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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2915_Библиотеки_им_академика_М_И_Перельмана.pdf
Soft Tissue Sarcoma
31
• Chemical exposure. Exposure to certain chemicals (such as arsenic, vinyl chloride,
herbicides containing phenoxyacetic acids, and wood preservatives containing
chlorophenols) may also increase the risk of developing soft tissue sarcoma.
• Family history. Family history may also be important, as some inherited conditions
increase the risk for developing soft tissue sarcomas. Diseases like Gardner’s
syndrome, neurofibromatosis, or Li-Fraumeni syndrome are examples of this.
Reference
Zahm SH, Fraumeni JF Jr. The epidemiology of soft tissue sarcoma. Semin Oncol.
1997;24(5):504.
3. Anatomy
SFTS can occur in anywhere of the body and the location of the tumor can be an
important variable that influences treatment and outcome. The anatomic distribution of SFTS
is described in figure-1.
This distribution is based on data from the American College of Surgeon, which
evaluated the location of more than 5000 SFTS.
Figure 1. Anatomic distribution of SFTS.
Gustavo Arruda Viani
32
Reference
Lawrence W Jr, Donegan WL, Natarajan N, Mettlin C, Beart R, Winchester D. Adult soft
tissue sarcomas. A pattern of care survey of the American College of Surgeons. Ann
Surg. 1987;205(4):349.
4. Clinical Features
• The most common clinical presentation of SFTS is a painless mass. The median
period between detection of the lesion and presentation to the clinician is
approximately 6 months (figure-2).
• The most common sites of STS are: lower extremity (45%), trunk (30%), upper
extremity (15%), and head and neck (10%).
• In the extremities liposarcoma, MFH, synovial sarcoma, fibrosarcoma, myxoid
liposarcoma are respectively the most frequent histological subtypes.
• In the retroperitoneal liposarcoma followed by leiomyosarcoma are the most
commom, and in the head and neck location the histological subtype most frequent is
MFH.
• Independent of site and histological subtype, pain, numbness, and swelling may
result from tumor invasion of bone or neurovascular bundles.
• Soft tissue sarcomas are often surrounded by a pseudocapsule, they can invade
muscles, nerves, vessels, and fascia and frequently envelop major neurovascular
structures.
• Although locally aggressive, they rarely extend into adjacent tissue compartments
until late in the course of disease. Local spread can, however, be facilitated by
surgical violation of pseudocapsule.
• Approximately 5% to 10% of patients have metastatic disease at diagnosis, manly to
the lungs.
Figure 2. Painless mass in the hand and the proximal part of the leg.
Soft Tissue Sarcoma
33
5. Diagnosis and Evaluation
• Patients with STS typically present with a painless, progressive swelling in an
extremity; all such swellings are suspect for malignancy.
• Head and neck sarcomas manifest as proptosis, masses, or neurological
abnormalities.
• Retroperitoneal sarcomas present with back pain, lower-extremity edema, and
abdominal masses. Bone sarcomas usually result in visible enlargement of bone and
pathological fractures.
• Core needle biopsy is preferred over fine-needle aspiration (FNA) as the diagnostic
tool of choice because the tissue specimen retrieved by core needle predicts type and
grade 90% of time.
• Occasional situations will require an open biopsy, in which case an incisional biopsy
should be performed. Excisional biopsy often contaminates surrounding tissue.
• Computed tomography (CT) or ultrasound-guided biopsies are increasingly
employed at initial diagnosis and in the evaluation of possible recurrences.
• Plain radiographs of soft tissues may demonstrate bone involvement. Stippled
calcification may be present within the mass.
• Patients with painful or enlarged bones should have radiographic study of these
areas. CT scans are most useful for evaluating retroperitoneal or head and neck
regions. CT scanning of the extremities appears to be effective in delineating the
extent of the tumor.
• MRI is the preferred over CT for the evaluation of soft tissue masses of the
extremities, trunk, and head and neck. CT is the most commonly used for evaluating
retroperitoneal sarcomas. Several studies report that MRI is superior to CT in
evaluating soft tissue sarcomas of the extremity as MRI provides multiplanar images
with better spatial orientation (figure-3).
Figure 3. T2 weighted MRI of lower extremity showing a mass in axial and coronal view.
• Arteriography may be useful in certain cases to plan surgical resection.
• Bone scan is performed in patients with bone sarcomas to search for multifocal
disease.
Gustavo Arruda Viani
34
Undifferentiated pleomorphic sarcoma (malignant fibrous histiocytoma)
Liposarcoma
Leiomyosarcoma
Synovial sarcoma
Malignant peripheral nerve sheath tumor
Rhabdomyosarcoma
Fibrosarcoma
Primitive neuroectodermal tumor/extraskeletal Ewing tumor
Angiosarcoma
Epithelioid sarcoma
Clear cell sarcomaAlveolar soft part sarcoma
Malignant mesenchymoma
• PET scanning is useful both for determining sites of disease and for assessing
response to therapy.
• CT of the thorax is necessary for all patients with sarcoma to detect lung metastases,
which may be resected after the primary tumor is managed.
Reference
Sinha S, Peach AH. Diagnosis and management of soft tissue sarcoma. BMJ. 2010; 41:c7170.
6. Pathology
STSs are classified histologically according to their cellular origin. They are a
heterogeneous group of tumors of mesenchymal origin, which includes more than 50 different
histologic subtypes. Pathologic diagnosis is based on histologic morphology, immunohistochemistry, and sometimes, molecular testing. Table-1 shows the most common sarcomas
seen in the clinical practice.
Table 1. Most common soft tissue sarcomas
Histologic classification alone does not always provide enough information to predict the
clinical behavior of STSs. THUS, histologic grading provides additional information that can
aid in predicting biologic behavior and planning treatment. Several grading systems have
been proposed, but the French system has been preferred (French FNCLCC).
The FNCLCC grade is determined by three parameters: differentiation (histology
specific), mitotic activity, and extent of necrosis
• GX Grade cannot be assessed
• G1 Grade 1
• G2 Grade 2
• G3 Grade 3
Soft Tissue Sarcoma
35
Reference
Fletcher CDM, Unni KK, Mertens F. World Health Organization Classification of tumours:
Pathology and Genetics of tumours of soft tissue and bone, IARC Press, Lyon 2002.
7. Routes of Spread
• Hematogenous route is the principal way for SFTS metastasize, and the lungs are the
most frequent sites committed by disease.
• Extremity sarcomas frequently metastasize to the lungs, while retroperitoneal STSs
metastasize to the liver.
• Isolated pulmonary metastases are the most frequent, accounting for nearly 50% of
all initial recurrence. Bone, liver, and skin involvement occurred in less than 5% of
patients.
• Lymph nodal metastases are rare and depend on grade and size of tumor. But, the
most frequent histological subtypes associated with lymph node metastases are; clear
cell sarcoma, RMS, epithelioid sarcoma, synovial sarcoma, and angiosarcoma,
respectively.
• There is some subtypes of SFTS that rarely metastasize: liposarcoma (myxoid and
welldifferentiated types), fibrosarcoma (infantile and well-differentiated types), MFH
(superficial type), dermatofibrosarcoma protuberans.
References
Potter DA, Glenn J, Kinsella T, et al: Patterns of recurrence in patients with high-grade soft-
tissue sarcomas. J Clin Oncol 1985; 3:353.
Vezeridis MP, Moore R, Karakousis CP: Metastatic patterns in soft-tissue sarcomas. Arch
Surg 1983; 118:915.
8. Prognostic Factors
• The most important prognostic factors for disease free survival (DFS) and distant
metastases are; tumor size, tumor grade, and location deep to the superfi cial
investing fascia.
• Prognostic factors for local control include: prior recurrence, microscopically
positive margins, age >50, and certain histologies (fibrosarcoma, peripheral nerve
sheath tumors).
• Other potential factors for local control may include non-extremity location and
nonuse of radiation. Tumor size, grade, and location (deep versus superficial) do not
seem to impact local control.
Gustavo Arruda Viani
36
Reference
Suit HD, Mankin HJ, Wood WC, Gebhardt MC, Harmon DC, Rosenberg A, Tepper JE,
Rosenthal D. Treatment of the patient with stage M0 soft tissue sarcoma. J Clin Oncol.
1988;6(5):854.
9. Treatment
• Soft tissue sarcomas (STS) are rare tumors that arise from skeletal and extraskeletal
connective tissues. They can arise from mesenchymal tissue at anywhere of the body.
Because of their rarity, they are better treated for a multidisciplinary team consisting
of surgical, medical oncologist, and radiation oncology.
• The major therapeutic goals for STS of the extremities are survival, followed of
reduced local recurrence, maintenance of a good function for the limb, with reduced
morbidity.
• Surgical resection of the primary tumor is the pivotal component of treatment for all
patients. The surgical principle is total en bloc excision of the primary tumor without
cutting into tumor tissue associated with safety margins. The exact width of the
safety margins is not known. Most surgeons recommend at least 1 cm in all
directions or include a facial barrier (figure-4).
Figure 4. Surgical resection of primary tumor of lower extremity found by MRI.
Soft Tissue Sarcoma
37
Study
Description
Pisters et al.
(1996)
Prospective randomized trial, 164 patients were randomized intraoperatively to
receive either adjuvant brachytherapy (BRT) or no further therapy (no BRT) after
complete resection of soft tissue sarcomas of the extremity or superficial trunk.
The adjuvant radiation was administered by iridium-192 implant, which delivered 42
to 45 Gy over 4 to 6 days.
With a median follow-up time of 76 months, the 5-year actuarial local control rates
were 82% and 69% in the BRT and no BRT groups (P = .04), respectively. Patients
with high-grade lesions had local control rates of 89% (BRT) and 66% (no BRT) (P
= .0025). BRT had no impact on local control in patients with low-grade lesions (P =
.49). The 5-year freedom-from-distant-recurrence rates were 83% and 76% in the
BRT and no BRT groups (P = .60), respectively.
Yang et al.
(1998)
Patients with extremity tumors and a limb-sparing surgical option were randomized
to receive or not receive postoperative adjuvant external-beam radiotherapy.
92 patients with high-grade lesions were randomized; 47 to receive radiotherapy
(XRT) and 44 to not receive XRT. With a median follow-up of 9.6 years, a highly
significant decrease (P2 = .0028) in the probability of LR was seen with radiation,
but no difference in OS was shown. Of 50 patients with low-grade lesions (24
randomized to resection alone and 26 to resection and postoperative XRT), there was
alsoa lower probability of LR (P2 = .016) in patients receiving XRT, again, without
a difference in OS.
• When possible, patients with an incompletely resected primary SFTS should be
reoperated to improve the local control. Patients, who refuse or are not candidates for
reoperation, or have the desire of preserving extremity function, should receive
adjuvant radiotherapy.
• Surgery followed by adjuvant radiation therapy has resulted in a better local control
than either modality alone. Moreover, adjuvant radiotherapy should be indicated for
high grade tumors, tumors >5 cm and with positive margins. The benefits of adjuvant
radiotherapy in this setting are in producing good functional outcomes, avoiding the
significant morbidity with radical resection (table-2).
Table 2. Clinical evidence for adjuvant radiotherapy for SFTS
References
Pisters PW, Harrison LB, Leung DH, Woodruff JM, Casper ES, Brennan MF. Long-term
results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma.
J Clin Oncol. 1996;14(3):859.
Yang JC, Chang AE, Baker AR, Sindelar WF, Danforth DN, Topalian SL, DeLaney T,
Glatstein E, Steinberg SM, Merino MJ, Rosenberg SA. Randomized prospective study of
the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the
extremity. J Clin Oncol. 1998;16(1):197.
• Adjuvant radiotherapy is no necessary for patients with low-grade SFTS, with tumors
of 5 cm or less in diameter and operated with adequate surgical margins. On the other
hand, adjuvant radiotherapy should be indicated for patients with intermediate-grade
and high-grade SFTS, as well as those with larger tumors (> 5 cm) and deep.
Gustavo Arruda Viani
38
Study
Description
NCIC (O’Sullivan
et al. 2002):
190 patients with extremity STS randomized pre-op RT (50 Gy) vs. post-op RT
(66 Gy).
If positive margins after pre-op RT a 16 Gy boost was given. No difference in
LC (93%), DM (25%), and PFS (65%). Initially, better OS with pre-op due to
deaths other than sarcoma in post-op arm, but on 6-year follow-up, no
difference in OS.
More wound healing problems with pre-op (35% vs. 15%), but increased late
fibrosis with post-op RT (48% vs. 31%, p = 0.07).
Pollack et al.
(1998):
Compared patients treated with post-op RT (60–66 Gy) or pre-op RT (50 Gy)
before excision or reexcision.
No difference in LC between pre vs. post-op (81%). For patients presenting
with gross disease, best LC with pre-op RT (88% vs. 67%).
More wound-healing problems with pre-op (25% vs. 5%).
• When adequate surgical margins may not be obtained, a reasonable option is to offer
preoperative radiotherapy. In this setting, preoperative radiotherapy can be extremely
useful for large and deep tumors. On the other hand, when surgeon feels that
adequate margins may be possible, the better option is to delay the decision regarding
radiation therapy until after review of the final pathology from the resection
specimen (tabe-3).
Table 3. Clinical evidence for neoadjuvant radiotherapy for SFTS
References
O’Sullivan B, Davis AM, Turcotte R, et al. Preoperative versus postoperative radiotherapy in
soft tissue sarcoma of the limbs: a randomised trial. Lancet 2002;359:2235-2241.
Pollack A, Zagars GK, Goswitz MS, et al. Preoperative vs. postoperative radiotherapy in the
treatment of soft tissue sarcomas: a matter of presentation. Int J Radiat Oncol Biol Phys
1998;42:563-572.
• Neoadjuvant chemotherapy can also be considered for large (> 8 cm) or recurrent
high-grade tumors. In these settings, RT is also commonly selected with or without
chemotherapy. However, how best to integrate radiation therapy, chemotherapy, and
surgery remains unknown.
• The role of adjuvant chemotherapy for SFTS remains open. Even after the
publication of several randomized trials and meta-analysis, its benefits mainly in
terms of overall survival remains questionable. Thus, the decision in offering
adjuvant chemotherapy should be individualized. When indicated the preferred
regimen contains both ifosfamide and doxorubicin (table-4).
References
Kraybill WG, Harris J, Spiro IJ et al. Long-term results of a phase 2 study of neoadjuvant
chemotherapy and radiotherapy in the management of high-risk, high-grade, soft tissue
Soft Tissue Sarcoma
39
Study
Description
Kraybill et al.
(2010)
Patients with high-grade soft tissue sarcoma≥8 cm in diameter of the extremities
and body wall received 3 cycles of neoadjuvant chemotherapy (mesna,
doxorubicin, ifosfamide, and dacarbazine) and preoperative RT (44 Gy), and 3
cycles of postoperative chemotherapy same regimen.
66 patients were analyzed. After chemotherapy and RT, 61 patients had surgery; 58
had R0 resections (5 amputations), and 3 had R1 resections. 97 % experienced
grade 3 or higher toxicity, including 3 deaths.
With a median follow-up of 7.7 years in surviving patients, the 5-year rates of
locoregional failure (including amputation), and distant metastasis were 22.2% and
28.1%.
Estimated 5-year rates of disease-free survival, distant disease-free survival, and
overall survival were 56.1%, 64.1%, and 71.2%, respectively.
Pervaiz et al.
(2008)
A comprehensive literature search was performed to identify RCTs of adjuvant
chemotherapy for adult patients diagnosed with localized resectable soft-tissue
sarcoma. The outcome measures were local, distant, and overall recurrence and
survival calculated through the fixed effect or random effect model.
A total of 18 trials representing 1953 patients to be included in the analysis. The
odds ratios (OR) for local recurrence was 0.73 (; P = .02) in favor of chemotherapy.
For distant and overall recurrence the OR was 0.67 (P = .0001) in favor of
chemotherapy. In terms of survival, doxorubicin alone had an OR of 0.84 (P = .09),
which as not statistically significant.
However, the OR for doxorubicin combined with ifosfamide was 0.56 (P = .01) in
favor of chemotherapy.
sarcomas of the extremities and body wall: Radiation Therapy Oncology Group Trial
9514. Cancer. 2010;116(19):4613.
Pervaiz N, Colterjohn N, Farrokhyar F, Tozer R, Figueredo A, Ghert M. A systematic meta-
analysis of randomized controlled trials of adjuvant chemotherapy for localized
resectable soft-tissue sarcoma. Cancer. 2008;113(3):573.
Table 4. Clinical evidence for adjuvant chemotherapy in SFTS
10. Radiotherapy Technique
Immobilization techniques vary due to different tumour sites, but for the common
tumours in upper or lower limbs, individually prepared vacuum bags are used. Laser lights are
used to minimize rotational movement, and craniocaudal movement should be prevented by
appropriate foot or hand restraints (figure-5).
When possible, preoperative and pre-radiotherapy CT scans should be taken with the
limb in the same position, and pre- and postoperative CT and/or MRI co-registered for
planning. However, changes in muscle configuration after surgery and the position of the scar
will alter appearances significantly, and it is essential for surgeon and radiation oncologist to
plan jointly all treatments for optimal local control and functional outcome. Postoperatively, a
CTV must be designed which includes the initial GTV, any likely sites of tumour
dissemination from surgery (such as scar) and a margin to encompass potential microscopic
spread, which will vary for different tumour types from 20 - 50 mm. Clips placed at surgery
may be helpful. With improved imaging, a GTV-CTV margin of 20 mm may be adequate.
Optimum treatment volume sizes are being studied (in the VORTEX trial). Incomplete
excision of very large tumors (which may be 15–20 cm long in the limbs) may make the CTV
Gustavo Arruda Viani
40
planned this way prohibitively large, and it may not be possible to encompass scars and
excision margins in full. EBRT may then be restricted to areas of bulky residual disease, for
example around vessels or nerves.
Figure 5. Immobilization device for lower extremity SFTS.
IMRT can be useful for SFTS of extremities, for avoiding excessive dose in long bones
as femur, and for reducing the total dose outside of PTV. Moreover, IMRT can reduce
radiotherapy dose in tumors located close to genital organs (figure-6).
Figure 6. Isodose distribution for IMRT compared with 3DCRT.
For preoperative radiotherapy dose of 44-50 Gy are delivered in conventional
fractionation. After surgery for tumors with positive margins an additional boost of 16 Gy is
delivered. In the postoperative setting dose of 60 Gy are recommended for tumors with
negative margins and 66 Gy for cases with positive margins (figure-7)