstances, FDG-PET is
not currently recommended for the initial
staging of patients
with soft tissue sarcoma.
Roberge and colleagues compared FDG-PET/CT
versus
chest CT alone in the initial staging of 75
patients with soft
tissue sarcoma and found that only one
patient had disease
upstaged as a result of PET, whereas two
had false-positive findings
and three had indeterminate findings with
no subsequent
development of metastasis.32 Previous studies
that reported a
marginal benefit of PET/CT for detecting
metastasis at the time
of sarcoma staging included patients with
more heterogeneous
tumors, such as osseous tumors, soft tissue
osteosarcomas,
Ewing’s sarcoma, and rhabdomyosarcoma.33-35
In patients with sarcoma, PET has primarily
been used
to assist with tumor grading and to assess
response to chemotherapy.
36-39 In 50 patients with resectable high-
grade soft
tissue tumors scheduled for preoperative
chemotherapy and
tumor resection, a 35% or greater reduction
in tumor FDG
uptake following an initial cycle of
chemotherapy was associated
with histopathologic tumor response defined
as pathologic
necrosis in 95% or more of the resected
specimen.40
Biopsy Techniques
Fine-Needle Aspiration. At centers where
cytopathologists
have experience with evaluation of
mesenchymal tumors,
fine-needle aspiration is an acceptable
method of diagnosing
when the results correlate
closely with clinical and radiologic
findings.41 Fine-needle
aspiration of primary tumors has a lower
diagnostic accuracy
rate (60%–90%) than core needle biopsy and
is often not sufficient
for establishing a specific histologic
diagnosis and grade.42
However, fine-needle aspiration is the
procedure of choice to
confirm or rule out the presence of a
metastatic focus or local
recurrence.43
Although fine-needle aspiration of
superficial lesions can
often be done in the clinic, fine-needle
aspiration of deeper
tumors may need to be done by an
interventional radiologist
under sonographic or CT guidance.
Generally, a 21- to 23-gauge
needle is introduced into the mass after
appropriate cleansing of
the skin and injection of local anesthetic.
Negative pressure is
applied, and the needle is moved back and
forth several times in
various directions. After the negative
pressure is released, the
needle is withdrawn, and the contents of
the needle are used to
prepare smears.44 A cytopathologist then
examines the slides
to determine whether sufficient diagnostic
material is present.
Core Needle Biopsy. Core needle biopsy is
safe, accurate,45,46
and economical47 and has become the preferred
technique for
diagnosing soft tissue lesions. Dupuy and
colleagues found that
core needle biopsy had an accuracy of 93%
in 221 patients with
musculoskeletal neoplasms.45
Sonography/CT guidance can prevent sampling
of nondiagnostic
necrotic or cystic areas of the tumor and
thus increase
the positive yield rate. Sonography/CT
guidance also permits
biopsy of tumors in otherwise inaccessible
locations and tumors
located near vital structures.
The tissue sample obtained from core needle
biopsy is
usually sufficient for several diagnostic
tests, such as electron
microscopy, cytogenetic analysis, and flow
cytometry.
The reported complication rate for core
needle biopsy is less
than 1%.45,46
Incisional Biopsy. Historically, an open
surgical biopsy was
the gold standard for achieving adequate
tissue for definitive
and specific histologic diagnosis of bone
or soft tissue sarcomas.
Contemporary guidelines recommend
incisional biopsy when
core needle biopsy cannot produce adequate
tissue for diagnosis
or when findings on core needle biopsy are
nondiagnostic.
The disadvantages of incisional biopsy
include the need
to schedule the procedure, the need for
general anesthesia, and
high costs. In addition, an inappropriately
placed incisions can
necessitate more extensive definitive
resection to encompass
the biopsy site. In a series of 107
patients with soft tissue sarcoma,
planned surgical treatments had to be
changed because
of poorly oriented biopsies in 25% of
cases.48 Complication
rates up to 17% have been reported after
incisional biopsies.44
Potential complications include hematoma,
infection, wound
dehiscence, and tumor fungation, any of
which can delay definitive
treatment.44
Incisional biopsies should be performed
only by surgeons
experienced in the management of soft
tissue sarcoma, ideally
in a center specializing in the treatment
of sarcoma and by the
surgeon who will perform the definitive
surgery. The biopsy
incision should be oriented longitudinally
along the extremity
to allow a subsequent wide local excision
that encompasses the
biopsy site, scar, and tumor en bloc. A
poorly oriented biopsy
incision often necessitates an excessively
large surgical defect
for a wide local excision, which in turn
can result in a larger
postoperative radiation therapy field to
encompass all tissues
at risk. Adequate hemostasis must be
achieved at the time of
biopsy to prevent dissemination of tumor
cells into adjacent tissue
planes by hematoma.
Excisional Biopsy. Excisional biopsy can be
performed
for easily accessible (superficial)
extremity or truncal lesions
smaller than 3 cm. However, excisional
biopsy rarely provides
benefits over other biopsy techniques.
Excisional biopsies
should not be performed for lesions
involving the hands and feet
because such biopsies may complicate
definitive re-excision.
For sarcomas with initial diagnosis
confirmed with excisional
biopsy, microscopic residual disease has
been reported in up
to 69% of re-excision specimens49,50; without
re-excision, the
reported rate of local recurrence is 30% to
40% when margins
are positive or uncertain.
Wide en bloc excision is seldom performed
as a diagnostic
procedure. When en bloc excision is done
for diagnosis, the margin
status is often not adequately evaluated
during pathologic
assessment of the specimen. Unless detailed
descriptions of the
surgical procedure and the pathology
specimen are provided, the
margins should be classified as uncertain
or unknown, a classification
associated with the same prognosis as
resection margins
that are positive for tumor cells. In
patients with uncertain or
unknown margins, re-excision should be
performed if possible
to ensure negative margins. The biopsy site
or tract (if applicable)
should be included en bloc with the re-
resected specimen.
Pathologic Assessment and
Classification
Sarcoma is generally diagnosed by
morphologic assessment
based on microscopic examination of
histologic sections by an
experienced sarcoma pathologist. However,
even expert sarcoma
pathologists disagree on the specific
histologic diagnosis
and the tumor grade in 25% to 40% of
cases.51
Morphologic assessment can be supported by
ancillary
techniques, including conventional
cytogenetics; immunohistochemistry;
and molecular genetic testing, which is
useful for
classifying soft tissue sarcoma subtypes
with multiple genetic
aberrations. Other molecular diagnostic
techniques include
cytogenetic analysis, fluorescence in situ
hybridization, and
polymerase chain reaction–based methods.52
However, molecular
genetic techniques are associated with
significant technical
limitations and should be interpreted in
the context of the sarcoma’s
morphologic features.
Some experts have suggested that pathologic
classification
of soft tissue sarcomas has more prognostic
significance
than does tumor grade when other
pretreatment variables are
taken into account. Tumors with limited
metastatic potential
include desmoid, atypical lipomatous tumor
(also called welldifferentiated
liposarcoma), dermatofibrosarcoma
protuberans,
and solitary fibrous tumor. Tumors with an
intermediate risk of
metastatic spread usually have a large
myxoid component and
include myxoid liposarcoma,
myxofibrosarcoma, and extraskeletal
myxoid chondrosarcoma. Among the highly
aggressive
tumors with substantial metastatic
potential are angiosarcoma,
clear cell sarcoma, pleomorphic and
dedifferentiated liposarcoma,
leiomyosarcoma, MPNST, rhabdomyosarcoma,
and
synovial sarcoma.
It has recently been noted that malignant
fibrous histiocytoma
is not associated with a distinct gene
cluster, suggesting
that malignant fibrous histiocytoma is not
a separate tumor
entity but rather a common morphologic
appearance of various
sarcoma subtypes.53,54 For example, most
tumors initially diagnosed
as malignant fibrous histiocytoma in the
retroperitoneum
have been reclassified using genomic
profiling as dedifferentiated
liposarcomas,55 whereas those in the
extremities have been
reclassified as leiomyosarcoma,
myxofibrosarcoma, or pleomorphic
undifferentiated sarcoma.
Guidelines for the pathologic reporting of
sarcoma have
been established.1 Included in the report
should be the primary
diagnosis, anatomic site, depth, size, and
histologic grade, presence
or absence of necrosis, status of excision
margins and
lymph nodes, TNM stage, and additional
features of the tumor
(i.e., mitotic rate and presence or absence
of vascular invasion).
Staging and Prognostic Factors
Soft tissue sarcoma is most commonly staged
using either the
American Joint Committee on Cancer (AJCC)
system (generally
used in the United States) or the World
Health Organization
system. A unique aspect of sarcoma staging
is the inclusion
of tumor grade, which is one of the most
important prognostic
factors.56
The seventh edition of the AJCC staging
system for soft
tissue sarcomas is based on histologic
grade of aggressiveness,
tumor size and depth, and the presence of
nodal or distant
metastases.57 This system does not apply to
GIST, fibromatosis
(desmoid tumor), Kaposi’s sarcoma, or
infantile fibrosarcoma.
Histologic Grade of Aggressiveness.
Histologic grade is the
most important prognostic factor for
patients with soft tissue
sarcoma. For accurate determination of
grade, an adequate tissue
sample must be appropriately fixed,
stained, and reviewed
by an experienced sarcoma pathologist. The
features that define
grade are cellularity, differentiation
(good, moderate, or poor/
anaplastic), pleomorphism, necrosis
(absent, <50%, or ≥50%),
and number of mitoses per high-power field
(<10, 10–19, or
≥20). Tumor grade has been shown to predict
metastasis and
overall survival.58 Metastasis has been
estimated to occur in 5%
to 10% of low-grade lesions, 25% to 30% of
intermediate-grade
lesions, and 50% to 60% of high-grade
lesions.
The number of grades varies according to
the classification
system used. The most common classification
systems,
those of the National Cancer Institute and
the French Federation
of Cancer Centers, use three-tier tumor
grades.59 The National
Cancer Institute system is based primarily
on histologic subtype,
location, and amount of necrosis. The
French Federation
of Cancer Centers system is based on tumor
differentiation
(good, moderate, or poor/anaplastic),
number of mitoses per
high-power field (<10, 10–19, or ≥20), and
amount of tumor
necrosis (absent, <50%, or ≥50%). A
comparative analysis of
the two systems suggested that the French
Federation of Cancer
Centers system has better prognostic
capability, predicting
5-year survival rates of 90%, 70%, and 40%
for grade 1, 2, and
3 tumors, respectively.59
Following the recommendation of the College
of American
Pathologists, the committee that developed
the 2008 AJCC
staging system changed the system from a
four-grade to a three-grade system in which
the grades are well differentiated
(grade 1), moderately differentiated (grade
2), and poorly differentiated
(grade 3).60 Grade 1 is considered low grade,
and
grades 2 and 3 are considered high grade.
Tumor Size and Location. Tumor size is an
important prognostic
variable in soft tissue sarcomas. Sarcomas
have classically
been stratified into two size groups; T1
lesions are 5 cm or
smaller, and T2 lesions are larger than 5
cm. Some authors have
suggested adding a third group for tumors
larger than 15 cm,
because such tumors are associated with a
worse prognosis than
tumors measuring between 5 and 15 cm. 61,62
Anatomic tumor location was incorporated
into the AJCC
staging system in 1998. Soft tissue
sarcomas above the superficial
investing fascia of the extremity or trunk
are designated “a”
lesions within the T category, whereas
tumors invading or deep
to the fascia and all retroperitoneal,
mediastinal, and visceral
tumors are designated “b” lesions.
Nodal Metastasis. Overall, lymph node
metastases arising
from soft tissue sarcomas are rare, 27 but the
incidence of nodal
involvement is higher for epithelioid
sarcoma, pediatric rhabdomyosarcoma,
clear cell sarcoma, synovial sarcoma,
myxofibrosarcoma,
and angiosarcoma. In the seventh edition of
the
AJCC staging system, sarcoma associated
with nodal metastases
was reclassified as stage III rather than
stage IV because
several studies reported better survival
for patients with isolated
regional lymph node metastases treated with
radical lymphadenectomy
than for patients with distant metastases. 27,
63-65 Patients
with clinically or radiologically
suspicious regional nodes
should have metastases confirmed or ruled
out by fine-needle
aspiration before radical lymphadenectomy.
Distant Metastasis. Distant metastases occur
most often in
the lungs (Fig. 36-4). Selected patients
with pulmonary metastases
may survive for long periods after surgical
resection and
chemotherapy. Other potential sites of
metastasis include bone
(Fig. 36-5), brain (Fig. 36-6), and liver
(Fig. 36-7). Visceral and retroperitoneal
sarcomas have a higher incidence of liver
and
peritoneal metastases.
Prognostic Factors. Prognostic variables in
soft tissue sarcoma
include primary tumor size, grade, and
depth, all of which
are incorporated into the staging system,
as well as histology,
tumor site, and presentation (local
recurrence or initial diagnosis).
Patient factors such as older age and
gender have also been
associated with recurrence and mortality in
several studies.66 A
positive microscopic margin and early
recurrence after resection
of an extremity sarcoma have been shown to
be associated with
decreased survival.67
Several groups have reported that Ki-67, a
proliferation
marker, is correlated with a poor clinical
outcome in high-grade
extremity sarcomas.68,69 E-cadherin and
catenins, proteins essential
for intercellular junctions, have been
associated with poor outcome
in patients with soft tissue sarcoma. 68
Similarly, higher CD100
expression has been shown to correlate with
higher proliferative
potential and poorer outcome.69
Prognostic Nomograms. Prognostic
nomograms for soft tissue
sarcoma have been introduced for use in
patient counseling,
selecting appropriate surveillance
strategies, and selecting
patients for clinical trials.70 One such
nomogram, developed
by Kattan and colleagues at Memorial Sloan-
Kettering Cancer
Center, considers age, histology, grade,
location, depth, and
size to determine the likelihood of 12-year
sarcoma-specific
survival.70 Two validation studies using the
nomogram demonstrated
good predictive value.71 More recently, the
same group
of investigators developed histology
subtype-specific nomograms
for patients with liposarcoma, synovial
sarcoma, and
GIST72 and demonstrated that they were
accurate in predicting
disease-specific survival. Other
investigators have just developed
a site-specific nomogram for patients with
retroperitoneal
sarcoma, demonstrating an accurate
prediction of survival and
disease recurrence.73
TREATMENT OF EXTREMITY AND
TRUNK
WALL SARCOMA
The goals of treatment of soft tissue
sarcoma are to maximize the
likelihood of long-term recurrence-free
survival while minimizing
morbidity and maximizing function. In the
past two decades,
a multimodality treatment approach with
optimal sequencing of
treatments for individual patients has been
shown to improve
survival.74 Furthermore, patients with soft
tissue sarcoma treated
at high-volume centers have been shown to
have improved survival
and functional outcomes.75 Care at such
centers is particularly
important for patients with high-risk and
advanced disease.
The overall 5-year survival rate for
patients with all stages
of soft tissue sarcoma is 50% to 60%. For
patients with extremity
sarcomas, a multidisciplinary treatment
approach has resulted
in local control rates exceeding 90% and 5-
year survival rates
exceeding 70%. Most patients who die of
soft tissue sarcoma die
of metastatic disease, which becomes
evident within 2 to 3 years
of initial diagnosis in 80% of cases.
Recommendations for evaluation and
treatment of patients
presenting with soft tissue masses are
summarized in Table 36-3.