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Journal of Indian Association of Pediatric Surgeons
Medknow Publications on behalf of the Indian Association of Pediatric Surgeons
ISSN: 0971-9261 EISSN: 1998-3891
Vol. 11, Num. 1, 2006, pp. 15-23
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Journal of Indian Association of Pediatric Surgeons, Vol. 11, No. 1, January-March, 2006, pp. 15-23
Review Article
Pediatric rhabdomyosarcomas and nonrhabdomyosarcoma soft tissue sarcoma
Agarwala Sandeep
Department of Pediatric Surgery, All India Institute of
Medical Sciences, New Delhi, India
Correspondence Address:Sandeep Agarwala, Department of Pediatric Surgery,
All India Institute of Medical Sciences, New Delhi - 110 029,
India. E-mail: sandpagr@hotmail.com
Code Number: ip06004
Abstract
Tumors arising from the soft tissues are uncommon in children, accounting
for about 6% of all childhood malignancies. More than half (53%) of these originate
from the striated muscles and are called rhabdomyosarcomas (RMS) the remaining
are nonrhabdomyosarcoma soft tissue sarcomas (NRSTS). Almost two-thirds of
RMS cases are diagnosed in children <6 years of age. They can arise at varied
locations like the head and neck region, genitourinary tract, extremities,
trunk and retroperitoneum. Pathologically RMS is now classified as superior,
intermediate and poor outcome histologies. For stratification of treatment
and also comparison of results the RMS are now staged both by the clinical
grouping and the TNM staging systems. The ultimate outcome depends on the site,
extent of disease and histology. Currently, approximately 70% of the patients
survive for 5 years or more and are probably cured. This is credited to the
use of multi-modal, risk-adapted therapy, refinements in tumor grouping and
better supportive care which has emerged out of cooperative studies like Intergroup
Rhabdomyosarcoma Study (IRS) and the International Society of Pediatric Oncology
studies (SIOP). The treatment involves chemotherapy, radiotherapy and organ/function
preserving surgery. The gold standard chemotherapy is still vincristine, actinomycin
D and cyclophosphamide (VAC) regime with high doses of intensity bone marrow
rescue with colony stimulating factors. The NRSTS are rare and of heterogenous
histologies and so it has been difficult to arrive at a treatment strategy
for these. What is definitely understood is that these are usually immature
and poorly differentiated tumors that respond poorly to chemotherapy and so
surgical resection forms the mainstay of treatment with adjuvant radiotherapy
and chemotherapy to prevent local recurrences. In all likelihood, the molecular
analysis of RMS will further refine current classification schemes and knowledge
of genetic features of the tumors will significantly improve the ability of
investigators to identify patients at lower or higher risk of treatment failures,
thus paving the way for advances in risk-based therapy.
Keywords: Children, nonrhabdomyosarcoma soft tissue sarcomas, rhabdomyosarcomas
The soft tissues refer to a wide range of different cell types and include connective tissues, lymphatics, vessels, smooth and striated muscles, fat, facsia, synovium, endothelium and reticuloendothelium. Tumors arising from these soft tissues are uncommon in children, accounting for about 6% of all childhood malignancies. More than half (53%) of these soft tissue sarcomas (STS) originate from the striated muscles and are called rhabdomyosarcomas (RMS).[1],[2] The remaining group (47%) consists of a heterogenous collection of subtypes referred to as nonrhabdomyosarcoma soft tissue sarcomas (NRSTS). Pediatric STS shows a striking difference in the incidence as compared to their adult counterparts. RMS, by far the commonest STS in children, is rare in adults. In children RMS is commonly of the embryonal histology as compared to pleomorphic variety in adults. Similarly among the NRSTS, malignant fibrous histiocytoma (MFH) comprises the most common histology in adults, but is exceedingly rare in children. Of the MFH also, only the angiomatoid variety, a low grade lesion of borderline behavior, occurs in children.
Rhabdomyosarcoma
Rhabdomyosarcoma is thought to arise from immature mesenchymal cells that
are committed to skeletal muscle lineage, but these tumors are also known to
arise in tissues in which striated muscle is not normally found, such as urinary
bladder. Among the extracranial solid tumors of childhood, RMS is the third
most common neoplasm after neuroblastoma and Wilms′ tumor, comprising 15% of all solid tumors. Almost two-thirds of cases of RMS are diagnosed in children < 6 years of age although there is another mid-adolescence peak. It is slightly more common in males than in females (1.3-1.4: 1). It is ubiquitous occurring almost everywhere but most commonly in the head and neck and the genitourinary (GU) areas. There are certain distinctive clusters of features regarding age at diagnosis, site of primary and histology. The head and neck tumors are most common in children younger than 8 years of age and if arising in the orbit, are almost always of embryonal histology. On the other hand, the extremity tumors are more commonly seen in adolescents and are more frequently of alveolar histology.
Currently local control in achieved in 80-90% of patients[3] and
approximately 70% of the patients survive for 5 years or more and are
probably cured.[4],[5] Recent
reports from IRS-IV showed a 3-year failure free survival (FFS) of 83% for
nonmetastatic embryonal RMS.[6] This
is credited to the use of multi-modal, risk-adapted therapy, refinements in
tumor grouping and better supportive care which has emerged out of cooperative
studies like Intergroup rhabdomyosarcoma study (IRS). In all likelihood, the
molecular analysis of RMS will further refine current classification schemes
and knowledge of genetic features of the tumors will significantly improve
the ability of investigators to identify patients at lower or higher risk of
treatment failures, thus paving the way for advances in risk-based therapy.
Pathology
Rhabdomyosarcomas are grossly firm, nodular and of variable size and consistency.
They are well circumscribed but not encapsulated and often tend to infilterate
extensively into adjacent tissues. Sarcoma botryoides subtype has characteristic
grape-like appearance with its grape like clusters of tumors arising from a
mucosa lined area. Histologically RMS falls into the broad category of small
blue round cell tumor. The standard classification is still the one proposed
by Horn and Enterline[7] in 1958
which divided the tumor into four subgroups: embryonal, alveolar, botryoid
and pleomorphic and noted that botryoid was actually a subtype of embryonal.
Since there was no overall agreement among the pathologists using the conventional
classification therefore an international classification system for childhood
RMS was proposed.[8] This system
is being used in all new IRS studies beginning IRS IV [Table
- 1]. The histologic
distribution of the tumor in IRS III[3] is
shown in [Table - 2]. Light microscopy diagnosis of RMS is based on the identification
of cross-striations, characteristic of skeletal muscle, or characteristic rhabdomyoblasts.
Cross-striations are seen in 50-60% of the cases. Histologically embryonal rhabdomyosarcoma (ERMS)
is composed of rhabdomyoblasts and small round cells. Rhabdomyoblast, the more
mature of the embryonal component, is characterized by bright eosinophilic
cytoplasm. Sarcoma botryoides and spindle cell variant are two subtypes of
embryonal RMS. Alveolar RMS (ARMS) consists of rhabdomyoblasts mixed
with a larger round cells with prominent eosinophilic cytoplasm. The tumor
grows in cords and produces cleft like spaces, namely alveoli. The pleomorphic RMS ,
which is extremely rare in children show anaplastic cells present in large
aggregates or as diffuse sheets. It occurs in the extremities and the trunk.
Electron microscopy and immunohistochemical analysis of tumors are now useful
tools for demonstrating characteristics of RMS, especially when light microscopy
is inconclusive. The diagnostic EM features of RMS are visible z-bands. Skeletal
muscle or muscle-specific proteins, like antidesmin, muscle-specific actin
and Myo D can be identified by immunohistochemical staining. Monoclonal antibodies,
like those to desmin, muscle-specific actin, sarcomeric actin and myoglogin
have also been used to confirm the myogenic lineage with very good specificity
and sensitivity.[10] Monoclonal
antibodies against Myo D can be used in frozen section analysis also. The ERMS
and ARMS have been associated with distinct clinical characteristics and genetic
alterations. And ARMS is associated with 2;13 or 1;13 chromosomal translocations,
which generate PAX3-FKHR and PAX7-FKHR fusion proteins respectively. In contrast,
ERMS have allelic loss at chromosome 11p15.5. Therefore despite similarities,
the striking cytogenetic and molecular differences between ARMS and ERMS indicate
distinct molecular etiologies in these tumor subtypes).[11]
Clinical staging
It is critical to assess the extent of tumor in every patient as the therapy
and prognosis depends on the degree to which the mass has spread beyond the
primary site. Several surgico-pathologic staging systems have been used historically,
but the clinical group staging system, developed by IRS in 1972 has been most
widely used. IRS committee has now adopted a modification of the so-called
TNM system[4] [Table
- 3].
Patterns of spread
The tumor spreads locally to invade adjacent structures and may also spread
distantly via lymphatics and hematogenous routes. Approximately 15% children
with RMS present with metastatic disease and their prognosis has not improved
over the last 15 years.[3],[4],[12],[13] The
most frequent sites of distant metastases are regional lymph nodes, lungs,
bone marrow, bones, central nervous system, heart, liver and the breast.[14] The
lung is the most frequent site of metastases (40-50%) and majority (74%)
of these have bilateral metastases.[15],[16] Less
common sites, either isolated or in conjunction with multi-metastatic disease,
are bone marrow (20-30%), bone (10%) and depending on the site of primary tumor, lymph node (up to 20%). Though visceral metastases is rare, but in cases of treatment failures, predominantly, visceral metastasis (e.g. brain or liver) may be seen. IRS-IV has reported that among children with metastases, 46% had lung as the only site of metastases while 50% had other sites. Interestingly, 29% of the patients with metastases had two sites of metastases and 16% had
three sites involved.[16]
Prognostic factors
The most important prognostic variables identified appear to be the extent
of disease, i.e. patients with CG-IV or TNM stage 4 fare worse than others.[17],[18] Amongst
localized RMS, those tumors which are completely excised surgically (CG-I)
have better survival rate than those with microscopic residue or those which
are locally extensive lesions (CG-II). Those with gross residual tumors (CG-III)
fare less well but are much better of than CG-IV patients. Histology is also
an important prognostic factor. Pooled data from IRS I, II and III show that
5-year survival is related to the histology with 95% for sarcoma botryoides, 75% for pleomorphic sarcoma, 66% for embryonal, 54% for alveolar and 40% for
undifferentiated RMS.[4],[7],[12],[19]
Other unfavorable prognostic variables are older age at diagnosis,[20] presence
of regional LN metastases for extremity and paratesticular tumors,[21],[22] presence
of extensive bony erosions in cranial parameningeal tumors,[23] DNA
proliferative activity (S-phase fraction> 15%),[24],[25] and
diploid embryonal tumors. The most meaningful prognostic variable is the response
to treatment, because those who never achieve complete obliteration of the
tumor do not survive.
Metastatic disease is the single most important predictor of clinical outcome
in patients with RMS.[16] Children
with metastatic RMS have a poorer prognosis with a 3-year FFS of only 25%.[3],[12] IRS-IV
studies have shown that children with lung-only metastases have a slightly
better prognosis as compared with metastases at other sites.[16]
Principles of treatment of RMS
There are three modalities of treating children with RMS. These are surgery,
radiation therapy for control of residual bulk or microscopic tumor and systemic
combination chemotherapy for primary cytoreduction and eradication of gross
and micrometastases.
Principles of surgical management
Surgery is the most rapid way to ablate the disease and should always
be done if subsequent function or cosmesis will not be greatly impaired. Surgery
includes complete resection of the primary tumor with surrounding margins of
uninvolved tissue during the initial surgery and any subsequent operation.
If microscopic residual disease is found after initial resection, re-excision
of the area is indicated before any other nonsurgical management. Debulking
procedures have no value as initial biopsy and neo-adjuvant therapy results
in shrinkage of the tumor allowing complete resection at second look operation.
This is better than partial or marginal resections. Overall surgical resections
for childhood RMS today are less exenterative or mutilating than those employed
three to four decades earlier.[26]
In sites such as vagina, bladder and most of head and neck an incisional biopsy
may be the only feasible surgical procedure. Open biopsy is the preferred technique
of obtaining a biopsy specimen and needle biopsy of fine needle aspiration
cytology is to be used only if open biopsy is surgically hazardous. Clinically
involved LN should always be sampled, while the histologic evaluation of the
clinically uninvolved nodes is site specific as detailed below.
Second-look procedures are required in two clinical situations: (1) to pathologically
verify the completeness of an apparently complete clinical (radiologic) remission
and (2) to resect any residual viable tumor cells that have survived induction
chemotherapy and local RT.
Principles of radiation therapy
Radiation therapy (RT) is a major tool in the treatment of RMS. It can
eradicate residual tumor cells, especially in the head and neck region and
the pelvis. According to IRSG protocols all RMS should get RT to achieve long-term
local control of tumors. The dose delivered may differ depending on many factors.
The International Society of Pediatric Oncology (SIOP) differs in this as shown
clearly by their study MMT-84. The major difference in therapeutic approach
between MMT-84 and IRSG studies was the omission of radiotherapy (and also
of second look surgery) in patients with nonmetastatic RMS who achieved complete
remission with chemotherapy alone. However, RT was given to patients < 5 years of age and having parameningeal tumors and to patients more than 12 years of age having tumors at any site. In this study with a median follow-up of 8 years, the 5-year event-free survival (EFS) was 53% and the overall survival was 68%.
The EFS was inferior to IRSG reports because of a higher rate of local recurrences.
There is also controversy regarding the role of pulmonary radiotherapy for
those with pulmonary metastases. IRS-IV report[16] seems
to suggest that pulmonary radiotherapy does provide some benefit as evidenced
by decreased incidence of pulmonary recurrences and improved FFS and overall
survival.
Principles of chemotherapy
All patients with RMS must receive combination chemotherapy as there is
ample evidence that the adjuvant or neoadjuvant therapy significantly improves
survival. The chemotherapy should begin as soon as possible after diagnostic
studies are completed or primary excision done, as the major role of chemotherapy
is the eradication of microscopic foci of disease (local and distant), thereby
improving both local control and survival. Preoperative chemotherapy may also
be used in unresectable tumors to reduce them to resectable size. The current
gold standard frontline chemotherapy consists of vincristine, actinomycin D
and cyclophosphamide (VAC) was pioneered by Wilbur et al. Two conventional
regimes, which are most commonly used are: intensive vincristine/actinomycin
D (intensive VA) and pulse vincristine/actinomycin D/cyclophosphamide (pulse
VAC).
Phase II trials from Europe and USA have shown that ifosfamide, as a single
agent, is an active drug against RMS. In combination with other drugs the response
rate is even better.[27] Irnotecan,
a topoisomerase I inhibitor also appears to have promising activity against
RMS, with minimal hematopoietic toxicity.[28]
Clinical presentation/management and outlook for specific sites
The clinically evident signs and symptoms of RMS are in two main ways:
The appearance of a mass lesion and disturbance of a normal body function by
an unsuspected, critically located enlarging mass. The common sites where RMS
is reported in children as per the IRS group III report is shown in [Table
- 4]. Thirty-five percent of the cases involve the head and neck region while
the second most common site is the GU tract (26%).[3]
Head and neck
The head and neck tumors are further divided into those that arise in
the parameningeal region (50%), orbit (25%) and head and neck superficial, i.e. nonparameningeal (25%)
[Table - 4].[29]
Orbital RMS produce proptosis, chemosis, eyelid or conjunctival mass, opthalmoplegia
and rarely blindness. These are usually diagnosed early before distant dissemination
has occurred. Parameningeal tumors usually cause nasal, aural or sinus obstruction.
These are often associated with cranial bone erosions that can manifest as
cranial nerve palsies. Erosion of contiguous bone at the cranial base and intracranial
extension may lead to headache, vomiting and systemic hypertension. Nasophranygeal
tumors can cause voice changes, airway obstruction, dysphagia and epistaxis
while sinus tumor can be painful in addition to be having persistent nasal
discharge and occasion epistaxis. Tumors of the middle ear or mastoid can present
as a polypoidal growth from the ear, otitis media, or facial palsy. Laryngeal
tumors can present with hoarseness. Regional lymph node metastases to cervical
lymph nodes may be present in upto 20% cases depending on the site.
Distant metastasis is primarily to the lungs or the bones. While the orbital
tumors have very good prognosis, the parameningeal tumors have the poorest
prognosis.
For orbital tumors nonexcisional therapy is standard. Initial biopsy followed
by chemotherapy and radiation leads to survival rates of > 90%. Routine lymph node sampling is not indicated as incidence of nodal spread is only 3%.
Orbital exenteration is now recommended only for recurrent disease. Nonorbital,
nonparameningeal tumors and head and neck tumors (superficial) are mostly unresectable.
These patients are best managed by an incisional biopsy followed by chemotherapy
appropriate for their group[3] Cervical
lymph node dissection is not warranted, however, the clinically suspicious
nodes must be biopsied and if histologically positive they must be included
in the RT portal. The 5-year survival rates are approximately 80%. These patients are treated with systemic chemotherapy and RT according to the group. RT is also necessary for the spinal cord if CSF is +ve for tumor cells. The 5-year survival rate is almost 70% for nonmetastatic disease, but only 43% for
metastatic disease.
Genitourinary tract
These tumors arise in the bladder, prostate, vagina, uterus, vulva, paratesticular
regions and rarely the kidneys and ureter and constitute nearly 26% of
all RMS cases[3] [Table
- 4]. The
embryonal histology is the commonest in this region and the most frequent of
the genitourinary rhabdomyosarcomas (GU RMS) are those of the bladder/prostate
(BP) [Table - 4]. Within this category of GU RMS are tumors with good prognosis,
namely vulva, vagina and paratesticular and those with poorer prognosis, namely
bladder and prostate (GU-BP). The bladder tumors usually grow intra-luminally,
in the region of the trigone and have a polypoidal appearance on gross or endoscopic
examination. Tumors arising from the dome of the bladder are uncommon as compared
to those from the trigone, but the dome tumors have a better outcome. Children
with bladder RMS are usually under 4 years of age and may present with hematuria,
urinary obstruction and rarely extrusion of tumor tissue. Prostatic tumors
can occur in relatively older children and usually present as large pelvic
masses with or without urethral strangury and/or constipation. Initial diagnostic
workup includes an ultrasound of the pelvis, micturating cystourethrogram and
a CECT or MRI of the abdomen. Workup for metastatic disease should include
an X-ray chest, bone marrow aspiration and biopsy from both iliac crests and
a bone scan besides evaluation for retroperitoneal nodes and liver secondaries
in the CECT or MRI. IRS-IV recommends initial endoscopic, perineal, or suprapubic
diagnostic biopsy followed by intensive chemotherapy and early RT. Initial
complete resection is done only for those patients who have a tumor of the
dome of the bladder and in whom the preservation of bladder and urethral function
can be assured. Anterior pelvic exenteration and total cystectomy is reserved
for patients who do not achieve local control after chemotherapy and RT. Currently,
60% of the patients retain a functional bladder and the overall survival rate exceeds 85%.[30],[31]
Paratesticular RMS arises in the distal area of the spermatic cord and may
invade the testis and the surrounding tissues. These usually present as a unilateral
painless scrotal swelling or a mass above the testis in pre- or postpubertal
boys. Almost 30% of the paratesticular tumors are of the spindle cell
variety which has an excellent prognosis.[32] Initial
inguinal orchiectomy with the removal of the entire spermatic cord should be
done. Scrotal violation or trans-scrotal biopsy should be avoided to prevent
scrotal contamination. In case there is scrotal violation then hemiscrotectomy
should be done to prevent metastases to the inguinal nodes (which are considered
distant metastases and not local). Now, because of the availability of sensitive
imaging techniques like spiral CT and MRI, IRS-IV does not recommend routine
RPLN dissection for patients with completely resected localized tumors and
negative imaging studies. The survival rates are now around 90% with
adjuvant chemotherapy and RT directed to known nodal or residual disease.[22],[33]
Vaginal tumors present at younger age than those of the uterine (mean age 2
years vs 14
years). Vaginal RMS is usually of the botryoid variety and present as mucosanguinous
discharge, bleeding, or a prolapsing polypoidal mass. Cervical and uterine
sarcomas are diagnosed in older children who present with a mass and history
of vaginal discharge. Vulval RMS is usually seen in older children as a mass
lesion extending from the vulval and can often be mistaken for an abscess.
At present the IRS approach for vaginal RMS is biopsy, to confirm diagnosis,
cystoscopy and CT scan of the pelvis to rule out local spread. Chemotherapy
is followed by repeat vaginal examinations and biopsy without resectional surgery.
Persistent disease is managed by local limited resection or partial vaginectomy.
Uterine tumors are also initially treated with chemotherapy and second look
surgery and radical resection (hysterectomy + proximal vaginectomy)
is required only for gross residual disease who have failed to achieve a complete
radiographic response within 6 months of induction chemotherapy and RT, or
those who have early progression.[34]
Extremities
RMS involving the extremities comprise 19% of all RMS [Table
- 4] and are characterized by a swelling in the affected body part. They involve the lower extremity more than the upper and distal limb involvement is more common than proximal. Pain, tenderness and redness may occur and almost 45% of
these are of alveolar histology.[35] Limb
sparing, wide resection of the tumor is recommended whenever feasible and without
loss of function since excision results in improved results.[36] Amputation
should be avoided. Since more than one-fourth of these patients have metastases
to the regional lymph nodes therefore IRS-IV recommends routine LN sampling,
even if clinically negative. Positive lymph nodes warrant their inclusion in
the RT portal. If surgical margins are microscopically positive the re-excision
should be done prior to chemotherapy and RT.[37] Postoperatively
all patients get chemotherapy and radiotherapy. The survival rate was 80% when lymph nodes were not involved as compared to 46% when
involved.[36] There is also an
increased rate of distant metastases when regional LN was involved.[38]
Retroperitoneum
Retroperitoneal (RP) tumors, excluding the GU tract, account for 11% of cases and can be either embryonal or alveolar. Complete resection of these tumors is often impossible for technical reasons and regional LN are often involved and distant metastases present at the time of diagnosis. Treatment includes chemotherapy and RT according to the clinical grouping. Patients with RP-RMS have the worst prognosis with a 5-year survival rate, of nonmetastatic tumor, being only 50%.
Trunk
These sites include tumors of the chest wall, paraspinal region and the
abdominal wall in decreasing order of frequency and constitute 10% of all cases of RMS. Most of these are of alveolar histology and < 30% are
amenable to complete resection at diagnosis.[32] Whenever
excised they have a tendency to recur locally. Treatment includes chemotherapy
and RT according to the clinical grouping.
Non-RMS soft tissue sarcomas in children
The rarity and histologic heterogenecity [Table
- 5] of NRSTS in children preclude careful study of their natural history and response to therapy. NRSTS like RMS can arise in any part of the body, but the most common sites are extremities, trunk, abdomen and pelvis.[39] The most frequent histologic types are synovial sarcoma, neurofibrosarcoma and fibrosarcoma. In the extremities the tumor occurs mostly in the lower limbs. While most of the extremity NRSTS in children are synovial sarcomas, tumors of the trunk are predominantly malignant fibrous histiocytomas (MFH), or neurogenic in origin.
Histiology and grading of NRSTS
Most of the NRSTS in children except for the MFH and fibrosarcomas are
immature and poorly differentiated with approximately half of the tumors having
a histiologic grade G-3.[40] Because
of the inconsistencies in predicted behavior, a grading scheme for pediatric
NRSTS is used, which takes into account the cytohistiologic features that are
used for adult sarcomas, but with caveats of the childhood lesions [Table
- 6]. This system is not used for RMS or for primitive neuroectodermal lesions,
which are always considered high grade tumors.
Prognostic factors for NRSTS
The prognostic factors for children with NRSTS include the presence of
or absence of metastatic disease, surgical respectability of the lesion, tumor
histiologic grade, tumor invasiveness and size of the lesion.[39] In
a review of 154 children with NRSTS treated at a single institution,[39] 31% of those with grade 1 or 2 lesions had treatment failures, while 73% of
the children with grade 3 disease developed recurrent disease.
Clinical evaluation and staging of NRSTS
In all children suspected to have NRSTS the clinical evaluation should
include routine hemograms, renal and liver function tests, bone scans and bone
marrow examination. MRI scan is considered the imaging modality of choice for
the evaluation of local and regional disease, particularly in the extremities,
the pelvis and head and neck regions. The staging system currently used for
NRSTS is the same as the modified TNM staging system used for RMS. The optimal
method for obtaining tissue for diagnosis in patients with NRSTS is again datable.
Although fine needle aspiration cytology (FNAC) is a useful diagnostic tool
in the initial evaluation of NRSTS or a possible metastatic lesion, needle
core biopsy (NCB) is better for providing enough tissue to permit accurate
histologic subtyping of a sarcoma. Excisional biopsy rarely should be used
in the initial evaluation of these tumors. Simple excision of the tumor violates
the tissue planes and results in dissemination of the tumor cells throughout
the operative field. Subsequent surgery in the region is thereby compromised.
An excisional biopsy is undertaken only in those instances when the tumor is
small (< 2.5 cm) or situated so that an eventual wide local resection can
be done without risk or functional deformity. When an incisional biopsy is
done it should be properly planned. For an extremity lesion, the incision should
be planned longitudinally or parallel to the neurovascular bundle.
Treatment and outcome of NRSTS
During the past few years the surgical management of these tumors has
undergone a considerable evolution with the realization that multimodal therapy
provides the best chance for survival. Unlike that for RMS, which is a highly
chemosensitive tumor, the mainstay of treatment of NRSTS is complete surgical
resection with or without adjuvant radiotherapy to prevent local recurrence.
Several prospective adult trials have failed to document survival benefit of
adjuvant chemotherapy.[9] The only
prospective pediatric trial addressing the value of adjuvant chemotherapy in
patients with NRSTS was conducted by the Pediatric Oncology Group (POG). In
this trial, 75 children with completely resected NRSTS lesions were assigned
to receive observation vs adjuvant
chemotherapy with VAC and doxorubicin. The 3-year disease-free survival rate
for the two groups did not differ (74% vs 76%). Sub-group
analysis disclosed that patients with grade 3 lesions fared significantly worse
than those with grades 1 and 2 lesions (3-year EFS, 75% vs 91%; P =
0.018).[9] Distant
relapses accounted for more than 80% of the failures in the high grade group. The outcome for children with metastatic NRSTS continues to be poor; fewer than 20% of
the patients are disease free at 3 years.[9] The
most active drugs against NRSTS include ifosfamide and doxorubicin. Currently
POG is investigating the clinical activity of some combination chemotherapies
for unresectable or metastatic NRSTS. If these prospective trials identify
some beneficial outcomes then these active agents may be also tried as adjuvant
chemotherapy in children with completely resected high grade NRSTS.
Wide local excision or en bloc resection should be the primary form of treatment
in children with NRSTS. All attempts should be made to obtain negative margins.
What consists of an adequate margin of tissue is still debated. In some areas
such as head and neck, mediastinum and retroperitoneum, wide local excision
with clear margins may be impossible to achieve[41] without
mutilating resections. The finding of microscopic involvement of surgical
margins is highly predictive for local disease recurrence, distant disease
recurrence
and diminished overall survival.[42],[43] This
is why primary re-excision should have priority over any adjuvant therapy.[44] Adjuvant
RT is recommended in all cases of NRSTS in adults as these tumors respond
to RT. This is not the case in childhood NRSTS. RT has been used sparingly
in
children because of its long-term effects.[45] Current
recommendations for children are to avoid RT for grades 1 and 2 completely
resected tumors, however, incompletely resected tumors require additional
therapy for local control.
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