Ewing sarcoma (ES), Askin tumor, and primitive neuroectodermal tumor genetically belong to the ES family of tumors with the same immunohistochemical and cytogenetic features.1–3 These tumors are composed of sheets of highly dedifferentiated purple, round or oval, small cells with high nuclear to cytoplasmic ratio. The scant eosinophilic cytoplasm usually contains glycogen, which is detected by periodic acid Schiff stain, and is diastase degradable.1,2 The nuclei are round, with finely dispersed chromatin, and 1 or more tiny nucleoli. Ewing family of tumor cells shows membranous expression of CD99 or MIC2 on immunohistochemistry.4 Antibody against FLI1, centered in the nucleus of the tumor cell, has been shown to be specific for these tumors.1,5 Depending on the degree of neuroectodermal differentiation, the tumor cells may also express neuron-specific enolase, synaptophysin, and S-100 protein 9. In 85% of cases, translocation t(11;22)(q24;q12) is seen. This fusion of EWS gene on 22q12 with the FLI1 gene on 11q24 results in a chimeric fusion transcript EWS-FLI1.1–3
Ewing sarcoma is the second most common primary malignant bone tumor after osteosarcoma.1,2 Depending on its anatomical location, 3 clinical subtypes of primary ES are recognized: medullary, extraskeletal, and periosteal.3,6,7 The most common medullary ES (MES) accounts for approximately 90% of these tumors with an annual incidence rate of 2.93 cases/1 million.1–3 It arises in medullary cavity of bone and accounts for about 6% to 8% of malignant primary bone tumors.1–3 Most MES are seen in the first 2 decades of life with peak incidence between 10 and 15 years (age range, 5 months to 83 years), and 80% of the cases occur in patients younger than 20 years.1,2 The tumor has slight male predilection with male to female ratio of 1.5:1.1–3
Extraskeletal ES (EES), first described by Angervall and Enzinger8 in 1975, arises in soft tissues and comprises ~10% of ESs.
The extremely rare periosteal ES (PES) differs in location from MES. It arises in periosteum, is located at bone surface between periosteum and cortex, and spares medullary cavity.3,4,6,7,9–16 A thin layer of periosteum separates the tumor from the adjoining soft tissues. Most PESs involve long bones. The tumor requires less extensive surgery, and overall has better prognosis than MES.
In this retrospective study, we have described symptoms, imaging features, treatment, and outcomes in 7 patients with PES and reviewed the literature. The main aim of the study was to highlight the roles of MRI and PET-CT in diagnosis and treatment of these rare surface bone tumors.
MATERIALS AND METHODS
The digital medical records of 7 patients with histologically proven PES treated between 2001 and 2020 at our institution were retrieved for analysis. To be included in this study, each of these surface bone tumors had to meet 2 strict imaging criteria: its subperiosteal location on bone surface and sparing of medullary cavity. Clinical data for each patient, including age, sex, race, presenting symptoms, duration of symptoms, treatment, and outcome, were obtained. Two MSK radiologists (R.K., senior MSK radiologist with experience of more than 45 years, and S.M., an MSK radiology fellow), individually and in consensus, analyzed all available pretreatment bone radiographs and CT images of each tumor for specific bone involvement, its location on bone (epiphyseal, metaphyseal, diaphyseal, or combination of these), tumor size and matrix mineralization, adjacent soft tissue involvement, bone erosion, periosteal reaction, and Codman triangle at cortical surface and cortical penetration by surface tumor with marrow involvement. 99mTc-MDP radionuclide bone scans (available in 3 patients) and positron emission tomography-computed tomography (PET-CT) images (available in 5 patients) were assessed for focal radiotracer activity and distant metastases. Most MR images had been obtained with different commercial 1.5 T MR scanners at outside medical facilities before referrals to our institution. The MR images included multiplanar fast spin-echo T1-weighted images (T1WI), fat-suppressed T2-weighted (T2W)/short tau inversion recovery (STIR) images, and postcontrast fat-suppressed T1WI obtained after intravenous injection of gadolinium (Gd). The MR images of the bone tumors were assessed for subperiosteal location, size, margins, periosteal reaction, Codman triangle, marrow involvement, relationship with adjoining soft tissues, and neurovascular structures. On MR images, each tumor was measured in 3 orthogonal planes, and its tissue signal characteristics were assessed on different MR pulse sequences. Treatment response during treatment was assessed on follow-up serial MR images by noting change in tumor size, enhancement pattern, and percentage of intratumoral necrosis. Radiographs of the affected bones after surgery were analyzed for healing and postoperative complications. In addition, chest radiographs and CT prior to, during and following treatment were studied for metastatic tumor spread.
Sex and Age
Our study group of 7 patients consisted of 4 males and 3 females (M/F = 1.3:1). The patients ranged in age from 11 to 66 years (mean age, 27.3 years). Five (71.4%) patients were between 11 years and 21 years of age.
Four (57.1%) patients presented with localized pain without soft tissue mass, 1 patient with painless soft tissue mass, and 2 patients complained of a painful tender soft tissue mass. Pain was the most common symptom seen in 6 (85.8%) patients. Duration of the symptoms at presentation varied from 2 weeks to 6 months (mean period, 3.4 months).
Among the 7 PESs, 3 surface tumors involved long bones (1 femur and 2 tibia), and 4 affected flat bones in pelvis (2 ilium and 2 superior pubic ramus). The radiographs were normal without apparent soft tissue mass or bone abnormality in 4 patients. Soft tissue mass with superficial cortical erosions was present with 2 long bone PES involving a femur and a tibia (Figs. 1, 2). No periosteal reaction, Codman triangle, tumor matrix mineralization, or tumor extension into medullary cavity was noted. The radiographs of the 4 patients with pelvic PES were normal.
On the nonenhanced CT images, the surface bone tumors presenting as soft tissue masses of variable size were hypodense to adjoining muscles in 2 patients, isodense in 3 patients, and heterogeneously hyperdense in 2 patients. Superficial cortical erosions were present with 3 long bone and an iliac bone tumors (Figs. 1, 2). Thus, CT was able to detect cortical erosions in 2 additional PESs, not apparent on the radiographs (Fig. 2). Computed tomography was able to confirm subperiosteal location and intimate contact with the underlying bone cortex. No tumor matrix mineralization, periosteal reaction, Codman triangle, or cortical penetration by the surface tumors into medullary cavity was present.
The 99mTc-MDP scintigrams available in 3 patients showed minimal focal cortical radiotracer uptake without increased radiotracer marrow activity by a tibial PES. In the other 2 patients, no increased radiotracer uptake by the surface tumors was seen.
Positron Emission Tomography-Computed Tomography
The PET-CT images available in 5 patients showed all surface tumors were 18F-fluorodeoxyglucose (18FFDG)-avid with SVUs ranging from 3.0 to 10.0. No medullary hypermetabolic activity was present in 4 patients (Figs. 2,3). The sole exception was an iliac PES with minimally increased FDG marrow activity (Fig. 4).
Magnetic Resonance Imaging
Magnetic resonance images of the tumors were available in all 7 patients. On MRI, the 3 long bone PESs arising at surfaces of a femoral and 2 tibial shafts were diaphyseal in location. The 4 pelvic PESs were located at cortical surface of the 2 iliac bones and 2 superior pubic rami. Three PESs were homogeneously isointense, 2 mildly heterogeneously hypointense, and 2 mildly heterogeneously hyperintense on T1WI relative to muscle. On the fat suppressed T2W/STIR MR images, all tumors were heterogeneously hyperintense in appearance. On the postcontrast fat suppressed T1WI after intravenous administration of Gd, all PESs showed heterogeneous enhancement (Figs. 2–4). The surface tumors with well-marginated peripheral borders varied from 3.6 × 3.2 × 2.8 cm to 15.0 × 4.5 × 3.0 cm (craniocaudal × transverse × AP) in size without infiltration of the adjoining muscles. Minimal hypervascularity in the adjoining soft tissues was seen with a femoral PES (Fig. 2). Magnetic resonance imaging showed superficial cortical erosions with 3 long and 2 flat bone surface tumors (Figs. 1–4). No periosteal reaction, Codman triangle, or medullary involvement was present with these surface bone tumors. However, cortical erosion with medullary extension on MRI by an iliac bone PES was noted (Fig. 4).
Treatment and Management
All 7 patients were initially treated with several cycles of standard chemotherapy. A patient with tibial PES had complete resolution of the tumor with neoadjuvant chemotherapy and radiation treatment; no surgery was performed (Fig. 3). The patient with femoral PES had tumor excision with hemicortical bone resection and allograft reconstruction (Fig. 2). Another patient with tibial PES already had solitary lung metastasis at onset. The patient was successfully treated with tumor resection and allograft bone reconstruction after chemotherapy and radiation treatment (Fig. 1), and lung metastasectomy. All 4 patients with pelvic bone PESs had hemipelvectomy. The patient with iliac bone PES with marrow extension also received local radiation treatment after hemipelvectomy.
Five patients (71.4%) had complete recovery and were free of disease at periods ranging from 7 to 11 years. The patient with iliac PES with marrow involvement rapidly developed metastases to his lungs and brain and died within 8 months of the diagnosis. The other patient with iliac bone PES and lung metastases died within 2 years.
Table 1 summarizes the demographic and clinical data of the 7 patients with PES.
TABLE 1 -
Demographic and Clinical Data of 7 Patients With PES
||10.4 × 6.4 × 7.7 cm
||Radical resection with hemicortical femur resection and allograft reconstruction
||Alive, complete cure, no recurrence, follow-up for 9 y
||6.7 × 1.2 × 3.3 cm
||Radical resection with intercalary allograft reconstruction
||Alive, complete cure, no recurrence, follow-up for 11 y
||Superior pubic ramus
||6.0 × 1.4 × 2.9 cm
||Type 3 internal hemipelvectomy and radical resection of sarcoma
||Alive, complete cure, no recurrence, follow-up for 10 y
||12.7 × 8.0 × 6.5 cm
||Right type 1 internal hemipelvectomy
||Yes—for lung metastasis
||Dead at 20 mo, developed lung metastases
||8.4 × 3.5 × 3.0 cm
||Yes—for primary tumor
||Alive, complete cure, no recurrence, follow-up for 9 y
||11.7 × 10.2 × 10.4 cm
||Right external hemipelvectomy with right partial sacrectomy and S1, S2, and S3 laminectomy
||Yes—for lung metastases
||Dead at 8 mo, developed lung and brain metastases
||Superior pubic ramus
||9.3 × 5.5. × 8.5 cm
||Alive, complete cure, no recurrence, follow-up for 7 y
The conventional intramedullary ES (MES) arises in medullary cavity of bone and accounts for about 6% to 8% of malignant primary bone tumors.1–3 Most cases are seen in the first 2 decades of life with peak incidence between 10 and 15 years (age range, 5 months to 83 years), and 80% of MES cases occur in patients younger than 20 years.1,2 The tumor shows slight male predilection (M/F ratio, 1.5:1).1–3 On imaging, MES involving a long bone presents as an ill-defined intramedullary lesion of variable size with bone destruction, aggressive periosteal reaction in the form of onion peel or sunburst, Codman triangle and cortical breakthrough, and is often associated large soft tissue component.1,6,9,13
In contrast, periosteal ES (PES), a distinct but rare variant of MES, arises in periosteum, is located on cortical surface of bone and spares medullary cavity.3,4,7,9,12 The tumor was described by Bator et al in 1986 as “… periosteal location without extension into either the bone or adjacent soft tissues.”2,7,13,14 However, based on the radiographic and histopathologic criteria, Sherman and Soong6 had described earlier 3 cases of the tumor as “cortical Ewing sarcoma of bone” in 1956. Shapeero et al7 reported a series of 11 PESs from multiple institutions in 1994. So far, approximately 30 cases of this surface bone tumor have been described in the literature.3,9 In addition, a case of PES involving temporal bone of skull in a 9-year-old girl has been reported.17
Ewing sarcoma, Askin tumor, and primitive neuroectodermal tumor genetically belong to the ES family of tumors with the same immunohistochemical and cytogenetic features.1–3 These tumors are composed of sheets of highly dedifferentiated purple, round, or oval, small cells with high nuclear to cytoplasmic ratio. The scant eosinophilic cytoplasm usually contains glycogen, which is detected by periodic acid Schiff stain, and is diastase degradable.1,2 The nuclei are round, with finely dispersed chromatin, and 1 or more tiny nucleoli. Ewing family of tumor cells show membranous expression of CD99 or MIC2 on immunohistochemistry.4 Antibody against FLI1, centered in the nucleus of the tumor cell, has been shown to be specific for these tumors.1,5 Depending on the degree of neuroectodermal differentiation, the tumor cells may also express neuron-specific enolase, synaptophysin, and S-100 protein 9. In 85% of cases, translocation t(11;22)(q24;q12) is seen. This fusion of EWS gene on 22q12 with the FLI1 gene on 11q24 results in a chimeric fusion transcript EWS-FLI1.1–3 Hokozaki et al11 have described similar immunochemistry in a patient with PES. On histopathology, these tumors may mimic lymphoma, alveolar rhabdomyosarcoma, small cell osteosarcoma, mesenchymal chondrosarcoma, or neuroblastoma.1,2,4 A thin layer of periosteum delineates the tumor from the surrounding soft tissues.11
While performing needle biopsy of surface tumor, caution should be observed not to penetrate the medullary cavity to prevent inoculation of tumor.10
Periosteal ES differs from the MES and EES variants of the tumor in location, sex preference, and absence of metastases at onset.3,7,9,12 In comparison with MES, PES, arising in periosteum at bone surface, has predilection for men, and does not involve medullary cavity.3,6,7,9 Periosteal ES is usually seen in the second and third decades of life (mean age, 16.8 years; range 11–36 years) like MES and EES.3,7,9 However, a 65-year-old patient with PES has been reported.3 In our cohort of 7 patients, the ages ranged between 11 and 66 years (mean age, 27.3 years). However, our 6 (85.6%) patients were between 11 and 21 years of age (average age, 19.2 years). Both MES and EES have only slight sex preference for males (M/F = 1.5:1 and 1.2:1, respectively).7,12 In contrast, PES has strong male predominance with reported M/F ratio varying from 2.2:1 to 5.7:1.3,9,12 However, in our small series, the gender ratio had only slight male preference (M/F = 1.3:1), same as MES and EES.
Clinically, PES presents as a localized painful tender soft tissue mass of a few weeks to a few months in duration.7,9 Pain is the most frequent complaint. This was true in 6 of our 7 patients who complained of pain of 2 weeks to 6 months (average, 3.4 months) duration, either with or without soft tissue mass. One of our patients presented with a painless soft tissue mass, and the other 2 patients had painful, tender soft tissue masses at onset. Fever, leukocytosis, local warmth and redness at surface tumor may be present. Dilated blood vessels over the tumor have been reported.9
Most PESs involve long bones of extremities.3,7,9 Of the previously reported 30 cases of PES, 29 tumors affected long bones: 18 tumors in lower extremities −15 femurs, 2 tibias and 1 fibula; the remaining 11 tumors involved humerus.9 Axial skeletal involvement by PES is highly unusual; only 1 proven case of PES involving scapula has been reported.16 In our small series, the 3 long bone PESs affected lower extremities—1 femur and 2 tibias. We had 4 additional tumors, which arose in flat bones of pelvis—2 iliac bones and 2 superior pubic rami.
Long bone PESs are either diaphyseal or metadiaphyseal in location.3,9 Among the previously reported 29 tumors affecting long bones, 25 (85.7%) tumors were diaphyseal, and 4 metadiaphyseal.9 Of the 3 long bones tumors in our patients, all were diaphyseal (Figs. 1–3).
Distant metastases usually to lungs are rare. Only 1 patient among the 30 reported cases of PES had distant metastases.1–3,7,12 In contrast, incidence of up to 30% of distant metastases, mostly to lungs, has been reported in patients with MES at time of diagnosis.1–3
Imaging plays crucial role in differentiating PES from MES and EES by demonstrating subperiosteal location, and absence of bone marrow and adjoining soft tissues involvement by PES. Occasionally, EES can mimic PES when it erodes adjoining cortex and incites periosteal reaction or causes surface bone erosion at adjoining bone. However, in such cases, CT and MRI can distinguish EES from PES by demonstrating non-subperiosteal soft tissue location of EES.7,9
The radiographic features of PES have been described previously and may mimic other benign and malignant surface bone tumors.1,4,7,9,12,13 Because of lack of matrix mineralization, PES is difficult to discern from adjoining soft tissues on radiographs unless the bone tumor displaces and compresses adjoining soft tissues.7 On radiographs, cortical erosions, periosteal reaction, Codman triangle and cortical saucerization often seen with PES suggest a paracortical surface soft tissue mass.1,4,7,9,12,13 Superficial cortical erosions with long bone PESs were noted in 2 of our patients on radiographs; however, no periosteal reaction or Codman triangle was present (Figs. 1, 2). Computed tomography is superior to radiographs in demonstrating these surface bone tumors by not only showing presence of a paracortical soft tissue mass but also revealing cortical erosions, periosteal reaction and Codman triangle, which may be too subtle to be appreciated on radiographs.7,13 We were able to detect cortical erosions by 2 PESs arising at tibia and iliac bone on CT, which were not apparent on the radiographs (Fig. 2). Computed tomography performed after intravenous administration of contrast facilitates delineation of hyperdense PES from nonenhancing adjoining normal soft tissues. No marrow involvement or tumor matrix mineralization with PES is seen on either radiographs or CT.
Since PES does not involve medullary cavity, one of the criteria to differentiate PES from MES is absence of marrow involvement by the surface tumor on MRI, and absence of radiotracer uptake in marrow on bone scintigraphy and PET.
Radionuclide scintigraphy may show faintly increased focal cortical radiotracer uptake; however, no intramedullary radiotracer uptake is present.3,9
No imaging characteristics of PES with PET-CT have been described previously. The surface tumors on the available PET-CT images in our 5 patients showed avid 18FFDG uptake with SVUs ranging from 3 to 10. No long bone PES showed hypermetabolic marrow activity (Figs. 2, 3).
Magnetic resonance imaging is the best imaging modality to confirm subperiosteal location, demonstration of normal marrow, and for assessment of tumor size of PES (Figs. 1–3).4,7,9,12,13,16 On MRI, PES is isointense to mildly hyperintense on T1WI, homogeneously to heterogeneously hyperintense on fat-suppressed T2W and STIR images and shows heterogeneous enhancement on postcontrast fat-suppressed T1WI. The surface tumor shows no medullary involvement (Figs. 1–3). However, an occasional PES arising at a bone with thin cortex may extend into medullary cavity as was observed on MRI in one of our patients with an iliac bone PES (Fig. 4).7,12
The significance of marrow involvement by a malignant surface bone tumor is controversial. In the case of periosteal osteosarcoma, some authors have suggested that medullary involvement by the surface tumor should not exclude its periosteal origin, provided the following 3 criteria are met: (a) the epicenter of the surface tumor remains within subperiosteal region, (b) the surface tumor is biologically less aggressive, and (c) histologic examination demonstrates the characteristic features of the tumor.18 However, such marrow extension by a malignant surface bone tumor may require more intensive surgery, and have prognostic implication.7,9,13 Our patients with PES arising in iliac bone with medullary extension rapidly developed lung and brain metastases; he died within 8 months of the diagnosis (Fig. 4). Shapeero et al7 have described PES with medullary extension and metastases in a patient, who died of his disease within months. However, they also mention a 15-year-old boy with PES involving medullary cavity with more than a 5-year survival without distant metastases or recurrence.7
Differential diagnoses for PES on imaging include primary benign and malignant bone- and cartilage-forming surface bone tumors, subperiosteal aneurysmal bone cyst, intracortical abscess, subperiosteal hematoma, ganglion, hemangioma and intracortical metastasis from lung cancer.7,9,13 In most cases, absence of matrix mineralization in PES differentiates it from other primary malignant bone surface tumors.7,9
All members of the Ewing family of sarcoma are managed in the same way.1 For eradication of micrometastases, the patient is initially treated with systemic chemotherapy.1 For local control of surface bone tumor itself, surgical resection after chemotherapy with optional neoadjuvant and/or adjuvant radiation treatment is used.1,3,9,13 Treatment regimen is tailored to the specific prognostic group, decided by factors, such as involvement of axial (especially, pelvis) or appendicular skeleton, tumor size (tumor volume > 100 cm3), tumor location, pathology, response to treatment, and in case of PES, rare medullary extension.1,13 All our patients were treated initially with several cycles of neoadjuvant chemotherapy using vincristine, adriamycin, cyclophosphamide alternating with ifosphamide and etoposide protocol. One of our patients with tibial PES treated with neoadjuvant chemotherapy and radiation had complete response and required no surgery (Fig. 3). However, most patients with long bone PES with partial response to chemotherapy require limited surgery without loss of bone continuity consisting of wide-margin tumor resection, hemicortical bone resection, and allograft reconstruction.3,9,10 Our patient with femoral shaft PES was treated in this manner (Fig. 2). Another patient with tibial PES was treated more aggressively with tumor resection and limb-salvage surgery (Fig. 1). As a rule, malignant pelvic bone tumors tend to be larger in size require more extensive surgery and have higher frequency of distant metastases with poorer prognosis than those involving long bones.2,9 We had 4 patients with PES involving pelvic bones. Two patients with PES arising at superior pubic ramus were treated with neoadjuvant chemotherapy, followed by hemipelvectomy and adjuvant chemotherapy. Both patients had uneventful recovery with long survival. However, the 2 other patients with large iliac bone PESs developed metastases and died within 2 years of the diagnosis.
Literature describes decreasing serum LDH levels as reliable indicator of good treatment response, whereas elevating levels after successful treatment usually indicate tumor recurrence and portend poor prognosis.1,2,9
Local recurrence of PES is rare, although Kolar et al16 had a patient with PES of humerus, who had local recurrence after 1 year after successful treatment.
Secondary osteosarcoma as complication of radiation treatment has been reported in a patient with PES.7
In general, a malignant surface bone tumor, including PES, arising in periosteum has better prognosis than its intramedullary counterpart.3,9,12,13 The reasons for this may be local pain caused by periosteal tumor bringing patient to early medical attention, subcortical confinement of tumor preventing it from metastasizing, and probably different cytogenic profile of tumor.3,11–13,17 Metastases with PES are rare and suggest poor prognosis.7 Shapeero et al7 mentioned a case of femoral PES with vertebral metastases, who died within 2 years after tumor excision. They also described a patient with unproven PES of scapula, who developed rapid metastases and died within 1 year after excision.7
Our 4 patients with PESs, 2 affecting long bones and 2 pubic bones, were treated successfully with chemotherapy and surgical tumor resection. They had no tumor recurrence or metastases in the follow-up periods ranging from 7 to 11 years. Another patient with tibial PES had complete response to chemotherapy and radiation treatment and required no surgery (Fig. 3). He was still alive at 9-year follow-up. However, the remaining 2 patients with iliac bone PESs and distant metastases died within 2 years of the diagnosis. Among the reported 29 patients with PES affecting long bones in the literature, ~88% had good response to treatment with long-term survival.3,9
The major limitation of this retrospective study is the fewer number of patients of this rare malignant surface bone tumor.
Periosteal ES is a rare variant of more common MES. The surface bone tumor arising in periosteum of bone usually affects adolescents and young adults. Most tumors involve long bones; however, flat bones can be involved. The tumor differs from MES because of male predominance, absence of marrow involvement, and lack of distant metastases at onset.7 Among our small group of 7 patients, we found almost equal sex incidence (1.3:1), 1 patient had solitary lung metastasis at the initial presentation, and another patient with iliac bone PES had medullary involvement. We are describing for the first time PET-CT features of PES, which shows avid 18F-FDG uptake by the surface tumor with normal marrow activity in contrast with MES.19 Patients with long bone PES are routinely treated with chemotherapy, hemicortical tumor resection, and bone allograft reconstruction and optional local radiation treatment and have better prognosis with long-term survival as compared with its medullary and extraskeletal counterparts. However, patients with pelvic bone PESs require more extensive surgery, have more distant metastases, and poorer prognosis with short-term survival.