Protocol for the Examination of Specimens from Patients with Soft

Protocol for the Examination of Specimens From Patients With Soft Tissue Tumors of Intermediate Malignant Potential, Malignant Soft Tissue Tumors, and Benign/Locally Aggressive and Malignant Bone Tumors

Brian P. Rubin, MD, PhD; Christopher D. M. Fletcher, MD, FRCPath; Carrie Inwards, MD; Anthony G. Montag, MD; Terrance Peabody, MD; Stephen J. Qualman, MD; Andrew E. Rosenberg, MD; Sharon Weiss, MD; Thomas Krausz, MD

he College of American Pathologists offers these pro- PROTOCOL FOR THE EXAMINATION OF SPECIMENS T tocols to assist pathologists in providing clinically FROM PATIENTS WITH SOFT TISSUE TUMORS OF useful and relevant information when reporting results of INTERMEDIATE MALIGNANT POTENTIAL, MALIGNANT examinations of surgical specimens. The College regards SOFT TISSUE TUMORS, AND BENIGN/LOCALLY the reporting elements in the ‘‘Surgical Pathology Cancer AGGRESSIVE AND MALIGNANT BONE TUMORS Case Summary (Checklist)’’ portion of the protocols as This protocol applies to soft tissue tumors of interme- essential elements of the pathology report. However, the diate malignant potential, malignant soft tissue tumors, manner in which these elements are reported is at the dis- and benign/locally aggressive and malignant bone tu- cretion of each specific pathologist, taking into account mors only. The American Joint Committee on Cancer clinician preferences, institutional policies, and individual (AJCC)/International Union Against Cancer (UICC) TNM practice. classification system is recommended. The College developed these protocols as an educational tool to assist pathologists in the useful reporting of rele- Background Documentation vant information. It did not issue the protocols for use in These recommendations are designed to be applied litigation, reimbursement, or other contexts. Nevertheless, principally to bone and soft tissue sarcomas in teenagers the College recognizes that the protocols might be used and adults, since pediatric sarcomas are, in general, treat- by hospitals, attorneys, payers, and others. Indeed, effec- ed under strict protocols that may differ significantly from tive January 1, 2004, the Commission on Cancer of the the recommendations supplied herein.1 American College of Surgeons mandated the use of the I. Biopsy checklist elements of the protocols as part of its Cancer A. Clinical Information Program Standards for Approved Cancer Programs. 1. Patient identification Therefore, it becomes even more important for patholo- a. Name gists to familiarize themselves with the document. At the b. Identification number same time, the College cautions that use of the protocols c. Birth date other than for their intended educational purpose may in- d. Sex volve additional considerations that are beyond the scope 2. Responsible physician(s) of this document. 3. Date of procedure 4. Other clinical information a. Relevant history Accepted for publication July 13, 2006. (1) duration of lesion From Anatomic Pathology, University of Washington Medical (2) relevant radiologic findings (note A) Center, Seattle (Dr Rubin); Surgical Pathology, Brigham & Women’s (3) preexisting conditions (eg, Paget disease Hospital, Boston, Mass (Dr Fletcher); Pathology, Mayo Clinic, Roch- of bone, bone infarction, osteomyelitis, be- ester, Minn (Dr Inwards); Department of Pathology, (Drs Montag and Krausz), and Orthopaedic Surgery and Rehabilitation, Univer- nign soft tissue tumor) or unusual expo- sity of Chicago (Dr Peabody), Chicago, Ill; Department of Labora- sures, especially radiation tory Medicine, Children’s Hospital, Columbus, Ohio (Dr Qualman); (4) history of familial predisposition syn- James Homer Wright Laboratories, Massachusetts General Hospital, drome (eg, Li-Fraumeni syndrome, Ollier Boston (Dr Rosenberg); and Pathology and Laboratory Medicine, disease, Mafucci syndrome, familial reti- Emory University, Atlanta, Ga (Dr Weiss). noblastoma syndrome, Rothmund-Thom- The authors have no relevant financial interest in the products or companies described in this article. son syndrome) Reprints:Brian Rubin, MD, PhD, University of Washington Medical (5) previous chemotherapy or radiation ther- Center, Anatomic Pathology, 1959 NE Pacific St, Box 356100, Seattle, apy WA 98195 (e-mail: [email protected]). b. Relevant clinical findings 1616 Arch Pathol Lab Med—Vol 130, November 2006 Bone and Soft Tissue Protocol—Rubin et al c. Clinical diagnosis hemorrhagic) (Note: if the specimen contains d. Relevant physical findings bone, it may require decalcification) (1) anatomic site (specify as much as possi- f. Margins (if excisional biopsy) ble) (1) circumscribed/encapsulated or infiltra- (2) depth and/or location of tumor tive i. soft tissue (2) measured as minimal distance to mar- (a) superficial gins; all margins Ͻ2 cm should be mea- (i) dermal sured and specified in the final report (ii) subcutaneous/suprafascial g. Photograph tumor (b) deep 3. Tissue submitted for microscopic examination (i) fascial a. One section per centimeter (note E) (ii) subfascial b. Frozen section tissue fragment(s) (iii) intramuscular 4. Tissue for special studies (iv) mediastinal a. Electron microscopy (v) intra-abdominal b. Cytogenetics (vi) retroperitoneal c. Flow cytometry (vii) head and neck d. Molecular studies (note F) ii. bone C. Microscopic Examination (a) location (long bones only) (note B) 1. Tumor (i) epiphysis a. Histologic classification (notes G and H) (ii) metaphysis b. Grade (note I) (iii) diaphysis c. Mitotic count (number of mitotic figures/10 (b) location (all bones) high-power fields) (optional) (i) cortical d. Necrosis (present or absent) (ii) medullary e. Margin status, if any (note J) (iii) surface 2. Results of special studies (c) joint (involved or uninvolved) a. Immunohistochemical studies (d) extension into soft tissue b. Electron microscopy e. Procedure c. Cytogenetics (1) soft tissue d. Flow cytometry i. fine-needle aspirate e. Molecular studies ii. core needle biopsy 3. Comments iii. incisional biopsy a. Correlation with intraoperative consultations, iv. excisional biopsy if any (2) bone b. Correlation with prior specimens, if any i. fine-needle aspirate c. Correlation with clinical findings, as appro- ii. core needle biopsy priate iii. incisional biopsy II. Excision; Re-excision; Metastectomy iv. excisional biopsy A. Clinical Information v. curettage 1. Patient identification a. Name B. Macroscopic Examination b. Identification number 1. Specimen c. Birth date a. Tissues received (specify components and d. Sex site) 2. Responsible physician(s) b. Unfixed/fixed (specify fixative) (note C) 3. Date of procedure c. Oriented or not 4. Other clinical information d. Number of pieces of tissue a. Relevant history e. Size of specimen in centimeters (3 dimen- (1) duration of lesion sions) (2) history of preoperative (neoadjuvant) che- f. Results of intraoperative consultation, if per- motherapy or radiation therapy formed (note D) (3) relevant radiologic findings (note A) 2. Tumor, if discernable (4) pre-existing conditions (eg, Paget disease a. Location of bone, bone infarction, osteomyelitis, be- b. Tissues involved nign soft tissue tumor) or unusual expo- (1) skin sures, especially radiation (2) subcutaneous adipose tissue (5) history of familial predisposition syn- (3) fascia drome (eg, Li-Fraumeni syndrome, Ollier (4) muscle disease, Mafucci syndrome, familial reti- (5) bone noblastoma syndrome, Rothmund-Thom- (6) joint son syndrome) c. Dimensions in centimeters (3 dimensions) b. Relevant clinical findings d. Presence or absence of necrosis c. Clinical diagnosis e. Other descriptive characteristics (eg, color, d. Relevant physical findings firm/soft, gritty, fatty, gelatinous, calcified, e. Anatomic site Arch Pathol Lab Med—Vol 130, November 2006 Bone and Soft Tissue Protocol—Rubin et al 1617 f. Depth and/or location of tumor g. Presence or absence of previous biopsy site or (1) soft tissue scar, with dimensions and relationship to re- i. superficial section margins (a) dermal h. Involvement or invasion of major structures (b) subcutaneous/suprafascial (eg, nerve, bone, major blood vessels) ii. deep i. Presence of satellite nodules of tumor away (a) fascial from main tumor mass (relationship to main (b) subfascial mass should be described, maximum mea- (c) intramuscular surement of each satellite nodule should be (d) mediastinal noted, and relationship to margins should be (e) intra-abdominal described) (f) retroperitoneal j. Presence of lymph nodes and description of (g) head and neck cut surface (note M) (2) bone k. Margins (note J) l. Photograph tumor i. location (long bones only) 3. Tissue submitted for microscopic examination (a) epiphysis a. One section per centimeter (note E) (b) metaphysis b. Frozen section tissue fragment(s) (c) diaphysis 4. Tissue for special studies ii. location (all bones) a. Electron microscopy (a) cortical b. Cytogenetics (b) medullary c. Flow cytometry (c) surface d. Molecular studies (note F) iii. joint (involved or uninvolved) C. Microscopic Examination iv. extension into soft tissue 1. Tumor g. Procedure (note K) a. Histologic classification (notes H and N) (1) intralesional (curetting or debulking) b. Grade (note I) (2) marginal/simple/local excision c. Mitotic count (number of mitotic figures/10 (3) wide local excision high-power fields) (optional) (4) segmental/en block resection (bone tu- d. Percentage necrosis (approximated) mors) e. Margin status (5) radical excision f. Lymphatic/vascular involvement (note O) (6) amputation (optional) B. Macroscopic Examination g. Lymph node involvement (note M) 1. Specimen 2. Results of special studies a. Tissues received (specify nature and site) a. Immunohistochemical studies b. Unfixed/fixed (specify fixative) (note B) b. Electron microscopy c. Oriented or not c. Cytogenetics d. Number of pieces of tissue d. Flow cytometry e. Size of specimen in centimeters (3 dimen- e. Molecular studies sions) 3. Comments f. Results of intraoperative consultation, if per- a. Correlation with intraoperative consultations, formed if any 2. Tumor, if discernable b. Correlation with prior specimens, if any a. Location c. Correlation with clinical findings, as appro- b. Tissues involved priate (1) skin EXPLANATORY NOTES (2) subcutaneous adipose tissue A: Relevant Radiologic Findings. Radiographic im- (3) muscle aging plays an especially critical role in the diagnosis of (4) bone bone tumors. Close collaboration with an experienced (5) joint musculoskeletal radiologist and orthopedic surgeon is rec- (6) major neurovascular bundles ommended. (7) attached organs (common in neck, thora- coabdominal, pelvic, and retroperitoneal B: Location of Neoplasms of Bone. The Figure is a tumors) diagrammatic representation of the ‘‘anatomic’’ regions of c. Size of tumor in centimeters (3 dimensions) a long bone. These locations are very important in classi- d. Other descriptive characteristics (eg, color, fying bone tumors. For instance, giant cell tumors almost firm/soft, fatty, gelatinous, calcified, hemor- always arise in the epiphysis. The greater trochanter is rhagic) (Note: if the specimen contains bone, also considered an epiphyseal region, even though it is not it may require decalcification) at the end of the bone. e. Presence or absence of necrosis (approximate C: Fixation. Tissue specimens from bone and soft tis- percentage) sue tumors optimally are received fresh/unfixed because f. Presence or absence of chemotherapy or ra- of the importance of ancillary studies such as cytogenetics, diation therapy effect (note L) which require fresh tissue. 1618 Arch Pathol Lab Med—Vol 130, November 2006 Bone and Soft Tissue Protocol—Rubin et al 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 fewer, excluding margins. Tumors with greater areas of heterogeneity may need to be sampled more thor- oughly. 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- Important anatomic landmarks for tumor diagnosis in long bones. specific molecular translocations (Table 1) that help in clas- Adapted from Gray’s Anatomy of the Human Body. Philadelphia, Pa: 3,4 Lea & Febiger; 1918. sifying bone and soft tissue tumors. In addition, treatment protocols increasingly require fresh tissue for cor- relative studies. Approximately 1 cm3 of fresh tissue (less is acceptable for small specimens, including core biopsies) D: Intraoperative Consultation. Histologic classifica- should be cut into small, 0.2-cm fragments, reserving suf- tion of bone and soft tissue tumors is sufficiently complex ficient tissue for histologic examination. This frozen tissue that, in many cases, it is unreasonable to expect a precise should ideally be stored at Ϫ70ЊC and can be shipped on classification of these tumors based on an intraoperative dry ice to facilities that perform molecular analysis. consultation. A complete understanding of the surgeon’s treatment algorithm is recommended before rendering a G: Tumor Classification From Biopsies. It is not al- frozen section diagnosis. In the case of primary bone tu- ways possible to classify bone and soft tissue tumors pre- mors, an intraoperative diagnosis of benign versus malig- cisely based on biopsy material, especially FNA and core nant will generally guide the immediate decision to cu- needle biopsy specimens. Whereas pathologists should rette, excise, or wait for permanent sections, and certain make every attempt to classify lesions in small biopsy therapeutic options may be lost if the wrong path is pur- specimens, on occasion stratification into very basic diag- sued. Intraoperative consultation is useful in assessing nostic categories, such as lymphoma, carcinoma, melano- whether ‘‘lesional’’ tissue is present and whether or not ma, and sarcoma, is all that is possible. In some cases, this tissue is necrotic, and in constructing a differential precise classification is only possible in open biopsy or diagnosis that can direct the proper triage of tissue for resection specimens. flow cytometry (lymphoma), electron microscopy, and molecular studies/cytogenetics. Tissue triage optimally is H: World Health Organzation Classification of Tu- performed at the time of frozen section. In many cases, it mors. Classification of tumors should be made according is important that a portion of tissue be submitted for an- to the World Health Organization (WHO) classification of cillary studies, even from fine-needle aspiration (FNA) bone and soft tissue tumors listed below.5 As part of the and core needle biopsy specimens, once sufficient tissue recent WHO classification of soft tissue tumors, a recom- has been submitted for histologic evaluation. mendation was made to divide tumors into 4 categories: benign, intermediate (locally aggressive), intermediate E: Tissue Submission for Histologic Evaluation. One (rarely metastasizing), and malignant. section per centimeter of maximum dimension is usually recommended, although fewer sections are needed for WHO Classification of Soft Tissue Tumors of Intermediate very large tumors, especially if they are homogeneous. Tu- Malignant Potential and Malignant Soft Tissue Tumors mors known to be high grade from a previous biopsy do not require as many sections as those that were previously Adipocytic Tumors diagnosed as low grade, as documentation of a high-grade Intermediate (locally aggressive) component will change stage and prognosis in the latter Atypical lipomatous tumor/Well-differentiated li- case. Sections should be taken of grossly heterogeneous posarcoma areas, and there is no need to submit more than 1 section Malignant of necrotic tumor (always with a transition to viable tu- Dedifferentiated liposarcoma mor), with the exception of chemotherapy effect on oste- Myxoid/round cell liposarcoma osarcomas and Ewing/primitive neuroectodermal tumor Pleomorphic liposarcoma (PNET) sarcomas.2 Occasionally, gross pathology can be Mixed-type liposarcoma misleading, and areas that appear to be grossly necrotic Liposarcoma, not otherwise specified may actually be myxoid or edematous. When this hap- Fibroblastic/Myofibroblastic Tumors pens, additional sections of these areas should be submit- Intermediate (locally aggressive) ted for histologic examination. When estimates of gross Superficial fibromatoses (palmar/plantar) Arch Pathol Lab Med—Vol 130, November 2006 Bone and Soft Tissue Protocol—Rubin et al 1619 Table 1. Characteristic Cytogenetic and Molecular Events of Bone and Soft Tissue Tumors* Histologic Type Cytogenetic Events Molecular Events Alveolar soft part sarcoma t(X;17)(p11;q25) ASPL-TFE3 fusion Aneurysmal bone cyst t(16;17)(q22;p13) CDH11-USP6 fusion Angiomatoid fibrous histiocytoma t(12;16)(q13;p11) FUS-ATF1 fusion Extraskeletal myxoid chondrosarcoma t(9;22)(q22;q12) EWS-NR4A3 fusion t(9;17)(q22;q11) TAF2N-NR4A3 fusion t(9;15)(q22;q21) TCF12-NR4A3 fusion Chondrosarcoma of bone Complex Clear cell sarcoma t(12;22)(q13;q12) EWS-ATF1 fusion Desmoplastic small round cell tumor t(11;22)(p13;q12) EWS-WT1 fusion Dermatofibrosarcoma protuberans Ring form of chromosomes 17 and 22 COL1A1-PDGFB fusion t(17;22)(q21;q13) COL1A1-PDGFB fusion Ewing sarcoma/PNET t(11;22)(q24;q12) EWS-FLI1 fusion t(21;22)(q12;q12) EWS-ERG fusion t(2;22)(q33;q12) EWS-FEV fusion t(7;22)(p22;q12) EWS-ETV1 fusion t(17;22)(q12;q12) EWS-E1AF fusion inv(22)(q12;q12) EWS-ZSG Fibrosarcoma, infantile t(12;15)(p13;q26) ETV6-NTRK3 fusion Trisomies 8, 11, 17, and 20 Inflammatory myofibroblastic tumor 2p23 rearrangement ALK fusion genes Leiomyosarcoma Deletion of 1p Liposarcoma Well-differentiated Ring form of chromosome 12 Myxoid/Round cell t(12;16)(q13;p11) FUS-CHOP fusion t(12;22)(q13;q12) EWS-CHOP fusion Pleomorphic Complex Low-grade fibromyxoid sarcoma t(7;16)(q33;p11) FUS-CREB3L2 fusion Malignant peripheral nerve sheath tumor Complex Myxofibrosarcoma (myxoid MFH) Ring form of chromosome 12 Osteosarcoma Low grade Ring chromosomes High grade Complex Rhabdoid tumor Deletion of 22q INI1 inactivation Rhabdomyosarcoma Alveolar t(2;13)(q35;q14) PAX3-FKHR fusion t(1;13)(p36;q14), double minutes PAX7-FKHR fusion Embryonal Trisomies 2q, 8, and 20 Loss of heterozygosity at 11p15 Synovial sarcoma Monophasic t(X;18)(p11;q11) SYT-SSX1 or SYT-SSX2 fusion Biphasic t(X;18)(p11;q11) Predominantly SYT-SSX1 fusion * PNET indicates primitive neuroectodermal tumor; MFH, malignant fibrous hystiocytoma.

Desmoid-type fibromatosis Giant cell tumor of soft tissues Lipofibromatosis Malignant Intermediate (rarely metastasizing) Pleomorphic malignant fibrous histiocytoma Solitary fibrous tumor and hemangiopericytoma (MFH)/Undifferentiated pleomorphic sarcoma (including lipomatous hemangiopericytoma) Giant cell MFH/Undifferentiated pleomorphic Inflammatory myofibroblastic tumor sarcoma with giant cells Low-grade myofibroblastic sarcoma Inflammatory MFH/Undifferentiated pleomorphic Myxoinflammatory fibroblastic sarcoma sarcoma with prominent inflammation Infantile fibrosarcoma Smooth Muscle Tumors Malignant Malignant Adult fibrosarcoma Leiomyosarcoma Myxofibrosarcoma Skeletal Muscle Tumors Low-grade fibromyxoid sarcoma/hyalinizing Malignant spindle cell tumor Embryonal rhabdomyosarcoma (including spindle Sclerosing epithelioid fibrosarcoma cell, botryoid, anaplastic) So-called Fibrohistiocytic Tumors Alveolar rhabdomyosarcoma (including solid, an- Intermediate (rarely metastasizing) aplastic) Plexiform fibrohistiocytic tumor Pleomorphic rhabdomyosarcoma 1620 Arch Pathol Lab Med—Vol 130, November 2006 Bone and Soft Tissue Protocol—Rubin et al Vascular Tumors Periosteal Intermediate (locally aggressive) High-grade surface Kaposiform hemangioendothelioma Fibrogenic Tumors Intermediate (rarely metastasizing) Desmoplastic fibroma (benign/locally aggressive) Retiform hemangioendothelioma Fibrosarcoma Papillary intralymphatic angioendothelioma Fibrohistiocytic Tumors Composite hemangioendothelioma Malignant fibrous histiocytoma Kaposi sarcoma Ewing Sarcoma/Primitive Neuroectodermal Tumor Malignant Ewing sarcoma/PNET Epithelioid hemangioendothelioma Hematopoietic Tumors Angiosarcoma of soft tissue Plasma cell myeloma Tumors of Peripheral Nerves Malignant lymphoma, not otherwise specified (NOS) Malignant Giant Cell Tumors Malignant peripheral nerve sheath tumor Giant cell tumor (benign/locally aggressive) Epithelioid malignant peripheral nerve sheath tu- Malignancy in giant cell tumor mor Notochordal Tumors Chondro-osseous Tumors Chordoma Malignant Vascular Tumors Mesenchymal chondrosarcoma Angiosarcoma Extraskeletal osteosarcoma Smooth Muscle Tumors Tumors of Uncertain Differentiation Leiomyosarcoma Intermediate (rarely metastasizing) Lipogenic Tumors Angiomatoid fibrous histiocytoma Liposarcoma Ossifying fibromyxoid tumor (including atypical/ Miscellaneous Tumors malignant) Adamantinoma Mixed tumor/Myoepithelioma/Parachordoma Metastatic malignancy Malignant Miscellaneous Lesions Synovial sarcoma Langerhans cell histiocytosis Epithelioid sarcoma I: Grading. Unlike with other organ systems, the stag- Alveolar soft part sarcoma ing of soft tissue sarcomas is largely determined by grade. Clear cell sarcoma of soft tissue Unfortunately, there is no generally agreed-upon scheme Extraskeletal myxoid chondrosarcoma (‘‘chordoid’’ for grading bone and soft tissue tumors.6 The most widely type) used soft tissue grading systems are the French Federation PNET/Extraskeletal Ewing tumor of Cancer Centers Sarcoma Group (FNCLCC) and Nation- peripheral primitive neuroectodermal tumor al Cancer Institute (NCI) systems.7,8 Both systems have 3 (pPNET) grades, evaluate mitotic activity, necrosis, and differenti- Extraskeletal Ewing tumor ation, and are highly correlated with prognosis.9 However, Desmoplastic small round cell tumor in addition to these criteria, the NCI system requires the Extrarenal rhabdoid tumor quantification of cellularity and pleomorphism for certain Malignant mesenchymoma subtypes of sarcomas, which is difficult to determine ob- Neoplasms with perivascular epithelioid cell dif- jectively. The FNCLCC system is easier to use, in our opin- ferentiation (PEComa) ion, and recent data suggest that it may be slightly better Intimal sarcoma in predicting prognosis than the NCI system.9 Other systems with 2 or 4 grades also have been used. Accurate WHO Classification of Benign/Locally Aggressive and grading requires an adequate sample of tissue, which is Malignant Bone Tumors not always available from FNA or core needle biopsy or Cartilage Tumors in tumors previously treated with radiation or chemother- Chondrosarcoma apy. Central, primary, and secondary FNCLCC Grading Peripheral Dedifferentiated The FNCLCC grade is based on 3 parameters: differ- Mesenchymal entiation, mitotic activity, and necrosis. Each of these pa- Clear cell rameters receives a score: differentiation (1–3), mitotic ac- Osteogenic Tumors tivity (1–3), and necrosis (0–2). The scores are summed to Osteosarcoma produce a grade. Conventional Grade 1: 2 or 3 Chondroblastic Grade 2: 4 or 5 Fibroblastic Grade 3: 6 to 8 Osteoblastic Differentiation.—Tumor differentiation is scored as fol- Telangiectatic lows (see Table 2). Small cell Low-grade central Score 1: Sarcomas closely resembling normal, adult Secondary mesenchymal tissue Parosteal Score 2: Sarcomas of certain histologic type Arch Pathol Lab Med—Vol 130, November 2006 Bone and Soft Tissue Protocol—Rubin et al 1621 Table 2. Tumor Differentiation Score According to have little to no metastatic potential are giant cell tumor Histologic Type in the Updated Version of the French and desmoplastic fibroma. Two bone tumors that are lo- Federation of Cancer Centers Sarcoma Group System* cally aggressive and metastasize infrequently, and thus Tumor Differentiation are usually low grade, are low-grade central osteosarcoma and parosteal osteosarcoma. Periosteal osteosarcoma is Histologic Type Score generally regarded as a grade 2 osteosarcoma. Primary Well-differentiated liposarcoma 1 bone tumors that are generally high grade include: malig- Myxoid liposarcoma 2 nant giant cell tumor, Ewing sarcoma/PNET, angiosar- Round cell liposarcoma 3 coma, dedifferentiated chondrosarcoma, conventional os- Pleomorphic liposarcoma 3 Dedifferentiated liposarcoma 3 teosarcoma, telangiectactic osteosarcoma, small cell oste- Fibrosarcoma 2 osarcoma, secondary osteosarcoma, and high-grade sur- Myxofibrosarcoma (myxoid MFH) 2 face osteosarcoma. Typical storiform MFH (sarcoma, NOS) 3 Grading of conventional chondrosarcoma is based on MFH, pleomorphic type (patternless pleomor- cellularity, cytologic atypia, and mitotic figures. Grade 1 phic sarcoma) 3 (low-grade) chondrosarcoma is hypocellular and similar Giant cell and inflammatory MFH (pleomorphic sarcoma, NOS with giant cells or in- histologically to enchondroma. Grade 2 (intermediate- flammatory cells) 3 grade) chondrosarcoma is more cellular than grade 1 Well-differentiated leiomyosarcoma 1 chondrosarcoma; has more cytologic atypia, greater hy- Conventional leiomyosarcoma 2 perchromasia and nuclear size; or has extensive myxoid Poorly differentiated/pleomorphic/epithelioid stroma. Grade 3 (high-grade) chondrosarcoma is hyper- leiomyosarcoma 3 cellular, pleomorphic, and contains prominent mitotic ac- Biphasic/monophasic synovial sarcoma 3 Poorly-differentiated synovial sarcoma 3 tivity. Mesenchymal chondrosarcoma, fibrosarcoma, leio- Pleomorphic rhabdomyosarcoma 3 myosarcoma, liposarcoma, angiosarcoma and other ‘‘soft Mesenchymal chondrosarcoma 3 tissue-type’’ sarcomas that rarely occur in bone can be Extraskeletal osteosarcoma 3 graded according to the FNCLCC grading system. Ewing sarcoma/PNET 3 Chordomas are locally aggressive lesions with a pro- Malignant rhabdoid tumor 3 pensity for metastasis late in their clinical course and are Undifferentiated sarcoma 3 not graded. Adamantinomas tend to have a low-grade 9 * Modified from Guillou et al, with permission from the American clinical course, but this is variable. Fortunately, they are Society of Clinical Oncology. Note: Grading of malignant peripheral nerve sheath tumor, embryonal and alveolar rhabdomyosarcoma, an- very rare. According to the WHO classification of tumors giosarcoma, extraskeletal myxoid chondrosarcoma, alveolar soft part of bone, adamantinomas are considered low grade. sarcoma, clear cell sarcoma, and epithelioid sarcoma is not recommended.5 MFH indicates malignant fibrous histiocytoma; NOS, not Bone Tumor Grades (Summary) otherwise specified; PNET, primitive neuroectodermal tumor. Benign/Locally Aggressive Desmoplastic fibroma Giant cell tumor Score 3: Synovial sarcomas, embryonal sarcomas, un- Grade 1 (Low Grade) differentiated sarcomas, and sarcomas of Low grade central osteosarcoma doubtful tumor type Parosteal osteosarcoma Adamantinoma Tumor differentiation is the most problematic aspect of Grade 2 the FNCLCC system. Its use is subjective and does not Periosteal osteosarcoma include every subtype of sarcoma. Nevertheless, it is an Grade 3 (High Grade) integral part of the system, and an attempt should be Malignant giant cell tumor made to assign a differentiation score. Ewing sarcoma/PNET Mitosis Count.—The count is made in the most mitoti- Dedifferentiated chondrosarcoma cally active area in 10 successive high-power fields (HPFs) Conventional osteosarcoma (a high-power field ϫ 400 ϭ 0.1734 mm2) (use the 40ϫ Telangiectactic osteosarcoma objective). Small cell osteosarcoma Secondary osteosarcoma Score 1: 0 to 9 mitoses per 10 HPFs High-grade surface osteosarcoma Score 2: 10 to 19 mitoses per 10 HPFs Variable Grade Score 3: 20 or more mitoses per 10 HPFs. Conventional chondrosarcoma of bone (grades 1–3) Tumor Necrosis.—Determined on histologic sections. Soft-tissue type sarcomas (eg, leiomyosarcoma) Ungraded Score 0: No tumor necrosis Chordoma Score 1: Less than or equal to 50% tumor necrosis Score 2: More than 50% tumor necrosis TNM Grading The grading of bone tumors is largely driven by the The American Joint Committee on Cancer (AJCC) stag- histologic diagnosis, and traditionally grading has been ing system for soft tissue and bone tumors includes a 4- grade system but effectively collapses into high grade and based on the system advocated by Broders, which assesses 11,12 cellularity and nuclear features/degree of anaplasia.10 We low grade. Grading in the TNM grading system is advocate a more pragmatic approach to grading aggres- based on differentiation only and does not apply to sar- sive and malignant primary tumors of bone. Two bone comas. tumors that have a tendency to be locally aggressive but GX Grade cannot be assessed 1622 Arch Pathol Lab Med—Vol 130, November 2006 Bone and Soft Tissue Protocol—Rubin et al G1 Well differentiated a percentage of total tumor area that is either necrotic or G2 Moderately differentiated replaced by fibrous or granulation tissue. Nonliquefied tu- G3 Poorly differentiated mor tissue from a cross section through the longest axis G4 Poorly differentiated or undifferentiated (4-tiered of the tumor should be sampled. At least 1 section of ne- systems only) crotic tumor (always with a transition to viable tumor) should be sampled to verify the gross impression of ne- For purposes of using the AJCC staging system, 3-grade crosis. Nonsampled necrotic areas should be included in systems such as FNCLCC can be converted to a 4-grade the estimate of necrosis and the percentage of tumor ne- (TNM) system as follows: grade 1 ϭ G1; grade 2 ϭ G2; ϭ crosis reported. The gross appearance can be misleading, and grade 3 G3 and G4. This means that FNCLCC/NCI and areas that appear grossly necrotic may actually be grade 2 tumors are considered ‘‘high grade’’ for the pur- myxoid or edematous. Additional sections from these ar- poses of stage grouping. eas should be submitted for histologic examination. When J: Margins. It has been recommended that for all mar- estimates of gross necrosis exceed those of histologic ne- gins Ͻ2 cm, the distance of the tumor from the margin crosis, the greater percentage of necrosis should be re- be reported in centimeters.13 However, there is a lack of corded on the surgical pathology report. It is essential to agreement on this issue. We recommend specifying the estimate neoadjuvant treatment effect in primary Ewing location of all margins Ͻ2 cm. Margins from bone and sarcoma/PNET and osteosarcoma of bone, as these have soft tissue tumors should be taken as perpendicular mar- been shown to have prognostic significance.2,14–18 An entire gins, if possible. If bones are present in the specimen and representative slice of the tumor taken through the long are not involved by tumor, or the tumor is Ͼ2cmfrom axis should be mapped using a grid pattern diagram, pho- the margin, the marrow can be scooped out and submit- tocopy, or radiologic film to indicate the site for each tu- ted as a margin. In addition, the status of the margin mor block. In addition, a section of tumor perpendicular should be listed according to the following scheme: to the long axis should be sampled at the rate of 1 section per centimeter. Areas of soft tissue extension and the in- ● Intralesional: within lesion (ie, the margin is positive) terface of tumor with normal tissue should also be sam- ● Ͻ Marginal: 2.0 cm of normal tissue around all mar- pled. Prognostically significant therapy response in oste- gins, less if bounded by fascia osarcoma, according to most series, is defined at 90%, ● Ն Wide: 2.0 cm of normal tissue around all margins, with those tumors showing Ն90% therapy response as- less if bounded by fascia sociated with a favorable prognosis.14,15 Therapy response K: Definition of Procedures. The following is a list of in Ewing sarcoma is expressed as grade I (macroscopic guidelines to be used in defining what type of procedure viable tumor), grade II (microscopic viable tumor), or grade III (no viable tumor), and is highly correlated with has been performed. 16,17 Intralesional Resection. Leaving gross tumor behind. 5-year survival. Partial debulking or curettage are examples. In general, M: Lymph Nodes. Regional lymph node metastasis is these procedures are palliative. uncommon in adult bone and soft tissue sarcomas. Nodes Marginal Resection. Removing the tumor and its pseu- are not sampled routinely, and it usually is not necessary docapsule with a relatively small amount of adjacent tis- to exhaustively search for nodes. When present, regional sue. There is no gross tumor at the margin; however, mi- lymph node metastasis has prognostic importance and croscopic tumor may be present. Note that occasionally, a should be reported. surgeon will perform an ‘‘excisional’’ biopsy, which effectively accomplishes the same thing as a marginal resec- N: Histologic Classification of Treated Lesions. Due tion. to extensive treatment effects, such as necrosis, fibrosis, Wide Resection. An intracompartmental resection. The and chemotherapy-induced and radiation-induced pleo- tumor is removed with pseudocapsule and a cuff of 2 cm morphism, it may not be possible to classify some lesions of normal tissue in all directions, but without the complete that were either never biopsied or where the biopsy was removal of an entire muscle group, compartment or bone. insufficient for a precise diagnosis. A cuff larger than 2.0 cm is typical, but it may be less when the margin is a fascial plane. O: Venous/Lymphatic Invasion. By American Joint Segmental/En Block Resection (Bone Only). This is simi- Committee on Cancer (AJCC)/International Union lar conceptually to a wide excision in soft tissue. A single Against Cancer (UICC) convention, vessel invasion (lym- piece of bone is resected, including the lesion and a cuff phatic or venous) does not affect the T category unless of normal bone. specifically included in the definition of a T category. In Radical Resection. The removal of an entire soft tissue all other cases, lymphatic and venous invasion by tumor compartment (for example, anterior compartment of the are coded separately as follows. thigh, the quadriceps) or bone, or the excision of the adjacent muscle groups if the tumor is extracompartmental. Lymphatic Vessel Invasion (L) Radical excisions include amputations and disarticula- LX Lymphatic vessel invasion cannot be assessed tions. L0 No lymphatic vessel invasion L1 Lymphatic vessel invasion L: Response to Chemotherapy/Radiation Therapy Ef- fect. While agreement has not been reached about mea- Venous Invasion (V) suring the effect of preoperative (neoadjuvant) chemo- VX Venous invasion cannot be assessed therapy/radiation therapy in soft tissue tumors, an at- V0 No venous invasion tempt should be made to quantify these effects, especially V1 Microscopic venous invasion in the research setting. Therapy response is expressed as V2 Macroscopic venous invasion Arch Pathol Lab Med—Vol 130, November 2006 Bone and Soft Tissue Protocol—Rubin et al 1623 P: TNM and Stage Groupings: Soft Tissue Tumors. Primary Tumor (T) The TNM Staging System for soft tissue tumors of the TX Primary tumor cannot be assessed American Joint Committee on Cancer (AJCC) and the In- T0 No evidence of primary tumor ternational Union Against Cancer (UICC) is recommend- 11,12 T1 Tumor 5 cm or less in greatest dimension ed. T1a Superficial tumor The staging system applies to all soft tissue sarcomas T1b Deep tumor except Kaposi sarcoma, dermatofibrosarcoma protuber- T2 Tumor more than 5 cm in greatest dimension ans, desmoid fibromatosis, infantile fibrosarcoma, and an- T2a Superficial tumor giosarcoma. In addition, sarcomas arising within the con- T2b Deep tumor fines of the dura mater, including the brain, and sarcomas arising in parenchymatous organs and from hollow vis- Note: Superficial tumor is located exclusively above the cera are not optimally staged by this system. superficial fascia without invasion of the fascia; deep tu- Pathologic (pTNM) staging consists of the removal and mor is located either exclusively beneath the superficial pathologic evaluation of the primary tumor and clinical/ fascia, superficial to the fascia with invasion of or through radiologic evaluation for regional and distant metastases. the fascia, or both superficial yet beneath the fascia. Ret- In circumstances where it is not possible to obtain accu- roperitoneal, mediastinal, and pelvic sarcomas are classi- rate measurements of the excised primary sarcoma spec- fied as deep tumors. imen, it is acceptable to use radiologic assessment of tumor size to assign a pT category. In examining the pri- Regional Lymph Nodes (N) mary tumor, the pathologist should subclassify the lesion NX Regional lymph nodes cannot be assessed and assign a histopathologic grade via an accepted grad- N0 No regional lymph node metastasis ing system. N1 Regional lymph node metastasis* Although size currently is designated within the TNM *Note: Presence of positive nodes (N1) is considered stage system as 5 cm or smaller vs larger than 5 cm, particular IV. emphasis should be placed on providing size measurements. Size should be regarded as a continuous variable, Distant Metastasis (M) with 5 cm as merely an arbitrary division that makes it possible to dichotomize patient populations. MX Distant metastasis cannot be assessed Depth is also an independent variable and is defined as M0 No distant metastasis follows. M1 Distant metastasis

1. Superficial Stage Groupings a. Lesion does not involve superficial fascia. 4-Tier 3-Tier 2-Tier 2. Deep System System System a. Lesion is deep to, or involves, the superficial fascia. Stage I T1a, 1b, 2a, N0 M0 G1–2 G1 Low b. All intraperitoneal visceral lesions, retroperitoneal 2b lesions, intrathoracic lesions, and the majority of Stage II T1a, 1b, 2a N0 M0 G3–4 G2–3 High head and neck tumors are considered deep. Stage III T2b N0 M0 G3–4 G2–3 High 3. Depth is evaluated in relation to tumor size (T) Stage IV Any T N1 M0 Any G Any G High or a. Tumor 5 cm or less: T1a ϭ superficial; T1b ϭ deep. Low b. Tumor Ͼ5 cm: T2a ϭ superficial; T2b ϭ deep. Any T N0 M1 Any G Any G High or Low Nodal involvement is rare in adult soft tissue sarcomas but, when present, has a very poor prognosis. The out- Q: TNM and Stage Groupings: Bone Tumors. The come of patients with N1 disease is similar to that of those TNM Staging System for bone tumors of the American with M1 disease. Patients whose nodal status is not deter- Joint Committee on Cancer (AJCC) and the International mined to be positive for tumor, either clinically or path- Union Against Cancer (UICC) is recommended.11,12 ologically, should be designated as N0. The classification is to be applied to all primary tumors of bone. Pathologic staging includes pathologic data ob- Restaging of Recurrent Tumors tained from examination of a resected specimen sufficient to evaluate the highest T category, histopathologic type The same staging should be used when a patient re- and grade, regional lymph nodes as appropriate, or dis- quires restaging of sarcoma recurrence. Such reports tant metastasis. Because regional lymph node involvement should specify whether patients have primary lesions or from bone tumors is rare, the pathologic stage grouping lesions that were previously treated and have subsequent- includes any of the following combinations: pT pG pN ly recurred. Reporting of possible etiologic factors such as pM, or pT pG cN cM, or cT cN pM. radiation exposure and inherited or genetic syndromes is encouraged. Appropriate workup for recurrent sarcoma Primary Tumor (T) usually includes cross-sectional imaging (computed to- TX Primary tumor cannot be assessed mography [CT] scan or magnetic resonance imaging T0 No evidence of primary tumor [MRI] scan) of the tumor, a CT scan of the chest, and a T1 Tumor 8 cm or less in greatest dimension tissue biopsy to confirm diagnosis prior to initiation of T2 Tumor more than 8 cm in greatest dimension therapy. T3 Discontinuous tumors in the primary bone site 1624 Arch Pathol Lab Med—Vol 130, November 2006 Bone and Soft Tissue Protocol—Rubin et al Regional Lymph Nodes (N) Additional Descriptors NX Regional lymph nodes cannot be assessed* Residual Tumor (R) N0 No regional lymph node metastasis Tumor remaining in a patient after therapy with cura- N1 Regional lymph node metastasis tive intent (eg, surgical resection for cure) is categorized *Note: Because of the rarity of lymph node involvement by a system known as R classification, shown below. in sarcomas, the designation NX may not be appropriate RX Presence of residual tumor cannot be assessed and could be considered N0 if no clinical involvement is R0 No residual tumor evident. R1 Microscopic residual tumor Distant Metastasis (M) R2 Macroscopic residual tumor MX Distant metastasis cannot be assessed For the surgeon, the R classification may be useful to M0 No distant metastasis indicate the known or assumed status of the completeness M1 Distant metastasis of a surgical excision. For the pathologist, the R classifi- M1a Lung cation is relevant to the status of the margins of a surgical M1b Other distant sites resection specimen. That is, tumor involving the resection margin on pathologic examination may be assumed to Stage Groupings correspond to residual tumor in the patient and may be classified as macroscopic or microscopic according to the 4-Tier 3-Tier findings at the specimen margin(s). System System References Stage IA T1 N0 M0 G1–2, Low- G1, Low- 1. Qualman SJ, Bowen J, Parham DM, Branton PA, Meyer WH. Protocol for grade grade the examination of specimens from patients (children and young adults) with Stage IB T2 N0 M0 G1–2, Low- G1, Low- rhabdomyosarcoma. Arch Pathol Lab Med. 2003;127:1290–1297. grade grade 2. Carpentiere DF, Qualman SJ, Bowen J, Krausz T, Marchevsky A, Dickman Stage IIA T1 N0 M0 G3–4, High- G2–3, High- PS. Protocol for the examination of specimens from pediatric and adult patients grade grade with osseous and extraosseous Ewing sarcoma family of tumors, including peripheral primitive neuroectodermal tumor and Ewing sarcoma. Arch Pathol Lab Stage IIB T2 N0 M0 G3–4, High- G2–3, High- Med. 2005;129:866–871. grade grade 3. Ladanyi M, Bridge JA. Contribution of molecular genetic data to the clas- Stage III T3 N0 M0 Any G Any G sification of sarcomas. Hum Pathol. 2000;31:532–538. Stage IVA Any T N0 M1a Any G Any G 4. Tomescu O, Barr FG. Chromosomal translocations in sarcomas: prospects Stage IVB Any T N1 Any M Any G for therapy. Trends Mol Med. 2001;7:554–559. 5. Pathology and Genetics of Tumours of Soft Tissue and Bone. Lyon, France: Any T Any N M1b Any G Any G IARC Press; 2002. World Health Organization Classification of Tumours. 6. Oliveira AM, Nascimento AG. Grading in soft tissue tumors: principles and problems. Skeletal Radiol. 2001;30:543–559. R: TNM Descriptors. For identification of special cas- 7. Coindre JM, Trojani M, Contesso G, et al. Reproducibility of a histopatho- es of TNM or pTNM classifications, the ‘‘m’’ suffix and logic grading system for adult soft tissue sarcoma. Cancer. 1986;58:306–309. ‘‘y,’’ ‘‘r,’’ and ‘‘a’’ prefixes are used. Although they do not 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. affect the stage grouping, they indicate cases needing sep- Cancer. 1984;53:530–541. arate analysis. 9. Guillou L, Coindre JM, Bonichon F, et al. Comparative study of the National The ‘‘m’’ suffix indicates the presence of multiple pri- 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 mary tumors in a single site and is recorded in parenthe- Oncol. 1997;15:350–362. ses: pT(m)NM. 10. Inwards CY, Unni KK. Classification and grading of bone sarcomas. He- The ‘‘y’’ prefix indicates those cases in which classifi- matol Oncol Clin North Am. 1995;9:545–569. 11. UICC TNM Classification of Malignant Tumours. 6th ed. New York, NY: cation is performed during or following initial multimo- Wiley-Liss; 2002. dality therapy (ie, neoadjuvant chemotherapy, radiation 12. AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer; 2002. therapy, or both chemotherapy and radiation therapy). 13. Association of Directors of Anatomic and Surgical Pathology. Recommen- dations for the reporting of soft tissue sarcomas. Mod Pathol. 1998;11:1257– The cTNM or pTNM category is identified by a ‘‘y’’ prefix. 1261. The ycTNM or ypTNM categorizes the extent of tumor 14. Picci P, Sangiorgi L, Rougraff BT, Neff JR, Casadei R, Campanacci M. Re- actually present at the time of that examination. The ‘‘y’’ lationship of chemotherapy-induced necrosis and surgical margins to local recurrence in osteosarcoma. J Clin Oncol. 1994;12:2699–2705. categorization is not an estimate of tumor prior to multi- 15. Raymond AK, Chawla SP, Carrasco CH, et al. Osteosarcoma chemotherapy modality therapy (ie, before initiation of neoadjuvant ther- effect: a prognostic factor. Semin Diagn Pathol. 1987;4:212–236. apy). 16. Bacci G, Ferrari S, Bertoni F, et al. Prognostic factors in nonmetastatic The ‘‘r’’ prefix indicates a recurrent tumor when staged 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. after a documented disease-free interval, and is identified 17. Picci P, Bohling T, Bacci G, et al. Chemotherapy-induced tumor necrosis by the ‘‘r’’ prefix: rTNM. as a prognostic factor in localized Ewing’s sarcoma of the extremities. J Clin The ‘‘a’’ prefix designates the stage determined at au- Oncol. 1997;15:1553–1559. 18. Abdul-Karim FW, Bauer TW, Kilpatrick SE, et al. Recommendations for the topsy: aTNM. reporting of bone tumors. Hum Pathol.35:1173–1178.

Arch Pathol Lab Med—Vol 130, November 2006 Bone and Soft Tissue Protocol—Rubin et al 1625 SURGICAL PATHOLOGY CANCER CASE SUMMARY (CHECKLIST) Soft Tissue: Biopsy Patient name:

Surgical pathology number: MACROSCOPIC (check 1 response unless Necrosis otherwise indicated) Absent Specimen Type Present Core needle biopsy Extent: % Incisional biopsy Cannot be determined Excisional biopsy Prebiopsy Treatment (check all that apply) Other (specify): No therapy Not specified Chemotherapy performed Radiation therapy performed Tumor Site Therapy performed, type not specified Specify (if known): Unknown Not specified Grade Tumor Depth (check all that apply) System used: Superficial French Federation of Cancer Centers Sarcoma Dermal Group (FNCLCC) Subcutaneous/suprafascial National Cancer Institute (NCI) Deep Other (specify): Fascial Specify grade: Subfascial Cannot be determined Intramuscular Mediastinal Regional Lymph Nodes Intra-abdominal Cannot be assessed Retroperitoneal No regional lymph node metastasis Head and neck Regional lymph node metastasis Other (specify): Specify: Number examined: Cannot be determined Number involved: Note: More than 1 tissue plane may be involved and should be indicated. Distant Metastasis Cannot be assessed Tumor Size Distant metastasis Greatest dimension: cm *Specify site(s), if known: *Additional dimensions: ϫ cm Cannot be determined (see Comment) Margins (for excisional biopsy only) Cannot be assessed MICROSCOPIC (check 1 response unless Margins uninvolved by sarcoma otherwise indicated) Distance of sarcoma from closest margin: cm Histologic Type (World Health Organization [WHO] clas- Specify margin: sification of soft tissue tumors) Specify other close (less than 2.0 cm) margin(s): Specify: Cannot be determined Margins involved by sarcoma Specify margin(s): Results of Ancillary Studies Specify: *Venous/Lymphatic (Large/Small Vessel) Invasion Not performed * Present * Absent *Mitotic Rate * Indeterminate *Specify: /10 high-power fields (1 HPF ϫ 400 ϭ 0.1734 mm2; ϫ40 objective; most pro- *Additional Pathologic Findings liferative area) *Specify:

*Comment(s)

* Data elements with asterisks are not required for accreditation purposes for the Commission on Cancer. These elements may be clinically important, but are not yet validated or regularly used in patient management. Alternatively, the necessary data may not be available to the pathologist at the time of pathologic assessment of this specimen.

1626 Arch Pathol Lab Med—Vol 130, November 2006 Bone and Soft Tissue Protocol—Rubin et al SURGICAL PATHOLOGY CANCER CASE SUMMARY (CHECKLIST) Soft Tissue: Resection

Patient name:

Surgical pathology number: MACROSCOPIC (check 1 response unless Preresection Treatment (check all that apply) otherwise indicated) No therapy Specimen Type Chemotherapy performed Intralesional resection Radiation therapy performed Marginal resection Therapy performed, type not specified Wide resection Unknown Radical resection Grade Other (specify): System used: Not specified French Federation of Cancer Centers Sarcoma Group Tumor Site (FNCLCC) Specify (if known): National Cancer Institute (NCI) Not specified Other (specify): Specify grade: Tumor Depth (check all that apply) Superficial Pathologic Staging (pTNM) Dermal Primary Tumor (pT) Subcutaneous/suprafascial pTX: Primary tumor cannot be assessed Deep pT0: No evidence of primary tumor Fascial pT1a: Tumor 5 cm or less in greatest dimension, super- Subfascial ficial tumor Intramuscular pT1b: Tumor 5 cm or less in greatest dimension, deep Mediastinal tumor Intra-abdominal pT2a: Tumor more than 5 cm in greatest dimension, su- Retroperitoneal perficial tumor Head and neck pT2b: Tumor more than 5 cm in greatest dimension, Other (specify): deep tumor Cannot be determined Note: More than 1 tissue plane may be involved and should be Regional Lymph Nodes (pN) indicated. pNX: Regional lymph nodes cannot be assessed pN0: No regional lymph node metastasis Tumor Size pN1: Regional lymph node metastasis Greatest dimension: cm Specify: Number examined: *Additional dimensions: ϫ cm Number involved: Cannot be determined (see Comment) Distant Metastasis (pM) MICROSCOPIC (check 1 response unless pMX: Cannot be assessed otherwise indicated) pM1: Distant metastasis *Specify site(s), if known: Histologic Type (WHO classification of soft tissue tumors) Specify: Margins Cannot be determined Cannot be assessed Margins uninvolved by sarcoma Results of Ancillary Studies Distance of sarcoma from closest margin: cm Specify: Specify margin: Not performed Specify other close (less than 2.0 cm) margin(s): *Mitotic Rate Margins involved by sarcoma *Specify: /10 high-power fields Specify margin(s): ϫ ϭ 2 ϫ (1 HPF 400 0.1734 mm ; 40 objective; most prolif- *Venous/Lymphatic (Large/Small Vessel) Invasion erative area) * Present Necrosis (macroscopic or microscopic) * Absent Absent * Indeterminate Present *Additional Pathologic Findings Extent: % *Specify: *Comment(s)

Arch Pathol Lab Med—Vol 130, November 2006 Bone and Soft Tissue Protocol—Rubin et al 1627 SURGICAL PATHOLOGY CANCER CASE SUMMARY (CHECKLIST) Bone: Biopsy

Patient name:

Surgical pathology number: MACROSCOPIC (check 1 response unless MICROSCOPIC (check 1 response unless otherwise indicated) otherwise indicated) Specimen Type Histologic Type (WHO classification of bone tumors) Core needle biopsy Specify: Curettage Cannot be determined Excisional biopsy Other (specify): Results of Ancillary Studies Not specified Specify: Not performed Bone Involved Specify (if known): *Mitotic Rate Not specified *Specify: /10 high-power fields (1 HPF ϫ 400 ϭ 0.1734 mm2; ϫ40 objective; most Tumor Location (check all that apply) proliferative area) Epiphysis Metaphysis Necrosis Diaphysis Absent Cortical Present Medullary cavity Extent: % Surface Cannot be determined Tumor involves joint Tumor extension into soft tissue Prebiopsy Treatment (check all that apply) Cannot be determined No therapy Note: More than 1 site may be involved and should be Chemotherapy performed indicated. Radiation therapy performed Therapy performed, type not specified Radiographs Unknown Radiographic images were correlated Radiographic images were not correlated Grade Specify: Tumor Size Cannot be determined Greatest dimension: cm *Additional dimensions: ϫ cm *Venous/Lymphatic (Large/Small Vessel) Invasion Cannot be determined (see Comment) * Present * Absent * Indeterminate

*Additional Pathologic Findings *Specify:

*Comment(s)

1628 Arch Pathol Lab Med—Vol 130, November 2006 Bone and Soft Tissue Protocol—Rubin et al SURGICAL PATHOLOGY CANCER CASE SUMMARY (CHECKLIST) Bone: Resection

Patient name:

Surgical pathology number: MACROSCOPIC (check 1 response unless otherwise Preresection Treatment (check all that apply) indicated) No therapy Chemotherapy performed Specimen Type Intralesional resection Radiation therapy performed Marginal resection Therapy performed, type not specified Wide local/segmental/en block resection Unknown Radical resection Other (specify): Grade Specify: Not specified Cannot be determined Bone Involved Specify (if known): Pathologic Staging (pTNM) Not specified Primary Tumor (pT) pTX: Primary tumor cannot be assessed Tumor Location (check all that apply) pT0: No evidence of primary tumor Epiphysis pT1: Tumor 8 cm or less in greatest dimension Metaphysis pT2: Tumor more than 8 cm in greatest dimension Diaphysis pT3: Discontinuous tumors in the primary bone site Cortical Medullary Regional Lymph Nodes (pN) Surface pNX: Regional lymph nodes cannot be assessed Tumor involves joint pN0: No regional lymph node metastasis Tumor extension into soft tissue pN1: Regional lymph node metastasis Cannot be determined Specify: Number examined: Note: More than 1 tissue plane may be involved and should be Number involved: indicated. Distant Metastasis (pM) Radiographs pMX: Cannot be assessed Radiographic images were correlated pM1: Distant metastasis Radiographic images were not correlated pM1a: Lung pM1b: Other distant sites Tumor Size *Specify site(s), if known: Greatest dimension: cm *Additional dimensions: ϫ cm Margins Cannot be determined Cannot be assessed Margins uninvolved by sarcoma MICROSCOPIC (check 1 response unless Distance of sarcoma from closest bone otherwise indicated) margin: cm Histologic Type (WHO classification of bone tumors) Specify bone margin: Specify: Distance of sarcoma from closest soft tissue margin, Cannot be determined if applicable: cm Specify soft tissue margin, if applicable: Results of Ancillary Studies Margins involved by sarcoma Specify: Specify margin(s): Not performed *Venous/Lymphatic (Large/Small Vessel) Invasion * Present *Mitotic Rate * *Specify: /10 high-power fields Absent * Indeterminate (1 HPF ϫ 400 ϭ 0.1734 mm2; ϫ40 objective; most proliferative area) *Additional Pathologic Findings Necrosis (macroscopic or microscopic) *Specify: Absent Present Extent: % *Comment(s)

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