Classic Osteosarcoma

Approximately 400 new cases of osteosarcoma are diagnosed in patients younger than 20 years in the United States annually. The second most common bone sarcoma (Ewing sarcoma, or primitive neuroectodermal tumor) is more common than classic osteosarcoma in those younger than 10 years. Generally, osteosarcoma occurs between the ages of 10 and 25 years, although it has been found in children as young as 5 years and in older adults. When osteosarcoma develops in an older person, the possibility of malignant transformation of a preexisting benign bone disease, such as Paget disease of bone, fibrous dysplasia, or a bone infarct, should be considered. *

* References .

† References .

The cause of osteosarcoma is unknown. Current thinking is that the development of osteosarcoma is likely because of an aberration in skeletal growth and remodeling, although no consistent pattern has been identified. Viral causes have been proposed in a number of studies, but most have been disproven in follow-up investigations. Trauma has also been proposed, but because of the frequency with which children injure themselves, this is probably only an association. Irradiation is known to cause osteosarcoma in patients irradiated for malignant diseases. Alkylating agents are also associated.

The genetics of osteosarcoma has received much attention. It is known to be a component tumor in familial cancer syndromes such as Li-Fraumeni syndrome, and alterations in genes such as Rb, p53, and others are common in these sarcomas. Patients with hereditary retinoblastoma have a high incidence of osteosarcoma, as do those with autosomal recessive Rothmund-Thomson syndrome. Patients with Rothmund-Thomson syndrome have been noted to have a mutation in the RECQL4 gene.

The tumor is usually situated near the metaphyseal region of a long bone, but on occasion it may be diaphyseal in location. The most common sites, accounting for more than 50% of cases, are the lower end of the femur and upper end of the tibia. The upper ends of the humerus and the femur are next in frequency. Less commonly, a classic osteosarcoma is encountered in the fibula, pelvic bones, or vertebral column. Occurrence in the distal part of a limb (hand or foot) is rare. However, the tumor has been described in every bone in the body. There are also numerous reports of multiple or multicentric osteosarcomas. ^‡

‡ References .

Pathology

The tumor ordinarily begins developing in the medullary cavity of a long bone near the metaphysis, but by the time it is recognized, it has already penetrated and extended through the cortex, raising the periosteum ( Fig. 30-1 ). ^§

Osteosarcoma of the proximal humerus. Shown in this photomicrograph is a sagittal section of an amputated specimen. The neoplasm is metaphyseal in location; it has perforated the cortex and raised the periosteum. The physis is unbroken; it does not become violated until later in the course of the disease (×10).

§ References .

In more advanced cases, the periosteal barrier may be broken, and a soft tissue tumor mass may be seen invading the adjacent muscle tissue. In general, the central portions of the neoplasm are more heavily ossified than the peripheral areas. The ossified portions are of a gritty consistency and have a yellowish appearance; the more cellular areas are softer and tan to whitish in color. In a sagittal section of an amputated specimen, the boundaries of the epiphyseal end of the tumor are not clearly distinguishable. The physis is less readily violated than the cortical wall and remains unpenetrated until later in the course of the disease. The articular hyaline cartilage serves to block the extension of the neoplasm into the joint. Transepiphyseal extension has been reported, but extension across the articular cartilage typically does not occur unless there has been a fracture. The tumor may enter the joint, however, by extending along ligamentous and capsular structures (e.g., the cruciate ligaments). Toward the diaphyseal end, the advancing tumor presents as a conical plug that marks the limit of growth of the lesion lengthwise along the shaft. Skip metastases (isolated foci of tumor in the same bone, but separated from the main tumor mass by normal marrow) occasionally occur; this is significant when determining the optimal level for resection. Skip metastases are usually detectable by bone scans and magnetic resonance imaging (MRI) and portend a poorer prognosis, similar to that of a patient with lung metastases.

The histologic findings of osteosarcoma usually show a frankly sarcomatous stroma and direct formation of neoplastic osteoid and bone ( Fig. 30-2 ). ^‖

Histologic findings in osteosarcoma. A, Photomicrograph showing the sarcomatous stroma and direct formation of neoplastic osteoid and bone (×100). B, Greater magnification (×250).

‖ References .

In some pathologic specimens, however, tumor osteoid bone cannot be demonstrated; only collagen strands interwoven with the tumor cells are seen. In anaplastic areas, the neoplasm consists of pleomorphic cells, with little intercellular substance. In other tumors, neoplastic cartilage and atypical spindle-shaped cells may be the predominant feature. Aegerter and Kirkpatrick have divided the microscopic picture of osteosarcoma into four types. In the first type, osteoid production is the predominant finding; in the second type, both osteoid and cartilage are formed. In the third type, neither osteoid nor cartilage is produced, but collagen is formed. In the fourth type, there is little or no indication of the presence of these intercellular substances. Attempts to correlate the four histologic types with the clinical manifestations of osteosarcoma have been futile. On the basis of histologic findings alone, one cannot predict the rate of growth, advent of metastasis, or duration of survival. It is important to remember that osteosarcoma may have large areas with little or no bone formation, but if any neoplastic bone is present, it is called osteosarcoma and treated as such. In an adolescent, the diagnosis of chondrosarcoma should be viewed with suspicion, despite the demonstration of only high-grade chondrosarcoma in a biopsy specimen. It is highly likely that examination of the entire specimen of a so-called chondrosarcoma in an adolescent will reveal neoplastic bone formation, indicating that it is chondroblastic osteosarcoma.

The pathologist determines the histologic grade of the tumor based on cellularity, atypia, pleomorphism, degree of tumor necrosis, and number of mitoses. A three- or four-grade system is used, depending on the pathologist. The prognostic significance of the number of mitotic figures is uncertain; at best, it is an index of the rate of growth. The histologic grade of the tumor is important in that a low-grade surface or central osteosarcoma has a much better prognosis than a high-grade (grade 2 or 3) osteosarcoma.

Clinical Features

Local pain in the affected part is the presenting complaint. Initially the pain is intermittent, but within a matter of weeks it becomes severe and constant. There may be a history of trauma that has precipitated discomfort from the tumor. It is often presumed that the trauma caused the tumor, but it is more likely that the injury merely called attention to the affected site. When a lower limb is affected, an antalgic limp may develop. As the condition progresses, a local mass that is hard and fixed to the underlying bone may be palpated ( Fig. 30-3 , A and B ). There may also be increased local heat and sensitivity to pressure. The firmness of the tumor varies, depending on the extent of ossification. The tumor may become visible as it enlarges. Limitation of joint motion and disuse atrophy of the muscles are other findings. It is important to recognize that the great majority of patients with osteosarcoma are not sick. They do not have fever, weight loss, or cachexia, and except for disease at the primary site, they appear to be healthy. This is one reason the diagnosis may be delayed. On rare occasions, however, in a patient with a rapidly growing neoplasm with pulmonary metastases, the patient may exhibit systemic symptoms. At other times, a pathologic fracture through the lesion may be the presenting condition.

Osteosarcoma of the right distal femur. A and B, Clinical appearance, showing swelling of the right lower thigh. C and D, Radiographs of the femora. Note the sunburst appearance and areas of increased radiopacity (neoplastic bone) and radiolucency (bone destruction). E, Radiograph of a gross specimen, sectional slab.

Radiographic Findings

Radiography

Osteosarcoma has a typical radiographic picture characterized by destructive and osteoblastic changes ( Figs. 30-4 to 30-6 ; see Fig. 30-3 , C to E ). It may be purely radiodense or purely radiolucent, but commonly it is a mixture of both. The neoplasm usually begins eccentrically in the metaphyseal region of a long bone. Bone destruction is evident, with loss of the normal trabecular pattern and the appearance of irregular, ill-defined, poorly marginated, ragged radiolucent defects. New bone formation may be neoplastic or reactive and appears as areas of increased radiopacity. The cortex is invaded by the growing tumor, as evidenced by destruction of the cortical wall and raising of the periosteum. There is an incomplete attempt to contain the tumor by periosteum, forming Codman’s triangle. The base of Codman’s triangle is perpendicular to the shaft and is created by the subperiosteal reactive new bone; it is not diagnostic of osteosarcoma because it is also seen in osteomyelitis and Ewing sarcoma. The sunburst appearance is produced by the formation of spicules of new bone laid down perpendicular to the shaft along the vessels passing from the periosteum to the cortex. A soft tissue mass is discernible on the radiographs as the tumor advances and transgresses the cortex. Pathologic fracture may occur.

Osteosarcoma of the distal femur in a 12-year-old girl. A and B, Radiographs of the femur. The normal trabecular pattern is lost as the neoplastic bone invades the cortex and raises the periosteum. Note the sunburst appearance and Codman’s triangle. The conical plug of the tumor in the midshaft (best seen on the lateral view) marks the proximal limit of the lesion lengthwise along the shaft.

Osteosarcoma of the right proximal humerus in an 8-year-old boy. The patient presented with pain and a mass in his arm. A and B, Radiographs demonstrate a large mass in the metaphysis abutting the physis. Periosteal elevation and the corresponding Codman’s triangle are seen along the diaphysis. C and D, MRI allows more precise identification of the local extent of the tumor. Areas of necrosis are seen on the axial section. The extent of the tumor in the medullary cavity can be appreciated on the coronal section. E, Resection specimen, demonstrating scattered areas of neoplastic bone. F, Example of proximal humeral allograft reconstruction in a different patient. G, Example of a lung metastasis ( arrows ).

Initial radiograph showing osteosarcoma of the proximal tibia.

Osteosarcomas do not always exhibit the classic radiographic pattern. They may be subtle in the early stages and may be radiolucent and diaphyseal, leading one to assume that they are Ewing sarcoma. We have seen one case detected serendipitously on a comparison radiograph obtained for a suspected fracture. Pathologic fracture ( Fig. 30-7 ) may make the diagnosis difficult, and it is not uncommon for patients to be treated for long bone fractures only to have an underlying neoplasm discovered weeks later. Aneurysmal bone cysts can mimic osteosarcomas, and osteosarcomas may have fluid-fluid levels on MRI scans, adding to the confusion. Clinical suspicion should be raised if a teenager presents with unexplained pain about the knee or shoulder, especially if the pain does not resolve quickly or is present at rest or at night. Radiographs in such cases should be analyzed critically and if there is any doubt, the patient should be further evaluated by MRI.

Pathologic fracture as the presentation of osteosarcoma of the distal femur. A and B, Radiographs demonstrate a displaced fracture of the distal femur. The medullary cavity immediately distal to the fracture demonstrates mixed radiolucent and radiodense areas. Note the periosteal elevation best seen on the lateral radiograph immediately proximal to the fracture, which is also suggestive of a pathologic fracture. C and D, MRI scans demonstrate the tumor mass extending into the soft tissues. Note the extensive edema associated with the fracture ( arrows ). E and F, At the time of needle biopsy, the fracture was reduced, and the patient was placed in a cast for stabilization of the fracture while the chemotherapy regimen was begun.

Magnetic Resonance Imaging and Computed Tomography

MRI and computed tomography (CT) are of great value in depicting the details of bone destruction and tumor bone production within the lesion. MRI has largely replaced CT as the optimal modality for imaging the primary tumor, and CT is used to evaluate the chest for pulmonary metastases. On CT, the neoplastic bone appears amorphous and not stress oriented ( Fig. 30-8 ). The areas of cortical erosion by the tumor tissue are well delineated. MRI optimally demonstrates the degree of soft tissue extension and relationship of the extracompartmental tumor to fascial planes and neurovascular structures. Perhaps the best feature of MRI is its ability to evaluate the extent of tumor in the medullary cavity precisely. Coronal T1-weighted images of the entire involved bone should be included. This is useful when planning limb-sparing resections. The radiologist can measure the extent of the tumor from fixed palpable landmarks to help the surgeon plan osteotomies. Occult skip metastases of 2 mm or more in long bones are well seen on MRI. MRI is also useful for evaluating the adjacent joint for tumor spread.

Osteosarcoma of the left distal femur. A, Plain anteroposterior radiograph. Note the distal metaphyseal and lower diaphyseal sclerotic lesion. B, CT scan showing bone-forming tumor. C and D, MRI scans showing the extent of the tumor and its relationship to the popliteal soft tissue. E, Bone scan with technetium-99m showing increased uptake in the distal femoral metaphyseal region.

Pulmonary metastases 3 to 7 mm or more in diameter can be identified with CT. Conventional radiographs of the chest (dual inspiration and expiration views) show metastatic nodules 10 mm or more in diameter. The importance of pulmonary CT in the staging of osteosarcoma cannot be overemphasized. Approximately 10% to 20% of patients with osteosarcoma present with radiographically detectable metastases at diagnosis. Most of these are in the lungs. Chest CT is superior to plain radiography in demonstrating these metastases, and spiral CT is superior to conventional CT for this purpose.

Bone Scanning

Bone scanning with technetium-99m shows a marked increase in the uptake of the radionuclide in the primary tumor. The increased uptake is caused by active formation of new tumor and host bone, as well as the vascularity of the lesion ( Fig. 30-9 ). Radionuclide bone scintigraphy is used to look for bony metastases in the involved bone (skip metastases) and at other skeletal sites. ^¶

Osteosarcoma of the right distal femoral metaphysis. Shown are bone scan findings with technetium-99m. Note the increased uptake in the area of the lesion ( arrows ).

¶ References .

Mineralized metastases are more likely to be detected by bone scanning than nonmineralized metastases at extrapulmonary sites. The intensity of the uptake increases with the vascularity of the lesion. Ordinarily, the margins of the increased isotope activity mark the extent of the osteosarcoma; this is not absolute, however, because the tumor may extend beyond the margin of increased radioisotope uptake.

Angiography

Angiography is of great value in delineating the extent of soft tissue extension and its relationship to adjacent neurovascular structures, but it is seldom used now because MRI can display this information more easily and less invasively. Angiography is also useful for demonstrating the response to preoperative chemotherapy, but dynamic MRI has replaced it for this purpose as well.

Treatment

The treatment of high-grade osteosarcoma occurs in two phases, administration of adjuvant chemotherapy and surgical resection of the tumor.

Chemotherapy

It is important to recognize that osteosarcoma is in most cases a systemic disease. Following amputation alone, metastatic disease, usually in the lungs, occurs in 80% to 90% of patients within the first 2 years. ^#

# References .

This implies that micrometastatic disease is present from the time that osteosarcoma is detected clinically. Because micrometastatic disease is often controlled by adjuvant chemotherapy, it was hypothesized in the 1960s and 1970s that the administration of chemotherapy might prevent the appearance of metastatic disease. This hypothesis proved to be true, although the premise was challenged initially. Randomized and nonrandomized studies have shown a disease-free and overall survival advantage in patients who receive adjuvant chemotherapy. Before the chemotherapy era, the probability of remaining disease-free after amputation for osteosarcoma was less than 20%. Currently, it is between 65% and 80%, or perhaps higher. * ^a

References .

The standard agents used include high-dose methotrexate, doxorubicin (Adriamycin), and cisplatin. These agents have been tested in large series of patients in national trials of the Pediatric Oncology Group and Children’s Cancer Group (now combined as the Children’s Oncology Group), providing a good example of how cooperative groups can carry out trials to study the outcomes of therapy for a rare disease. Initially there was doubt about the effectiveness of chemotherapy. A randomized study definitively addressed this issue and conclusively demonstrated that adjuvant chemotherapy improves the disease-free and overall survival rates of osteosarcoma patients. The dramatic improvement in the ability to cure patients with osteosarcoma has come at a price, however. The drugs used are highly toxic; adverse effects include infection from neutropenia, cardiotoxicity, renal toxicity, and hearing loss. ^†a

†a References .

The next advance in treatment was the use of preoperative, or neoadjuvant, chemotherapy. By administering chemotherapy before resection, one can treat the micrometastatic disease earlier, perhaps shrink the tumor to make resection easier, and study the histologic response to the drugs. There was concern, however, that if the patient’s tumor did not respond, it might progress during the preoperative period. This also was studied in a randomized trial, and it appears that the outcome is similar regardless of whether chemotherapy is administered both pre- and postoperatively, or only postoperatively. The study was difficult to complete, however, because by the time it was opened, surgeons already had a bias toward preoperative chemotherapy. Because of poor patient accrual, the power to detect a 15% difference in the two groups was only 80%. Nevertheless, preoperative chemotherapy is now standard.

One of the main advantages of preoperative chemotherapy is that it provides prognostic information. The pathologist can examine the specimen for the percentage of histologic necrosis following resection. Patients with a higher degree of necrosis (>90%) have a better outcome than those with less necrosis. It seems logical that giving alternative chemotherapy to patients with less tumor necrosis would improve outcome, but to date this has not been the case in studies addressing the issue. A large, prospective, international multi-institutional trial of the addition of ifosfamide and etoposide to postoperative regimens for poor responders, EURAMOS1, has been completed, but results have not been published yet. Another cooperative trial in the United States studied the results of the addition of ifosfamide and an immunostimulant, muramyl tripeptide (MTP), in a randomized trial to determine whether the addition of either or both of these agents improved the survival of patients with osteosarcoma. It concluded that the addition of ifosfamide in the adjuvant setting did not improve event-free survival compared with the standard combination of cisplatin, doxorubicin, and high-dose methotrexate, but it was confounded by the use of MTP, which appeared to have a beneficial effect in the ifosfamide arm of the study. Further investigation is needed to determine whether this is a reproducible effect.

Many advances have been made in the treatment of osteosarcoma, but 20% to 40% of patients do not respond to treatment despite similar histology, staging, and other patient characteristics. Just as there are some patients who could benefit from more aggressive chemotherapy, there are others who may need very little or no chemotherapy. It is hoped that more information about the molecular makeup of these tumors will provide insight in this regard and allow us to target therapy more precisely. This has led to research efforts in drug resistance mechanisms, genetic alterations in these sarcomas, and novel radiographic approaches to detect nonresponders at diagnosis. Multidrug resistance has been demonstrated in osteosarcoma and is a powerful prognostic indicator. The P-glycoprotein membrane pump actively exports agents such as doxorubicin out of the cell and can be detected by various immunohistochemical methods. The exciting aspect of these findings is that the resistance pump can be blocked by other agents, offering a potential means of overcoming resistance in these patients. Unfortunately, this has not been translated into clinically relevant treatment strategies, and the results of these studies have been mixed, probably because there are multiple resistance mechanisms available to the cancer cell and we are only beginning to understand them.

Genetic alterations in tumor suppressor genes have also been demonstrated in osteosarcomas, and there is some indication that in addition to providing clues to the cause of the tumor, they may be of prognostic and possibly therapeutic import. ^‡a

‡a References .

Human epidermal growth factor receptor 2 (HER2/erbB-2) appears to be overexpressed in patients with advanced disease (greater expression in metastatic osteosarcomas) in some studies but not in others. A monoclonal antibody to HER2/erbB-2, trastuzumab (Herceptin), has been studied to determine its therapeutic value in advanced metastatic disease. Determination of expression is difficult, however, and it is not clear that immunohistochemical techniques are sufficiently accurate. The significance of HER2/erbB-2 in osteosarcoma awaits further study.

Finally, more aggressive or intensified administration of chemotherapy and novel agents may further improve outcome. Some of these avenues are currently being investigated in cooperative trials.

Surgical Treatment

In addition to advances in the medical management of osteosarcoma, surgical treatment has improved. Amputation was once the standard of care and remains an important part of the armamentarium of the tumor surgeon, especially in children. Currently, however, most patients who present with osteosarcoma are treated with limb-sparing procedures. There was initial concern about the effect of limb salvage on survival rates, and no randomized studies have been carried out that compare limb salvage and amputation. ^§a

§a References .

Nonrandomized studies, however, do not show a survival advantage for patients treated with amputation, and the local recurrence rate after limb salvage procedures is similar to that after cross-bone amputation. ^‖a

‖a References .

Some studies have actually shown a worse prognosis for patients treated by amputation, but it is likely that this is the result of selection bias—amputations being performed in those with larger, more aggressive tumors or those with pathologic fractures. One large retrospective study of distal femoral osteosarcomas showed a higher local recurrence rate after limb salvage procedures and cross-bone amputation than after hip disarticulation, but the three groups did not differ in overall or disease-free survival. It is apparent that achieving a wide margin is important and doing so, coupled with a good response to chemotherapy, is associated with a low incidence of local recurrence. A less than wide margin or a less than good histologic response dramatically increased the recurrence rate in one study.

Amputation.

Irrespective of the method chosen to treat osteosarcoma, the local tumor must be completely excised with negative margins. Although amputation is performed less frequently than in the past, it remains the gold standard of local control, and in the lower extremity it may be the most functional reconstruction in young athletic patients. The primary indications for amputation are as follows: very young age, when limb length inequality would be a major problem (lower extremity); displaced pathologic fractures; large soft tissue masses involving neurovascular structures; disease progression during chemotherapy; and local recurrence following limb salvage procedures. In the upper extremity, one usually tries to preserve at least hand function, because prosthetic limbs are not nearly as good as a functional hand. However, in the lower extremity, modern prosthetics are very functional ( Fig. 30-10 ).

Osteosarcoma of the distal left fibula in a 5-year-old girl. Initial radiographs of the left leg showed a destructive lesion of the distal metaphysis of the fibula with periosteal new bone formation and soft tissue swelling. Chest CT and bone scan showed no other lesions. Histologic examination of a biopsy specimen disclosed the tumor to be osteosarcoma. Because of the location of the tumor and the age of the patient, she was treated with a below-knee amputation and adjuvant chemotherapy.

The level of amputation is determined by close scrutiny of conventional radiographs, bone scans, and MRI scans. These surgical staging studies should be performed immediately before definitive surgery is undertaken and after completion of preoperative chemotherapy. The entire involved bone should be carefully evaluated by MRI for skip metastases. Usually, a wide cross-bone amputation is performed rather than a radical (whole-bone) amputation. Exceptions might be a young child with a tibial osteosarcoma, in whom knee disarticulation or above-knee amputation is performed, or a hindfoot osteosarcoma requiring a below-knee amputation. For distal femoral lesions, a hip disarticulation is seldom performed and is not routinely necessary, as shown by a study from the Musculoskeletal Tumor Society. The operative techniques of amputation and disarticulation at various levels in the upper and lower limbs are described and illustrated in Plates 30-1 to 30-9 on pages 1158-1195.

In very young children, residual limb overgrowth may be a problem. For below-knee amputations, this can be addressed by placing a metacarpal plug in the distal tibial canal if the ipsilateral foot is uninvolved by tumor. Furthermore, in very young children, the predicted length of the residual limb at maturity may be very short if a growth plate is resected. For foot tumors, this can be addressed with a Syme-type amputation rather than a below-knee amputation ; for proximal tibial lesions, a knee disarticulation may be preferable to an above-knee amputation. These can be revised at maturity if necessary for prosthetic fitting.

Rotationplasty.

An alternative to amputation for distal femoral osteosarcomas is the rotationplasty ( Fig. 30-11 ). Young children with high-grade sarcomas of the knee area have limited options for reconstruction following resection of the sarcoma. An above-knee amputation for a distal femoral osteosarcoma in a very young patient leaves the child with a very short lever arm to power a prosthesis, and it becomes relatively shorter as the child grows. The operation described by Borggreve and adapted for congenital defects (e.g., proximal femoral focal deficiency) by van Ness has been applied to tumors and provides a reconstruction option in certain situations. ^¶a

Osteosarcoma in a 10-year-old boy. A, Lateral radiograph of the femur showing a radiodense lesion of the distal femur with a large soft tissue mass. There is a starburst type of periosteal reaction of the soft tissue mass ( arrow ). Codman’s triangle is seen along the anterior cortex. A biopsy confirmed the diagnosis of osteosarcoma. B, Sagittal MRI scan showing the extent of the soft tissue mass and extension into the marrow ( arrows ). Anteriorly, the tumor approaches but does not invade the joint. Posteriorly, the femoral vessels are close to the mass but do not appear to be encased, and the posterior knee capsule is uninvolved. C, Axial MRI scan showing that the vessels and nerves are uninvolved ( lower arrow ) and revealing the extent of the soft tissue mass ( upper arrow ). The patient elected to have a rotationplasty because of his age and desire to play sports. D, Radiograph of the lower extremity obtained 1 year later. The boy remained free of disease and fully active 5 years later.

¶a References .

It can be thought of as an intercalary amputation of the distal femur (or proximal tibia). The reconstruction uses the distal leg, which is rotated 160 to 180 degrees, resulting in a longer lever arm and an active knee joint provided by the ankle and foot.

The indications for rotationplasty include a distal femoral or proximal tibial osteosarcoma in a skeletally immature patient or one who wants to continue sporting activities, a failed distal femoral reconstruction, or a pathologic fracture. It must be possible to preserve the sciatic nerve and its branches, although the vessels may be divided and anastomosed to increase the margin if necessary. The advantages of a rotationplasty are the wide margin, which includes the skin, adjacent knee joint, and all thigh muscles, avoidance of phantom pain, rapid healing of the osteosynthesis site, and relatively low complication rate. The obvious drawback is the appearance, which some find repulsive. Interestingly, young children usually do not view the procedure as an amputation because the foot remains and with a good prosthesis, they can function better than and appear similar to standard amputees.

Follow-up studies have not demonstrated any adverse psychological outcomes, and in our experience, the patients who have undergone the procedure are happy with the results. Preoperative discussions must be honest and complete so that the child and family are aware of the nature of the procedure and expected outcome. It is helpful for them to meet with a physical therapist who is familiar with this procedure, view videos of patients who have undergone the procedure and, ideally, meet a patient with a rotationplasty. We use all these modalities and spend considerable time explaining the rationale and relative advantages and disadvantages of this and the other options, such as amputation and limb-sparing procedures. Recently, the number of patients willing to undergo this procedure has diminished; many prefer to try a limb-sparing procedure and reserve rotationplasty if that fails. The procedure itself is well described in the literature. ^#a

#a References .

It is important to plan the skin flaps carefully, and modifications of the rhomboid incision described by Kotz are satisfactory. In our experience, there is a tendency to make the thigh long so that the rotated knee appears to be distal to the contralateral knee. It is difficult to predict the amount of growth remaining accurately because the distal tibial physis and tarsals become analogous to the contralateral distal femoral growth plate. One can attempt to plot the growth remaining using standard tables but in general, a boy older than 14 years and a girl older than 12 years should probably have the rotationplasty knee placed opposite the contralateral knee. For younger patients, placing it 2 to 4 cm more caudal is appropriate. The vessels may be resected with the specimen to increase the amount of normal tissue margin. An anastomosis of the vein and artery can be completed after achieving osteosynthesis. An alternative is to dissect the vessels free from the tumor and loop them carefully back on themselves with the nerves. The skin closure is difficult and must be done carefully to avoid postoperative wound complications. The limb is immobilized with the ankle in extension. At 6 weeks, the osteosynthesis is usually healed sufficiently to begin prosthetic wear.

In addition, this procedure has been described for tumors of the proximal tibia, with successful results. Modifications of this procedure have also been described for lesions about the hip or involving a large portion of the proximal femur. The ilium and distal femur must be preserved for this procedure to provide a hip and knee.

Rotationplasty for a distal femoral osteosarcoma offers a durable and functional, if cosmetically displeasing, reconstruction option for selected patients. For very young patients with distal femoral lesions, it avoids the repeated surgical procedures necessary to achieve limb length equality and allows the child to run and play exceedingly well. The other useful indication is for a failed limb salvage procedure when amputation is the only alternative.

The child and parents may need psychological support when considering amputation and rotationplasty. Initially, there is tremendous emotional resistance to ablation of a limb. It is helpful for these patients to see other children with amputations and prostheses before the operation. A physical therapy consultation and visit to a prosthetist are also valuable. Treatment of these children and adolescents in a children’s hospital with a specialized multidisciplinary oncology team is of great value. Fitting with a temporary prosthesis immediately after amputation may also be of psychological benefit, although these temporary prostheses seldom function well. Usually, a permanent prosthesis can be made 6 to 8 weeks after the amputation or rotationplasty.

Limb Salvage.

After a complete staging workup, biopsy, and (usually) preoperative chemotherapy, the primary tumor is assessed for response. MRI often shows a reduction in the amount of edema surrounding the tumor, but the mass seldom decreases in size because of the matrix within the tumor. There is no proven way to judge or predict accurately the histologic response of the tumor preoperatively, but dynamic MRI, dynamic contrast-enhanced MRI subtraction, diffusion-weighted MRI, and position emission tomography (PET) may eventually be useful in this regard. None of these techniques has yet shown a correlation with event-free survival, and it remains to be seen whether earlier evaluation with dynamic MRI or PET can identify poor responders and allow modification of therapy before definitive surgical resection.

Limb salvage is considered if there has been no progression of disease locally or distantly and if the nerves and blood vessels are free of tumor. The most important issue is the ability to resect the tumor completely with wide margins. The adjacent joint and growth plates are assessed for tumor involvement, and the amount of involved muscle is determined. There is no agreement regarding the safe amount of normal tissue that must surround the resected specimen but in general, at least a 2- to 5-cm bone marrow margin and 5- to 10-mm soft tissue margin are desirable. The thickness of the soft tissue margin depends on the type of tissue. A fascial margin is considered a more substantial barrier to tumor spread than a similar thickness of fat. The resection should be planned with the goal of achieving local control; reconstruction options are a secondary consideration.

In expendable bones such as the clavicle, fibula, scapula, and rib, resection without reconstruction can be considered. Lesions of the radius and ulna are rare and can usually be resected with minimal reconstruction or with fibular autografts or allografts used for reconstruction. Lesions of the hands and feet usually require amputation, although ray amputation and partial amputations that preserve some hand or foot function can sometimes be performed. For lesions of the extremities that are deemed resectable, the reconstruction can be complex and depends on the age of the patient and location of the tumor in reference to joints and growth plates. For most distal femoral and proximal tibial osteosarcomas, an intracompartmental, intraarticular resection can be carried out. The same is usually possible for lesions of the proximal humerus. Reconstruction is achieved with an osteoarticular allograft or a metallic prosthesis. There are no proven advantages of one over the other, and the choice is usually based on surgeon and patient preference. In boys younger than 12 to 14 years and girls younger than 10 to 12 years with lesions about the knee, growth considerations come into play. Limb length is usually not a major concern and can be addressed by standard limb equalization techniques (e.g., epiphysiodesis, limb lengthening, limb shortening) after chemotherapy is completed. Alternatively, a metallic prosthesis that expands as the child grows can be used ( Fig. 30-12 ). * ^b

Expandable prosthesis used to reconstruct the extremity after resection of an osteosarcoma from the proximal tibia of a 6-year-old girl. A, Initial radiographs demonstrate a radiodense lesion of the proximal tibia ( arrows ). B and C, Reconstruction after tumor resection with an expandable prosthesis. Note that the distal femur and its physis are preserved to maximize future growth.

References .

For older patients, with growth remaining, it is usually possible to make the reconstruction 1 to 2 cm longer than the amount resected, resulting in almost equal limb lengths at maturity.

The choice of metallic prosthesis versus allograft is debatable. The prosthesis is more stable initially and returns the patient to function earlier than an allograft, but there is concern about the longevity of the implant in this young age group. Loosening, particle disease, and metal and polyethylene failure are unsolved problems. We prefer allograft reconstructions in skeletally immature children ( Figs. 30-13 and 30-14 ). Allografts offer the advantage of restoring bone stock but require a longer recuperation period and are associated with relatively high fracture, infection, and nonunion rates. ^†b

High-grade osteosarcoma in a 16-year-old boy. A, Anteroposterior (AP) radiograph of the tibia. There is a destructive lesion of the proximal metaphysis with internal mineralization ( arrow ). It is poorly marginated, has destroyed the cortex, and appears to stop at the growth plate. At this age, osteosarcoma is the most likely diagnosis. B, T1-weighted MRI scan showing the medullary extent of the tumor and soft tissue mass ( arrow ). The epiphysis appears to be uninvolved except for a linear signal abnormality that may represent a fracture. The adjacent joint appears to be uninvolved. C, Axial MRI scan showing the extent of the soft tissue mass and relationship of the lesion to the popliteal vessels ( arrow ). The vessels are uninvolved. An incisional biopsy showed that the tumor was a high-grade osteosarcoma. D, AP radiograph obtained following preoperative chemotherapy. There is mineralization of the tumor and a more complete periosteal shell of bone around the periphery of the lesion ( arrow ). This is considered to be a sign of response to chemotherapy. The patient subsequently underwent an intraarticular wide resection of the osteosarcoma and reconstruction with an osteoarticular allograft. E, AP radiograph showing the reconstruction, with early healing of the osteosynthesis site 9 months after reconstruction.

Allograft reconstruction of a distal femoral lesion. A, Radiograph of the lesion in the left distal femur ( arrow ). B, Bone scan confirms no other sites of disease ( arrows ). C and D, MRI scans of the lesion ( arrows ). E and F, Allograft reconstruction of the distal femur. The reconstructed limb is slightly longer than the contralateral side to minimize limb length discrepancy at skeletal maturity.

†b References .

The longevity of the articular cartilage is also a concern, and some patients require conversion to a more standard joint replacement over time ( Fig. 30-15 ). One advantage to using osteoarticular allografts in children is the ability to preserve the adjacent growth plate. In the proximal tibia, the ability to reattach the patellar tendon to the allograft tendon is another advantage. Similarly, the ability to reconstruct the rotator cuff in the shoulder is an advantage of allografts in that location.

Sarcoma of the proximal femur in a 13-year-old boy. Appearance of the tumor ( arrows ) on a radiograph ( A ) and MRI scan ( B ). Note the involvement of the abductor insertion on the proximal femur, requiring resection. C, Allograft prosthetic composite reconstruction allows restoration of bone stock and repair of the allograft abductor tendon to the host abductor musculature.

For diaphyseal osteosarcomas, intercalary resections are often possible. These resections allow preservation of the adjacent joints and sometimes the growth plates. The defects can be reconstructed with allografts, vascularized fibulae, or metallic spacers and because the joints are preserved, function is usually superior to that following osteoarticular resection ( Fig. 30-16 ). It is critical to assess the MRI scan accurately to plan tumor-free marrow margins. If the growth plate must be sacrificed, standard limb equalization procedures can be used later.

Ewing sarcoma or peripheral primitive neuroectodermal tumor (PNET) in a 15-year-old boy. A, Anteroposterior radiograph showing a permeative destructive lesion of the femoral diaphysis ( arrow ). There is a suggestion of a soft tissue mass. B, Lateral radiograph. The mass is better seen, and there is erosion of the posterior cortex ( arrow ). C, Coronal MRI scan showing the medullary extent of the tumor ( arrow ). D, Axial MRI scan showing that a huge soft tissue mass almost completely surrounds the femur ( arrow ). This appearance is typical of Ewing sarcoma or PNET. Because the tumor does not make tumorous bone or cartilage, there is no mineralization such as that seen in osteosarcoma. A biopsy confirmed the diagnosis of Ewing sarcoma or PNET. E, Axial MRI scan obtained following induction chemotherapy. There has been considerable reduction in the extent and size of the soft tissue mass ( arrow ). After discussing the alternatives of radiation therapy and surgery for local control, the patient elected to undergo surgical resection. F to H, Radiographs showing the reconstruction. An intercalary resection with wide margins was performed, and an allograft reconstruction was carried out. Both the hip and the knee joints were preserved. Both osteosyntheses healed, with very good function.

Pelvic osteosarcomas are an extremely difficult challenge. Tumors of the ilium that spare the acetabulum can be resected with little functional loss but if the acetabulum is involved, there is no adequate reconstruction option, and it is often difficult to achieve tumor-free margins. The adjacent sacrum is frequently involved, making it necessary to sacrifice nerve roots at times. Nevertheless, resections of the ilium and acetabulum, even with little or no reconstruction, can result in decent ambulatory function. Options for reconstruction include osteoarticular allografts, allograft arthrodeses, pseudarthroses of the femur to the remaining pubis, and metallic prostheses. The complication rate is high, and careful attention to soft tissue coverage is required. Adjuvant radiotherapy may be necessary if it is not possible to achieve microscopically negative margins.

Metastatic Osteosarcoma

Patients who present with osteosarcoma are carefully scrutinized for the presence of gross metastatic disease. The most common site is the lung, followed in frequency by bone. The prognosis for patients with metastases at diagnosis is much poorer than that for patients with no demonstrable metastatic disease. However, efforts to develop new drugs to treat these patients are ongoing. Some studies have shown that if aggressive chemotherapy plus resection of all gross disease can be accomplished, it is possible to achieve long-term survival in approximately 30% to 40% of patients with metastatic disease at diagnosis. Patients whose disease cannot be completely resected and those with bony metastases usually do not survive. In general, patients with lung metastases are more likely to survive than patients with metastases to other sites. Patients presenting with bony metastases have a dismal prognosis, with few reported survivors, but because they may survive functionally and remain pain-free for long periods, aggressive treatment is warranted.

It is difficult to distinguish a patient with multifocal osteosarcoma from one with metastatic osteosarcoma; the definitions are somewhat arbitrary. Multifocal osteosarcoma may be synchronous (multiple bony lesions at the time of diagnosis) or metachronous (secondary bone lesions occurring years later). ^‡b

‡b References .

§b References .

Pathology

On gross inspection, the neoplasm appears as a whitish-gray soft tissue mass that arises in the marrow spaces of the affected bone. Necrotic and hemorrhagic areas in the tumor are frequent. Anatomic involvement of bone is much more extensive than is apparent on radiographs, although MRI reliably demonstrates the extent of bone marrow involvement. The neoplastic tissue destroys and replaces the involved bone. The periosteum is elevated and is often perforated. There is a almost always a large soft tissue mass extending well beyond the bony boundaries. The tumor is not encapsulated and invades the surrounding muscle. When an innominate bone is involved, the soft tissue mass protrudes into the iliacus, often displacing the pelvic organs toward the midline; laterally, the mass invades the abductor muscles. Not infrequently, the soft tissue mass crosses the sacroiliac joint and invades the adjacent sacrum.

Histologic examination discloses compact sheets of small polyhedral cells with pale cytoplasm and ill-defined boundaries. It is one of a group of tumors referred to as small round cell tumors. Ewing sarcoma or PNET must be distinguished from neuroblastoma, non-Hodgkin lymphoma, and rhabdomyosarcoma. The nuclei in Ewing sarcoma are uniform, are round or oval, and contain scattered areas of chromatin ( Fig. 30-17 ). The cytoplasm is scant. There are multiple thin-walled vascular channels among a scant stroma. Reticulin fibers are not a consistent feature of Ewing sarcoma or PNET. Another distinguishing histochemical finding is the presence of glycogen in the cells of Ewing sarcoma; in lymphoma, the cells do not contain glycogen. The cytoplasmic material is periodic acid–Schiff positive and diastase-digestible, but this finding is not specific for Ewing sarcoma or PNET. Occasional rosette or pseudorosette formations may be present, and some pathologists view this finding as evidence of PNET.

Histologic findings in Ewing sarcoma. Photomicrograph shows the round cells, which are polyhedral, with pale cytoplasm and small hyperchromatic nuclei (×400).

On light microscopic examination, the cytologic findings may be difficult to differentiate from those of neuroblastoma, lymphoma, or other round cell lesions. Special immunohistochemical stains, electron microscopy, and cytogenetic studies are sometimes necessary to establish the correct diagnosis. ^‖b

‖b References .

Ultrastructural studies have shown small to medium-sized cells, round or polyhedral in shape, with round nuclei, scant membranous organelles, abundant glycogen, absence of filaments, and primitive intercellular junctions.

Monoclonal antibodies (HBA-71 and 12E7) to p30/32MIC2 (CD99), a cell surface glycoprotein encoded by the MIC2 gene, have been useful in diagnosing Ewing sarcoma and PNET. The MIC2 gene is a pseudoautosomal gene located on the short arms of human chromosomes X and Y. Glycoprotein expression is not specific for these tumors—it is expressed on T cells—but Ewing sarcoma and PNET cells express the MIC2 gene in very high amounts, which helps distinguish them from other round cell tumors. Mesenchymal chondrosarcomas, small cell osteosarcomas, and malignant lymphomas do not routinely express this product. MIC2 staining should not be relied on as the sole diagnostic criterion because false-negative results can occur in Ewing sarcoma and related tumors, and positive results can occur in tumors other than PNET. In some studies of Ewing sarcoma and PNET, 91% to 97% have shown a diffuse, strong membranous pattern, suggesting that MIC2 expression is highly reliable when the results are interpreted in the context of clinical and pathologic parameters. Hence, MIC2 is a useful screen for Ewing sarcoma and is used routinely in most pathology laboratories.

The most definitive test for Ewing sarcoma or PNET is demonstration of the chromosomal translocation t(11;22) by reverse transcriptase–polymerase chain reaction (RT-PCR) assay or fluorescence in situ hybridization (FISH). ^¶b

¶b References .

Interestingly, variability in the presence of these transcripts in patients with Ewing sarcoma and PNET may be of prognostic significance. It is hoped that in the future, vaccines to elicit T cell immunity with specificity for the tumor-specific fusion peptides in Ewing sarcoma and PNET can be used as therapy for these and other tumors, such as rhabdomyosarcoma. Given that these are unique proteins that normal cells do not express, it should be possible to design treatment strategies that target the tumor cell and not the normal cell.

Clinical Features

Local pain and swelling are the presenting complaints. The pain may be present for months or years before the patient seeks medical attention ; in one study, 50% of patients had symptoms for 6 months or longer. The delay was less in those with constant symptoms and the presence of a mass, and it did not adversely affect outcome. In the extremities, a tender local mass is invariably present. Some degree of stiffness of the adjacent joint is common in cases of long bone involvement, and a limp is usually present. Other symptoms depend on the site of the lesion. When a rib is involved, a pleural effusion may be noted. When the lesion is in the lumbar spine, the nerve roots may be involved, producing symptoms resembling those of disk herniation, such as sciatic pain, tingling sensations, or motor weakness. Rectal and urinary complaints may result when the neoplasm is located in an innominate bone and impinges on pelvic organs or involves the sacral nerve roots. On occasion, the presenting feature is pathologic fracture of an involved femur or tibia.

On physical examination, one can usually palpate a tumor mass (possible in 61% of cases in a Mayo Clinic series ) that is tender on pressure. It is larger than the bony lesion seen on radiographs, indicating that the neoplasm has violated the cortex and spread extraosseously into the surrounding soft tissues. In approximately 20% of cases, the presenting lesion is in some part of the innominate bone. If the pubis or ischium is involved, an irregular globular mass may be palpated on rectal examination; if the ilium is the site of the lesion, a tumor mass may be present in the lower quadrant of the abdomen or in the gluteal region. Pathologic fracture may also be a presenting finding in the case of primary tumor in the long bones (16% in the Mayo Clinic series ).

It is important to appreciate that in osteosarcoma, Ewing sarcoma, or PNET, patients are not systemically ill at presentation and seldom become so until late in the disease. Fever, weight loss, secondary anemia, leukocytosis, and an increase in the ESR are not seen until the disease is advanced. When present, these findings may lead to confusion with osteomyelitis and lymphoma. These findings are hallmarks of a fulminating course and are more likely to be present if there are metastases at diagnosis. LDH levels may be elevated, which has been shown to correlate with a worse prognosis in some studies.

Radiographic Findings

The radiographic appearance is fairly characteristic but not pathognomonic ( Figs. 30-18 to 30-20 ; also see Fig. 30-16, A and B ). It is typically described as a permeative lesion with mottled rarefaction of the medullary cavity and invasion through the overlying cortex, reflecting rapid bone destruction. The bone at the site of the lesion may show some enlargement. Periosteal new bone formation, often of the laminated onion peel type, is common but not specific for Ewing sarcoma. A soft tissue mass adjacent to the area of bone destruction is frequently seen on radiographs, indicating that the neoplasm has perforated the cortex and spread to the adjacent soft tissues. In the long bones, the lesion is frequently diaphyseal in location, and involvement is extensive. Pathologic fractures are uncommon and may occur at presentation or later in the disease, which portends a poorer prognosis and may suggest recurrence or a second malignancy.

Ewing sarcoma of the right pubis. A, Initial radiograph. Treatment consisted of irradiation and chemotherapy. B, Some healing is apparent 9 months later. However, the disease metastasized, and the patient died a year later.

Ewing sarcoma of the humerus. Note the mottled areas of rarefaction and subperiosteal reaction.

Ewing sarcoma of the proximal tibia in a 9-year-old girl. A and B, Mottled areas of rarefaction are seen in the proximal tibia ( arrow ). C, Appearance of the lesion on an MRI scan ( arrow ), allowing a determination of the bony extent of the tumor. D, Bone scan demonstrating uptake in the proximal tibia ( arrows ). In this case, there is uptake in the distal femur as well. E, MRI scan demonstrates signal abnormality in the distal femur ( arrow ), corresponding to the uptake seen on the bone scan. F and G, Allograft prosthetic composite reconstruction allowed resection of the proximal tibia and distal femur and reconstruction of the extensor mechanism, with allograft to host patellar tendon repair.

The radiographic findings resemble those of histiocytosis, lymphoma, osteosarcoma, metastatic neuroblastoma, Wilms tumor, leukemia, and osteomyelitis. MRI scans may only add to the confusion, because the inflammatory reaction around the bone and the medullary extent of histiocytosis may be extensive and mimic the findings of Ewing sarcoma, although it is usually possible to make the distinction.

Staging

The staging of Ewing sarcoma and PNET is similar to that for osteosarcoma, although there are no specific staging systems for the former tumors. MRI is useful to determine the extent of the lesion within the bone and adjacent soft tissue (see Fig. 30-16, C to E ). In general, tumor involvement of the bone marrow is best assessed on T1-weighted sequences, and tumor involvement of the soft tissue is best seen on T2-weighted sequences. Although it may be inferior to CT for assessing cortical destruction, MRI is very helpful for assessing the extent of bone marrow involvement, soft tissue tumor extent, and relationship of the tumor to neurovascular structures. Because Ewing sarcoma and PNET may extend throughout the entire medullary cavity, and skip metastases may rarely be present, the whole bone should be imaged by MRI. Subtraction and diffusion techniques and dynamic MRI have made it possible to use this modality to assess the response to chemotherapy, although this may not be as predictive of outcome as initial tumor volume.

Metastatic disease is present at diagnosis in approximately 25% of patients. Approximately 50% of patients who present with metastases have pulmonary involvement, approximately 25% have bony metastases, and approximately 20% have bone marrow involvement. Liver and lymph node metastases are rare. CT is performed to search for metastatic disease in the chest. A bone scan is obtained to search for other areas of bone involvement or skip metastases. A bone marrow biopsy specimen is obtained to look for detectable disease in the marrow. Usually this can be accomplished by light microscopy but RT-PCR techniques have been used to look for bone marrow and peripheral blood cells that amplify EWS/HumFLI1. The usefulness of PET in the initial staging of Ewing sarcoma is still unclear. Several studies indicate that it may be more sensitive than bone scan in detecting bone metastases, but thin cut chest CT is superior for identifying pulmonary metastases.

Biopsy

The definitive diagnosis is made from histologic study of tissue sections obtained at open or needle biopsy. Until recently, an open biopsy was usually done to establish the diagnosis, but needle biopsy or fine-needle aspiration (FNA) has proved to be useful in many cases. When an open biopsy is selected, the usual precautions of avoiding neurovascular structures and creating a longitudinal incision that can be included with the resected specimen are followed. In Ewing sarcoma, it is best to avoid making a cortical defect in a long bone, because if radiation is chosen for local control, the chances of pathologic fracture are greater. It is crucial that the surgeon obtain a frozen section and review it with the pathologist to ensure that adequate tissue is obtained for histologic, immunohistochemical, and sometimes cytogenetic studies. The histologic differential diagnosis of these small round cell tumors includes neuroblastoma, rhabdomyosarcoma, malignant lymphoma, small cell osteosarcoma, Wilms tumor, desmoplastic small cell tumor, histiocytosis, and osteomyelitis. Needle biopsy is especially useful in sites that are difficult to access surgically (e.g., vertebral bodies), but adequate amounts of tissue must be obtained for immunohistochemistry, cytogenetics, and culture. Radiographic guidance should be used unless there is a large palpable mass to ensure that the specimen is taken from the correct site. Frozen sections are also advisable to ensure that representative tissue has been obtained. Tumor necrosis may make the tissue appear to be a purulent exudate and lead to confusing Ewing sarcoma or PNET with osteomyelitis.

Prognosis

In the past, the outlook for patients with Ewing sarcoma or PNET was uniformly poor, with an overall 10% 5-year survival rate. With the advent of adjuvant chemotherapy and proper local control, the outlook has been considerably better, with some studies showing 5-year and event-free survival rates of approximately 70%. Patients with large central lesions, especially in the pelvis, have a worse outcome than those with distal tumors. ^#b

#b References .

References .

Other factors that portend a poorer prognosis are large tumor volume, size larger than 8 cm, elevated LDH level, and age older than 17 years. Response to chemotherapy is another important prognostic factor. If a significant viable-appearing tumor is present in the resection specimen at the time of surgery, outcomes are worse than cases in which no tumor or microscopic foci of residual tumor are present. Controversy exists regarding whether the designation of Ewing sarcoma versus PNET is related to prognosis. In some studies, PNET had a worse prognosis, whereas in others it had the same or better prognosis.

Treatment

Nonmetastatic Ewing Sarcoma

The treatment of patients with nonmetastatic Ewing sarcoma consists of the administration of multiagent chemotherapy and efforts to achieve local control.

Chemotherapy

Ewing sarcoma and PNET tumors are systemic diseases with a very poor prognosis when treated by local measures alone. Beginning in the 1960s, it was shown that adjuvant chemotherapy offered a survival benefit in these patients. The standard chemotherapy regimens include v incristine, d oxorubicin, c yclophosphamide, and (in the past) a ctinomycin D (VDCA) ; the addition of ifosfamide and etoposide has been shown to offer an additional benefit in some but not all studies. To test this observation, the Pediatric Oncology Group and the Children’s Cancer Group carried out a randomized study comparing the standard VDCA regimen with the standard regimen plus ifosfamide and etoposide. They found that the addition of ifosfamide and etoposide was associated with significantly better 5-year, relapse-free survival compared with VDCA alone (69% versus 54%) in patients with nonmetastatic Ewing sarcoma or PNET. Overall survival was also significantly better among patients in the experimental therapy group than in the standard therapy group (72% versus 61%; P = .01). In that study, patients with metastatic disease failed to demonstrate a similar benefit from the additional drugs.

A similar outcome was shown with a slightly different regimen in two other single-institution studies. Four to six cycles of chemotherapy were given before local control. Clinical response to preoperative chemotherapy was indicated by a decrease in tumor size, decrease in LDH level, and tumor necrosis in the resected specimen. Postoperatively, additional cycles of the same treatment were given, and the total duration of therapy was approximately 48 weeks. It is a very toxic regimen, but offers significant survival benefits to these patients. Recent focus has been on intensifying therapy early in the course of treatment by using higher doses of standard drugs or by decreasing the interval between chemotherapy cycles. The most recent Children’s Oncology Group (COG) study demonstrated significant improvement in event-free survival in patients receiving chemotherapy every 2 weeks compared with every 3 weeks; this is now the standard of care for nonmetastatic Ewing sarcoma.

Radiation Therapy

Radiation therapy has traditionally been used to treat local disease. This treatment became established partly because the tumor responds to radiotherapy and partly because before chemotherapy was available, physicians were reluctant to perform amputation in patients with such a dismal prognosis. Radiation therapy effectively controls local disease, especially when combined with chemotherapy. The usual dose is 55.8 to 60 Gy to the affected tissues, and adequate dosages result in local control in 53% to 86% of cases. Attempts to lower the radiation dose when this modality is combined with chemotherapy have not been successful. Initially it was thought that the entire bone should be irradiated because of the difficulty in judging the medullary extent; however, because MRI can demonstrate the extent of disease accurately, this is no longer the case. A study by the Pediatric Oncology Group showed no difference in local control when the initial tumor volume plus a 2-cm margin was treated compared with whole-bone irradiation. The local recurrence rate in patients with small distal tumors is reported to be 10% or less, but in those with large bulky tumors (e.g., pelvic tumors), it may be 30% or more. In young children with lower extremity primary tumors, growth is a consideration. Irradiation of one or more growth plates in the lower extremity can lead to significant limb length inequality in young children ( Fig. 30-21 ). In patients in whom the biopsy created a hole in the cortex, pathologic fracture may be a significant problem if the bone is also irradiated ( Fig. 30-22 ). Despite internal fixation and bone grafting, union of these fractures is difficult to obtain in irradiated bone. Vascularized fibular grafts may be necessary.

Ewing sarcoma of the proximal femur in a 5-year-old boy. Anteroposterior ( A ) and lateral ( B ) radiographs of the proximal femur showing subperiosteal reaction and mottling of the outer cortex. C and D, Immediate postradiation radiographs.

Subtrochanteric pathologic fracture in Ewing sarcoma of the proximal femur treated by internal fixation with a plate and screws. A, Prefracture radiograph showing the sclerosis and radiolucent changes in bone. B, Anteroposterior radiograph of the femur showing the subtrochanteric pathologic fracture ( arrow ). C, Postoperative anteroposterior radiograph showing internal fixation with plate and screws.

Perhaps the most concerning adverse effect of radiation therapy (combined with alkylating agents) is the late occurrence of a secondary malignancy in the involved bone. This phenomenon was not observed until relatively recently, because most patients died from their disease; however, now that patients are surviving longer, secondary malignancies have become a significant concern. The exact incidence is unknown, but secondary malignancies are believed to occur in 5% to 30% of survivors treated with alkylating agents and radiation therapy. ^†c

†c References .

Surgical Treatment

Concern about secondary neoplasms, and the observation in some studies that surgically treated patients have a better prognosis, have led treating physicians to reconsider surgical ablation of the primary tumor. Techniques of limb salvage learned from treating osteosarcoma have been applied successfully to patients with Ewing sarcoma. With adequate chemotherapy, the soft tissue mass usually shrinks considerably, unlike osteosarcoma, making it possible to resect less tissue than might be anticipated at initial presentation (see Fig. 30-16 ). The obvious advantage is the avoidance of secondary neoplasms. Local control rates appear to be equal to or better than those obtained with radiation therapy. Many studies have shown that the outcome is superior in patients whose primary tumors are resected, but it should be noted that none of these studies were randomized, and patients whose tumors become resectable after preoperative chemotherapy probably had other favorable prognostic factors in addition to the resection. ^‡c

‡c References .

In other studies, patients who underwent surgical resection did not have a survival advantage when retrospectively compared with patients whose primary tumors were treated by radiation therapy alone.

The relative functional results are even more difficult to compare. Each modality has advantages and disadvantages in that regard. Radiation therapy has the advantage of obviating the surgical resection of major bones and muscles, but advances in limb salvage have made it possible to perform resection and functional reconstruction in many of these patients. Resection offers the ability to assess the histologic response to preoperative chemotherapy. As for osteosarcoma, it appears that histologic necrosis following preoperative chemotherapy is a good measure of response and prognosis.

One area of considerable concern is the pelvis. Resection of the iliac wing with preservation of the acetabulum offers reasonably good function, but when the acetabulum must be resected, a satisfactory functional reconstruction is almost impossible to obtain. Obviously, if it were clear that the outcome was superior with resection than with irradiation, one would sacrifice function, but the results are not clear. There are no randomized studies of surgery versus radiation therapy in the pelvis or elsewhere. Some studies have shown an improvement with resection of pelvic Ewing sarcoma or PNET ; others have shown no benefit. A recent COG study showed no difference in event-free or overall survival when surgery alone or surgery plus radiation was compared with radiation alone for pelvic primary tumors. The local treatment was not randomized, and this was a retrospective review of local control. Thus the decision of which modality or combination of modalities to use for local control of pelvic Ewing sarcoma or PNET is difficult and requires careful consideration by the treatment team, as well as discussions with the patient and family.

Local control is best delivered after induction chemotherapy, which often decreases the size of the soft tissue mass. Induction chemotherapy may make resection possible or avoid the need for postoperative radiation therapy. The approach used at our institution is to restage the patient completely following the induction phase of chemotherapy. If there has been a good response and if resection can be carried out with a reasonable expectation of negative margins and a good functional result, surgical resection is advised. Both radiation therapy and surgery are discussed with all patients, and they are offered the choice. We believe that the main advantage of resection is the avoidance of secondary malignancies. Margins and histologic necrosis in the resected specimen are examined; if the margins are widely negative or negative with a good histologic response, no further local control is advised. If the margin is positive, postoperative radiation therapy is advised, but the dose is lower than if the patient were treated with radiation therapy alone. Patients with tumors in so-called expendable bones, such as the fibula, clavicle, and ribs, do not undergo reconstruction. Patients with primary tumors in major long bones undergo reconstructions similar to those used in osteosarcoma patients.

Patients with a poor histologic response, especially those with very close or positive margins, are advised to receive radiation therapy postoperatively. Patients with large bulky tumors after induction chemotherapy, especially pelvic tumors, are usually advised to receive radiation therapy and are then reassessed for the possibility of resection. Patients with tumors in sites at which resection would be functionally devastating or impossible (e.g., sacrum, spine) or those with widespread metastatic disease are usually treated by irradiation for control of the bony disease. Those with periacetabular lesions are often treated by radiation therapy because of the lack of a good reconstruction option for this site and the absence of a demonstrably better outcome with resection.

Amputation and/or rotationplasty are considered for very young patients with lower extremity primary tumors, especially about the knee, where irradiation would result in growth arrest and limb length discrepancy. Other indications for amputation include pathologic fractures and bulky tumors that do not respond to chemotherapy and irradiation.

Pathology

On gross inspection, chondrosarcoma has a lobulated appearance and seems to consist of gray, unmineralized cartilage intermixed with chalky white cartilage. It feels firm on palpation. There may be areas of necrosis and degeneration.

The histologic appearance varies with the grade of the lesion and requires the expertise of an experienced bone pathologist. In low-grade lesions, the cell-to-matrix ratio is low (i.e., relatively more matrix than cells), with the malignant chondrocytes grouped in small clusters among wide areas of chondroid matrix. Malignant chondrocytes with double nuclei are a feature of chondrosarcoma. In high-grade lesions, the cell-to-matrix ratio is high, with no clustering pattern; the hyperchromatic chondrocytes are multinuclear and show numerous mitoses and the chondroblastic tumor can be seen to erode into the native bone and haversian systems. When a biopsy shows such an area in an enostotic lesion, more tissue should be obtained to look for the presence of neoplastic bone. In most cases, a high-grade chondrosarcoma in a child is actually a chondroblastic osteosarcoma, and this becomes evident when the entire specimen is available for review. In our opinion, these patients should be treated with adjuvant chemotherapy, as for any osteosarcoma.

Radiographic Findings

Radiographic features of a secondary chondrosarcoma show evidence of the preexisting benign cartilaginous lesion, exostosis or enchondroma. These are described elsewhere (see Chapter 29 ). In exostotic lesions, sarcomatous proliferation of the cartilage cells occurs from the cartilaginous cap that extends and protrudes into the surrounding soft tissues. Calcifications of the cartilaginous cap may be present. Septal enhancement on MRI scans after the intravenous (IV) administration of gadopentetate dimeglumine aids in the characterization of cartilaginous tumors and may assist in distinguishing low-grade chondrosarcoma from osteochondroma. The process is indolent, and the sarcomas are usually of low grade. It is important to understand that benign osteochondromas can become large and grow during the years of skeletal maturity without having malignant features. We do not advise removing a solitary osteochondroma to prevent malignancy but they should be removed when symptoms occur. An exception may be a pelvic osteochondroma. Enchondromas are much less commonly encountered in children, probably because they are completely asymptomatic.

In the rare exostotic chondrosarcoma, radiographs show an irregular cartilaginous mass with calcification of varying density around the periphery of the exostosis and minimal or no permeative reaction of the underlying cortex. Some authors use the thickness of the cartilaginous cap as a guide to malignancy, but it is the histology of the cap, not the thickness, that dictates whether it is a chondrosarcoma. It may be difficult to distinguish a sessile osteochondroma or periosteal chondroma from a periosteal osteosarcoma or a chondrosarcoma. Perhaps the best guideline is that a sessile chondrosarcoma would be very rare in childhood; in addition, it shares a cortex with the underlying bone, and the medullary cavities communicate. A periosteal osteosarcoma does not have these features; the underlying cortex is present, indicating that it is a juxtacortical neoplasm. Similarly, a periosteal chondrosarcoma has an underlying cortex and is a surface lesion. It is sometimes difficult to distinguish a periosteal chondroma from a periosteal osteosarcoma.

A central chondrosarcoma, which may arise in the area of a preexisting enchondroma, has radiographic features indicative of its malignant character. These features include medullary radiolucency, poorly marginated bone destruction, and the presence of a soft tissue mass that may be variably mineralized. Endosteal scalloping with gradual erosion or widening and thickening of the cortex occurs. The preexisting enchondroma is usually mineralized, whereas the malignant area is radiolucent. The cortex may respond with endosteal and periosteal thickening, which may mask the malignant nature of the lesion.

MRI and CT are useful for assessing the cartilaginous nature of these lesions and their soft tissue and medullary extent. Osteochondromas with large bursae can mimic chondrosarcoma; MRI is particularly useful for making this distinction. A radionuclide bone scan shows increased uptake and is not helpful for the primary lesion, but it demonstrates other lesions in patients suspected of having Ollier syndrome or multiple exostoses. Radionuclide scintigraphy is not helpful in distinguishing benign from malignant cartilage neoplasms, but if a patient is followed by sequential bone scans, an increase in uptake may be a worrisome sign. A lesion that does not exhibit marked uptake is a reassuring sign. Chest CT is needed to search for pulmonary metastases from high-grade cartilage tumors, but these lesions are most likely to be chondroblastic osteosarcomas.

Treatment

True chondrosarcomas are treated by surgical resection. For low-grade lesions, this should be sufficient, and there is a high probability of cure. There has been some movement recently to consider aggressive curettage, local adjuvants, and graft or cement packing of low-grade chondrosarcomas of the extremity. This less aggressive approach is predicated on the difficulty of distinguishing benign from low-grade malignant cartilage tumors radiographically and histologically. Some believe that we have overtreated these lesions using resection in the past and that a more limited excision runs the potential risk of local recurrence but not metastasis. Clear data to support or refute this concept are lacking, and experience and judgment must be used to decide between these two treatment approaches—curettage versus resection.

High-grade lesions are probably best treated in a manner similar to that for high-grade osteosarcomas. Limb salvage resection or amputation following neoadjuvant chemotherapy is the proper management. In the very rare case of a true high-grade chondrosarcoma, surgical ablation with wide margins is the most reasonable treatment. The role of chemotherapy in these cases is not well established, but chemotherapy is used in patients with unresectable primary lesions or metastatic disease.

Rhabdomyosarcoma

Rhabdomyosarcomas account for 4% of malignant tumors in children 15 years of age or younger. The incidence is from 4 to 7/million children, and approximately 350 new cases are diagnosed annually in the United States. Rhabdomyosarcoma occurs in the first and second decades of life. Boys are affected slightly more often than girls, and black and Asian children have a lower incidence than white children. Rhabdomyosarcoma can occur in all parts of the body, including the head and neck (26% of cases), orbit (9%), mediastinum and abdomen (22%), genitourinary system (24%), and extremities (19%). This discussion focuses on extremity rhabdomyosarcoma.

Radiographic Findings

Patients who present with deep soft tissue masses should be evaluated for possible sarcomas. This requires a complete history and physical examination; laboratory studies, including CBC and differential, liver function tests, and determination of electrolyte, calcium, and phosphorus levels; and plain radiography for extremity and trunk lesions. The differential diagnosis includes nontumorous conditions such as hematoma and myositis ossificans and benign neoplasms such as schwannomas and lipomas. Growth of a painless mass in the absence of trauma should be viewed with suspicion.

A bone scan is obtained to exclude bony metastases, but MRI is more accurate for demonstrating adjacent bone involvement. MRI is also useful for determining the extent of the soft tissue mass and its relationship to surrounding neurovascular structures and bone ( Fig. 30-23 ). Chest CT should be performed to assess for the presence of lung metastases. Unlike in bone sarcomas, regional lymph nodes are involved with tumor in approximately 15% of cases, which worsens the prognosis. One study of extremity sarcomas achieved histologic documentation of lymph node status in 70% of patients, and histologically positive nodes were found in 40%. The regional lymph nodes should be carefully assessed clinically and by MRI.

Rhabdomyosarcoma in the calf of a 14-year-old girl. A and B, MRI scans of an alveolar rhabdomyosarcoma ( arrow ) located in the flexor hallucis longus muscle.

Nonrhabdomyosarcoma Soft Tissue Sarcoma

Soft tissue sarcomas other than rhabdomyosarcoma are rare, collectively accounting for less than 50% of soft tissue sarcomas in children. For the most part, these lesions appear and behave similarly to adult soft tissue sarcomas, except in the very young. In children younger than 5 years, the histopathology of soft tissue sarcomas is somewhat different, and the biologic behavior is more benign than in adults.

Congenital and Infantile Fibrosarcoma

Congenital and infantile fibrosarcoma is encountered in neonates. Fibrosarcoma is one of the more common nonrhabdomyosarcomas in childhood and is the most common soft tissue sarcoma in children younger than 1 year. There is a second peak in incidence between 10 and 15 years of age. In general, congenital fibrosarcoma has a more benign clinical course than fibrosarcoma in older children, which behaves more like the adult counterpart.

Pathology

The histology is that of a high-grade, spindle cell sarcoma arranged in a herringbone pattern intermixed with collagen fibers. It is a very cellular lesion with many mitoses but despite this appearance, surgical treatment alone is curative in more than 90% of cases. It may be difficult to distinguish congenital fibrosarcoma from congenital fibromatosis, but chromosomal alterations have been identified in congenital fibrosarcoma but not in other fibrosarcomas. The most common alteration is a nonrandom gain of chromosome 11, yielding a trisomy 11. Chromosomal alterations can be demonstrated with FISH techniques on paraffin-embedded tissue and can be helpful for confirming the diagnosis. Congenital and infantile fibrosarcomas also have a novel recurrent reciprocal translocation t(12;15)(p13;q25), resulting in the gene fusion ETV6-NTRK3 (ETS variant gene 6, neurotrophic tyrosine kinase receptor type 3). The use of RT-PCR methods to detect ETV6-NTRK3 fusion transcripts in archival, formalin-fixed, paraffin-embedded tissue can help distinguish these tumors from other soft tissue sarcomas.

Clinical Features

Congenital fibrosarcoma presents as a rapidly growing mass at birth or shortly thereafter ( Fig. 30-24 ). It is commonly in the extremities, usually in the distal extremity. As is the case for all soft tissue sarcomas, there is nothing in the history or physical examination to alert the physician that this is a malignant process, and initially congenital fibrosarcomas are often mistaken for hemangiomas, lymphangiomas, or lipomas. Metastases are present at diagnosis in less than 20% of cases and are more frequent for trunk lesions.

Only gold members can continue reading. Log In or Register to continue

Share this:

• Click to share on Twitter (Opens in new window)
• Click to share on Facebook (Opens in new window)

Related

Related posts:

Back Pain Other Anatomic Disorders of the Spine Slipped Capital Femoral Epiphysis Legg-Calvé-Perthes Disease Limb Length Discrepancy Poliomyelitis

Stay updated, free articles. Join our Telegram channel

Join