Cancers Staged Using This Staging System
Osteosarcoma, chondrosarcoma, Ewing's sarcoma, spindle cell sarcoma, hemangioendothelioma, angiosarcoma, fibrosarcoma/myofibroid sarcoma, chordoma, adamantinoma, and other cancers arising in the bone
Cancers Not Staged Using This Staging System
| These histopathologic types of cancer… | Are staged according to the classification for… | and can be found in chapter… |
|---|---|---|
| Primary malignant lymphoma | Hodgkin and Non-Hodgkin Lymphoma | 79 |
| Multiple myeloma | Multiple Myeloma and Plasma Cell Disorders | 82 |
Summary of Changes
| Change | Details of Change | Level of Evidence |
|---|---|---|
| Definitions of AJCC TNM | Pelvis and spine each have a separate and distinct TNM classification but not a separate stage grouping. | III |
| AJCC Prognostic Stage Groups | Stage III is reserved for G2 and G3. | III |
| Histologic Grade (G) | G4 designation has been eliminated (G1, low grade; G2 and G3, high grade). | III |
ICD-O-3 Topography Codes
| Code | Description |
|---|---|
| C40.0 | Long bones of upper limb, scapula, and associated joints |
| C40.1 | Short bones of upper limb and associated joints |
| C40.2 | Long bones of lower limb and associated joints |
| C40.3 | Short bones of lower limb and associated joints |
| C40.8 | Overlapping lesion of bones, joints, and articular cartilage of limbs |
| C40.9 | Bone of limb, NOS |
| C41.0 | Bones of skull and face and associated joints |
| C41.1 | Mandible |
| C41.3 | Rib, sternum, clavicle, and associated joints |
| C41.8 | Overlapping lesion of bones, joints, and articular cartilage |
| C41.9 | Bone, NOS |
WHO Classification of Tumors
This list includes histology codes and preferred terms from the WHO Classification of Tumors and the International Classification of Diseases for Oncology (ICD-O). Most of the terms in this list represent malignant behavior. For cancer reporting purposes, behavior codes /3 (denoting malignant neoplasms), /2 (denoting in situ neoplasms), and in some cases /1 (denoting neoplasms with uncertain and unknown behavior) may be appended to the 4-digit histology codes to create a complete morphology code.
| Code | Description |
|---|---|
| 8800 | Sarcoma, NOS |
| 8801 | Undifferentiated spindle cell sarcoma |
| 8801 | Spindle cell sarcoma |
| 8804 | Epithelioid sarcoma |
| 8804 | Undifferentiated epithelioid sarcoma |
| 8810 | Fibrosarcoma of bone |
| 8815 | Malignant solitary fibrous tumor |
| 8830 | Undifferentiated high-grade pleomorphic sarcoma of bone |
| 8850 | Liposarcoma of bone |
| 8890 | Leiomyosarcoma of bone |
| 8900 | Rhabdomyosarcoma |
| 9040 | Synovial sarcoma, NOS |
| 9120 | Angiosarcoma |
| 9133 | Epithelioid hemangioendothelioma |
| 9180 | Osteoblastic osteosarcoma |
| 9181 | Chondroblastic osteosarcoma |
| 9182 | Fibroblastic osteosarcoma |
| 9183 | Telangiectatic osteosarcoma |
| 9184 | Secondary osteosarcoma |
| 9185 | Small cell osteosarcoma |
| 9187 | Low-grade central osteosarcoma |
| 9192 | Parosteal osteosarcoma |
| 9193 | Periosteal osteosarcoma |
| 9194 | High-grade surface osteosarcoma |
| 9220 | Chondrosarcoma, grade II, grade III |
| 9221 | Juxtacortical chondrosarcoma |
| 9231 | Myxoid chondrosarcoma |
| 9240 | Mesenchymal chondrosarcoma |
| 9242 | Clear cell chondrosarcoma |
| 9243 | Dedifferentiated chondrosarcoma |
| 9250 | Malignancy in giant cell tumor of bone |
| 9261 | Adamantinoma |
| 9364 | Ewing sarcoma |
| 9370 | Chordoma, NOS |
| 9371 | Chondroid chordoma |
| 9372 | Dedifferentiated chordoma |
| 9540 | Malignant peripheral nerve sheath tumor |
Histology is not ideal for clinical use in patient care, as it describes an unspecified or outdated diagnosis. Data collectors may use this code only if there is not enough information in the medical record to document a more specific diagnosis.
Fletcher CDM, Bridge JA, Hogendoorn P, Mertens F, eds. World Health Organization Classification of Tumours of Soft Tissue and Bone. Fourth Edition. Lyon: IARC; 2013.
International Agency for Research on Cancer, World Health Organization. International Classification of Diseases for Oncology. ICD-O-3-Online.http://codes.iarc.fr/home. Accessed August 16, 2017. Used with permission.
This classification is used for all primary malignant tumors of bone except primary malignant lymphoma and multiple myeloma. These tumors are relatively rare, representing less than 0.2% of all malignancies. Osteosarcoma (35%), chondrosarcoma (30%), and Ewing sarcoma (16%) are the three most common forms of primary bone cancer. Osteosarcoma and Ewing sarcoma develop mainly in children and young adults, whereas chondrosarcoma is usually found in middle-aged and older adults. Data from these three histologies, analyzed at multiple institutions, predominantly influence this staging system. In the staging of bone sarcomas, patients are evaluated with regard to the pathological features of the tumor as well as the local and distant extent of disease. Bone sarcomas are staged based on the histologic type, grade, size, and location of the tumor and the presence and location of metastases. The system is designed to help stratify patients according to known risk factors.
Primary Site(s)
All bones of the skeleton are included in this system. The current staging system takes into account anatomic site, because anatomic site is known to influence outcome.
Site groups for bone sarcoma:
Regional Lymph Nodes
Regional lymph node metastases from primary bone tumors are extremely rare.
Clinical Classification
Clinical staging includes all relevant data prior to primary definitive therapy, including patient history and physical examination, imaging, and biopsy. It depends on the location and TNM characteristics of the identified tumor.
Patients presenting with primary bone sarcomas frequently demonstrate a mass or swelling and note crescendo pain symptoms, often occurring at night. This constellation of symptoms is most common for the appendicular skeleton, whereas patients with spine or pelvic tumors may note vague pain without mass effect because of the anatomic depth of the tumor location.
The prognosis of bone sarcoma is affected by the location of the primary tumor, which is reflected in the T classification as follows:
For extremity, trunk, skull, and facial bones, T is divided into lesions with a maximum dimension of 8 cm or less (T1) and those greater than 8 cm (T2). T3 has been redefined to include only high-grade tumors, discontinuous, within the same bone.
Imaging
Metastatic disease should be evaluated for and described. In general, lymph node metastasis from a bone sarcoma is uncommon, and a negative clinical examination for lymphadenopathy is sufficient to warrant a classification of N0.
The radiograph remains the mainstay in determining whether a bone lesion requires staging and usually is the modality that permits reliable assessment of the type of bone tumor. The minimum clinical staging workup of a bone sarcoma should include axial imaging using magnetic resonance (MR) and/or computed tomography (CT), a contrast-enhanced CT scan of the chest, and technetium scintigraphy of the entire skeleton.
Local staging of all bone sarcomas is achieved most accurately by MR imaging. Axial imaging, complemented by either coronal or sagittal imaging planes using T1- and T2-weighted spin-echo sequences, most often provides an accurate depiction of intra- and extraosseous tumor. To improve assessment in locations such as the pelvis or vertebrae, these sequences may be augmented by fat-suppressed pulse sequences. The maximum dimension of the tumor in three dimensions must be measured before any treatment. The decision to use intravenous gadolinium contrast should be based on medical appropriateness.
CT has a limited role in local staging of primary bone tumors. Some patients have contraindications to MR imaging evaluation (e.g., an implanted cardiac pacemaker), and axial imaging is best accomplished by CT in these cases. In other situations, in which characterization of a lesion by radiography may be incomplete or difficult because of inadequate visualization of the matrix of a lesion, CT may be preferred over MR imaging. The role of CT in these circumstances is to characterize the lesion and determine whether it is potentially malignant, and the CT images obtained may suffice for local staging. Contrast-enhanced chest CT remains the examination of choice for evaluating the presence or absence of pulmonary metastases.
Technetium scintigraphy is the assessment of choice for evaluating the entire skeleton to determine whether multiple bony lesions exist. The role of positron emission tomography in the evaluation and staging of bone sarcomas remains promising, although standards for its use are still evolving and are incompletely defined. Reports indicate its usefulness in detecting extrapulmonary metastases, evaluating response to chemotherapy, and determining local recurrence adjacent to prosthetic implants.
The same staging should be used in patients who require restaging of sarcoma recurrence. Such reports should specify whether the patient has a primary lesion or lesions that were treated previously and recurred. The identification and reporting of etiologic factors such as radiation exposure and inherited or genetic syndromes are encouraged.
Biopsy
Biopsy of the tumor completes the clinical staging process. Patients with suspected primary bone sarcomas should undergo biopsy at a referral center with expertise in pathology and surgical treatment of sarcomas, if possible. In general, appropriate core needle biopsy or planned open biopsy is preferred. The location of the biopsy must be planned carefully to allow for eventual en bloc resection of the entire biopsy tract at the time of definitive resection of a malignant primary bone neoplasm. Imaging assessment of the lesion should precede biopsy. Limited biopsy specimens may not be truly representative and this may affect both classification and grading of bone sarcomas. Imaging the tumor after biopsy may compromise the accuracy of the staging process.
Pathological Classification
The classification of bone sarcomas is accomplished by evaluating tissue retrieved from needle biopsy, open biopsy, and resection specimens. The classification scheme of bone sarcomas is based on the normal cell or tissue type that the tumors recapitulate. The vast majority of sarcomas differentiate along the cell lines or tissue types that compose the skeletal system, such as bone and cartilage; only a few have consistent and distinctive clinicopathologic features but lack a normal tissue counterpart. Further subclassification of sarcomas is based on their specific histologic characteristics, their relationship to the underlying bone, and the presence of preexisting conditions. Basic parameters of assessing a bone sarcoma are the identification of cell morphology; type of stroma, including matrix; degree of differentiation, including cytologic atypia; mitotic activity and atypical mitoses; and necrosis. If needed, ancillary studies, such as immunohistochemistry (IHC) and molecular analyses, should be performed to confirm a diagnosis. Importantly, the pathological diagnosis should be correlated with the clinical findings and imaging studies.
Pathological staging pTNM includes pathological data obtained from examination of a resected specimen, histopathologic type and grade, regional lymph nodes as appropriate, or distant metastasis. Because regional lymph node involvement from bone tumors is rare, the pathological stage grouping includes any of the following combinations: pT pN c/pM pG, pT cN c/pM pG, or cT cN pM1. Biological grade should be assigned to all bone sarcomas, and based on published outcomes data, the current staging system accommodates a two-tiered (low- vs. high-grade) system for recording grade. Histologic grading (G) uses a three-tiered system: G1 is considered low grade, and G2 and G3 are grouped together as high grade for biological grading.
Prognostic Factors Required for Stage Grouping
A three-tier system of grading, similar to that used for soft tissue sarcomas, is now recommended for assessing bone sarcomas. The grade of bone sarcomas is based on a combination of histologic type, cellularity, cytologic atypia, mitotic activity, necrosis, and degree of differentiation. Some sarcomas are definitionally G3 (high grade; e.g., Ewing sarcoma), whereas others range from G1 to G3 depending on their pathological features. This classification, however, is based on level III-IV data owing to the rarity of most subtypes of bone sarcomas. Neoadjuvent therapy may affect tumor cell morphology and interfere with grading. In problematic cases, the grade of the pretreatment specimen should take precedence.
Additional Factors Recommended for Clinical Care
Known prognostic factors for malignant bone tumors are as follows:
Smaller and anatomically confined tumors have a better prognosis than larger and more extensive ones. For both extremity and pelvic tumors, the size threshold of 8 cm is a reporting standard. For spine and pelvic tumors, T classifications now include definitions that reflect the poorer prognosis associated with a) the increased number of anatomic bone segments involved, b) extraosseous extension, and c) extension into the spinal canal or involvement of the great vessels.
Histopathologic low-grade (G1) sarcomas have a better prognosis than high-grade (G2, G3) sarcomas.
Patients with tumors of the extremities have a better prognosis than those with tumors arising in the pelvis and spine. Anatomically resectable primary tumors are associated with a better outcome than those that are nonresectable.
Clinical staging is performed from three dimensions, as reported from either MR imaging or CT scaning. Pathological staging is based on the final pathology report on the resected specimen.
The size of less than or equal to 8 cm in greatest dimension remains a critical threshold. Ewing sarcoma patients with a tumor less than or equal to 8 cm in greatest dimension have a better prognosis than those with a tumor greater than 8 cm. Osteosarcoma patients with a tumor less than or equal to 9 cm in greatest dimension have a better prognosis than those with a tumor greater than 9 cm.
Patients who have a localized primary tumor have a better prognosis than those with metastases.
Certain anatomic sites of metastases are associated with a poorer prognosis; for example, bone metastases convey a much worse prognosis than do lung metastases, and patients with solitary lung metastasis have a better prognosis than those with multiple lung lesions. Therefore, it is important to document the number of lung metastases.
Patients with Ewing sarcoma or osteosarcoma whose tumors have a “good” response (i.e., greater than or equal to 90% tumor necrosis) to systemic therapy have a better prognosis than those with less necrosis. Histologic response of the primary tumor to neoadjuvant chemotherapy is a prognostic factor for osteosarcoma and Ewing sarcoma. A variety of systems to stratify postchemotherapy tumor necrosis for both osteosarcoma and Ewing sarcoma have been proposed, ranging from two to six tiers. A condensed two-tiered system in which greater than ore equal to 90% tumor necrosis is considered a good response is used most commonly. A cutoff of greater than or equal to 90% necrosis also predicted survival in a univariate analysis in Ewing sarcoma. Sampling the tumor to assess chemotherapy response is accomplished by processing one full cross-sectional slab of tumor at its greatest cross-section area and then taking one section per centimer of tumor from the remaining hemispheres of the neoplasm. The sum of all viable areas measured microscopically is divided by the total cross-sectional area occupied by tumor to arrive at a percentage. Level II and III evidence supports these findings and cutoffs. For other types of bone sarcoma (fibrosarcoma, chondrosarcoma) treated with neoadjuvant chemotherapy, the prognostic significance of chemotherapeutic response to neoadjuvant therapy is unknown.
P16 expression by untreated osteosarcoma as assessed by IHC has been found to correlate with percentage of necrosis. Its use in pretreatment biopsies may predict which osteosarcomas will have a good response to standard neoadjuvant chemotherapy.
Patients with osteosarcoma who experience pathological fractures may have a poorer prognosis, particularly if their fracture does not heal during chemotherapy.
Molecular Abnormalities
Current investigations are searching for molecular abnormalities that provide information related to prognosis and treatment; however, the field is still in the early stage of development. The following summarizes the critical molecular abnormalities of the most important sarcomas of bone.
Critical Molecular Abnormalities of Primary Sarcomas of Bone
Osteosarcoma
High-grade conventional osteosarcoma. Osteo¬sarcomas are characterized by complex DNA copy number altera¬tions, with few recurrent abnormalities and a high level of genomic instability. To date, the search for common molecular therapeutic targets in osteosarcoma has been disappointing. However, the genomic chaos characteristic of osteosarcoma is shedding light on new mutation pat¬terns through recent whole-genome sequencing studies. Approximately 33% of primary osteosarcomas show evi¬dence of chromothripsis, defined as a single catastrophic event resulting in massive genomic rearrangements and remodeling of a chromosome, compared with 2-3% of cancers overall. Furthermore, half of all osteosarcomas exhibit kataegis, a pattern of localized hypermutation colocalized with regions of somatic genome rearrangements. The regions affected by kataegis are not recur¬rent, and most mutated genes are not located in these regions. Up to 80% of primary osteo¬sarcoma samples harbor RB1 gene aberrations, whereas 20% of osteosarcomas have either a deletion of CDKN2A (encoding p16-INK4A) or an amplification of CDK4. These findings, along with the reciprocal relationship between RB1 and CDKN2A alterations, suggest that G1/S de¬regulation by RB1 loss, CDK4 amplification, or CDKN2A loss is nearly universal in osteosarcoma. Another gene significantly associated with osteosarcoma is TP53. The frequency of somatic TP53 mutations in osteosarcomas ranges from 19-38%, and TP53 mutations are associated with high levels of genomic instability. An additional 5% of conventional osteosar¬comas harbor gene amplification of MDM2 . A high copy number gain of the MYC oncogene at 8q24 was found in 43% of osteosarcomas.
Low-grade osteosarcoma. The presence of ring chromosomes resulting from 12q13-15 gains/amplifications is the cytogenetic hallmark of parosteal osteosarcoma. This abnormality may be investigated in clinical practice either by fluorescence in situ hybridization (FISH) for MDM2/CDK4 gene amplifications or by IHC showing overexpression for MDM2 and/or CDK4 in most cases. Thus, MDM2/CDK4 gene amplification and/or protein overexpression represents a useful adjunct test in challenging diagnoses, reliably distinguishing low-grade osteosarcoma from benign histologic mimics. Although a small subset of conventional high-grade osteosarcomas have been documented to harbor MDM2 gene amplifications, it is likely that high-grade osteosarcomas showing coexpression of MDM2 and CDK4 represent dedifferentiated examples of low-grade osteosarcomas; careful examination in these cases to identify the low-grade component, corroborated with detailed radiographic review, might facilitate accurate subclassification.
Although GNAS mutations initially were detected exclusively in fibrous dysplasia, a more recent study showed GNAS mutations in five of nine cases (55%) of parosteal osteosarcoma, regardless of the presence of a dedifferentiation. These results have not been confirmed in more recent, larger studies, and their validity remains questionable.
Chondrosarcoma
The most prevalent genetic alteration detected in cartilaginous tu¬mors is the somatic mutation of isocitrate dehydrogenase (IDH) genes. Mutations in IDH1 and IDH2 are present in 56-61% of chondrosarcomas. Among cartilaginous tumors, IDH mutations appear to be limited to enchondromas, periosteal chondrosarcomas, and central (intramedullary) chondrosarcomas of conventional or dedifferentiated histology. IDH mutations have not been found in secondary peripheral chondrosarcomas, which instead share some of the molecular characteristics of osteochondromas. IDH1 and IDH2 mutations also appear to be absent in osteochondromas and osteosarcomas, including chondroblastic osteosarcomas; thus, this molecular test has been proposed as useful in challenging diagnoses. However, a recent report identified the presence of IDH mutations in a subset of conventional osteosarcomas (25%); further studies are needed to validate this finding.
The common IDH mutations in chondrosarcoma affect IDH1 R132 (∼90% of IDH-mutant cases) and IDH2 at the homologous position, R172 (∼10%). These mutations also are common in gli¬oma and acute myeloid leukemia. The mutations block the ability of the enzymes to convert isocitrate to α-ketoglutarate, which in turn increases levels of HIF1A, a subunit of a transcription fac¬tor that facilitates tumor growth in hypoxic environments and also interferes with enzymes responsible for demethylation of histones and DNA.
Additionally, a recent whole-exome sequencing study showed that 37% of chondrosarcomas have insertions, deletions, or rearrangements of COL2A1, which encodes the α-chain of type II collagen fibers, the major collagen constituent of articular cartilage. These mutations may interfere with the production of mature collagen fibrils. This study also showed muta¬tions in IDH1/2 (59%), TP53 (20%), and genes of the RB1 path¬way (33%) and the Hedgehog pathway (18%).
Ewing Sarcoma/PNET
Ewing sarcoma/PNET is characterized by translocations that fuse EWSR1, located at chromosome 22q12, and a gene of the ETS family of transcription factors. In 90-95% of cases, there is a recurrent t(11;22)(q24;q12), resulting in an EWSR1-FLI1 gene fusion, which contains the N-terminal portion of EWSR1 and the C-terminal portion of FLI1. In the EWSR1-FLI fusion protein, the EWSR1 portion functions as a strong transcriptional activation domain, whereas the FLI portion contributes an ETS-type DNA-binding domain. An EWSR1-ERG fusion, resulting from a t(21;22)(q22;q12), is found in 5-10% of cases. Less frequently, EWSR1 is fused to ETV1 (7p22), E1A-F (17q21), or FEV (2q35-36).
EWSR1-FLI1 is structurally heterogeneous, with at least 18 possible types of in-frame EWSR1-FLI1 chimeric transcripts. The two main types, fusion of EWSR1 exon 7 to FLI1 exon 6 (type 1) and fusion of EWSR1 exon 7 to FLI1 exon 5 (type 2), account for about 85-90% of EWSR1-FLI1 fusions. The molecular methods used in clinical practice for detecting this recurrent translocation include reverse transcription polymerase chain reaction (RT-PCR) and FISH. Because of the multiple variants of EWSR1-FLI1 fusion transcripts, several RT-PCR assays with different primer pair designs typically are needed to reliably exclude the presence of an EWSR1-FLI1 fusion. Furthermore, depending on fixation methods, the RNA quality extracted from archival material is suboptimal in up to 30-50% of cases. For these technical reasons, FISH testing for the presence of EWSR1 gene rearrangements has been applied widely and has increasingly replaced the RT-PCR method in most cases. One important caveat regarding FISH assay is that it interrogates abnormalities in only one fusion gene (i.e., EWSR1) and does not provide information on the status of its fusion partner; thus, a positive result may be insufficient to rule out other EWSR1-rearranged positive mesenchymal neoplasms.
Un/Poorly Differentiated Small Round/Spindle Cell Sarcoma with Alternative Gene Fusions (SRC/SCT)EWSR1-positive small blue round/spindle cell tumors (SRC/SCTs) with alternative non-ETS partners.
Rare cases of small blue round cell tumors (SRC/SCTs) recently were reported to carry a fusion between EWSR1 and genes outside the ETS gene family members. Among this group, a few cases showed EWSR1 fusions with genes encoding a member of the zinc-finger family of proteins, including EWSR1-PATZ1 or EWSR1-SP3; the NFATc2 gene, encoding for a member of the nuclear factor of activated T cells (NFAT) transcription factor family; or SMARCA5, a chromatin-reorganizing gene.
FUS-rearranged SRC/SCTs. In a handful of cases, FUS (fused in sarcoma) has been found to substitute for the EWSR1 gene, being fused to members of the ETS transcription factor family, with FUS-ERG fusion in five cases and FUS-FEV in one case.
CIC-DUX4-positive SRC/SCTs. CIC-DUX4 fusions are emerging as the most prevalent genetic event in EWSR1-negative SRC/SCTs, accounting for two thirds of cases in this group. CIC-DUX4 fusion results from two possible translocation events, either a t(4;19)(q35;q13) or t(10;19)(q26.3;q13). In contrast to classic Ewing sarcoma, these tumors occur preferentially in the soft tissue (90%) and in an older age group (young adults). Microscopically, CIC-DUX4-positive SRC/SCTs are associated with a higher degree of heterogeneity in nuclear shape and size compared with the consistent appearance seen with classic Ewing sarcoma. In some tumors, the neoplastic cells may be spindled. Furthermore, the CD99 immunostain is less diffuse, ranging from patchy to occasionally negative. Preliminary data regarding neoadjuvant therapy and response in metastatic disease indicate that this sarcoma subtype is less sensitive than Ewing sarcoma to standard chemotherapy agents (doxorubicin/ifosfamide or combination five-drug therapy with vincristine/doxorubicin/cyclophosphamide with ifosfamide/etoposide). However, the finding of a CIC rearrangement in nonpediatric patients with an EWSR1-negative SRC/SCT may support adapting the therapeutic plan according to the Ewing sarcoma family of tumors rather than following the adult-type soft tissue sarcoma guidelines.
BCOR-CCNB3-positive SRC/SCTs. A novel X-chromosomal paracentric inversion, resulting in a BCOR-CCNB3 fusion, was described recently in a subset of SRC/SCTs occurring preferentially in bone and often in young male patients. Despite remarkable clinical and pathological (some tumors may contain spindle cells) similarities with the Ewing sarcoma group, gene profiling and single-nucleotide polymorphism array analyses indicate that this group of tumors is biologically distinct from Ewing sarcoma and does not share the EWSR1-ETS expression signature. The latter subset may be identified by detecting CCNB3 overexpression using IHC.
Chordoma
T gene, encoding the protein brachyury, has been implicated in the pathogenesis of chordoma. Brachyury is a tissue-specific transcription factor expressed in the nucleus of notochord cells and is essential for proper notochord development and maintenance. Copy number gain of T gene (amplifications, polysomy, minor allelic gain) has been reported in sporadic chordomas, with similar percentages in sacrococcygeal, mobile spine, and skull base tumors.
Recently, a common genetic variant in T (rs2305089) was significantly associated with the risk of sporadic chordoma. The susceptibility related to T, however, appears to be complex, involving multiple mechanisms, including T duplication (essentially seen only in families), and multiple common and rare variants. Among sporadic cases, another common variant (rs3816300) was significantly associated with risk, and the association was significantly stronger in cases with early-age onset, including cases of skull base chordoma.
Update on Molecular Aberrations in Relation to Prognosis
Ewing Sarcoma/PNET
Based on retrospective studies, the survival of patients whose tumors contain the type 1 EWSR1-FLI1 fusion appears to be better than that of patients with other EWSR1-FLI1 fusion types. However, in contrast, prospective evaluation did not confirm a prognostic benefit for type 1 EWSR1-FLI1 fusions. The EWSR1-ERG fusion is associated with clinical phenotypes indistinguishable from those of EWSR1-FLI1-positive Ewing sarcoma. Whole-genome sequencing has shown that Ewing sarcomas harboring mutations in STAG2 and TP53 have a poor outcome.
The AJCC recently established guidelines that will be used to evaluate published statistical prediction models for the purpose of granting endorsement for clinical use. Although this is a monumental step toward the goal of precision medicine, this work was published only very recently. Therefore, the existing models that have been published or may be in clinical use have not yet been evaluated for this cancer site by the Precision Medicine Core of the AJCC. In the future, the statistical prediction models for this cancer site will be evaluated, and those that meet all AJCC criteria will be endorsed.
The new staging strategies for appendicular skeleton, trunk, skull, and facial bones; spine; and pelvis should be incorporated in clinical trial design. Additionally, stratification based on surgical margin reporting (R0, R1, and R2) is strongly recommended. As newly modified, reporting of pathological grade should use a three-grade system.
Definition of Primary Tumor (T)
| T Category | T Criteria |
|---|---|
| TX | Primary tumor cannot be assessed |
| T0 | No evidence of primary tumor |
| T1 | Tumor less than or equal to 8 cm in greatest dimension |
| T2 | Tumor greater than 8 cm in greatest dimension |
| T3 | Discontinuous tumors in the primary bone site |
Definition of Regional Lymph Node (N)
| N Category | N Criteria |
|---|---|
| NX | Regional lymph nodes cannot be assessed. Because of the rarity of lymph node involvement in bone sarcomas, the designation NX may not be appropriate, and cases should be considered N0 unless clinical node involvement clearly is evident. |
| N0 | No regional lymph node metastasis |
| N1 | Regional lymph node metastasis |
Definition of Distant Metastasis (M)
| M Category | M Criteria |
|---|---|
| M0 | No distant metastasis |
| M1 | Distant metastasis |
| M1a | Lung |
| M1b | Bone or other distant sites |
Definition of Grade (G)
| G | G Definition |
|---|---|
| GX | Grade cannot be assessed |
| G1 | Well differentiated, low grade |
| G2 | Moderately differentiated, high grade |
| G3 | Poorly differentiated, high grade |
| When T is… | and N is… | and M is… | and Grade is... | Then the stage group is… |
|---|---|---|---|---|
| T1 | N0 | M0 | G1, GX | IA |
| T2 | N0 | M0 | G1, GX | IB |
| T3 | N0 | M0 | G1, GX | IB |
| T1 | N0 | M0 | G2, G3 | IIA |
| T2 | N0 | M0 | G2, G3 | IIB |
| T3 | N0 | M0 | G2, G3 | III |
| Any T | N0 | M1a | Any G | IVA |
| Any T | N1 | Any M | Any G | IVB |
| Any T | Any N | M1b | Any G | IVB |
Classification of primary malignant bone tumors:
The survival curves presented here were generated based on the most recent National Cancer Data Base (NCDB) cohort available, with at least 60 months of follow-up time. Data are based specifically on diagnosis years 2002 to 2008. Staging was based on the AJCC Cancer Staging Manual, 6th Edition at time of accrual. The topography codes used included the following: appendicular skeletal bones (C40.0-C40.3, C40.8-C40.9, and C41.3).The histology codes used included osteosarcoma (9180-9195), chondrosarcoma (9220, 9221, 9230, 9231, 9240, 9242, and 9243), and Ewing sarcoma/PNET (9260, 9261, and 9365). For this time period, 9,507 patients were identified, with AJCC staging available for 5,671 patients who were analyzed according to an actuarial 5-year approach by the NCDB.
