Childhood Soft Tissue Sarcoma Treatment (PDQ®)—Health Professional Version - National Cancer Institute

Childhood Soft Tissue Sarcoma Treatment (PDQ®)–Health Professional Version

Staging and Grading Systems for Childhood Soft Tissue Sarcoma

Clinical staging has an important role in predicting the clinical outcome and determining the most effective therapy for pediatric soft tissue sarcomas. 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 soft tissue sarcoma does not exist, two systems are currently in use for staging pediatric nonrhabdomyosarcomatous soft tissue sarcoma:[1]

Surgico-pathologic staging system: The surgico-pathologic staging system used by the Intergroup Rhabdomyosarcoma Study is based on the amount, or extent, of tumor that remains after initial surgery and whether the disease has metastasized (refer to the Intergroup Rhabdomyosarcoma Study Staging System section of this summary for more information). This staging system was used in early pediatric trials.[2]
TNM staging system: The TNM staging system is a collaborative effort between the AJCC (United States) and the International Union Against Cancer (worldwide). 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). Refer to Tables 3, 4, 5, and 6 for the staging of soft tissue sarcoma from the eighth edition of the AJCC Cancer Staging Manual.[3-7] The last Children's Oncology Group (COG) trial used the sixth edition AJCC Cancer Staging Manual for soft tissue sarcoma (with central pathology review).[1] A review of children with non-rhabdomyosarcoma soft tissue sarcomas was performed with data from the Surveillance, Epidemiology, and End Results (SEER) program and identified 941 patients between 1988 and 2007.[8] The COG risk stratification was validated in this cohort.

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.
- Group IIA: Localized, grossly resected tumor with microscopic residual disease.
- Group 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.
- Group 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 soft tissue sarcoma that recurs after initial treatment or progresses after radiation therapy, chemotherapy, or initial surgery.

TNM Staging System

The eighth edition of the AJCC Cancer Staging Manual has designated staging by the four criteria of tumor size, nodal status, histologic grade, and metastasis and by anatomic primary tumor site (head and neck; trunk and extremities; abdomen and thoracic visceral organs; retroperitoneum; and unusual histologies and sites) (refer to Tables 3, 4, 5, and 6).[3-7] For information on unusual histologies and sites, refer to the AJCC Cancer Staging Manual.[7]

Table 3. Definition of Primary Tumor (T) for Soft Tissue Sarcoma of the Trunk, Extremities, and Retroperitoneum; Head and Neck; and Abdomen and Thoracic Visceral Organsa

T Category	Soft Tissue Sarcoma of the Trunk, Extremities, and Retroperitoneum	Soft Tissue Sarcoma of the Head and Neck	Soft Tissue Sarcoma of the Abdomen and Thoracic Visceral Organs
aAdapted from O'Sullivan et al.,[3] Yoon et al.,[4] Raut et al.,[5] and Pollock et al.[6]
TX	Primary tumor cannot be assessed.	Primary tumor cannot be assessed.	Primary tumor cannot be assessed.
T0	No evidence of primary tumor.
T1	Tumor ≤5 cm in greatest dimension.	Tumor ≤2 cm.	Organ confined.
T2	Tumor >5 cm and ≤10 cm in greatest dimension.	Tumor >2 to ≤4 cm.	Tumor extension into tissue beyond organ.
T2a			Invades serosa or visceral peritoneum.
T2b			Extension beyond serosa (mesentery).
T3	Tumor >10 cm and ≤15 cm in greatest dimension.	Tumor >4 cm.	Invades another organ.
T4	Tumor >15 cm in greatest dimension.	Tumor with invasion of adjoining structures.	Multifocal involvement.
T4a		Tumor with orbital invasion, skull base/dural invasion, invasion of central compartment viscera, involvement of facial skeleton, or invasion of pterygoid muscles.	Multifocal (2 sites).
T4b		Tumor with brain parenchymal invasion, carotid artery encasement, prevertebral muscle invasion, or central nervous system involvement via perineural spread.	Multifocal (3–5 sites).
T4c			Multifocal (>5 sites).

Table 4. Definition of Regional Lymph Node (N) for Soft Tissue Sarcoma of the Head and Neck; Trunk and Extremities; Abdomen and Thoracic Visceral Organs; and Retroperitoneuma

aAdapted from O'Sullivan et al.,[3] Yoon et al.,[4] Raut et al.,[5] and Pollock et al.[6]
bFor soft tissue sarcoma of the abdomen and thoracic visceral organs, N0 = no lymph node involvement or unknown lymph node status and N1 = lymph node involvement present.
N0	No regional lymph node metastasis or unknown lymph node status.b
N1	Regional lymph node metastasis.b

Table 5. Definition of Distant Metastasis (M) for Soft Tissue Sarcoma of the Head and Neck; Trunk and Extremities; Abdomen and Thoracic Visceral Organs; and Retroperitoneuma

aAdapted from O'Sullivan et al.,[3] Yoon et al.,[4] Raut et al.,[5] and Pollock et al.[6]
bFor soft tissue sarcoma of the abdomen and thoracic visceral organs, M0 = no metastases and M1 = metastases present.
M0	No distant metastasis.b
M1	Distant metastasis.b

Table 6. AJCC Prognostic Stage Groups for Soft Tissue Sarcoma of the Trunk, Extremities, and Retroperitoneuma

Stage	T	N	M	Grade
T = primary tumor; N = regional lymph node; M = distant metastasis.
aAdapted from Yoon et al. [4] and Pollock et al.[6]
bStage IIIB for soft tissue sarcoma of the retroperitoneum; stage IV for soft tissue sarcoma of the trunk and extremities.
IA	T1	N0	M0	G1, GX
IB	T2, T3, T4	N0	M0	G1, GX
II	T1	N0	M0	G2, G3
IIIA	T2	N0	M0	G2, G3
IIIB	T3, T4	N0	M0	G2, G3
IIIB/IVb	Any T	N1	M0	Any G
IV	Any T	Any N	M1	Any G

Soft Tissue Sarcoma Tumor Pathological Grading System

In most cases, accurate histopathologic classification alone of soft tissue sarcomas does not yield optimal information about their clinical behavior. Therefore, several histologic parameters are evaluated in the grading process, including the following:

Degree of cellularity.
Cellular pleomorphism.
Mitotic activity.
Degree of necrosis.
Invasive growth.

This process is used to improve the correlation between histologic findings and clinical outcome.[9] In children, grading of soft tissue sarcoma 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 the validity of 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 soft tissue sarcomas other than rhabdomyosarcoma and devised the POG grading system. Analysis of outcome for patients with localized soft tissue sarcomas 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 soft tissue sarcoma.[9-11]

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.[9] It is an older grading system of historical value that is no longer being used for treatment.

Grade I

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

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

Grade II

Grade II lesions are soft tissue sarcomas 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):

Alveolar soft part sarcoma.
Extraskeletal osteogenic sarcoma.
Malignant Triton tumor.
Mesenchymal chondrosarcoma.
Pleomorphic or round-cell liposarcoma.
Any other sarcoma not in grade I with >15% necrosis and/or ≥5 mitotic figures per 10 high-power fields (40X objective). 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 soft tissue sarcoma. The purpose of the grading system is to predict which patients will develop metastasis and subsequently benefit from postoperative chemotherapy.[12,13] The system is described in Table 7 and Table 8.

Table 7. FNCLCC Histologic Grading System

FNCLCC = Fédération Nationale des Centres de Lutte Contre Le Cancer; HPF = high-power field.
Tumor Differentiation
Score 1	Sarcoma closely resembling normal adult mesenchymal tissue (e.g., well-differentiated liposarcoma)
Score 2	Sarcomas for which histologic typing is certain (e.g., myxoid liposarcoma)
Score 3	Embryonal and undifferentiated sarcomas, sarcomas of doubtful type, and synovial sarcomas

Mitotic Count
Score 1	0–9 mitoses per 10 HPF
Score 2	10–19 mitoses per 10 HPF
Score 3	≥20 mitoses per 10 HPF

Tumor Necrosis
Score 0	No necrosis
Score 1	<50% tumor necrosis
Score 2	≥50% tumor necrosis

Table 8. Histologic Grade Determined by Total Score

Total Score	Histologic Grade
2–3	Grade I
4–5	Grade II
6–8	Grade III

Prognostic Significance of Tumor Grading

The POG and FNCLCC grading systems have proven to be of prognostic value in pediatric and adult nonrhabdomyosarcomatous soft tissue sarcomas.[14-18] In a study of 130 tumors from children and adolescents with nonrhabdomyosarcomatous soft tissue sarcoma 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 patients whose tumors received discrepant grades (POG grade 3, FNCLCC grade 1 or 2) had outcomes between concurrent grade 3 and grades 1 and 2. A mitotic index of 10 or greater emerged as an important prognostic factor.[19]

The completed COG-ARST0332 trial will analyze data comparing the POG and FNCLCC pathologic grading systems to determine which system better correlates with clinical outcomes. The closed COG trial (ARST1321 [NCT02180867]) used the FNCLCC system to assign histological grade.

References

American Joint Committee on Cancer: AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002.
Maurer HM, Beltangady M, Gehan EA, et al.: The Intergroup Rhabdomyosarcoma Study-I. A final report. Cancer 61 (2): 209-20, 1988. [PUBMED Abstract]
O'Sullivan B, Maki RG, Agulnik M, et al.: Soft tissue sarcoma of the head and neck. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 499-505.
Yoon SS, Maki RG, Asare EA, et al.: Soft tissue sarcoma of the trunk and extremities. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 507-15.
Raut CP, Maki RG, Baldini EH, et al.: Soft tissue sarcoma of the abdomen and thoracic visceral organs. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 517-21.
Pollock RE, Maki RG, Baldini EH, et al.: Soft tissue sarcoma of the retroperitoneum. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 531-7.
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