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Childhood Soft Tissue Sarcoma Treatment (PDQ®)

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Last Modified: 09/08/2014

Staging and Grading Systems for Childhood Soft Tissue Sarcoma

Intergroup Rhabdomyosarcoma Study Staging System
        Nonmetastatic disease
        Metastatic disease
        Recurrent/progressive disease
TNM Staging System
Soft Tissue Sarcoma Tumor Pathological Grading System
        POG grading system
        FNCLCC grading system
Prognostic Significance of Tumor Grading

Clinical staging has an important role in predicting the clinical outcome and determining the most effective therapy for pediatric soft tissue sarcomas (STSs). As yet, there is no well-accepted staging system that is applicable to all childhood sarcomas. The system from the American Joint Committee on Cancer (AJCC) that is used for adults has not been validated in pediatric studies.

Although a standardized staging system for pediatric nonrhabdomyosarcomatous STS does not exist, the last Children's Oncology Group (COG) trial used the sixth edition AJCC cancer staging manual for STSs (with central pathology review) (see Tables 3–6 below).[1]

Two systems are currently in use for staging pediatric nonrhabdomyosarcomatous STS tumors.

  • Surgico-pathologic staging system: The surgico-pathologic staging system used by the Intergroup Rhabdomyosarcoma Study (see below) is based on the amount, or extent, of tumor that remains after initial surgery and whether the disease has metastasized.[2]
  • TNM staging system: The other system typically used to stage pediatric soft tissue tumors is the TNM system of the International Union Against Cancer. Staging is based on the extent of the tumor (T), the extent of spread to the lymph nodes (N), and the presence of metastasis (M).[3]
Intergroup Rhabdomyosarcoma Study Staging System

Nonmetastatic disease
  • Group I: Localized tumor, completely resected with histologically negative margins.
  • Group II: Grossly resected tumor with microscopic residual tumor at the margin(s) and/or extension into regional lymph nodes.
    • IIA: Localized, grossly resected tumor with microscopic residual disease.
    • IIB: Regional disease with involved nodes completely resected with no microscopic disease. The most proximal (to the patient, most distal to the tumor) regional lymph node must be negative.
    • IIC: Regional disease with involved nodes grossly resected but with evidence of residual microscopic disease at the primary site and/or histologic involvement of the most proximal regional lymph node in the dissection.
  • Group III: Localized tumor, incompletely resected, or biopsy only, with gross residual tumor.
Metastatic disease
  • Group IV: Any localized or regional tumor with distant metastases present at the time of diagnosis. This includes the presence of malignant cells in effusions (pleural, peritoneal) and/or cerebrospinal fluid (rare).
Recurrent/progressive disease
  • Any STS that recurs after initial treatment or progresses after radiation therapy, chemotherapy, or initial surgery.
TNM Staging System

The AJCC has designated staging by the four criteria of tumor size, nodal status, histologic grade, and metastasis.[4]

Table 3. Primary Tumor (T)a
TXPrimary tumor cannot be assessed.
T0No evidence of primary tumor.
T1Tumor ≤5 cm in greatest dimension.b
T1aSuperficial tumor.
T1bDeep tumor.
T2Tumor >5 cm in greatest dimension.b
T2aSuperficial tumor.
T2bDeep tumor.

aReprinted with permission from AJCC: Soft tissue sarcoma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 291-8.
bSuperficial tumor is located exclusively above the superficial fascia without invasion of the fascia; deep tumor is located either exclusively beneath the superficial fascia, superficial to the fascia with invasion of or through the fascia, or both superficial yet beneath the fascia.

Table 4. Regional Lymph Nodes (N)a
NXRegional lymph nodes cannot be assessed.
N0No regional lymph node metastasis.
N1bRegional lymph node metastasis.

aReprinted with permission from AJCC: Soft tissue sarcoma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 291-8.
bPresence of positive nodes (N1) in M0 tumors is considered Stage III.

Table 5. Distant Metastasis (M)a
aReprinted with permission from AJCC: Soft tissue sarcoma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 291-8.
M0No distant metastasis.
M1Distant metastasis.

Table 6. Anatomic Stage/Prognostic Groupsa
Stage T N M Grade 
aReprinted with permission from AJCC: Soft tissue sarcoma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 291-8.
IAT1aN0M0G1, GX
T1bN0M0G1, GX
IBT2aN0M0G1, GX
T2bN0M0G1, GX
IIAT1aN0M0G2, G3
T1bN0M0G2, G3
IIBT2aN0M0G2
T2bN0M0G2
IIIT2a, T2bN0M0G3
Any TN1M0Any G
IVAny TAny NM1Any G

Soft Tissue Sarcoma Tumor Pathological Grading System

In most cases, accurate histopathologic classification of STSs alone does not yield optimal information about their clinical behavior. Therefore, several histologic parameters, including degree of cellularity, cellular pleomorphism, mitotic activity, degree of necrosis, and invasive growth, are evaluated in the grading process. This process is used to improve the correlation between histologic findings and clinical outcome.[5] In children, grading of STSs is compromised by the good prognosis of certain tumors, such as infantile fibrosarcoma and hemangiopericytoma, which have a good prognosis in children younger than 4 years, and also angiomatoid fibrous histiocytoma and dermatofibrosarcoma protuberans, which may recur locally if incompletely excised, but usually do not metastasize.

Testing a grading system within the pediatric population is difficult because of the rarity of these neoplasms. In March 1986, the Pediatric Oncology Group (POG) conducted a prospective study on pediatric STSs other than rhabdomyosarcoma and devised the grading system that is shown below. Analysis of outcome for patients with localized STSs other than rhabdomyosarcoma demonstrated that patients with grade 3 tumors fared significantly worse than those with grade 1 or grade 2 lesions. This finding suggests that this system can accurately predict the clinical behavior of nonrhabdomyosarcomatous STS.[5-7]

The grading systems developed by the POG and the French Federation of Comprehensive Cancer Centers (Fédération Nationale des Centres de Lutte Contre Le Cancer [FNCLCC]) Sarcoma Group are described below. These grading systems are being compared by the central review pathologists on the COG-ARST0332 study. The study has closed and results are pending.

POG grading system

The POG grading system is described below:[5]

Grade I

Grade I lesions are based on histologic type, well-differentiated cytohistologic features, and/or age of the patient.

  • Liposarcoma–myxoid or well-differentiated.
  • Well-differentiated or infantile (aged ≤4 years) fibrosarcoma.
  • Well-differentiated or infantile (aged ≤4 years) hemangiopericytoma.
  • Well-differentiated malignant peripheral nerve sheath tumor.
  • Angiomatoid fibrous histiocytoma.
  • Dermatofibrosarcoma protuberans.
  • Myxoid chondrosarcoma.
Grade II

Grade II lesions are STSs not included in grade I or III by histologic diagnosis (with <5 mitoses/10 high-power fields or <15% necrosis):

  • 15% or less of the surface area shows necrosis (primary criteria).
  • The mitotic count is <5 mitotic figures per 10 high-power fields (40X objective) (primary criteria).
  • Nuclear atypia is not marked (secondary criteria).
  • The tumor is not markedly cellular (secondary criteria).
Grade III

Grade III lesions are similar to Grade II lesions and include certain tumors known to be clinically aggressive by virtue of histologic diagnosis and non-Grade I tumors (with >4 mitoses per 10 high-power fields or >15% necrosis):

  • Pleomorphic or round-cell liposarcoma.
  • Mesenchymal chondrosarcoma.
  • Extraskeletal osteogenic sarcoma.
  • Malignant triton tumor.
  • Alveolar soft part sarcoma.
  • Any other sarcoma not in grade I with >15% necrosis and/or ≥5 mitotic figures per 10 high-power fields (40X objective).

Any other sarcoma not included in grade I in which more than 15% of the surface area is necrotic or in which there are more than four mitotic figures per ten high-power fields (40X objective) is considered a grade III lesion. Marked atypia and cellularity are less predictive but may assist in placing tumors in this category.

FNCLCC grading system

The FNCLCC histologic grading system was developed for adults with STS. The purpose of the grading system is to predict which patients will develop metastasis and subsequently benefit from adjuvant chemotherapy.[8,9] The system is described in Tables 7 and 8.

Table 7. FNCLCC Histologic Grading System
FNCLCC = Fédération Nationale des Centres de Lutte Contre Le Cancer; HPF = high-power field.
Tumor Differentiation
Score 1Sarcoma closely resembling normal adult mesenchymal tissue (e.g., well-differentiated liposarcoma)
Score 2Sarcomas for which histologic typing is certain (e.g., myxoid liposarcoma)
Score 3Embryonal and undifferentiated sarcomas, sarcomas of doubtful type, and synovial sarcomas
Mitotic Count
Score 10–9 mitoses per 10 HPF
Score 210–19 mitoses per 10 HPF
Score 3≥20 mitoses per 10 HPF
Tumor Necrosis
Score 0No necrosis
Score 1<50% tumor necrosis
Score 2≥50% tumor necrosis

Table 8. Histologic Grade Determined by Total Score
Total Score Histologic Grade 
2–3Grade I
4–5Grade II
6–8Grade III

Prognostic Significance of Tumor Grading

The two grading systems described above have proven to be of prognostic value in pediatric and adult nonrhabdomyosarcomatous STSs.[10-14] In a study of 130 tumors from children and adolescents with nonrhabdomyosarcomatous STS enrolled in three prospective clinical trials, a correlation was found between the POG-assigned grade and the FNCLCC-assigned grade. However, grading did not correlate in all cases; 44 tumors received discrepant grades and their clinical outcome was intermediate between those who were assigned grades 1 and 2 or 3 in both systems. A mitotic index of 10 or greater emerged as an important prognostic factor.[15] The recently completed COG-ARST0332 trial will analyze data comparing the POG and FNCLCC pathologic grading systems to determine which system better correlates with clinical outcomes.

In a review of a large adult series of nonrhabdomyosarcomatous STSs, superficial extremity sarcomas had a better prognosis than deep tumors. Thus, in addition to grade and size, the depth of invasion of the tumor should be considered.[16]

Several adult and pediatric series have shown that patients with large or invasive tumors have a significantly worse prognosis than do those with small, noninvasive tumors. A retrospective review of STSs in children and adolescents suggests that the 5 cm cutoff used for adults with STS may not be ideal for smaller children, especially infants. The review identified an interaction between tumor diameter and body surface area.[17] This relationship requires further study to determine the therapeutic implications of the observation.

References
  1. American Joint Committee on Cancer: AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002. 

  2. Maurer HM, Beltangady M, Gehan EA, et al.: The Intergroup Rhabdomyosarcoma Study-I. A final report. Cancer 61 (2): 209-20, 1988.  [PUBMED Abstract]

  3. Harmer MH, ed.: TNM Classification of Pediatric Tumors. Geneva: UICC, 1982. 

  4. Soft tissue sarcoma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 291-6. 

  5. Parham DM, Webber BL, Jenkins JJ 3rd, et al.: Nonrhabdomyosarcomatous soft tissue sarcomas of childhood: formulation of a simplified system for grading. Mod Pathol 8 (7): 705-10, 1995.  [PUBMED Abstract]

  6. Recommendations for the reporting of soft tissue sarcomas. Association of Directors of Anatomic and Surgical Pathology. Mod Pathol 11 (12): 1257-61, 1998.  [PUBMED Abstract]

  7. Skytting B, Meis-Kindblom JM, Larsson O, et al.: Synovial sarcoma--identification of favorable and unfavorable histologic types: a Scandinavian sarcoma group study of 104 cases. Acta Orthop Scand 70 (6): 543-54, 1999.  [PUBMED Abstract]

  8. Coindre JM, Terrier P, Guillou L, et al.: Predictive value of grade for metastasis development in the main histologic types of adult soft tissue sarcomas: a study of 1240 patients from the French Federation of Cancer Centers Sarcoma Group. Cancer 91 (10): 1914-26, 2001.  [PUBMED Abstract]

  9. Guillou L, Coindre JM, Bonichon F, et al.: Comparative study of the National Cancer Institute and French Federation of Cancer Centers Sarcoma Group grading systems in a population of 410 adult patients with soft tissue sarcoma. J Clin Oncol 15 (1): 350-62, 1997.  [PUBMED Abstract]

  10. Rao BN: Nonrhabdomyosarcoma in children: prognostic factors influencing survival. Semin Surg Oncol 9 (6): 524-31, 1993 Nov-Dec.  [PUBMED Abstract]

  11. Pisters PW, Leung DH, Woodruff J, et al.: Analysis of prognostic factors in 1,041 patients with localized soft tissue sarcomas of the extremities. J Clin Oncol 14 (5): 1679-89, 1996.  [PUBMED Abstract]

  12. Coindre JM, Terrier P, Bui NB, et al.: Prognostic factors in adult patients with locally controlled soft tissue sarcoma. A study of 546 patients from the French Federation of Cancer Centers Sarcoma Group. J Clin Oncol 14 (3): 869-77, 1996.  [PUBMED Abstract]

  13. Pappo AS, Fontanesi J, Luo X, et al.: Synovial sarcoma in children and adolescents: the St Jude Children's Research Hospital experience. J Clin Oncol 12 (11): 2360-6, 1994.  [PUBMED Abstract]

  14. Pratt CB, Maurer HM, Gieser P, et al.: Treatment of unresectable or metastatic pediatric soft tissue sarcomas with surgery, irradiation, and chemotherapy: a Pediatric Oncology Group study. Med Pediatr Oncol 30 (4): 201-9, 1998.  [PUBMED Abstract]

  15. Khoury JD, Coffin CM, Spunt SL, et al.: Grading of nonrhabdomyosarcoma soft tissue sarcoma in children and adolescents: a comparison of parameters used for the Fédération Nationale des Centers de Lutte Contre le Cancer and Pediatric Oncology Group Systems. Cancer 116 (9): 2266-74, 2010.  [PUBMED Abstract]

  16. Brooks AD, Heslin MJ, Leung DH, et al.: Superficial extremity soft tissue sarcoma: an analysis of prognostic factors. Ann Surg Oncol 5 (1): 41-7, 1998 Jan-Feb.  [PUBMED Abstract]

  17. Ferrari A, Miceli R, Meazza C, et al.: Soft tissue sarcomas of childhood and adolescence: the prognostic role of tumor size in relation to patient body size. J Clin Oncol 27 (3): 371-6, 2009.  [PUBMED Abstract]