PERSPECTIVE, PATTERNS OF SPREAD, AND PATHOLOGY
Knowledge of the relationship of the bone growth, its polarity, and amplification, particularly the amplification at each physis growth plate, and the modeling process is essential to understanding the classification and behavior of bone tumors.
PERSPECTIVE AND PATTERNS OF SPREAD
Primary malignant tumors of bone have been challenging for the multidisciplinary American Joint Committee on Cancer (AJCC)/International Union Against Cancer committees to develop a coherent classification and staging system. Although bone cancer is not common, it peaks in incidence in children, particularly in adolescence at the time of growth spurts. Because of the therapeutic specter of amputation, there is an emotional aspect in the management of both the patient, most often pediatric, and her or his family. There are approximately 2,500 new malignant bone and joint tumors annually in the United States. Although a virtual death warrant for most children afflicted in the 1950s and 1960s, bone cancers have with the multidisciplinary approach become curable with limb preservation. Despite the high incidence in teenagers, bone malignancies are only 5% to 6% of pediatric tumors.
From the first edition of the AJCC staging manual, the focus has been on histopathologic typing and grade. The determination traditionally of the bone tumor type has allowed for bone imaging to be an intrinsic part of bone tumor pathology analysis. The relationship of the bone growth and the modeling process to the classification of bone tumors had been advocated by pathologists. The histopathologic types are tabulated in Fig. 53.1B as a function of bone growth and modeling, providing their site of origin and location. Cytogenetic alterations and aberrations are being uncovered but have not been formally included in staging. However, bone sarcoma grade, as in soft tissue sarcomas, plays an important part in staging and substaging.
Clinical detection is usually stimulated by persistence of bone pain in the area of the lesion, often initially being attributed to trauma from playing sports. Swelling and mass are signs of tumor progression, as are pathologic fractures. If the lesion is near a joint, unexplained sympathetic effusions and stiffness may be a presenting sign.
The initial staging criteria were influenced by tumor location and whether the osseous mass on film was confined to bone, within its cortex, or extended beyond the cortex. Tumefaction size has recently been added. Location in epiphysis, physis, metaphysis, or diaphysis is as noted earlier. Patterns of spread are within bone or beyond into soft tissues. The major concern is whether the neurovascular bundle is compromised in the lower extremity as the femoral artery wraps around the femoral shaft. Sites of rapid growth, such as the distal end of the femur and the proximal end of the tibia and humerus, are common sites of malignancies (Fig. 53.1A; Table 53.1).
With regard to bone tumors, oncogene overexpression or deletion is at the maximal growth, which is in the first 5 to 6 years of life, when skeletal growth is persistent, and then slows over the next 5 to 6 years. With puberty, there is a maximal growth spurt over the next 5 to 6 years. Malignancy in bone appears at those sites that grow the most, namely, the distal femur and proximal tibia and proximal humeri in adolescence.
Figure 53.1 | A. Patterns of spread. Bone and skeletal sarcomas that spread in various bone compartments are color coded: T0,yellow; T1, green; T2, blue; T3, purple; and T4, red (into soft tissue). B. Location of primary bone tumors in long tubular bones. The concept of visualizing patterns of spread to appreciate the surrounding anatomy is well demonstrated by the sixdirectional pattern (SIMLAP, Table 53.1). Assuming origin in the distal metastasis of the femur.
OVERVIEW OF HISTOGENESIS AND HISTOPATHOLOGY
There is a logic to bone growth and modeling that can be applied to the classification of bone tumors. Skeletal growth is the critical factor in determining the probable location of the bone tumor. Borrowing from the concepts that were developed from research on the dynamic classification of bone dysplasias, the anatomy of bone and proposed terminology are presented to provide a broader basis for understanding the modeling and remodeling process of bone shaping in skeletal growth. Anatomic physiologic correlation is shown histologically with the vectors of bone growth and modeling in an idealized growing end of bone (Fig. 53.2A–D; Table 53.2).
• Epiphyseal segment or epiphysis: The epiphysis grows in the form of a hemisphere from the subarticular cartilage zone; thus the term hemispherization is used. It is recognized that the ultimate shape of any epiphysis is rarely a true hemisphere, but nevertheless the term allows us to visualize its growth pattern.
• Physeal segment or growth plate: By cellular division, the cartilage disk increases its length interstitially and increases in diameter by apposition. Thus, the normal tendency is toward expansion in this segment. The simplest and most appropriate term for this segment is growth.
• Metaphyseal segment: The normal tendency in this zone is toward a reduction in shaft caliber by internal and external absorption. The term “constriction” is deeply entrenched in the literature but is not descriptively accurate. The vascular erosion and osteoclastic absorption are not constrictive but are reductive in caliber. If one were to select a new term for these processes, it would be “funnelization.” It preserves the image of these absorptive activities at the ends of the shaft, which allow for progressive narrowing of caliber and the resultant concave shape of the metaphysis as one passes from the end toward the middle of the shaft.
• Diaphyseal segment: There is a tendency in the middle of the shaft to maintain a certain structural balance between the flaring, growing ends. To maintain this balance, the diameter of the diaphysis increases in width as the tubular bone grows in length. Proliferation of osteoblasts on the periosteal surface exceeds osteoclastic endosteal absorption, in that the cortex thickens and the marrow cavity widens as the tubular bone matures.
The term “cylindrization” is applied to the vectors of the diaphyseal growth, which are such as to ensure a cylindrical shape to the shaft. The concept of the periosteum acting as a shaping force to narrow diaphyseal caliber has no functional basis. Similarly, a lax periosteum does not lead to widening of the shaft.
• Hemispherization: Growth in the epiphysis at first extends in all directions, but for most of its development the epiphysis grows as a hemisphere from the subarticular zone.
• Growth: The zone of resting cartilage grows by apposition, increasing the transverse diameter at the shaft.
• Funnelization: The metaphysis is shaped like a funnel, the shape being due to active bone resorption by osteoclasis, which results in a progressive reduction in shaft caliber.
• Cylindrization: The shaft of the bone increases in diameter by thickening of the cortex and expansion of the marrow by appositional periosteal growth.
The large variety of histopathology in bone is a function of the numerous derivative normal cells (Table 53.2). The histopathology of some of the common bone tumors is shown in Fig. 53.2E–G.
Figure 53.2 | Overview of oncoanatomy. A. Anatomic–histologic correlation of the end of a growing long bone: epiphysis, physis, metaphysis, and diaphysis. B. Bone modeling at the same end of a growing long bone.
Figure 53.2 | C, D. The relationship of modeling processes to bone tumors. E. Osteosarcoma. A photomicrograph reveals pleomorphic malignant cells, tumor giant cells, and mitoses. The tumor produces woven bone that is focally calcified. F. Chondrosarcoma. A photomicrograph of a chondrosarcoma shows malignant chondrocytes with pronounced atypia. G. Ewing's sarcoma A biopsy specimen shows fairly uniform small cells with round, dark-blue nuclei, paucity of mitotic activity, and poorly defined cytoplasm. A periodic acid–Schiff (PAS) stain demonstrates abundant intracellular glycogen (inset).
TNM STAGING CRITERIA
TNM STAGING CRITERIA
The staging criteria have remained simple, with a major modification in the sixth edition of the AJCC manual. T1 changed from confined within cortex and T2 beyond the cortex to tumors that are T1 (8 cm) and T2 (>8 cm). T3 was added as a discontinuous primary tumor, that is, two separate anatomic sites in the same bone as metaphysis and diaphysis of the shaft. Stage III, previously undefined, is currently T3. Curiously, MIa lung metastases are regarded as more favorable than regional nodes N1, translating into stages IVA and IVB, respectively. Pathologic grade impacts the TNM anatomic stage, depending on whether the tumor grade is I or II (low grade) or III or IV (high grade). The substage designation of A or B depends on low or high grade, respectively, for stages I and II.
SUMMARY OF CHANGES SEVENTH EDITION AJCC
• Stage III is reserved for G3, G4 (Fig. 53.3)
The TNM staging matrix is color coded for identification of stage group once T and N stages are determined (Table 53.3).
BONE
Figure 53.3 | TNM stage criteria are color-coded bars. Note the importance of tumor grade in addition to anatomic extent. Bone sarcomas are characterized by early invasion of bone marrow sinuses in cancellous bone with rapid dissemination hematogenously to lung. Early detection of M1 lung nodules can be resected with long-term survival. Note that lymph node metastasis (N1) carries a poorer prognosis and worse stage than lung metastasis (M1). Stage I, green; II, blue; III, purple; IV, red; and metastatic, black.
T-ONCOANATOMY
T-ONCOANATOMY: POLARITY AND AMPLIFICATION OF SKELETAL GROWTH AND MODELING
To more fully understand normal skeletal growth, there are three basic considerations: (i) amplification or actual increases in size of bone, (ii) polarity or direction of growth, and (iii) time or scale of measurement (Fig. 53.4A).
• Amplification is the concept that the bone showing the greatest growth potential shows the greatest change because it magnifies the same defect to a greater degree.
• Polarity is the concept that tubular bones grow in a differential pattern, with one end predominating over the other. The maximal direction of longitudinal growth is its polarity
Traditionally, in classifying skeletal bone anatomy the orientation is regional. There are eight regions—head, neck, thorax, abdomen, back, pelvis, and upper and lower extremities.
• Head: skull, facial bones, and mandible
• Neck: cervical vertebrae (C1–C7), hyoid bone, and clavicle
• Thorax: ribs, thoracic vertebrae (T1–T12), sternum manubrium, and pectoral girdle
• Abdomen: lumbar vertebrae (L1–L5) and pelvic girdle (false pelvis)
• Back: vertebrae composing the spine—cervical (C4–C7), thoracic (T1–T12), lumbar (L1–L5), and sacral (S5–S1)
• Pelvis: sacrum (S1–S5), coccyx, and true pelvis
• Upper limb: pectoral girdle, arm, forearm, and hand
• Lower limb: pelvic girdle, thigh, leg, and foot
Bone typing (Fig. 53.4B–E) is based on size, shape, and modeling, and provides an insight into normal growth, which is a dynamic balance between appositional growth of endochondral bone and the resorption and regeneration of intramembranous bone. Each bone grows and models differently. Tumefactions are the sites of most active growth and resorption activities. The five types of bone shapes are long, short, irregular, flat, and special bones.
• Long: upper—humerus, radius, ulna; lower—femur, tibia, fibula
• Short: metacarpal, metatarsal, and phalanges
• Irregular: vertebrae
• Flat: ribs, scapula, and pelvis
• Special: skull, face, and mandible
The skeletal anatomic sites can be divided into five basic bone types for the purposes of presentation. Each site is presented diagrammatically to indicate sites of maximal bone growth and modeling as a correlate as to the most likely sites for bone tumors.
Figure 53.4 | A. Polarity and amplification of skeletal growth and modeling.
Femur
The femur (Fig. 53.4B, part A) is the longest bone and, as expected, grows more in actual length from birth to age 12 years than any other bone in the body. By measurement, approximately 75% of its length is achieved at the distal growth plate. Appositional growth is greatest here and, because it is the widest growth plate, it is logically the site for tumefaction and for studying modeling errors. The proximal growth plate of the femur adds the other 25% to the shaft length, with growth occurring mainly from the cartilage disk juxtaposed to the femoral head.
Tibia
The tibia (Fig. 53.4B, part B) grows with even polarity at both ends, with a slight margin favoring the proximal growth plate. The appositional growth is slightly greater at the knee (60%), but not so great as in the femur. In the lateral projection, most of the growth is in the anterior direction at the knee region rather than posteriorly as in the femur.
Radius and Ulna
Most of the growth is at the wrist, with very modest activity at the elbow (Fig. 53.4B, part C).
Humerus
Virtually all of the appositional growth is proximal in the humeral neck (Fig. 53.4B, part D). The distal elbow end has only modest growth. Humeral growth exceeds that of the radius and ulna.
Figure 53.4 | B. Bone modeling as a dynamic process. (A) Femur, (B) tibia and fibula, (C) radius and ulna, (D) humerus. Striated black/white areas are reabsorbed by osteoclasts. Dashed lines indicate growth by apposition. Bone cancers arise in sites of more active growth and modeling.
Figure 53.4 | C. Modeling in bones. (A) Vertebra, (B) carpal, (C) pelvis, (D) scapula, (E) rib, (F) skull. Striated black/white is resorption of bone. Dashed line indicates bone opposition.
Other Bone Types
Cuboid Bones
The vertebrae (Fig. 53.4C, part A) at birth consist of three ossification centers—one in the body and two nuclei in the neural arch, one in each pedicle. Once again, comparing the vertebral body to a tubular bone, we find that growth in length occurs exclusively from the proliferating cartilage plates at the cephalad and caudal surfaces. Vertebral bodies grow as a series of congruous rectangles in the first years, and growth is much greater along the anterior and lateral borders than posteriorly. The amount of growth in height and width is comparable, and funnelization processes as recognized in the long bones are nil. Growth in width is a function of periosteal or intramembranous bone formation as it is in long bones.
Carpal Bone
Carpal bone (Fig. 53.4C, part B) is organized as an ossification center in a cuboid-shaped bone.
Flat Bones
Scapula (Fig. 53.4C, part D) modeling is most active on its free margin.
Ribs (Fig. 53.4C, part E) are modeled more posteriorly than anteriorly.
Special Bones
Skull (Fig. 53.4C, part F) grows by endochondral bone at its base and is intramembranous in its vault.
Facial bones are largely intramembranous bone formation.
Mandible is a combination of endochondral bone at the angle of the mandible (Meckle's cartilage), and the remainder of the horseshoe is formed by intramembranous bone formation.
T-ONCOANATOMY
In osseous sarcomas, the anatomy of lower extremity is emphasized since this is the most common site for bone malignancies and as noted, the distal femoral physis and proximal tibial physis by virtue of their growth potential are the most prone sites.
• Lower limb: The basic design of muscle compartments is related to limb motion: anterior (flexion), posterior (extension), medial (adduction), and lateral (abduction). All of the compartments are not present in all parts of the limb, being more common proximally than distally, where rotation becomes more important.
• Knee: The distal femoral physis and proximal tibia physis are most readily visualized on the MRI coronal section and are highlighted by the arrow head (>) in Fig. 53.4D,E. The number and letters of anatomy are correlated in the MRI with labels in the coronal section. In the sagittal view of the knee, the surrounding soft tissue anatomy is more readily appreciated (Fig. 53.4F,G).
Figure 53.4 | D, E, F: Compartments of lower limb are designated in (D), then defined in (E) thigh, and (F) leg.
Figure 53.4 | G, H, I, J. Anatomy of the two most active sites of bone growth: distal femur and proximal tibia are correlated in (H) coronal and (J) sagittal MRIs. Letters and numbers define specific structures which are noted in (#) anatomy illustrations (G/I).
N-ONCOANATOMY AND M-ONCOANATOMY
N-ONCOANATOMY
Bone and bone marrow are richly supplied with blood and lymphatics are intimately related to regional veins that also drain surrounding soft tissue, which so often are invaded owing to penetration of cortex. Only the major regional nodes are listed here, and only the lower extremity regional nodes are shown in Fig. 53.5A–D.
• Femoral nodes: lower limb and lower half of the truncal skeleton
• Axillary: upper limb and upper half of the truncal skeleton
• Neck nodes: skull and facial bones
Figure 53.5 | N-oncoanatomy of the lower limb. A. Anterior view. B. Anteromedial. C. Posterior. D. Superficial and deep inguinal nodes and superficial veins. E. Dissected femoral triangle presents the order of neurovascular bundle and lymph nodes – Nerve, Artery, Vein, Lymph Node (NAVEL), from lateral to medial.
M-ONCOANATOMY
The venous drainage surrounding the skeletal anatomy is a rich network and accounts for both skip lesions in the same bone and the propensity of bone tumors to metastasize to other bones (Fig. 53.6A). The rich axial intervertebral venous network readily explains why once one vertebra is involved, others are at risk.
To complete the picture, the neurovascular bundle is presented in Fig. 53.6B (popliteal fossa with nerve, artery, vein) and lymph nodes (not shown but are medial in location similar to NAVEL of femoral triangle).
Figure 53.6 | A. Anterior view. Deep veins lie internal to the deep fascia. Although only the anterior and posterior tibial veins are depicted as paired structures in this schematic illustration, typically in the limbs deep veins occur as paired, continually interanastomosing accompanying veins surrounding and sharing the name of the artery they accompany. B. Posterior view. Neurovascular bundle and lymph nodes maintain NAVEL, i.e., tibial nerve, popliteal artery, vein, and lymph nodes are lateral to medial.
STAGING WORKUP
RULES OF CLASSIFICATION AND STAGING
Clinical Staging and Imaging
Clinical staging and imaging includes physical examination, modern cross-sectional imaging, and image-guided biopsies. Standard bone radiographs identify the osseous malignancy but need to be supplemented with magnetic resonance imaging (MRI) and enhanced computed tomography (CT). MRI is superior for soft tissue and bone marrow invasion and enhanced CT for bone cortex erosion. Tumor size is estimated for staging: 8 cm or >8 cm. The entire skeleton deserves to be overviewed for metastases using 99mTc colloid. Chest CT is essential for surveying lungs for pulmonary metastases.
Image-guided biopsy is essential, but a note of caution is warranted. The biopsy site needs to be carefully planned to allow for eventual en bloc resection of the entire biopsy tract with excision of the malignant bone tumor (Table 53.4).
Pathologic Staging
Pathologic staging incorporates the clinical findings, the complete imaging file, and the completely resected specimen. Histopathologic analyses for sarcoma grade affect cancer staging more than tumor type. Resected regional lymph nodes need to be included. Suspicious metastatic lesions in long or other bones should be needled and confirmed by histopathology.
Oncoimaging Annotations
• MRI is the dominant imaging modality for determining intracompartmental and extracompartmental extent of an intraosseous tumor and its relationship to critical neurovascular structures.
• CT allows accurate determination of intraosseous and extraosseous extension and invasion of tumor.
• The routine radiograph remains the most reliable predictor of the histologic nature of a bone lesion.
• Metastases account for 65% of all malignant bone tumors in adults.
• All suspected sarcomas of bone should be staged with MRI before rather than after biopsy. As a consequence of post-biopsy edema and hemorrhage, MRI often overestimates the size and extent of tumor.
• With osteosarcoma and Ewing's sarcoma, which are known to produce skip lesions, it is important to examine the entire long bone with MRI.
• Systemic metastatic disease, usually to the lungs, and local recurrence have their maximum hazard rates within the first 2 years, defining the most frequent follow-up intervals for the first 2 years and tapering over a total of 5 years for osseous sarcomas.
• Geographic lesions are well circumscribed, and they frequently have a well-defined, sclerotic border. There is typically no extension of the tumor beyond the radiographically evident lesion border, implying a slow growth rate. This, typically, is seen in benign tumors, such as osteoblastomas, giant cell tumors, or nonossifying fibromas. This pattern also can be observed in low-grade malignant lesions, such as a low-grade chondrosaroma.
• A so-called moth-eaten pattern suggests an aggressive tumor, with multiple lytic areas and, frequently, cortical destruction. The tumor extends within the bone beyond the radiographically evident lytic areas and suggests an intermediate rate of growth.
• A permeative pattern implies extremely rapid and infiltrative growth, with diffuse areas of lytic destruction invading the bone. Permeative lesions are often associated with cortical disruption and extraosseous soft tissue mass, and they are characteristic of high-grade lesions. However, acute infection also can have this appearance, as well as, occasionally, benign tumors, such as eosinophilic granulomas. This overlap underscores the necessity for accurate diagnostic biopsy.
PROGNOSIS AND CANCER SURVIVAL
• Periosteal reactions can be of several types. A so-called sunburst periosteal reaction implies very proliferative malignant bone formation, and it is characteristic of an aggressive tumor, such as osteosarcoma or Ewing's sarcoma.
• Codman's triangle refers to the raised, normal periosteum at the margin of a bone tumor associated with reactive periosteal new bone formation; it can be seen with a variety of malignant bone tumors. A lamellar periosteal reaction (onion skin) implies rapid cyclic tumor growth, and it is most classically associated with Ewing's sarcoma, although it is not specific for this tumor. Spiculated periosteal reactions also occur in aggressive, rapidly growing tumors such as Ewing's sarcoma, and they represent reactive periosteal bone being deposited along periosteal vessels, as the expanding tumor stretches the periosteum.
PROGNOSTIC FACTORS
Clinically significant:
• Three dimensions of tumor size
• Percentage necrosis post neoadjuvant systemic therapy from pathology report
• Number of resected pulmonary metastases from pathology report*
From Edge SB, Byrd DR, and Compton CC, et al, AJCC Cancer Staging Manual, 7th edition. New York, Springer, 2010, p. 289.
Figure 53.7 | Trajectory of bone sarcoma curability.
In addition to known prognostic factors of tumor size, histopathology, and grade, the following factors are incorporated in the staging system:
• Lung metastases do better than bony or hepatic metastases.
• Histologic response to chemotherapy is good, >90% tumor necrosis.
• Pathologic fractures are a poor response if now healing after chemotherapy.
• Molecular aberrations and fusion genes are under investigation in different bone sarcomas.
• Ewing's Sarcoma: EWS-FLI1 type 1 fusion gene predicts for longer relapse free survival. Aberrant P53, p16 INK4A and p14ARF are associated with more aggressive behavior and metastases, p27 correlates with improved survival.
• Osteosarcoma: P-glycoprotein predicts 9× increase of death and 5× increase in metastases. HER2/erbB-2 expression is associated with increased risk of metastases but correlates with response to chemotherapy. KI-67 is a marker for pulmonary metastases and HSP27 is associated with a negative prognosis.
• Chondrosarcoma: Decreased Hedgehog signaling and loss of INK 4A/p16 correlates with tumor progression in peripheral tumors.
CANCER STATISTICS AND SURVIVAL
Soft tissue sarcomas account for 10,520 cases annually, whereas bone sarcomas occur in only 2,650 patients. Together, musculoskeletal tumors reached an incidence of 13,170 patients; 50% will die. When compared with primary cancer sites, the current gains in survival over five decades dramatize the reversal of incurability of musculoskeletal sarcomas (10%) in the 1940s and 1950s to its 60% to 70% survival rate. This is a 700% increase in survival with limb preservation (see Fig. 53.6). There are 2,650 new cases of bone sarcoma in the United States, slightly more in males 1,530 than in females 1120. Approximately 40% become long-term survivors, with deaths resulting in 60% of this population. In children, the most common tumors form a very small percentage of pediatric malignancies, that is, osteosarcomas (2.5%) and Ewing's tumor (1.6%).