S. Agarwala Department of Pediatric Surgery, All India Institute of Medical Sciences, New Delhi, India

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1 Review Article Full text online at Pediatric rhabdomyosarcomas and nonrhabdomyosarcoma soft tissue sarcoma S. Agarwala Department of Pediatric Surgery, All India Institute of Medical Sciences, New Delhi, India Correspondence: Sandeep Agarwala, Department of Pediatric Surgery, All India Institute of Medical Sciences, New Delhi , India. sandpagr@hotmail.com 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. KEY WORDS: 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). It is ubiquitous occurring almost everywhere but most commonly in the 15

2 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 crossstriations, 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 Table 1: International classification system for childhood rhabdomyosarcomas [9] I II Superior prognosis a) Botryoid b) Spindle cell Intermediate prognosis a) Embryonal III Poor prognosis a) Alveolar b) Undifferentiated sarcomas Table 2: Histologic distribution of childhood rhabdomyosarcoma [21] Histologic type Percentage Embryonal 59.4 Alveolar 18.5 Pleomorphic 0.5 Undifferentiated 0.5 RMS, type undetermined 13 Extraosseous Ewing s sarcoma* 3.6 RMS, rhabdomyosarcoma, *No longer defined as rhabdomyosarcoma. 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, musclespecific 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 16

3 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 Table 3a: Clinical grouping system used by the IRS I through III [4] Group I: Localized disease, completely resected A Confined to the organ or muscle of origin. B Infiltration outside organ or muscle of origin; regional nodes not involved. Group II: Total gross resection with evidence of regional spread A Grossly resected tumors with microscopic residual tumor. B Regional disease completely resected with regional nodes involved, tumor extension into adjacent organs or both. Group III: Incomplete resection or biopsy with gross residual disease remaining. A Localized or locally extensive tumor, gross residual disease after biopsy only. B Localized or locally extensive tumor, gross residual disease after major resection (>50% debulking). Group IV: Any size primary tumor, with or without regional lymphnode involvement, with distant metastases, irrespective of surgical approach to the primary tumor. 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, Table 3b: TNM pretreatment staging classification for RMS [4] Staging prior to treatment requires thorough clinical examination and laboratory and imaging examinations. Biopsy is required to establish the histologic diagnosis. Pretreatment size is determined by external measurement or MRI or CT, depending upon the anatomic location. For less accessible primary sites, CT is employed as a means of lymphnode assessment as well. Metastatic sites require some form of imaging (but not histologic confirmation, except for bone marrow examination) confirmation. Stage Sites T Size N M 1 Favorable T1 or T2 a or b N0 or N1 or Nx M0 2 Unfavorable T1 or T2 a N0 or Nx M0 3 Unfavorable T1 or T2 a N1 M0 b N0 or N1 or Nx M0 4 Either T1 or T2 a or b N0 or N1 M1 Definitions: Site: Favorable sites are orbit, head and neck (excluding parameningeal), or genitourinary (excluding bladder/prostate) Unfavorable sites are bladder/prostate, parameningeal, extremities, trunk and all others Tumor: T1 = Tumor confined to anatomic site of origin a) <5 cm in diameter b) >5 cm in diameter T2 = Extension and/or fixation to surrounding tissues a) <5 cm in diameter b) >5 cm in diameter Regional nodes: N0, Regional nodes not clinically involved N1, Regional nodes clinically involved by tumor Nx, Clinical status of regional nodes unknown (specially sites which preclude lymph node evaluation) Metastasis: M0, No distant metastases M1, Metastases present 17

4 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 longterm 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 18

5 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 Table 4: The site of primary tumor as reported in IRS-III [21] Site Total Total 1062 All Head/neck 375 (35) Orbit 109 (10) Superficial 111 (10) Parameningeal 155 (15) GU (not BP) 167 (16) GU-BP 110 (10) Extremity 202 (19) Others 208 (20) BP, bladder/prostate, Figures in parenthesis are in percentage 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 19

6 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 onefourth 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, 20

7 Table 5: Some common and uncommon NRSTS seen in children Common Rare Synovial sarcoma Angiosarcoma Fibrosarcoma Hemangiopericytoma Peripheral neuroectodermal tumor Clear cell sarcoma Malignant fibrous histiocytoma Epitheloid cell sarcoma Leiomyosarcoma Intra-abdominal desmoplastic tumor Neurogenic tumors Malignant mesenchymoma - Malignant schwanoma - Neurofibrosarcoma - Malignant peripheral nerve sheath tumor Extra skeletal chondrosarcoma 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] Table 6: POG schema for grading of NRSTS in children Grade 1 - Myxoid well-differentiated liposarcoma - Deep seated dermatofibrosarcoma protuberans - Well-differentiated or infantile (age <5 years) fibrosarcoma. - Well-differentiated or infantile (age <5 years) hemangiopericytoma - Well-differentiated malignant peripheral nerve sheath tumor. - Angiomatoid malignant fibrous histiocytoma Grade 2 Sarcomas not specifically included in grade 1 or 3; <15% of tumor showing geographic necrosis or the mitotic index is <5 per 10 high power fields. Grade 3 - Pleomorphic or round cell liposarcoma - Mesenchymal chondrosarcoma - Extra-skeletal osteosarcoma - Malignant triton tumor - Alveolar soft part sarcoma 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%; 21

8 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 reexcision 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. REFERENCES 1. Miller RW, Young JL, Jr, Novakovic B. Childhood cancer. Cancer 1995;75: Miser JS, Triche TJ, Kinsella TJ, Pritchard DJ. 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