Soft Tissue and Bone

Protocol applies to soft tissue tumors of intermediate
malignant potential, malignant soft tissue tumors, and benign/locally aggressive and malignant bone tumors

Protocol web posting date: July 2006

Protocol effective date: April 2007

Based on AJCC/UICC TNM, 6th edition

Procedures

• Biopsy

• Resection

Authors

Brian P. Rubin, MD, PhD

Department of Anatomic Pathology, University of Washington Medical Center, Seattle, Washington

Christopher D.M. Fletcher, MD, FRCPath

Department of Anatomic Pathology, Brigham and Women’s Hospital, Boston, Massachusetts

Carrie Y. Inwards, MD

Department of Pathology, Mayo Clinic, Rochester, Minnesota

Anthony G. Montag, MD

Department of Pathology, University of Chicago Medical Center, Chicago, Illinois

Terrance D. Peabody, MD

Department of Orthopedic Surgery, University of Chicago Medical Center, Chicago, Illinois

Stephen J. Qualman, MD

Department of Laboratory Medicine, Children’s Hospital, Columbus, Ohio

Andrew E. Rosenberg, MD

Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts

Sharon W. Weiss, MD

Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia

Thomas Krausz, MD, FRCPath

Department of Pathology, University of Chicago Medical Center, Chicago, Illinois

For the Members of the Cancer Committee, College of American Pathologists

© 2006. College of American Pathologists. All rights reserved.

The College does not permit reproduction of any substantial portion of these protocols without its written authorization. The College hereby authorizes use of these protocols by physicians and other health care providers in reporting on surgical specimens, in teaching, and in carrying out medical research for non-profit purposes. This authorization does not extend to reproduction or other use of any substantial portion of these protocols for commercial purposes without the written consent of the College.

The College of American Pathologists offers these protocols to assist pathologists in providing clinically useful and relevant information when reporting results of surgical specimen examinations of surgical specimens. The College regards the reporting elements in the “Surgical Pathology Cancer Case Summary (Checklist)” portion of the protocols as essential elements of the pathology report. However, the manner in which these elements are reported is at the discretion of each specific pathologist, taking into account clinician preferences, institutional policies, and individual practice.

The College developed these protocols as an educational tool to assist pathologists in the useful reporting of relevant information. It did not issue the protocols for use in litigation, reimbursement, or other contexts. Nevertheless, the College recognizes that the protocols might be used by hospitals, attorneys, payers, and others. Indeed, effective January 1, 2004, the Commission on Cancer of the American College of Surgeons mandated the use of the checklist elements of the protocols as part of its Cancer Program Standards for Approved Cancer Programs. Therefore, it becomes even more important for pathologists to familiarize themselves with the document. At the same time, the College cautions that use of the protocols other than for their intended educational purpose may involve additional considerations that are beyond the scope of this document.

Summary of Changes to Checklist(s)

Protocol web posting date: July 2006

Protocol effective date: April 2007

This is a new protocol.

Surgical Pathology Cancer Case Summary (Checklist)

Protocol web posting date: July 2006

Protocol effective date: April 2007

Based on AJCC/UICC TNM, 6th edition
Protocol applies to soft tissue tumors of intermediate malignant
potential and malignant soft tissue tumors only

SOFT TISSUE: Biopsy

Patient name:

Surgical pathology number:

Note: Check 1 response unless otherwise indicated.

MACROSCOPIC

Specimen Type

___ Core needle biopsy

___ Incisional biopsy

___ Excisional biopsy

___ Other (specify): ____________________________

___ Not specified

Tumor Site

Specify (if known): ____________________________

___ Not specified

Tumor Depth (check all that apply)

___ Superficial

        ___ Dermal

        ___ Subcutaneous/suprafascial

___ Deep

        ___ Fascial

        ___ Subfascial

        ___ Intramuscular

        ___ Mediastinal

        ___ Intra-abdominal

        ___ Retroperitoneal

        ___ Head and neck

        ___ Other (specify): ____________________________

___ Cannot be determined

Note: More than 1 tissue plane may be involved and should be indicated.

Tumor Size

Greatest dimension: ___ cm

*Additional dimensions: ___ x ___ cm

___ Cannot be determined (see Comment)

MICROSCOPIC

Histologic Type (World Health Organization [WHO] classification of
soft tissue tumors)

Specify: ____________________________

___ Cannot be determined

Results of Ancillary Studies

Specify: ____________________________

___ Not performed

*Mitotic Rate

*Specify: ___ /10 high-power fields

(1 HPF x 400 = 0.1734 mm2; x40 objective; most proliferative area)

Necrosis

___ Absent

___ Present

        Extent: ___%

___ Cannot be determined

Prebiopsy Treatment (check all that apply)

___ No therapy

___ Chemotherapy performed

___ Radiation therapy performed

___ Therapy performed, type not specified

___ Unknown

Grade

System used:

___ French Federation of Cancer Centers Sarcoma Group (FNCLCC)

___ National Cancer Institute (NCI)

___ Other (specify): ____________________________

Specify grade: ___

___ Cannot be determined

Regional Lymph Nodes

___ Cannot be assessed

___ No regional lymph node metastasis

___ Regional lymph node metastasis

Specify:        Number examined: ___

        Number involved: ___

Distant Metastasis

___ Cannot be assessed

___ Distant metastasis

        *Specify site(s), if known: ____________________________

Margins (for excisional biopsy only)

___ Cannot be assessed

___ Margins uninvolved by sarcoma

        Distance of sarcoma from closest margin: ___ cm

        Specify margin: ____________________________

        Specify other close (less than 2.0 cm) margin(s): ________________________

___ Margins involved by sarcoma

        Specify margin(s): ____________________________

*Venous/Lymphatic (Large/Small Vessel) Invasion

*___ Present

*___ Absent

*___ Indeterminate

*Additional Pathologic Findings

*Specify: ____________________________

*Comment(s)

Surgical Pathology Cancer Case Summary (Checklist)

Protocol web posting date: July 2006

Protocol effective date: April 2007

Based on AJCC/UICC TNM, 6th edition
Protocol applies to soft tissue tumors of intermediate malignant
potential and malignant soft tissue tumors only

SOFT TISSUE: Resection

Patient name:

Surgical pathology number:

Note: Check 1 response unless otherwise indicated.

MACROSCOPIC

Specimen Type

___ Intralesional resection

___ Marginal resection

___ Wide resection

___ Radical resection

___ Other (specify): ____________________________

___ Not specified

Tumor Site

Specify (if known): ____________________________

___ Not specified

Tumor Depth (check all that apply)

___ Superficial

        ___ Dermal

        ___ Subcutaneous/suprafascial

___ Deep

        ___ Fascial

        ___ Subfascial

        ___ Intramuscular

        ___ Mediastinal

        ___ Intra-abdominal

        ___ Retroperitoneal

        ___ Head and neck

        ___ Other (specify): ____________________________

___ Cannot be determined

Note: More than 1 tissue plane may be involved and should be indicated.

Tumor Size

Greatest dimension: ___ cm

*Additional dimensions: ___ x ___ cm

___ Cannot be determined (see Comment)

MICROSCOPIC

Histologic Type (WHO classification of soft tissue tumors)

Specify: ____________________________

___ Cannot be determined

Results of Ancillary Studies

Specify: ____________________________

___ Not performed

*Mitotic Rate

*Specify: ___ /10 high-power fields
(1 HPF x 400 = 0.1734 mm2; x40 objective; most proliferative area)

Necrosis (macroscopic or microscopic)

___ Absent

___ Present

        Extent: ___%

Preresection Treatment (check all that apply)

___ No therapy

___ Chemotherapy performed

___ Radiation therapy performed

___ Therapy performed, type not specified

___ Unknown

Grade

System used:

___ French Federation of Cancer Centers Sarcoma Group (FNCLCC)

___ National Cancer Institute (NCI)

___ Other (specify): ____________________________

Specify grade: ___

Pathologic Staging (pTNM)

Primary Tumor (pT)

___ pTX:        Primary tumor cannot be assessed

___ pT0:        No evidence of primary tumor

___ pT1a:        Tumor 5 cm or less in greatest dimension, superficial tumor

___ pT1b:        Tumor 5 cm or less in greatest dimension, deep tumor

___ pT2a:        Tumor more than 5 cm in greatest dimension, superficial tumor

___ pT2b:        Tumor more than 5 cm in greatest dimension, deep tumor

Regional Lymph Nodes (pN)

___ pNX:        Regional lymph nodes cannot be assessed

___ pN0:        No regional lymph node metastasis

___ pN1:        Regional lymph node metastasis

Specify:        Number examined:___

        Number involved:___

Distant Metastasis (pM)

___ pMX:        Cannot be assessed

___ pM1:        Distant metastasis

        *Specify site(s), if known: ____________________________

Margins

___ Cannot be assessed

___ Margins uninvolved by sarcoma

        Distance of sarcoma from closest margin: ___ cm

        Specify margin: ____________________________

        Specify other close (less than 2.0 cm) margin(s): ________________________

___ Margins involved by sarcoma

        Specify margin(s): ____________________________

*Venous/Lymphatic (Large/Small Vessel) Invasion

*___ Present

*___ Absent

*___ Indeterminate

*Additional Pathologic Findings

*Specify: ____________________________

*Comment(s)

Surgical Pathology Cancer Case Summary (Checklist)

Protocol web posting date: July 2006

Protocol effective date: April 2007

Based on AJCC/UICC TNM, 6th edition
Protocol applies to aggressive and malignant
bone tumors only

BONE: Biopsy

Patient name:

Surgical pathology number:

Note: Check 1 response unless otherwise indicated.

MACROSCOPIC

Specimen Type

___ Core needle biopsy

___ Curettage

___ Excisional biopsy

___ Other (specify): ____________________________

___ Not specified

Bone Involved

Specify (if known): ____________________________

___ Not specified

Tumor Location (check all that apply)

___ Epiphysis

___ Metaphysis

___ Diaphysis

___ Cortical

___ Medullary cavity

___ Surface

___ Tumor involves joint

___ Tumor extension into soft tissue

___ Cannot be determined

Note: More than 1 site may be involved and should be indicated.

Radiographs

___ Radiographic images were correlated

___ Radiographic images were not correlated

Tumor Size

Greatest dimension: ___ cm

*Additional dimensions: ___ x ___ cm

___ Cannot be determined (see Comment)

MICROSCOPIC

Histologic Type (WHO classification of bone tumors)

Specify: ____________________________

___ Cannot be determined

Results of Ancillary Studies

Specify: ____________________________

___ Not performed

*Mitotic Rate

*Specify: ___ /10 high-power fields

(1 HPF x 400 = 0.1734 mm2; x40 objective; most proliferative area)

Necrosis

___ Absent

___ Present

        Extent: ___%

___ Cannot be determined

Prebiopsy Treatment (check all that apply)

___ No therapy

___ Chemotherapy performed

___ Radiation therapy performed

___ Therapy performed, type not specified

___ Unknown

Grade

Specify: ___

___ Cannot be determined

*Venous/Lymphatic (Large/Small Vessel) Invasion

*___ Present

*___ Absent

*___ Indeterminate

*Additional Pathologic Findings

*Specify: ____________________________

*Comment(s)

 Surgical Pathology Cancer Case Summary (Checklist)

Protocol web posting date: July 2006

Protocol effective date: April 2007

Based on AJCC/UICC TNM, 6th edition
Protocol applies to aggressive and malignant
bone tumors only

BONE: Resection

Patient name:

Surgical pathology number:

Note: Check 1 response unless otherwise indicated.

MACROSCOPIC

Specimen Type

___ Intralesional resection

___ Marginal resection

___ Wide local/segmental/en block resection

___ Radical resection

___ Other (specify): ____________________________

___ Not specified

Bone Involved

Specify (if known): ____________________________

___ Not specified

Tumor Location (check all that apply)

___ Epiphysis

___ Metaphysis

___ Diaphysis

___ Cortical

___ Medullary

___ Surface

___ Tumor involves joint

___ Tumor extension into soft tissue

___ Cannot be determined

Note: More than 1 tissue plane may be involved and should be indicated.

Radiographs

___ Radiographic images were correlated

___ Radiographic images were not correlated

Tumor Size

Greatest dimension: ___ cm

*Additional dimensions: ___ x ___ cm

___ Cannot be determined

MICROSCOPIC

Histologic Type (WHO classification of bone tumors)

Specify: ____________________________

___ Cannot be determined

Results of Ancillary Studies

Specify: ____________________________

___ Not performed

*Mitotic Rate

*Specify: ___ /10 high-power fields

(1 HPF x 400 = 0.1734 mm2; x40 objective; most proliferative area)

Necrosis (macroscopic or microscopic)

___ Absent

___ Present

Extent: ___%

Preresection Treatment (check all that apply)

___ No therapy

___ Chemotherapy performed

___ Radiation therapy performed

___ Therapy performed, type not specified

___ Unknown

Grade

Specify: ___

___ Cannot be determined

Pathologic Staging (pTNM)

Primary Tumor (pT)

___ pTX:        Primary tumor cannot be assessed

___ pT0:        No evidence of primary tumor

___ pT1:        Tumor 8 cm or less in greatest dimension

___ pT2:        Tumor more than 8 cm in greatest dimension

___ pT3:        Discontinuous tumors in the primary bone site

Regional Lymph Nodes (pN)

___ pNX:        Regional lymph nodes cannot be assessed

___ pN0:        No regional lymph node metastasis

___ pN1:        Regional lymph node metastasis

Specify:        Number examined:___

        Number involved:___

Distant Metastasis (pM)

___ pMX:        Cannot be assessed

___ pM1:        Distant metastasis

___ pM1a:        Lung

___ pM1b:        Other distant sites

        *Specify site(s), if known: ____________________________

Margins

___ Cannot be assessed

___ Margins uninvolved by sarcoma

        Distance of sarcoma from closest bone margin: ___ cm

        Specify bone margin: ____________________________

        Distance of sarcoma from closest soft tissue margin, if applicable: ___ cm

        Specify soft tissue margin, if applicable: ____________________________

___ Margins involved by sarcoma

        Specify margin(s): ____________________________

*Venous/Lymphatic (Large/Small Vessel) Invasion

*___ Present

*___ Absent

*___ Indeterminate

*Additional Pathologic Findings

*Specify: ____________________________

*Comment(s)

Background Documentation

Protocol web posting date: July 2006
Protocol effective date: April 2007

These recommendations are designed to be applied principally to bone and soft tissue sarcomas in teenagers and adults, since pediatric sarcomas are, in general, treated under strict protocols which may differ significantly from the recommendations supplied herein.1 

I.        Biopsy

A.        Clinical Information

1.        Patient identification

a.        Name

b.        Identification number

c.        Birth date

d.        Sex

2.        Responsible physician(s)

3.        Date of procedure

4.        Other clinical information

a.        Relevant history

(1)        duration of lesion

(2)        relevant radiologic findings (note A)

(3)        pre-existing conditions (eg, Paget disease of bone, bone infarction, osteomyelitis, benign soft tissue tumor) or unusual exposures, especially radiation

(4)        history of familial predisposition syndrome (eg, Li-Fraumeni syndrome, Ollier disease, Mafucci’s syndrome, familial retinoblastoma syndrome, Rothmund-Thomson syndrome)

(5)        previous chemotherapy or radiation therapy

b.        Relevant clinical findings

c.        Clinical diagnosis

d.        Relevant physical findings

(1)        anatomic site (specify as much as possible)

(2)        depth and/or location of tumor

i.        soft tissue

(a)        superficial

(i)        dermal

(ii)        subcutaneous/suprafascial

(b) deep

(i)        fascial

(ii)        subfascial

(iii)        intramuscular

(iv)        mediastinal

(v)        intra-abdominal

(vi)        retroperitoneal

(vii)        head and neck

ii.        bone

(a)        location (long bones only) (note B)

(i)        epiphysis

(ii)        metaphysis

(iii)        diaphysis

(b)        location (all bones)

(i)        cortical

(ii)        medullary

(iii)        surface

(c)        joint (involved or uninvolved)

(d)        extension into soft tissue

e.        Procedure

(1)        soft tissue

i.        fine-needle aspirate

ii.        core needle biopsy

iii.        incisional biopsy

iv.        excisional biopsy

(2)        bone

i.        fine-needle aspirate

ii.        core needle biopsy

iii.        incisional biopsy

iv.        excisional biopsy

v.        curettage

B.        Macroscopic Examination

1.        Specimen

a.        Tissues received (specify components and site)

b.        Unfixed/fixed (specify fixative) (note C)

c.        Oriented or not

d.        Number of pieces of tissue

e.        Size of specimen in centimeters (3 dimensions)

f.        Results of intraoperative consultation, if performed (note D)

2.        Tumor, if discernable

a.        Location

b.        Tissues involved

(1)        skin

(2)        subcutaneous adipose tissue

(3)        fascia

(4)        muscle

(5)        bone

(6)        joint

c.        Dimensions in centimeters (3 dimensions)

d.        Presence or absence of necrosis

e.        Other descriptive characteristics (eg, color, firm/soft, gritty, fatty, gelatinous, calcified, hemorrhagic) (Note: if the specimen contains bone, it may require decalcification)

f.        Margins (if excisional biopsy)

(1)        circumscribed/encapsulated or infiltrative

(2)        measured as minimal distance to margins; all margins that are less than 2 cm should be measured and specified in the final report

g.        Photograph tumor

3.        Tissue submitted for microscopic examination

a.        One section per centimeter (note E)

b.        Frozen section tissue fragment(s)

4.        Tissue for special studies

a.        Electron microscopy

b.        Cytogenetics

c.        Flow cytometry

d.        Molecular studies (note F)

C.        Microscopic Examination

1.        Tumor

a.        Histologic classification (notes G and H)

b.        Grade (note I)

c.        Mitotic count (number of mitotic figures/10 high-power fields) (optional)

d.        Necrosis (present or absent)

e.        Margin status, if any (note J)

2.        Results of special studies

a.        Immunohistochemical studies

b.        Electron microscopy

c.        Cytogenetics

d.        Flow cytometry

e.        Molecular studies

3.        Comments

a.        Correlation with intraoperative consultations, if any

b.        Correlation with prior specimens, if any

c.        Correlation with clinical findings, as appropriate

II.        Excision; Re-excision; Metastectomy

A.        Clinical Information

1.         Patient identification

a.        Name

b.        Identification number

c.        Birth date

d.        Sex

2.        Responsible physician(s)

3.        Date of procedure

4.        Other clinical information

a.        Relevant history

(1)        duration of lesion

(2)        history of preoperative (neoadjuvant) chemotherapy or radiation therapy

(3)        relevant radiologic findings (note A)

(4)        pre-existing conditions (eg, Paget disease of bone, bone infarction, osteomyelitis, benign soft tissue tumor) or unusual exposures, especially radiation

(5)        history of familial predisposition syndrome (eg, Li-Fraumeni syndrome, Ollier disease, Mafucci’s syndrome, familial retinoblastoma syndrome, Rothmund-Thomson syndrome)

a.        Relevant clinical findings

b.        Clinical diagnosis

c.        Relevant physical findings

d.        Anatomic site

e.        Depth and/or location of tumor

 (1)        soft tissue

i.        superficial

(a)        dermal

(b)        subcutaneous/suprafascial

ii.        deep

(a)        fascial

(b)        subfascial

(c)        intramuscular

(d)        mediastinal

(e)        intra-abdominal

(f)        retroperitoneal

(g)        head and neck

(2)        bone

i.        location (long bones only)

(a)        epiphysis

(b)        metaphysis

(c)        diaphysis

ii.        location (all bones)

(1)        cortical

(2)        medullary

(3)        surface

iii.        joint (involved or uninvolved)

iv.        extension into soft tissue

f.        Procedure (note K)

(1)        intralesional (curetting or debulking)

(2)        marginal/simple/local excision

(3)        wide local excision

(4)        segmental/en block resection (bone tumors)

(5)        radical excision

(6)        amputation

B.        Macroscopic Examination

1.         Specimen

a.        Tissues received (specify nature and site)

b.        Unfixed/fixed (specify fixative) (note B)

c.        Oriented or not

d.        Number of pieces of tissue

e.        Size of specimen in centimeters (3 dimensions)

f.        Results of intraoperative consultation, if performed

2.        Tumor, if discernable

a.        Location

b.        Tissues involved

(1)        skin

(2)        subcutaneous adipose tissue

(3)        muscle

(4)        bone

(5)        joint

(6)        major neurovascular bundles

(7)        attached organs (common in neck, thoracoabdominal, pelvic, and retroperitoneal tumors)

c.        Size of tumor in centimeters (3 dimensions)

d.        Other descriptive characteristics (eg, color, firm/soft, fatty, gelatinous, calcified, hemorrhagic) (Note: if the specimen contains bone, it may require decalcification)

e.        Presence or absence of necrosis (approximate percentage)

f.        Presence or absence of chemotherapy or radiation therapy effect (note L)

g.        Presence or absence of previous biopsy site or scar, with dimensions and relationship to resection margins

h.        Involvement or invasion of major structures (eg, nerve, bone, major blood vessels)

i.        Presence of satellite nodules of tumor away from main tumor mass (relationship to main mass should be described, maximum measurement of each satellite nodule should be noted, and relationship to margins should be described)

j.        Presence of lymph nodes and description of cut surface (note M)

k.        Margins (note J)

l.        Photograph tumor

3.        Tissue submitted for microscopic examination

a.        One section per centimeter (note E)

b.        Frozen section tissue fragment(s)

4.        Tissue for special studies

a.        Electron microscopy

b.        Cytogenetics

c.        Flow cytometry

d.        Molecular studies (note F)

C.        Microscopic Examination

1.        Tumor

a.        Histologic classification (notes H and N)

b.        Grade (note I)

c.        Mitotic count (number of mitotic figures/10 high-power fields) (optional)

d.        Percentage necrosis (approximated)

e.        Margin status

f.        Lymphatic/vascular involvement (note O) (optional)

g.        Lymph node involvement (note M)

2.        Results of special studies

a.        Immunohistochemical studies

b.        Electron microscopy

c.        Cytogenetics

d.        Flow cytometry

e.        Molecular studies

3.        Comments

a.        Correlation with intraoperative consultations, if any

b.        Correlation with prior specimens, if any

c.        Correlation with clinical findings, as appropriate

Explanatory Notes

A.        Relevant Radiologic Findings

Radiographic imaging plays an especially critical role in the diagnosis of bone tumors, Close collaboration with an experienced musculoskeletal radiologist and orthopedic surgeon is recommended.

B.        Location of Neoplasms of Bone

The figure is a diagrammatic representation of the “anatomic” regions of a long bone. These locations are very important in classifying bone tumors. For instance, giant cell tumors almost always arise in the epiphysis. The greater trochanter is also considered an epiphyseal region, even though it is not at the end of the bone.

C.        Fixation

Tissue specimens from bone and soft tissue tumors optimally are received fresh/unfixed because of the importance of ancillary studies such as cytogenetics, which require fresh tissue.

D.        Intraoperative Consultation

Histologic classification of bone and soft tissue tumors is sufficiently complex that, in many cases, it is unreasonable to expect a precise classification of these tumors based on an intraoperative consultation. A complete understanding of the surgeon’s treatment algorithm is recommended before rendering a frozen section diagnosis. In the case of primary bone tumors, an intraoperative diagnosis of benign versus malignant will generally guide the immediate decision to curette, excise, or wait for permanent sections, and certain therapeutic options may be lost if the wrong path is pursued. Intraoperative consultation is useful in assessing if “lesional” tissue is present and whether or not this tissue is necrotic, and in constructing a differential diagnosis that can direct the proper triage of tissue for flow cytometry (lymphoma), electron microscopy, and molecular studies/cytogenetics. Tissue triage optimally is performed at the time of frozen section. In many cases, it is important that a portion of tissue be submitted for ancillary studies, even from fine-needle aspiration (FNA) and core needle biopsy specimens, once sufficient tissue has been submitted for histologic evaluation.

E.        Tissue Submission for Histologic Evaluation

One section per centimeter of maximum dimension is usually recommended, although fewer sections are needed for very large tumors, especially if they are homogeneous. Tumors known to be high-grade from a previous biopsy do not require as many sections as those that were previously diagnosed as low-grade, as documentation of a high-grade component will change stage and prognosis in the latter case. Sections should be taken of grossly heterogeneous areas, and there is no need to submit more than 1 section of necrotic tumor (always with a transition to viable tumor), with the exception of chemotherapy effect on osteosarcomas and Ewing/PNET sarcomas.2 Occasionally, gross pathology can be misleading, and areas that appear to be grossly necrotic may actually be myxoid or edematous. When this happens, additional sections of these areas should be submitted for histologic examination. When estimates of gross necrosis exceed those of histologic necrosis, the greater percentage of necrosis should be recorded on the surgical pathology report. In general, most tumors require 12 sections or less, excluding margins. Tumors with greater areas of heterogeneity may need to be sampled more thoroughly.

Fresh tissue for special studies should be submitted at the time the specimen is received. Note that classification of many subtypes of sarcoma is not dependent upon special studies, such as cytogenetics or molecular genetics, but frozen tissue is often needed to enter patients into treatment protocols. Discretion should be used in triaging tissue from sarcomas. Adequate tissue should be submitted for conventional light microscopy before tissue has been taken for cytogenetics, electron microscopy, or molecular analysis.

F.        Molecular Studies

It is important to snap freeze a small portion of tissue whenever possible. This tissue can be used for a variety of molecular analyses for tumor-specific molecular translocations (see Table 1) that help in classifying bone and soft tissue tumors.3,4 In addition, treatment protocols increasingly require fresh tissue for correlative studies. Approximately 1 cm3 of fresh tissue (less is acceptable for small specimens, including core biopsies) should be cut into small 0.2-cm fragments, reserving sufficient tissue for histologic examination. This frozen tissue should ideally be stored at –70oC and can be shipped on dry ice to facilities that perform molecular analysis.

Table 1. Characteristic Cytogenetic and Molecular Events of
Bone and Soft Tissue Tumors

G.        Tumor Classification from Biopsies

It is not always possible to classify bone and soft tissue tumors precisely based on biopsy material, especially FNA and core needle biopsy specimens. Whereas pathologists should make every attempt to classify lesions in small biopsy specimens, on occasion stratification into very basic diagnostic categories, such as lymphoma, carcinoma, melanoma, and sarcoma, is all that is possible. In some cases, precise classification is only possible in open biopsies or resection specimens.

H.        WHO Classification of Tumors

Classification of tumors should be made according to the World Health Organization (WHO) classification of bone and soft tissue tumors listed below.5 As part of the recent WHO classification of soft tissue tumors, a recommendation was made to divide tumors into 4 categories: benign, intermediate (locally aggressive), intermediate (rarely metastasizing), and malignant.

WHO Classification of Soft Tissue Tumors of Intermediate Malignant Potential and Malignant Soft Tissue Tumors

Adipocytic Tumors

Intermediate (locally aggressive)

Atypical lipomatous tumor / Well differentiated liposarcoma

Malignant

Dedifferentiated liposarcoma

Myxoid/round cell liposarcoma

Pleomorphic liposarcoma

Mixed-type liposarcoma

Liposarcoma, not otherwise specified

Fibroblastic / Myofibroblastic Tumors

Intermediate (locally aggressive)

Superficial fibromatoses (palmar / plantar)

Desmoid-type fibromatoses

Lipofibromatosis

Intermediate (rarely metastasizing)

Solitary fibrous tumor and hemangiopericytoma (including lipomatous hemangiopericytoma)

Inflammatory myofibroblastic tumor

Low grade myofibroblastic sarcoma

Myxoinflammatory fibroblastic sarcoma

Infantile fibrosarcoma

Malignant

Adult fibrosarcoma

Myxofibrosarcoma

Low grade fibromyxoid sarcoma/hyalinizing spindle cell tumor

Sclerosing epithelioid fibrosarcoma

So-called Fibrohistiocytic Tumors

Intermediate (rarely metastasizing)

Plexiform fibrohistiocytic tumor

Giant cell tumor of soft tissues

Malignant

Pleomorphic malignant fibrous histiocytoma (MFH) / Undifferentiated pleomorphic sarcoma

Giant cell MFH / Undifferentiated pleomorphic sarcoma with giant cells

Inflammatory MFH / Undifferentiated pleomorphic sarcoma with prominent inflammation

Smooth Muscle Tumors

Malignant

Leiomyosarcoma

Skeletal Muscle Tumors

Malignant

Embryonal rhabdomyosarcoma (including spindle cell, botryoid, anaplastic)

Alveolar rhabdomyosarcoma (including solid, anaplastic)

Pleomorphic rhabdomyosarcoma

Vascular Tumors

Intermediate (locally aggressive)

        Kaposiform hemangioendothelioma

Intermediate (rarely metastasizing)

Retiform hemangioendothelioma

Papillary intralymphatic angioendothelioma

Composite hemangioendothelioma

Kaposi sarcoma

Malignant

Epithelioid hemangioendothelioma

Angiosarcoma of soft tissue

Tumors of Peripheral Nerves

Malignant

Malignant peripheral nerve sheath tumor

Epithelioid malignant peripheral nerve sheath tumor

Chondro-osseous Tumors

Malignant

Mesenchymal chondrosarcoma

Extraskeletal osteosarcoma

Tumors of Uncertain Differentiation

Intermediate (rarely metastasizing)

Angiomatoid fibrous histiocytoma

Ossifying fibromyxoid tumor (including atypical / malignant)

Mixed tumour / Myoepithelioma / Parachordoma

Malignant

Synovial sarcoma

Epithelioid sarcoma

Alveolar soft part sarcoma

Clear cell sarcoma of soft tissue

Extraskeletal myxoid chondrosarcoma (“chordoid” type)

PNET / Extraskeletal Ewing tumor
pPNET
Extraskeletal Ewing tumor

Desmoplastic small round cell tumor

Extra-renal rhabdoid tumor

Malignant mesenchymoma

Neoplasms with perivascular epithelioid cell differentiation (PEComa)
Intimal sarcoma

WHO Classification of Benign/Locally Aggressive and Malignant Bone Tumors

Cartilage Tumors

Chondrosarcoma

Central, primary, and secondary

Peripheral

Dedifferentiated

Mesenchymal

Clear cell

Osteogenic Tumors

Osteosarcoma

Conventional

Chondroblastic

Fibroblastic

Osteoblastic

Telangiectatic

Small cell

Low grade central

Secondary

Parosteal

Periosteal

High grade surface

Fibrogenic Tumors

Desmoplastic fibroma (benign/locally aggressive)

Fibrosarcoma

Fibrohistiocytic Tumors

Malignant fibrous histiocytoma

Ewing Sarcoma / Primitive Neuroectodermal Tumor

Ewing sarcoma / PNET

Haematopoietic Tumors

Plasma cell myeloma

Malignant lymphoma, NOS

Giant Cell Tumors

Giant cell tumor (benign/locally aggressive)

Malignancy in giant cell tumor

Notochordal Tumors

Chordoma

Vascular Tumors

Angiosarcoma

Smooth Muscle Tumors

Leiomyosarcoma

Lipogenic Tumors

Liposarcoma

Miscellaneous Tumors

Adamantinoma

Metastatic malignancy

Miscellaneous Lesions

Langerhans cell histiocytosis

I.        Grading

Unlike other organ systems, the staging of soft tissue sarcomas is largely determined by grade. Unfortunately, there is no generally agreed upon scheme for grading bone and soft tissue tumors.6 The most widely used soft tissue grading systems are the French Federation of Cancer Centers Sarcoma Group (FNCLCC) and National Cancer Institute (NCI) systems.7,8 Both systems have 3 grades and evaluate mitotic activity, necrosis, and differentiation, and are highly correlated with prognosis.9 However, in addition to these criteria, the NCI system requires the quantification of cellularity and pleomorphism for certain subtypes of sarcomas, which is difficult to determine objectively. The FNCLCC system is easier to use, in our opinion, and recent data suggest that it may be slightly better in predicting prognosis than the NCI system.9 Other systems with 2 or 4 grades also have been used. Accurate grading requires an adequate sample of tissue, which is not always available from FNA or core needle biopsy or in tumors previously treated with radiation or chemotherapy.

FNCLCC Grading

The FNCLCC grade is based on 3 parameters: differentiation, mitotic activity, and necrosis. Each of these parameters receives a score: differentiation (1 to 3), mitotic activity (1 to 3), and necrosis (0 to 2). The scores are summed to produce a grade.

Grade 1:        2 or 3

Grade 2:        4 or 5

Grade 3:        6 to 8

Differentiation: Tumor differentiation is scored as follows (see Table 2).

Score 1:        Sarcomas closely resembling normal, adult mesenchymal tissue

Score 2:        Sarcomas of certain histologic type

Score 3:        Synovial sarcomas, embryonal sarcomas, undifferentiated sarcomas, and sarcomas of doubtful tumor type

Tumor differentiation is the most problematic aspect of the FNCLCC system. Its use is subjective and does not include every subtype of sarcoma. Nevertheless, it is an integral part of the system, and an attempt should be made to assign a differentiation score.

Table 2. Tumor Differentiation Score According to Histologic Type in the Updated Version of the FNCLCC System

Tumor Differentiation

Modified from Guillou et al.9 Note: Grading of malignant peripheral nerve sheath tumor, embryonal and alveolar rhabdomyosarcoma, angiosarcoma, extraskeletal myxoid chondrosarcoma, alveolar soft part sarcoma, clear cell sarcoma, and epithelioid sarcoma is not recommended.5

Mitosis Count: The count is made in the most mitotically active area in 10 successive high-power fields (HPFs) (a high-power field X 400 = 0.1734 mm2) (use the 40X objective).

Score 1:        0 to 9 mitoses per 10 HPFs

Score 2:        10 to19 mitoses per 10 HPFs

Score 3:        20 or more mitoses per 10 HPFs.

Tumor Necrosis: Determined on histologic sections.

Score 0:        No tumor necrosis

Score 1:        Less than or equal to 50% tumor necrosis

Score 2:        More than 50% tumor necrosis

The grading of bone tumors is largely driven by the histologic diagnosis, and traditionally grading has been based on the system advocated by Broders, which assesses cellularity and nuclear features/degree of anaplasia.10 We advocate a more pragmatic approach to grading aggressive and malignant primary tumors of bone. Two bone tumors that have a tendency to be locally aggressive but have little to no metastatic potential are giant cell tumor and desmoplastic fibroma. Two bone tumors that are locally aggressive and metastasize infrequently, and thus are usually low-grade, are low-grade central osteosarcoma and parosteal osteosarcoma. Periosteal osteosarcoma is generally regarded as a grade 2 osteosarcoma. Primary bone tumors that are generally high-grade include: malignant giant cell tumor, Ewing sarcoma/PNET, angiosarcoma, dedifferentiated chondrosarcoma, conventional osteosarcoma, telangiectactic osteosarcoma, small cell osteosarcoma, secondary osteosarcoma, and high-grade surface osteosarcoma.

Grading of conventional chondrosarcoma is based on cellularity, cytologic atypia, and mitotic figures. Grade 1 (low-grade) chondrosarcoma is hypocellular and similar histologically to enchondroma. Grade 2 (intermediate-grade) chondrosarcoma is more cellular than grade 1 chondrosarcoma, has more cytologic atypia, greater hyperchromasia and nuclear size, or has extensive myxoid stroma. Grade 3 (high-grade) chondrosarcoma is hypercellular, pleomorphic, and contains prominent mitotic activity. Mesenchymal chondrosarcoma, fibrosarcoma, leiomyosarcoma, liposarcoma, angiosarcoma and other “soft tissue-type” sarcomas that rarely occur in bone can be graded according to the FNCLCC grading system.

Chordomas are locally aggressive lesions with a propensity for metastasis late in their clinical course and are not graded. Adamantinomas tend to have a low-grade clinical course, but this is variable. Fortunately, they are very rare. According to the WHO classification of tumors of bone, adamantinomas are considered low-grade.

Bone Tumor Grades (Summary)

Benign/Locally Aggressive

Desmoplastic fibroma

Giant cell tumor

Grade 1 (Low-Grade)

Low-grade central osteosarcoma

Parosteal osteosarcoma

Adamantinoma

Grade 2

Periosteal osteosarcoma

Grade 3 (High-Grade)

Malignant giant cell tumor

Ewing sarcoma / PNET

Dedifferentiated chondrosarcoma

Conventional osteosarcoma

Telangiectactic osteosarcoma

Small cell osteosarcoma

Secondary osteosarcoma

High-grade surface osteosarcoma

Variable Grade

Conventional chondrosarcoma of bone (grades 1 to 3)

Soft-tissue type sarcomas (eg, leiomyosarcoma)

Ungraded

Chordoma

TNM Grading

The American Joint Committee on Cancer (AJCC) staging system for soft tissue and bone tumors includes a 4-grade system but effectively collapses into high-grade and low-grade.11,12 Grading in the TNM grading system is based on differentiation only and does not apply to sarcomas.

GX        Grade cannot be assessed

G1        Well differentiated

G2        Moderately differentiated

G3        Poorly differentiated

G4        Poorly differentiated or undifferentiated (4-tiered systems only)

For purposes of using the AJCC staging system, 3-grade systems such as FNCLCC can be converted to a 4-grade (TNM) system as follows: grade 1 = G1; grade 2 = G2; and grade 3 = G3 and G4. This means that FNCLCC/NCI grade 2 tumors are considered “high grade” for the purposes of stage grouping.

J.        Margins

It has been recommended that for all margins less than or equal to 2 cm, the distance of the tumor from the margin be reported in centimeters.13 However, there is a lack of agreement on this issue. We recommend specifying the location of all margins less than 2 cm. Margins from bone and soft tissue tumors should be taken as perpendicular margins, if possible. If bones are present in the specimen and are not involved by tumor, or the tumor is greater than 2 cm from the margin, the marrow can be scooped out and submitted as a margin. In addition, the status of the margin should be listed according to the following scheme:

Intralesional = within lesion (ie, the margin is positive)

Marginal = < 2.0 cm of normal tissue around all margins, less if bounded by fascia

Wide = > 2.0 cm of normal tissue around all margins, less if bounded by fascia

K.        Definition of Procedures

The following is a list of guidelines to be used in defining what type of procedure has been performed.

Intralesional Resection

Leaving gross tumor behind. Partial debulking or curettage are examples. In general, these procedures are palliative.

Marginal Resection

Removing the tumor and its pseudocapsule with a relatively small amount of adjacent tissue. There is no gross tumor at the margin; however, microscopic tumor may be present. Note that occasionally, a surgeon will perform an “excisional” biopsy, which effectively accomplishes the same thing as a marginal resection.

Wide Resection

An intracompartmental resection. The tumor is removed with pseudocapsule and a cuff of 2 cm of normal tissue in all directions, but without the complete removal of an entire muscle group, compartment or bone. A cuff larger than 2.0 cm is typical, but may be less when the margin is a fascial plane.

Segmental / En Block Resection (Bone Only)

This is similar conceptually to a wide excision in soft tissue. A single piece of bone is resected, including the lesion and a cuff of normal bone.

Radical Resection

The removal of an entire soft tissue compartment (for example, anterior compartment of the thigh, the quadriceps) or bone, or the excision of the adjacent muscle groups if the tumor is extracompartmental. Radical excisions include amputations and disarticulations.

L.        Response to Chemotherapy/Radiation Therapy Effect

While agreement has not been reached about measuring the effect of preoperative (neoadjuvant) chemotherapy/radiation therapy in soft tissue tumors, an attempt should be made to quantify these effects, especially in the research setting. Therapy response is expressed as a percentage of total tumor area that is either necrotic or replaced by fibrous or granulation tissue. Nonliquefied tumor tissue from a cross-section through the longest axis of the tumor should be sampled. At least 1 section of necrotic tumor (always with a transition to viable tumor) should be sampled to verify the gross impression of necrosis. Nonsampled necrotic areas should be included in the estimate of necrosis, and the percentage of tumor necrosis reported. The gross appearance can be misleading, and areas that appear grossly necrotic may actually be myxoid or edematous. Additional sections from these areas should be submitted for histologic examination. When estimates of gross necrosis exceed those of histologic necrosis, the greater percentage of necrosis should be recorded on the surgical pathology report. It is essential to estimate neoadjuvant treatment effect in primary Ewing sarcoma/PNET and osteosarcoma of bone, as these have been shown to have prognostic significance.2,14-18 An entire representative slice of the tumor taken through the long axis should be mapped using a grid pattern diagram, photocopy, or radiologic film to indicate the site for each tumor block. In addition, a section of tumor perpendicular to the long axis should be sampled at the rate of 1 section per centimeter. Areas of soft tissue extension and the interface of tumor with normal tissue should also be sampled. Therapy response is expressed as a percentage of total tumor area that is either necrotic or replaced by fibrous or granulation tissue. Prognostically significant therapy response in osteosarcoma, according to most series, is defined at 90%, with those tumors showing greater than or equal to 90% therapy response associated with a favorable prognosis.14,15 Therapy response in Ewing sarcoma is expressed as grade I (macroscopic viable tumor), grade II (microscopic viable tumor), or grade III (no viable tumor), and is highly correlated with 5-year survival.16,17

M.        Lymph Nodes

Regional lymph node metastasis is uncommon in adult bone and soft tissue sarcomas. Nodes are not sampled routinely, and it usually is not necessary to exhaustively search for nodes. When present, regional lymph node metastasis has prognostic importance and should be reported.

N.        Histological Classification of Treated Lesions

Due to extensive treatment effects, such as necrosis, fibrosis, and chemotherapy and radiation-induced pleomorphism, it may not be possible to classify some lesions that were either never biopsied or the biopsy was insufficient for a precise diagnosis.

O.        Venous / Lymphatic Invasion

By American Joint Committee on Cancer (AJCC) / International Union Against Cancer (UICC) convention, vessel invasion (lymphatic or venous) does not affect the T category unless specifically included in the definition of a T category. In all other cases, lymphatic and venous invasion by tumor are coded separately as follows.

Lymphatic Vessel Invasion (L)

LX        Lymphatic vessel invasion cannot be assessed

L0        No lymphatic vessel invasion

L1        Lymphatic vessel invasion

Venous Invasion (V)

VX        Venous invasion cannot be assessed

V0        No venous invasion

V1        Microscopic venous invasion

V2        Macroscopic venous invasion

P.        TNM and Stage Groupings: Soft Tissue Tumors

The TNM Staging System for soft tissue tumors of the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC) is recommended.11,12

The staging system applies to all soft tissue sarcomas except Kaposi’s sarcoma, dermatofibrosarcoma protuberans, desmoid fibromatosis, infantile fibrosarcoma, and angiosarcoma. In addition, sarcomas arising within the confines of the dura mater, including the brain, and sarcomas arising in parenchymatous organs and from hollow viscera are not optimally staged by this system.

Pathologic (pTNM) staging consists of the removal and pathologic evaluation of the primary tumor and clinical/radiologic evaluation for regional and distant metastases. In circumstances where it is not possible to obtain accurate measurements of the excised primary sarcoma specimen, it is acceptable to use radiologic assessment of tumor size to assign a pT category. In examining the primary tumor, the pathologist should subclassify the lesion and assign a histopathologic grade via an accepted grading system.

Although size currently is designated within the TNM system as 5 cm or smaller, or larger than 5 cm, particular emphasis should be placed on providing size measurements. Size should be regarded as a continuous variable, with 5 cm as merely an arbitrary division that makes it possible to dichotomize patient populations.

Depth is also an independent variable and is defined as follows.

1.        Superficial

a.        Lesion does not involve superficial fascia

2.        Deep

a.        Lesion is deep to, or involves, the superficial fascia

b.        All intraperitoneal visceral lesions, retroperitoneal lesions, intrathoracic lesions, and the majority of head and neck tumors are considered deep

3.        Depth is evaluated in relation to tumor size (T)

a.        Tumor 5 cm or less: T1a = superficial, T1b = deep

b.        Tumor greater than 5 cm: T2a = superficial, T2b = deep

Nodal involvement is rare in adult soft tissue sarcomas but, when present, has a very poor prognosis. The outcome of patients with N1 disease is similar to those with M1 disease. Patients whose nodal status is not determined to be positive for tumor, either clinically or pathologically, should be designated as N0.

Restaging of Recurrent Tumors

The same staging should be used when a patient requires restaging of sarcoma recurrence. Such reports should specify whether patients have primary lesions or lesions that were previously treated and have subsequently recurred. Reporting of possible etiologic factors such as radiation exposure and inherited or genetic syndromes is encouraged. Appropriate workup for recurrent sarcoma usually includes cross-sectional imaging (computed tomography [CT] scan or magnetic resonance imaging [MRI] scan) of the tumor, a CT scan of the chest, and a tissue biopsy to confirm diagnosis prior to initiation of therapy.

Primary Tumor (T)

TX        Primary tumor cannot be assessed

T0        No evidence of primary tumor

T1        Tumor 5 cm or less in greatest dimension

T1a        Superficial tumor

T1b        Deep tumor

T2        Tumor more than 5 cm in greatest dimension

T2a        Superficial tumor

T2b        Deep tumor

Note: Superficial 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. Retroperitoneal, mediastinal, and pelvic sarcomas are classified as deep tumors.

Regional Lymph Nodes (N)

NX        Regional lymph nodes cannot be assessed

N0        No regional lymph node metastasis

N1        Regional lymph node metastasis#

# Note: Presence of positive nodes (N1) is considered stage IV.

Distant Metastasis (M)

MX        Distant metastasis cannot be assessed

M0        No distant metastasis

M1        Distant metastasis

Stage Groupings

Q.        TNM and Stage Groupings: Bone Tumors

The TNM Staging System for bone tumors of the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC) is recommended.11,12

The classification is to be applied to all primary tumors of bone. Pathologic staging includes pathologic data obtained from examination of a resected specimen sufficient to evaluate the highest T category, histopathologic type and grade, regional lymph nodes as appropriate, or distant metastasis. Because regional lymph node involvement from bone tumors is rare, the pathologic stage grouping includes any of the following combinations: pT pG pN pM, or pT pG cN cM, or cT cN pM.

Primary Tumor (T)

TX        Primary tumor cannot be assessed

T0        No evidence of primary tumor

T1        Tumor 8 cm or less in greatest dimension

T2        Tumor more than 8 cm in greatest dimension

T3        Discontinuous tumors in the primary bone site

Regional Lymph Nodes (N)

NX        Regional lymph nodes cannot be assessed#

N0        No regional lymph node metastasis

N1        Regional lymph node metastasis

# Note: Because of the rarity of lymph node involvement in sarcomas, the designation NX may not be appropriate and could be considered N0 if no clinical involvement is evident.

Distant Metastasis (M)

MX        Distant metastasis cannot be assessed

M0        No distant metastasis

M1        Distant metastasis

M1a        Lung

M1b        Other distant sites

Stage Groupings

R. TNM Descriptors

For identification of special cases of TNM or pTNM classifications, the “m” suffix and “y,” “r,” and “a” prefixes are used. Although they do not affect the stage grouping, they indicate cases needing separate analysis.

The “m” suffix indicates the presence of multiple primary tumors in a single site and is recorded in parentheses: pT(m)NM.

The “y” prefix indicates those cases in which classification is performed during or following initial multimodality therapy (ie, neoadjuvant chemotherapy, radiation therapy, or both chemotherapy and radiation therapy). The cTNM or pTNM category is identified by a “y” prefix. The ycTNM or ypTNM categorizes the extent of tumor actually present at the time of that examination. The “y” categorization is not an estimate of tumor prior to multimodality therapy (ie, before initiation of neoadjuvant therapy).

The “r” prefix indicates a recurrent tumor when staged after a documented disease-free interval, and is identified by the “r” prefix: rTNM.

The “a” prefix designates the stage determined at autopsy: aTNM.

Additional Descriptors

Residual Tumor (R)

Tumor remaining in a patient after therapy with curative intent (eg, surgical resection for cure) is categorized by a system known as R classification, shown below.

RX        Presence of residual tumor cannot be assessed

R0        No residual tumor

R1        Microscopic residual tumor

R2        Macroscopic residual tumor

For the surgeon, the R classification may be useful to indicate the known or assumed status of the completeness of a surgical excision. For the pathologist, the R classification is relevant to the status of the margins of a surgical resection specimen. That is, tumor involving the resection margin on pathologic examination may be assumed to correspond to residual tumor in the patient and may be classified as macroscopic or microscopic according to the findings at the specimen margin(s).

References

1.          Qualman SJ, Bowen J, Parham DM, Branton PA, Meyer WH. Protocol for the examination of specimens from patients (children and young adults) with rhabdomyosarcoma. Arch Pathol Lab Med. 2003;127:1290-1297.

2.                Carpentiere DF, Qualman SJ, Bowen J, Krausz T, Marchevsky A, Dickman PS. Protocol for the examination of specimens from pediatric and adult patients with osseous and extraosseous Ewing sarcoma family of tumors, including peripheral primitive neuroectodermal tumor and Ewing sarcoma. Arch Pathol Lab Med. 2005;129:866-871.

3.         Ladanyi M, Bridge JA. Contribution of molecular genetic data to the classification of sarcomas. Hum Pathol. 2000;31:532-538.

4.         Tomescu O, Barr FG. Chromosomal translocations in sarcomas: prospects for therapy. Trends Mol Med. 2001;7:554-559.

5.          World Health Organization Classification of Tumours. Pathology and Genetics.  Tumours of Soft Tissue and Bone. Lyon: IARC Press; 2002.

6.         Oliveira AM, Nascimento AG. Grading in soft tissue tumors: principles and problems. Skeletal Radiol. 2001;30:543-559.

7.         Coindre JM, Trojani M, Contesso G, et al. Reproducibility of a histopathologic grading system for adult soft tissue sarcoma. Cancer. 1986;58:306-309.

8.         Costa J, Wesley RA, Glatstein E, Rosenberg SA. The grading of soft tissue sarcomas: results of a clinicohistopathologic correlation in a series of 163 cases. Cancer. 1984;53:530-541.

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. 1997;15:350-362.

10.        Inwards CY, Unni KK. Classification and grading of bone sarcomas. Hematol Oncol Clin North Am. 1995;9:545-569.

11.         UICC TNM Classification of Malignant Tumours. 6th ed. New York: Wiley-Liss; 2002.

12.         AJCC Cancer Staging Manual. 6th ed. New York: Springer; 2002.

13.         Association of Directors of Anatomic and Surgical Pathology. Recommendations for the reporting of soft tissue sarcomas. Mod Pathol. 1998;11:1257-1261.

14.         Picci P, Sangiorgi L, Rougraff BT, Neff JR, Casadei R, Campanacci M. Relationship of chemotherapy-induced necrosis and surgical margins to local recurrence in osteosarcoma. J Clin Oncol. 1994;12:2699-2705.

15.        Raymond AK, Chawla SP, Carrasco CH, et al. Osteosarcoma chemotherapy effect: a prognostic factor. Semin Diagn Pathol. 1987;4:212-236.

16.         Bacci G, Ferrari S, Bertoni F, et al. Prognostic factors in nonmetastatic Ewing's sarcoma of bone treated with adjuvant chemotherapy: analysis of 359 patients at the Istituto Ortopedico Rizzoli. J Clin Oncol. 2000;18:4-11.

17.        Picci P, Bohling T, Bacci G, et al. Chemotherapy-induced tumor necrosis as a prognostic factor in localized Ewing's sarcoma of the extremities. J Clin Oncol. 1997;15:1553-1559.

18.        Abdul-Karim FW, Bauer TW, Kilpatrick SE, et al. Recommendations for the reporting of bone tumors. Hum Pathol. 35:1173-1178.