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Extraskeletal Myxoid Chondrosarcoma- Rare ‘Non-chondroid’ soft tissue Sarcoma!!!
Volume 2 | Issue 1 | Jan-Apr 2016 | Page 36-38 |Shital Biradar, Sujit Joshi, Yogesh Panchwagh, Vikram Ghanekar, Pradeep Kothadiya.
Authers: Shital Biradar[1], Sujit Joshi[1], Yogesh Panchwagh[2], Vikram Ghanekar[3], Pradeep Kothadiya[4].
[1]Dept. of Pathology, Deenanath Mangeshkar hospital, Pune.
[2]Histopathologist, Deenanath Mangeshkar hospital, Pune.
[3]Orthopedic Onco-surgeon, Deenanath Mangeshkar hospital, Pune.
[4]Surgical oncologist, S.G.M. Hospital; Chiplun.
[5]Orthopedic Surgeon, Kothadiya Hospital; Solapur.
Address of Correspondence
Dr. Sujit Joshi
Flat No: 2, Lunawat Reality, Opp. Vanaz Company, Paud road, Kothrud, Pune-411038.
Email ID: sujitjoshi30@gmail.com
Abstract
Extraskeletal myxoid chondrosarcoma (ESMC) is an uncommon but distinct entity with clearly different clinicopathological, immunohistochemical and cytogenetic features from those of conventional skeletal chondrosarcoma. Because of its better prognosis as compared to conventional skeletal chondrosarcoma, an accurate diagnosis is essential. We present 2 cases of this tumor with different clinical presentations.
1. 40 year old house wife presenting with a 9x8cm size mass around lower end of femur. On imaging, it was a soft tissue mass abutting the femoral surface with minimal bone invasion.
2. 50 year old lady presenting with a huge fungating soft tissue mass over left lower leg and foot associated with similar cutaneous nodules over right arm and left thigh. The left leg mass had caused destruction of entire lower end of fibula.
Histopatholgical evaluation of both cases showed features of Extraskeletal Myxoid Chondrosarcoma (ESMC). Characteristic histopathological features include a malignant soft tissue neoplasm with lobulated growth pattern, abundant myxoid matrix and fairly bland looking tumor cells. There is no convincing evidence of cartilagenous differentiation or chondroid matrix production. Immunohistochemistry has a limited role.
ESMC is a tumor with long survival but a prolonged follow up is necessary in view of high local recurrence, high metastatic rates and high disease related mortality. The diagnosis of this tumor largely depends upon knowledge of this entity and its characteristic histopathological features.
Key words: Extra-skeletal myxoid chondrosarcoma; ESMC.
Introduction
Extraskeletal myxoid chondrosaroma (ESMC) is a rare malignant soft tissue sarcoma described as a distinct clinico-pathologic entity by Enzinger and Shiraki in 1972 [1]. WHO categorized this tumor as a tumor of uncertain differentiation since there is paucity of convincing evidence of cartilagenous differentiation. It is a rare tumor, accounting for less than 3% of soft tissue sarcomas [2,3]. The tumor usually develops in deep parts of the proximal extremities and in middle-aged adults [4]. More than two-thirds of the tumors occur in the proximal extremities and limb girdles, especially the thigh and popliteal fossa. Here, we are presenting the detailed clinico-pathological findings of two such cases, which were diagnosed in our institute.
Case Report
Case 1: 40 year old housewife presented with lower limb swelling and pain just above the knee joint which started since 5 months (Fig 1). Plain radiographs reveal a soft tissue mass abutting the femoral surface with minimum bony involvement in supracondylar region of femur suggestive of a soft tissue neoplasm (Fig. 2). MRI revealed a large extra-osseous soft tissue lesion with minimal intra-osseous extension suggestive of a juxtacortical neoplasm or soft tissue sarcoma (Fig. 3). Open biopsy was done elsewhere and reports were reviewed at authors institute. It showed microscopic features of ESMC. Considering the interosseous involvement and safe oncological margins, a wide resection was planned. The patient underwent limb salvage surgery in form of wide local excision of distal femur along with the mass and reconstruction with a megaprosthesis. Pathological Findings: On gross examination of the wide local excision specimen of distal femur, there was an extra-osseous mass at the lower end of femur on the postero-lateral aspect measuring 9×8 cm in size. It was a soft to firm, ovoid, lobulated mass which on cut section, was gelatinous, mucoid and gray-white. There was no evidence of necrosis or haemorrhage noted (Fig 4). Microscopically, it showed a characteristic multi-nodular pattern. Tumor cells were small round with hyperchromatic nuclei and a narrow rim of cytoplasm (Fig 5a). Cells were arranged in cords and strands separated by abundant myxoid material (Fig 5b,c). No cartilaginous matrix production was seen in the stroma. On Immuno-histochemestry (IHC) the cells showed strong positivity for Vimentin and focal positivity for S-100 protein. These cells were negative for Cytokeratin, EMA, Synaptophysin and Chromogranin. Based on morphological and IHC findings, a diagnosis of Extra-skeletal myxoid chondrosarcoma (ESMC) was reached.
Case 2: 50 year old lady presented with a huge fungating soft tissue mass over left foot associated with similar cutaneous nodules over right arm and left thigh. The foot lesion was progressively increasing over a year but not associated with pain. (Figure 6a, 6b)
X-ray of left foot and lower limb revealed a large soft tissue mass destroying the metatarsals , devoid of any matrix and periosteal reaction (Fig. 7a). Similar lesion was seen destroying the ipsilateral distal fibula (Fig. 7b). Biopsies from the foot mass and the arm nodule revealed histopathological and IHC findings consistent with Extraskeletal Myxoid Chondrosarcoma (ESMC). This patient defaulted for further treatment and follow up.
Discussion:
Extraskeletal myxoid chondrosarcoma (ESMC) is a rare, morphologically distinct soft tissue sarcoma with characteristic nodular architecture & abundant myxoid matrix. In 1972, Enzinger and Shiraki were the first ones who coined ESMC as a distinct entity [1]. In spite of it’s name, Extraskeletal myxoid chondrosarcoma (ESMC) is considered as a “Tumor of uncertain differentiation” because there is no definite evidence of cartilage matrix production in the tumor. Histogenesis of ESMC is still subject of controversy. Incidence of this tumor is only 2.3% of all soft tissue sarcomas as reported by Tsuneyosi et al [2]. Mainly the adult age group (35 years and above) is affected by this tumor, with equal sex predilection [3]. Most common sites are deep soft tissues of the proximal extremities and limb girdles, especially the musculature [4]. However, few uncommon sites are also been described like mediastinum, retroperitoneum, abdomen and the digits [5-7]. In both of our cases, imaging showed that it was a lobulated soft tissue mass without bony periosteal reaction or any radiologically evident matrix production. Histopathologically, both cases showed presence of uniform eosinophilic cells arranged in cords & deposited in an abundant myxoid stroma. There was no evidence of cartilage/osteoid matrix deposition.
The most important clue to the diagnosis of this rare entity is the typical arrangement of cells in cords and columns with a very prominent myxoid background [8]. ESMC appears to exhibit a high tendency of local recurrence & distant metastases, predominantly to the lungs, sometimes years after the initial diagnosis [9]. ESMC should be considered an intermediate grade tumor rather than a low-grade malignant neoplasm as the estimated 5, 10 and 15-year survival rates described by Meis-Kindblom et al were 90%, 70% & 60% respectively [4]. Wide local excision of the tumor is the treatment of choice. If a wide margin can not be obtained, a high rate of local recurrence is observed with poor response to chemotherapy & radiotherapy. Therefore, surgery with appropriate adequate margins continues to be the treatment of choice, for primary as well as recurrent or metastatic tumors.
On follow up part, our first patient is disease free at 6 years from date of surgery with excellent function in the operated limb (MSTS score 97%). The second patient defaulted for further treatment and was lost to follow up. Some adverse pathological prognostic factors reported in literature include Tumor size ≥ 10 cm, high cellularity, anaplasia or rhabdoid features, mitotic activity more than two per 10 high-power fields, and Ki-67 proliferative index of ≥ 10%. These indicate more aggressive behavior, requiring a closer follow-up of the patient [10]. In summary, ESMC is an uncommon but distinct soft tissue sarcoma, clearly different from conventional skeletal chondrosarcoma. Knowledge of this entity and accurate diagnosis is essential because of the difference in its behaviour and prognosis.
References
1. Enzinger FM, Shiraki M. Extraskeletal myxoid chondrosarcoma. An analysis of 34 cases.Hum Pathol 3: 421-35,1972.
2. Tsuneyoshi M, Enjoji M, Iwasaki H and Shirahama N: Extraskeletal myxoid chondrosarcoma: a clinicopathologic and electron microscopic study. Acta Pathol Jpn 31: 201-208, 1981.
3. Antonescu CR, Argani P, Erlandson RA, et al: Skeketal and extraskeletal myxoid chondrosarcoma: a comparative clinicopathologic, ultrastructural, and molecular study. Cancer 83:1504-1521, 1998.
4. Meis-Kindblom JM, Bergh P, Gunterberg B, et al: Extraskeletal myxoid chondrosarcoma: a reappraisal of its morphologic spectrum and prognostic factors based on 117 cases. Am J Surg Pathol 23: 636-650, 1999.
5. Oliveira AM, Sebo TJ, McGrory JE, et al: Extraskeletal myxoid chondrosarcoma; A clinocopathologic, immunohistochemical, and ploidy analysis of 23 cases. Mod Pathol 13: 900-908, 2000.
6. Patel SR, Burgess MA, Papadopculos NE, Linke KA and Benjamin RS: Extraskeletal myxoid chondrosarcoma: long-term experience with chemotherapy. Am J Clin Oncol 18: 161-163,
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7. Okamoto S, Hara K, Sumita S, et al: Extraskeletal myxoid chondrosarcoma arising in the finger. Skeletal Radiol 31: 296-300, 2002.
8. Jakowski JD, Wakely PE Jr. Cytopathology of extra-skeletal myxoid chondrosarcoma: Report of 8 cases. Cancer 2001; 111:298-305
9. Weiss SW and Goldblum JR: Extraskeletal myxoid chondrosarcoma. In: Soft Tissue Tumors 4th Edition. Mosby, St. Louis,pp1368-1379, 2001.
10. Oliveria Am, Sebo TJ, McGrory JE, Gaffey TA, Rock MG, Nascimento AG. Extraskeletal myxoid chondrosarcoma: A clinicaqopthologic, immunohistochemical & ploidy analysis of 23 cases. Mod Pathol 2000; 13:900-8.
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Fibrous Dysplasia – an Update
Volume 2 | Issue 1 | Jan-Apr 2016 | Page 39-43 | Ashish Gulia, Pankaj Kumar Panda.
Author: Ashish Gulia [1] , Pankaj Kumar Panda [2]
[1]Orthopaedic Oncologist, Tata Memorial Hospital, Mumbai.
[2]Post-graduate Student, Clinical Research, Tata Memorial Hospital, Mumbai
Address of Correspondence
Dr Ashish Gulia
Associate Professor, Orthopedic Oncology, Dept. of Surgical Oncology, Tata Memorial Hospital,
Mumbai – 400012, India.
Email: aashishgulia@gmail.com
website: animaljam2.net
Abstract
Background: Fibrous dysplasia (FD) belongs to a group of non-hereditary benign pathologies in which immature bone and fibrous stroma replaces normal medullary bone. The gene for FD is located on band 20q13, an area that codes for the α subunit on G-protein receptors. It is most commonly diagnosed in the first three decades of life. Amongst the 4 major clinical forms of FD (namely monostotic, polyostotic, McCune-Albright syndrome, Mazabraud’s syndrome) the monostotic form predominates (70-80%) in comparison to the polyostotic form. “Ground Glass appearance is a characteristic appearance on plain radiograph. Histopathologically fibrous component is relatively avascular, composed of cytologically bland spindle cells with few trabecular structures. The management ranges from watchful observation to surgical intervention.
Key-words: Fibrous dysplasia, polyostotic, monostotic, bone grafting, bisphosphonates.
Introduction
Fibrous dysplasias (FD) are a group of non-hereditary benign pathologies in which immature bone and fibrous stroma replace normal medullary bone as a result of abnormal differentiation of osteoblasts characterized by solitary (monostotic) or multi focal medullary (polyostotic) fibro osseous lesions. They contain mutated fibroblast cells and osteoblasts of varying functionality, which produce abnormally immature woven bone [1]. They are accounted for 2.5% of all the bone tumors and 5–7% of all benign bone tumors [2]. The detailed description as a benign developmental disorder of the bone was given by Lichtenstein and Jaffe in 1942 and thus it is referred as Lichtenstein-Jaffe disease [3]. The dormancy of FD increases from childhood to adulthood, however there is a life time risk of malignant transformation that of around 1–4% [4].
Etiopathogenesis
Cessation of bone maturation process at the stage of woven bone formation leading to inability to produce mature lamellar bone accounts for development of fibrous dysplasia. There have been many theories which have tried to explain the genesis of fibrous dysplasia. Excessive production of interleukin-6 production at local site has been related to increased resorption of bone by increasing the numbers of osteoclasts in these lesions. Genetic theory postulates that somatic mutation early in embryonic life causes a gene mosaicism. The earlier the mutation occurs, the more widespread the effects will be. The gene is located on band 20q13, an area that codes for the α subunit on G-protein receptors Mutations in the gene (GNAS I) result in a cascade which may lead to alteration in cellular differentiation and osteoblastic proliferation [5, 6]. According to hormonal theory, osteoblasts in fibrous dysplastic lesions have an elevated number of hormone receptors and thus have altered responses of bone formation. Hormonal alteration occurring during life, like in pregnancy usually sees exuberated growth of these lesions, thus explaining its hormonal genesis. Another theory explains that cAMP also activates Fos, which inhibits osteoblastic specific genes as well as stimulating cytokines that promote bone resorption by osteoclasts. Hypophosphatemia/phosphaturia, sometimes found in FD, is caused by excess secretion of a phosphatonin fibroblast growth factor [7].
Clinical Presentation and evaluation
FD is most commonly observed between 3 to 15 years age group, and majority of the cases are diagnosed in the first three decades of life. Polyostotic lesions usually present earlier as they are associated with a more severe form of the disease. Males and females are equally affected [9, 10]. Majority of patients with the polyostotic form of FD are symptomatic before the age of 10 years [7]. The monostotic form predominates (70-80%) in comparison to the polyostotic form [8]. Site affection may vary with the form of the disease. According to the sites of involvement for the polyostotic form femur, tibia are most commonly involved followed by skull and facial bones, pelvis, rib, humerus, radius and ulna, lumbar spine, clavicle, and cervical spine. The lesions may be unilateral or, less commonly, bilateral. Symptoms are related to the severity of the disease. Monostotic lesions may be asymptomatic and found incidentally. Polyostotic lesions present early with more symptoms in 60% of the patients. Pain along with swelling and deformity are the most common presenting complaints which is due to structural weakness and micro fractures in the affected bone. Deformity occurs due to abnormal bone growth or micro fractures and subsequent remodeling. Deformities of the lower limb especially the proximal femur can cause an antalgic gait and have a high risk of developing leg length discrepancies and pathological fractures. Common deformities are varus deformity of the proximal femur also known as the “shepherd’s crook deformity”, tibial bowing, bossing of the skull, prominent jaw, rib and chest wall masses. Symptoms may get exacerbated during pregnancy [7, 11].
Four types of fibrous dysplasias have been reported so far based on clinical conditions [11].
Monostotic FD: This represents around 70-80% of all FDs. This is the only form where craniofacial bones are affected. It occurs mostly in the age group of 20-30 years. Non-osteogenetic fibroma, aneurysmal bone cyst, giant cell tumor of bone, adamantinoma, eosionophilic granuloma and plasma cell myeloma should be considered in the differential diagnosis of monostotic FD [8, 12]
Polysototic FD: It accounts for 20-25% of all FDs. More than one of the bones in the skeletal and craniofacial system is affected and it occurs in the first decade of life. Hyperparathyroidism, polyostotic Paget’s disease, neurofibromatosis and cherubism should be considered in the differential diagnosis of polyostotic FD [8, 12].
McCune-Albright syndrome: It is a triad of polyostotic fibrous dysplasia, cutaneous café-au-lait spots and endocrine dysfunction. The syndrome was named after 2 physicians, Donovan McCune and Fuller Albright, who separately described the triad in 1937. It accounts for about 3% of all fibrous dyplasias and 35% to 50% of cases of polyostotic fibrous dysplasias. Females are affected more than males. Patient suffering from this syndrome will have hyperpigmented skin lesions with irregular “coast of Maine” borders with ipsilateral bony ground glass lesions. Endocrinopathies include hyperprolactinemia, gonadotropin-independent precocious puberty, growth hormone excess, hyperthyroidism, FGF23-mediated renal phosphate wasting and Cushing’s syndrome [13].
Mazabraud’s syndrome: Patients suffering from this syndrome present with soft tissue myxomas with polyostotic fibrous dysplasia. The myxomas generally develop later than FD adjacent to the affected bones. These are more commonly seen in extremities alongside long bones. [14].
Cherubism: It is an autosomal dominant disorder which is characterized by symmetric involvement of both the mandible and maxilla and manifests during the second decade of life. These lesions generally become static at skeletal maturity [15].
Radiological evaluation
Plain radiograph: Plain radiograph is the gold standard to evaluate a fibrous dysplasia lesion. It typically shows a well defined medullary lesion, which is usually mildly expansile and is centered in either metaphysis or diaphysis with or without endosteal scalloping with a varying degree of translucency. The medullary canal is replaced with fibrous tissue formed of delicate woven bone spicules that give the tissue its “ground glass” appearance. There may be endosteal scalloping of the inner cortex, but the periosteal surface is smooth and nonreactive. [16]. The deformities (shephard’s crook curvature of femur and coxa vara deformity of the knee) may vary in severity (Figure 1: Radiograph (AP view) of the pelvis showing polyostotic fibrous dysplasia with classic “Shephard’s Crook Deformity”). Radiological characteristics of the lesions differ with respect to the bone and fibrous matrix ratio and are usually seen as three different patterns. Firstly the pagetoid pattern where the rate of the bone–fibrous matrix is equal, secondly sclerotic pattern in which the bone structure is in the foreground and thirdly the radiolucent pattern where the fibrous matrix is in the foreground [17].
Computed tomography: A CT scan demonstrates the extent of the lesion. The appearance may vary according to the amount of calcification and ossification in the lesion. CT Imaging may be more useful in evaluation of craniofacial FDs. [11].
Bone scintigraphy: It is helpful in detecting the extent of disease and distribution particularly of active lesions in adolescent period [18]. It may also be helpful in detecting stress fractures.
Magnetic resonance Imaging (MRI): MRI is helpful in assessing the exact location, extent, shape and content of FD lesion. It characteristically demonstrates a low-intensity signal on T1-weighted images due to its fibrous content. T2-weighted images demonstrate moderately intense signals which are darker than signal of malignant tissue, fat or fluid. MRI is also helpful in detecting malignant transformation of a FD lesion, which may be evident with features like cortical bone erosion, destruction and soft tissue masses [19].
Histopathological evaluation
The lesions show an expanded bone with well-circumscribed, tan grey mass that is dense and variably fibrous with a gritty consistency due to the presence of bone trabeculae. It may show cystic areas in older lesions with some yellow-tinged fluid. A glassier, blue-tinged appearance may be found in cases with chondroid metaplasia [7].
Microscopic appearance: Microscopic evaluation shows varying proportions of fibrous and osseous tissue. The fibrous component is avascular and composed of cytologically bland spindle cells demonstrating low mitotic rate without atypia. Trabecular structures show an abnormal arrangement resembling Chinese letters which is composed of woven bone. Secondary myxoid and aneurysmal bone cyst like changes can be seen. Occasional nodules of benign hyaline cartilage may also be seen. Osteoblastic cells create fibrous tissue instead of a normal bone tissue in the bone medulla [20, 21]
Differential Diagnosis
The differential diagnosis of FD varies based on location, extent of lesion and age of the patient. These mainly include simple bone cyst, enchondroma, eosinophilic granuloma, brown tumor of hyperparathyroidism, giant cell tumor, neurofibromatosis, osteoblastoma, hemangioma of bone. osteofibrous dysplasia, fracture callus, non-ossifying fibroma, and low-grade Osteosarcoma can be included in the differential diagnosis based on histopathological findings. Low-grade chondrosarcoma may be part of the differential diagnosis if there is a prominent chondroid component. Osteofibrous dysplasia and fracture callus can be differentiated by the history and location of the lesion, and they typically have prominent osteoblastic rimming around the bone trabeculae[7].
Treatment
Management of FD should focus on reducing pain, optimizing function, and managing endocrinopathies, if they exist. The choice of treatment is usually guided by, site & extent of lesion, growth of lesion, related symptoms and age of the patient; it can vary from a watchful observation to surgical intervention. Monostotic asymptomatic lesions can be observed and followed up with serial radiographs to look for progression of the lesion. Large symptomatic lesions especially in the lower limb require active management, which may include non surgical (medical) or surgical management. Surgical interventions should be dealt with caution as complete resections are not possible mostly and incomplete resections have high chances of recurrence [22]. Medical management with bisphosphonates is helpful in most sympotomatic monostotic lesions without fractures or deformity. Third generation bisphosphonates (zolendronic acid) have shown remarkable success rate in relieving bone pain and healing of lesions. This is radiologically evident by improved cortical thickness, ossification of the lesion and improved function. These have also shown to reduce the rate of complications like pathological fracture. Intravenous 4 mg zolendronic acid along with vitamin D and oral calcium supplements is the choice of treatment [23]. Denosumab also appears to be effective in reducing bone turnover in adult patients with active FD. However, caution should be exercised, and patients should be monitored carefully as significant fluctuations in biochemical and hormonal indices can occur [24] and hence Denosumab is not recommended for regular use. Surgical intervention is indicated in cases of failure of nonsurgical therapy, large painful lesions, progressive deformity, non-union or malignant transformation. Curettage and bone grafting is the main cornerstone of surgical management. Cortical strut allograft should be used whenever possible as cancellous grafts may get resorbed due to natural disease process. Appropriate internal fixation should be used judiciously. Deformities especially in lower limb require surgical correction. Valgus osteotomy and medial displacement osteotomy are used to correct these deformities. (Figure 2: (a) Radiograph showing Fibrous dysplasia (mixed lytic sclerotic expansile lesion) in the proximal metadiaphyseal region of the right tibia. (b) Post treatment radiograph showing curettage and bone grafting and interfixation) [24].
Prognosis: Generally the prognosis of FD patient is excellent in the absence of malignant transformation. Monostotic FDs have better prognosis than polyostotic or syndromal FDs. Medical management is also more successful in monostotic lesions. Femoral lesions, younger age group patients, polyostotic disease and surgical interventions without internal fixation are the negative prognostic factors for surgical management. Malignant transformation is rare (Figure 3: Radiograph of right femur showing malignant transformation in a pre existing fibrous dysplasia lesion) [25].
Complications: Main complications related to FD are uncontrolled pain, deformities, pathological fractures, limb length discrepancy and malignant transformation. Malignant transformation commonly occurs to osteosarcoma or fibrosarcoma. It generally presents with increase intensity of pain with associated progressively increasing mass with or without pathological fracture. It is more common in polyostotic disease with Endocrinopathies. The rates of malignant transformation have been estimated to be about 0.5% with monostotic FD and about 4% with McCune-Albright syndrome [26]. Prognosis is usually poor. These are managed with multimodality treatment including surgery and chemotherapy [27]
Conclusion
Fibrous Dysplasia even though has good prognosis, there is a wide range of severity in patients all over. While some are minimally affected, some present with numerous fractures and significant deformities. With the advent of advanced imaging modalities and molecular pathology, a better understanding of the pathogenesis of FD has been possible. Non-surgical treatment regimens are increasingly being followed owing to their better compliance and overall improvement in patients’ quality of life by minimizing pain.
References
1. Araghi HM, Haery C. Fibro-osseous lesions of craniofacial bones. The role of imaging. Radiol Clin North Am 1993 Jan;31(1):121–34.
2. Gupta A, Mehta VS, Sarkar C. Large cystic fibrous dysplasia of the temporal bone: case report and review of literature. J Clin Neurosci 2003;10(3):364–7.
3. Lichtenstein L. Polyostic fibrous dysplasia. Arch Surg 1938;36:874.
4. StantonRP. Surgery for fibrous dysplasia. J Bone Miner Res 2006; 21(Suppl 2): P105–P109.
5. Diaz A, Danon M, Crawford J. McCune-Albright syndrome and disorders due to activating mutations of GNAS1. J Pediatr Endocrinol Metab. 2007; 20(8): 853–880.
6. Lietman SA, Schwindinger WF, Levine MA. Genetic and molecular aspects of McCune-Albright syndrome. Pediatr Endocrinol Rev. 2007; 4(suppl 4):380–385.
7. Riddle ND , Bui MM. Fibrous Dysplasia. Arch Pathol Lab Med. 2013;137:134–138
8. Grabias SL, Campbell CJ. Fibrous dysplasia. Orthop Clin North Am 1997; 8:771–83.
9. Sharma RS, Mahapatra AK, Pawar SJ, et al. Symptomatic cranial fibrous dysplasia: clinico-radiological analysis in a series of 8 operative cases with follow-up results. J Clin Neurosci 2002; 9(4):381–90.
10. Rajendran R, Sivapathasundharam R. Shafer’s textbook of oral pathology 5th edition. New Delhi, India: Elsevier, a division of Reed Elsevier India Private Limited; 2006. p. 971–9.
11. DiCaprio MR, Enneking WF. Fibrous dysplasia: pathophysiology, evaluation, and treatment. J Bone Joint Surg Am. 2005; 87(8):1848–1864.
12. Resnick D. Diagnosis of bone and joint disorders. 4th ed. Philadelphia, PA: Saunders; 2002. 4285–4840.
13. Campanacci M. Bone and soft tissue tumors: clinical features, imaging, pathology and treatment. 2nd ed. Wien, Austria: Springer; 1999. p. 435–60.
14. Iwasko N, Steinbach LS, Disler D, et al. Imaging findings in Mazabraud’s syndrome: seven new cases. Skeletal Radiol 2002; 31:81–7.
15. Ruggieri P, Sim FH, Bond JR, et al. Malignancies in fibrous dysplasia. Cancer 1994;73:1411–24.
16. Nager GT, Kennedy DW, Kopstein E. Fibrous dysplasia: a review of the disease and its manifestations in the temporal bone. Ann Otol Rhinol Laryngol 1982(Suppl 92):1–52.
17. Fitzpatrick KA, Taljanovic MS, Speer DP, Graham AR, Jacobson JA, Barnes GR, Hunter TB. Imaging findings of fibrous dysplasia with histopathologic and intraoperative correlation. AJR Am J Roentgenol 2004; 182:1389–98.
18. Zhibin Y, Quanyong L, Libo C, Jun Z, Hankui L, Jifang Z, Ruisen Z. The role of radionuclide bone scintigraphy in fibrous dysplasia of bone. Clin Nucl Med 2004; 29:177–80.
19. Yavuzer R, Khilnani R, Jackson IT, Audet B. A case of atypical McCune-Albright syndrome requiring optic nerve decompression. Ann Plast Surg 1999; 43(4): 430-5.
20. Parekh SG, Donthineni-Rao R, Ricchetti E, Lackman RD. Fibrous dysplasia. J Am Acad Orthop Surg 2004; 12(5):305–13.
21. Sargin H, Gozu H, Bircan R, Sargin M, et al. A case of McCune-Albright syndrome associated with Gs alpha mutation in the bone tissue. Endocr J 2006; 53(1):35–44.
22. Amit M, Collins MT, FitzGibbon EJ, Butman JA, Fliss DM, Gil Z 2011 Surgery versus watchful waiting in patients with craniofacial fibrous dysplasia–a meta-analysis. PLoS One. 2011;6(9):e25179
23. Wu Di, Ma Jie , Bao Suqing , Guan Haixia. Continuous effect with long-term safety in zoledronic acid therapy for polyostotic fibrous dysplasia with severe bone destruction. Rheumatol Int. 2015 Apr;35(4):767-72
24. Ganda K, Seibel MJ. Rapid biochemical response to denosumab in fibrous dysplasia of bone: report of two cases. Osteoporos Int. 2014 Feb;25(2):777-82
25. Yabut SM Jr, Kenan S, Sissons HA, Lewis MM. Malignant transformation of fibrous dysplasia. A case report and review of the literature. Clin Orthop Relat Res. 1988; 228:281-9.
26. Jhala DN, Eltoum I, Carroll AJ, et al. Osteosarcoma in a patient with McCune-Albright syndrome and Mazabraud’s syndrome: a case report emphasizing the cytological and cytogenetic findings. Hum Pathol. 2003; 34(12):1354–1357.
27. Bielack SS, Kempf-Bielack B, Heise U, Schwenzer D, Winkler K; Cooperative German-Austrian-Swiss Osteosarcoma Study Group. Combined modality treatment for osteosarcoma occurring as a second malignant disease. J Clin Oncol 1999; 17(4):1164.
28. Eversole R, Su L, ElMofty S. Benign fibro-osseous lesions of the craniofacial complex. A review. Head Neck Pathol. 2008 Sep;2(3):177-202
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Guest Editorial: Osteosarcoma – Has it really been a Success Story?
Volume 2 | Issue 1 | Jan-Apr 2016 | Page 3-5 | Shekhar M Kumta.
Author: Dr. Shekhar M Kumta [1].
[1] Department of Orthopaedic Surgery, The Prince of Wales Hospital, Chinese University of Hong Kong.
Address of Correspondence
Prof. Shekhar Madhukar Kumta
Department of Orthopaedic Surgery, The Prince of Wales Hospital,
Chinese University of Hong Kong. Shatin NT, Hong Kong.
Email: Kumta@cuhk.edu.hk.
Guest Editorial: Osteosarcoma – Has it really been a Success Story?
Osteosarcoma was once considered a fatal disease, but following the successful development of chemotherapy in the early 1970’s, spectacular improvements in survival have been reported. Neo-adjuvant chemotherapy is now a mandatory necessity not only for survival but also for the successful local control of disease as it facilitates surgical excision and has extended the limits of functional limb salvage in the extremity as well as in the pelvis. The current data suggests that 56- 79% of Osteosarcoma patients should expect to survive at least 5 years, while 52-70% may remain alive, 10 years after primary eradication of disease [1,2, 3].
The remarkable reduction of fatality in Osteosarcoma was often touted as a major medical success story, particularly in comparison with other more prevalent and dismally fatal visceral cancers such as that of the Lung, Liver and breast. But in recent years, advances in Genomic studies and newer understandings of molecular-genetic pathways that control neoplasia and response to drugs, have facilitated the development of targeted therapies for a variety of visceral and haemopoetic malignancies, resulting in equally impressive reversal of fatalities and optimization of treatments, particularly in breast, colon, lung and liver carcinomas [4]. Very little of these developments have translated to better outcomes for Osteosarcoma patients.
Indeed the so-called success of Osteosarcoma therapy has eluded significant population groups, particularly in developing countries. Seldom do survival rates exceed 40-50 % in many developing countries and long term survival outcomes data from high-volume centres, even from large countries such as India, is not freely available. Treatment costs remain a significant burden and even if generic drugs are made available, the nutritional, physical and psychosomatic support required for successful long term survival and coping with burden of disease, are either poorly developed or out of reach of most patients in many such countries.
Another important and often overlooked aspect is the burden of disease. The difficulties with access to health care services in many populations, amongst many other reasons, often results in delayed presentations. Such patients may present with huge tumors, sometimes with metastases at presentation. While tumor burden is known to be negatively associated with response to drugs and therefore survival, no effective adjustments, either to drugs, the dose-intensity of treatment, or surgical alternatives, have been recommended through proper controlled studies, conducted specifically in the context of such patients. Instead this has been left to the decisions of individuals. Balancing the decision between risking life and abandoning limb salvage is not an easy task, particularly if it is based only upon empirical data and personal experiences.
A closer look at global Osteosarcoma data suggests that disease relapses in 30-40% of cases, despite optimal treatments in patient’s presenting with early disease; only 20% of these patients may survive 5 years or longer [5]. Relapse may also occur in patients who have shown excellent response to chemotherapy and in some patients, late relapse 8-15 years after clinical remission, has been noted. The small repertoire of drugs available for Osteosarcoma significantly reduces the chances of salvage with secondary and tertiary agents; indeed without surgical induction of remission there is no possibility of survival [5,6].
The surgical treatment for disease eradication in Osteosarcoma is fairly well established and based on validated principles. Impressive rates of limb salvage (81-91%) are now possible in most patients presenting with early extremity disease.
It is the failure of disease despite optimum treatments that remains frustrating, and demands a strategic look at integration of emerging technologies and the development of novel approaches to treat this disease.
1. Genomic Studies and Molecular Genetic Pathways
Following the success of the Human Genome project, new technologies have enabled the rapid sequencing and identification of Genes involved in neoplasia and other diseases. NEXT-Gen [7]sequencing technologies have now made it possible to identify groups of cancer-specific genes expressed in individual patients and even in single cells, opening up the possibility of classifying tumors and identifying patients not only on the histological identification of the tumor but on the genetic signature expressed in their neoplastic cells.
While some disease have a well-defined genetic abnormality, either in terms of a known gene or group of mutant genes and translocations, conventional Osteosarcoma does not have a typical genetic profile. Nonetheless, given that neoplasms are driven by genetic perturbations, a bio-informatics approach may, in the near future, help us identify prognostic features, expression of drug resistance, molecular signaling and metabolic pathways as potential actionable targets for therapeutic considerations. Collecting and storing tumor tissues in bio-banks and tagging tissues with clinical outcomes data is therefore crucial. Given that Osteosarcoma is a relatively rare disease, the greater the sample base the more relevant and applicable the results of genomic and bioinformatics analysis are likely to be.
2.Targeted Therapies and Less-Toxic Drugs
Conventional drugs for Osteosarcoma are highly toxic. This imposes significant limitations to dose-intensification even in the context of primary chemo-naive disease. In the case of large tumors, systemic toxicity limits dose-escalation in proportion to tumor burden, leading to the development of drug resistance. Addition of drugs that act synergistically or target metabolic processes and pathways specific to neoplastic cells are attractive possibilities. Drugs targeting the mTOR [8] and CREB pathways have shown great promise in Pediatric Neuroblastoma. Rapidly growing neoplastic cells rely on extracellular arginine to support necessary biological processes. Arginine auxotrophy is a characteristic of neoplastic cells and arginine deiminase (ADI) and arginase I, target arginine metabolism and are a promising novel therapy for Osteosarcoma [9].
3. Improvements in Drug Delivery and Reversal of Drug Resistance
Given that the neoplastic cells in Osteosarcoma are embedded within a dense matrix of osteoid, the optimal penetration of drugs has always been a concern. The conjugation of cytotoxic drugs with bone-seeking compounds, polymer-based nano-particles to expedite and improve intracellular delivery of drugs are attractive possibilities, but as yet, remain under investigation [10, 11].
Drug resistance is rarely present at diagnosis. This may be associated with expression of MDM2, P-glycoprotein and several other known factors. Importantly drug resistance is often developed during the course of the disease and is an acquired feature of the disease. A number of small molecules targeting key intra-cellular kinases [12] involved in modulating drug resistance have shown promising in-vitro results.
4.A Reexamination of Surgical Strategy – Ablation Verses Limb Salvage
Preservation of limb function with good limb salvage is goal that must be concomitant with long-term survival. Quite often, especially with large tumors that are likely to be refractory to neo-adjuvant chemotherapy, the dogmatic adherence to the doctrine of limb salvage may jeopardize survival. The difficulty lies with the lack of objective criteria and reliable evidence base upon which such criteria could be established, so as to facilitate decision-making. It is only in the most obvious of cases, such as those with neurovascular involvement, compartmental obliteration, or fungation, we can convince ourselves to proceed with amputations. The difficulty of accepting amputation from the patient’s perspective is completely understandable, but the reluctance of the surgeon, particularly in borderline cases, may put the patient’s life in jeopardy.
Are we bold enough to go back to the drawing board and reexamine this issue?
With what degree of certainty can we identify poor responders prior to therapy?
Will early amputation followed by adjuvant therapy improve survival in patients with large tumors unlikely to respond to therapy?
There have been enormous improvements in amputation prosthetic knee mechanisms including bone-anchored abutments and lightweight exoskeletons. This has enabled dramatic improvements in ambulation even with high trans-femoral amputations.
5. The Emergence of Precision Medicine
In recent years there has been a major push towards the integration of research and fundamental knowledge of human biology, behavior, genetics, environment through bioinformatics data science and computation, with the goal of developing more accurate and specific approaches towards common as well as rare diseases. Instead of a “one-size-fits-all” approach the precision medicine approach to oncology [13] may enable us to categorize neoplasms on their genetic signature and combined with a large computational database, also enable specific therapies towards common traits and cohorts. In the near future there is hope for the development of target therapies, for accurate diagnosis, identification of drug resistance and potential failure. Pharmaco-genetics is an emerging field and may help identify molecular genetic profiles in Osteosarcoma that are likely to respond to specific drugs.
Exciting and far-reaching developments in medicine and fundamental biology will enable us to have a better understanding of Osteosarcoma and its biology. However it remains critical for us to develop knowledge networks for information exchange and to categorize the diverse clinical behaviors of tumors. Accurate, reliable and credible information needs to be made available not only to the clinician and scientist, but also to our patients in a comprehensible way, so that they may participate in a much more informed manner, in the complex decision making that is involved in Osteosarcoma care.
Finally, it is not only Science that fails us in our goals towards eradication or control of disease. The challenges of economic disparity and the consequences of inequity in health resource availability are beyond the scope of this discussion; clinicians treating Osteosarcoma will need to acknowledge and address these critical issues through innovative means without losing sight of the guiding principles of oncologic care.
References
1. Mankin HJ, Hornicek FJ, Rosenberg AE, Harmon DC, Gebhardt MC. Survival data for 648 patients with osteosarcoma treated at one institution. Clin Orthop Relat Res. 2004 Dec;(429):286-91.
2. Hagleitner MM, de Bont ES, Te Loo DM (2012) Survival trends and long-term toxicity in pediatric patients with osteosarcoma. Sarcoma 2012: 636405.
3. Whelan JS, Jinks RC, McTiernan A, Sydes MR, Hook JM, Trani L, Uscinska B, Bramwell V, Lewis IJ, Nooij MA, van Glabbeke M, Grimer RJ, Hogendoorn PC, Taminiau AH, Gelderblom H. Survival from high-grade localised extremity osteosarcoma: combined results and prognostic factors from three European Osteosarcoma Intergroup randomised controlled trials. Ann Oncol. 2012 Jun;23(6):1607-16..
4. Abramson, R. 2015. Overview of Targeted therapies for cancer. https://www.mycancergenome.org/content/molecular-medicine/overview-of-targeted-therapies-for-cancer/
5. Kempf-Bielack B, Bielack SS, Jürgens H, Branscheid D, Berdel WE, Exner GU, Göbel U, Helmke K, Jundt G, Kabisch H, Kevric M, Klingebiel T, Kotz R, Maas R, Schwarz R, Semik M, Treuner J, Zoubek A, Winkler K. Osteosarcoma relapse after combined modality therapy: an analysis of unselected patients in the Cooperative Osteosarcoma Study Group (COSS). J Clin Oncol. 2005 Jan 20;23(3):559-68..
6.Wong KC, Lee V, Shing MMK, Kumta S. Surgical Resection of Relapse May Improve Postrelapse Survival of Patients With Localized Osteosarcoma. Clinical Orthopaedics and Related Research. 2013;471(3):814-819.
7. What is Next-Gen sequencing http://www.illumina.com/technology/next-generation-sequencing.html
8. Zhang H, Dou J, Yu Y, Zhao Y, Fan Y, Cheng J, Xu X, Liu W, Guan S, Chen Z, shi Y, Patel R, Vasudevan SA, Zage PE, Zhang H, Nuchtern JG, Kim ES, Fu S, Yang J. mTOR ATP-competitive inhibitor INK128 inhibits neuroblastoma growth via blocking mTORC signaling. Apoptosis. 2015 Jan;20(1):50-62.
9. Wells JW, Evans CH, Scott MC, Rütgen BC, O’Brien TD, Modiano JF, Cvetkovic G, Tepic S. Arginase treatment prevents the recovery of canine lymphoma and osteosarcoma cells resistant to the toxic effects of prolonged arginine deprivation. PLoS One. 2013;8(1):e54464.
10. Wang B, Yu X-C, Xu S-F, Xu M. Paclitaxel and etoposide co-loaded polymeric nanoparticles for the effective combination therapy against human osteosarcoma. Journal of Nanobiotechnology. 2015;13:22.
11. Susa M, Iyer AK, Ryu K, et al. Inhibition of ABCB1 (MDR1) Expression by an siRNA Nanoparticulate Delivery System to Overcome Drug Resistance in Osteosarcoma. Rich BE, ed. PLoS ONE. 2010;5(5):e10764.
12. Chen H, Shen J, Choy E, Hornicek FJ, Duan Z. Targeting protein kinases to reverse multidrug resistance in sarcoma. Cancer Treat Rev. 2016 Feb;43:8-18.
13. Collins FS, Varmus H. A new initiative on precision medicine. N Engl J Med. 2015 Feb 26;372(9):793-5..
14. Stuart A. Scott, Personalizing medicine with clinical pharmacogenetics Genet Med. 2011 Dec; 13(12): 987–995.
Prof. Shekhar M. Kumta
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Tata Memorial Centre – Torch bearer for Care of Cancer in India
Vol 2 | Issue 1 | Jan- Apr 2016 | page:1-2 | Dr. Yogesh Panchwagh & Dr. Ashok Shyam.
Author: Dr. Yogesh Panchwagh [1], Dr. Ashok Shyam [2,3].
[1]Orthopaedic Oncology Clinic, Pune, India.
[2] Indian Orthopaedic Research Group, Thane, India
[3] Sancheti Institute for Orthopaedics &Rehabilitation, Pune, India
Address of Correspondence
Dr. Yogesh Panchwagh.
Orthopaedic Oncology Clinic, 101, Vasanth plot 29, Bharat Kunj Society -2, Erandwana, Pune – 38, India.
Email: drpanchwagh@gmail.com
Editorial: Tata Memorial Centre – Torch bearer for Care of Cancer in India
“Only a life lived in the service to others is worth living”: Albert Einstein.
Rarely does a place, a hospital in particular along with its healthcare providers, epitomise Einstein’s words as closely as India’s topmost tertiary cancer care hospital: Tata Memorial Hospital (TMH), Mumbai. As this editorial is being penned, TMH celebrates its platinum jubilee following its motto of service, education and research religiously throughout these years. This editorial is thus dedicated to this fine institution, which is also Asia’s largest cancer care hospital. Inaugurated on 28th February 1941, by the then governor of Mumbai Sir Roger Lumley, was a 80 bedded, 15000 square meters building. It was then expected to be a center where specialized treatment could be given and one which could lead the path of newer treatment modalities for others to follow. And it has not disappointed. It has now reached new heights with 700 beds and 75000 square meters campus, all in the service of cancer patients not just from all across India but also from the other Asian, African and Middle Eastern nations as well. TMH today leads the war against cancer in India, as Sir Lumley expected it to do. It is recognized amongst the top 5 cancer care institutes globally. This is evident from the current annual numbers of 45,000 new patients and 4,50,000 follow up patients that this institute takes care of. A philanthropic gesture by the Dorabjee Tata trust to start with, later on bloomed into a clinical wing (Tata Memorial Hospital) and a research wing (Cancer Research Institute) which together grew as Tata Memorial Centre (TMC). It was later on brought under the aegis of the Government of India. The research activities in clinical branches and basic sciences fields are carried on in the dedicated unit of ACTREC (Advanced Centre for Treatment, Research and Education in Cancer) at Kharghar, Navi Mumbai, India. The educational activities include training of students in specialty and super specialty courses affiliated to Homi Bhabha National Institute. In fact most of the practicing doctors in field of oncology in various corners of the country, including the editorial board of Journal of Bone and Soft Tissue Tumors, have been associated with this premier institute at some point of time in their lives and correctly take pride in their alma mater. The work done by the Disease managemen t group (DMG) of Bone and soft tissue services at TMH is worth noticing since this unit deals with the subject related to JBST. As per figures from DMG, the outpatient department (OPD) numbers have increased from 800 in the year 2000 to the present number of 2000 new patients in 2014. In 2014, this unit catered to around 300 new osteosarcoma cases, 200 new Ewing sarcomas, 57 Chondrosarcomas and 339 soft tissue sarcomas apart from 275 benign bone and soft tissue tumors. This forms a significant 5% of the entire work at TMH. Thousands of cancer patients and their relatives are the ones that are benefited in turn, bearing fruit to the very roots on which this institution stands firmly. The numerous individuals who dedicated their entire lives to the betterment of this institute, including some not amongst us today, would certainly and rightfully be very proud today. The editorial board of JBST salutes the passion, determination and dedication of Team TMC.
Dr Yogesh Pachwagh
Dr Ashok Shyam
(some facts and figures are based on the information taken from the TMC platinum jubilee website and B.S.T, D.M.G, T.M.H)
Yogesh Panchwagh & Ashok Shyam
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Radiological Review of Extremity Osteosarcoma
Volume 2 | Issue 1 | Jan-Apr 2016 | Page 13-18 Amit Janu, Nikshita Jain, Shashikant Juvekar, Ashish Gulia.
Author: Amit Janu[1], Nikshita Jain[1], Shashikant Juvekar[1], Ashish Gulia[2].
[1]Dept of Radiodiagnosis, Tata Memorial Hospital, Parel, Mumbai. India.
[2]Orthopedic Oncology, Dept. of Surgical Oncology, Tata Memorial Hospital, Parel, Mumbai, India.
Address of Correspondence
Dr Ashish Gulia, MS (Ortho), Mch (Surgical Oncology)
Associate Professor, Orthopedic Oncology, Dept. of Surgical Oncology, Tata Memorial Hospital,
Mumbai – 400012, India.
Email: aashishgulia@gmail.com
Abstract
The paradigm shift in the overall outcomes of osteosarcoma is multi factorial. Be it introduction of chemotherapy, introduction of better
imaging or advances in the technology to produce better prosthesis, the crux lies in the correct and timely diagnosis. Radiology along with
clinical evaluation and histopathological confirmation is an essential part of the three tier system which leads to an accurate diagnosis
which forms the platform to initiate an ideal treatment to have desired oncological and functional outcomes. Plain radiography has been
the age old diagnostic tool which is still as important as was in yester century. Inclusion of high end cross sectional imaging likeCT and
MRI has not only helped in early and price diagnosis but has also proved to be a boon to operative surgeons to stage the disease locally and
plan complex limb salvage strategies. In the present article we have discussed the radiological features of various sub types of osteosarcoma
to help a clinician to assess these complex varieties of lesions.
Keywords: osteosarcoma, radiological assessment.
Introduction
Osteosarcoma is the most common primary nonhematologic bone malignancy and is the most common primary bone malignancy in children. There are various subtypes of osteosarcoma, each with distinct clinical and imaging characteristics and variable survival and an incidence of 0.2 to 0.3 per 100,000/year. Osteosarcomas can be classified as intramedullary (high grade, telangiectatic, low grade, small cell, osteosarcomatosis, gnathic), juxtacortical (parosteal, periosteal, intracortical, high-grade surface), or secondary lesions [1]. Though majority of cases are of conventional high grade intramedullary osteosarcoma accounting for 75%- 90%, it is important to differentiate them from other low grade and (low grade central and parosteal osteosarcoma) and intermediate grade osteosarcoma (Periosteal osteosarcoma). An understanding of the systematic imaging approach helps to more accurately diagnose these lesions and direct effective treatment. This article provides an organized approach to analyzing and subtyping of osteosarcoma based on radiographs and guiding the referring physician if any further imaging is warranted as there is frequently overlap with other benign and malignant entities, creating substantial diagnostic challenges. For accurate diagnosis, it is important to be aware of radiographic and cross-sectional imaging features that allow differentiation of each subtype of osteogenic sarcoma from its mimics. Osteosarcoma is a malignant tumor that is characterized by production of osteoid matrix (immature bone) and variable amounts of cartilage matrix and fibrous tissue [2]. Each subtype of the osteosarcoma exhibit distinct imaging features mimicking different benign and malignant entities, however with critical evaluation of specific features a correct diagnosis can be made. Furthermore, important prognostic information, as well therapeutic options can be evaluated based on imaging.
Conventional osteosarcoma
Conventional intramedullary osteosarcoma is the most common subtype of osteosarcoma, accounting for 75% of all cases. Conventional osteosarcoma is a high-grade neoplasm produces osteoid matrix by the tumour cells centrally within the bone and eventually involves the entire width of the bone. It is often described as amorphous, fluffy, cloud-like, solid, cotton like or ivory like on the plain radiographs. It appears as homogenously increased density within bone and in soft tissues. Approximately 90 % of the osteosarcomas show some degree of osteoid matrix on radiographs [3]. Histologically osteosarcoma is pleomorphic and can produce variable amounts of cartilage, fibrous tissue, or other components. Some osteosarcomas produce more than one type of matrix and depending on the dominant cell type, they can be further subdivided into osteoblastic (50%–80%), fibroblastic-fibrohistiocytic (7%–25%), chondroblastic (5%–25%), telangiectatic (2.5%–12%), or small cell (1%) (4). Most cases of conventional osteosarcoma are seen in second and third decades of life, peaking when patients are aged 10 to 15 years, while they are unusual in patients younger than 6 years or older than 60 years [5]. The imaging characteristics of the various subtypes of osteosarcoma are summarized in Table 1.
Conventional osteosarcoma most frequently affects long bones (70%–80%), particularly near the knee, in the femur, tibia, and humerus. This lesion originates in the metaphysis, with extension to the epiphysis (seen in up to 80% of MR imaging studies) (Fig. 1C), however initial manifestation in epiphysis alone is extremely rare [6]. Patients with conventional osteosarcoma may present with pathologic fractures. Skip lesions also occur in about 5% of patients. The intraosseous and extraosseous extent of tumor seen in cross sectional imaging should be measured and documented which is vital in preoperative assessment and staging of osteosarcoma. Joint involvement is seen in 19% to 24% of cases and is diagnosed when hyaline cartilage is penetrated and synovial involvement is rarely seen [7]. Radiographic findings are characteristic, osteosarcoma tends to destroy cortex without expanding osseous contours, reflects its aggressive nature with osteoid matrix having a pattern of fluffy opacities, with aggressive periosteal reaction (laminated, hair-on-end, sunburst, or Codman triangle) and with a soft tissue mass in 80-90 % of the cases (Fig.1). Occasionally, the lesions are purely lytic (fibroblastic) or sclerotic (osteoblastic), but most common pattern seen is mixed lytic and sclerotic [8]. MR imaging is the examination of choice for local staging and for planning biopsies or surgery because of superior contrast resolution and multiplanar imaging. The entire involved bone should be scanned to evaluate for skip metastases. The lytic areas appears low signal on T1-weighted images and high signal on T2-weighted images, whereas the mineralized matrix appears low signal on both T1- weighted (see Fig.1C) and T2-weighted images. The T1- weighted images gives vital information regarding the anatomical extent of the marrow involvement, invasion into epiphysis and skip lesions. Treatment includes chemotherapy followed by wide surgical resection and limb salvage or amputation. Local recurrence is high if there has been a pathologic fracture. Staging work-up should include a non contrast chest CT and a whole-body bone scan. Approximately 15% to 20 % of patients present with radiographic metastases. Most common site for metastasis are lungs followed by other bones. All high-grade osteosarcoma are treated with a multimodality management. The standard sequence include a multiagent chemotherapy (Doxorubicin, cisplatin, high-dose methotrexate, etoposide and ifosphamide) followed by wide surgical excision of the primary tumor which is followed by adjuvant chemotherapy. Addition of chemotherapy has dramatically improved the overall outcomes of extremity osteosarcomas from a mere 20% to 60–70%.
Telangiectatic osteosarcoma
Telangiectatic osteosarcoma accounts for 2 %–7% of all osteosarcomas cases and most commonly occurs in the 1st and 2nd decades of life. Telangiectatic osteosarcomas are located in the metaphysis of long bones and show asymmetric expansion, geographic lysis of bone, with an aggressive growth pattern (ill defined margins) with cortical destruction, minimal sclerosis and soft tissue mass [9, 10]. On pathological analysis, it shows dilated cavities filled with blood and septa and a small solid mass or a rim that contains high-grade osteosarcomatous cells. Commonly it appears low attenuation mass on computed tomography (CT), low signal on T1-weighted MR imaging, and high signal on T2-weighted MR imaging with fluid-fluid levels are seen in up to 90% of these lesions (Fig. 2). The imaging and pathologic features of these lesions may be confused with those of aneurysmal bone cysts, giant cell tumor, metastases and chondroblastic conventional osteosarcoma [11, 12]. The presence of thick, nodular, solid tissue within or around the cystic spaces, best seen on contrast-enhanced MR imaging along with aggressive pattern of growth and presence of matrix mineralization, is also helpful in making the diagnosis. Matrix mineralization in these lesions may be subtle on radiographs and it is better seen on CT. Imaging also helps to guide biopsy of the viable tumour areas. It is of utmost importance that these tumors must not be confused with other differentials and a biopsy should be performed before embarking on any form of definitive surgical procedure. The staging work up and management of telangiectatic osteosarcoma is similar to that of a conventional osteosarcoma.
Small-cell osteosarcoma
Small cell osteosarcoma is a distinct but rare subtype of conventional osteosarcoma which represents approximately 1- 4% of osteosarcoma cases. It most often affects patients in the 2nd and 3rd decades of life. The pathologic characteristics may be mistaken for Ewing sarcoma or primitive neuro- ectodermal tumor because its cells are small and have round and hyperchromatic nuclei, but cells of small cell osteosarcoma lack uniformity and consistently produce osteoid [13]. These lesions are most commonly seen in the metaphysis like conventional osteosarcoma, but they can be seen purely in the diaphysis in 15% of cases [14, 15]. Small-cell osteosarcoma is an intramedullary, permeative lytic lesion that is associated with cortical destruction, aggressive periosteal reaction, and soft tissue mass (Fig. 3) [16]. Differential diagnosis includes Ewing sarcoma, lymphoma, and conventional osteosarcoma. Although osteoid matrix is typically seen, purely lytic lesions may occur in up to 40% of cases. The prognosis is poor than that of conventional osteosarcoma. Some centres modify the chemotherapy like that of Ewing sarcoma due to presence of round cells but no standard concensus exist [14]. Over all staging and management of these tumors is also similar to other high grade osteosarcoma.
Low-grade central osteosarcoma
Low-grade central osteosarcoma is uncommon variant of conventional osteosarcoma also referred to as well differentiated or sclerosing osteosarcoma [20]. The mean age of presentation is slightly older and occurs in 3rd or 4th decade of life [21]. The radiologic and pathologic findings simulates those of fibrous dysplasia and benign fibro-osseous lesions often resulting in erroneous radiographic and histologic diagnosis. The presence of aggressive features like cortical destruction, permeative pattern or a soft tissue mass is helpful in differentiation of low-grade central osteosarcoma from benign fibro-osseous lesions which are better seen on CT and MRI. These cases are usually staged with a chest radiograph only. Surgery forms the main cornerstone of the management. Chemotherapy is not warranted and these are treated with wide surgical excision. The outcomes are usually excellent with wide excision, however intra-lesional resection and curettage can result in high local recurrences and transformation of initial lesion into high grade sarcoma as well [22].
Juxtacortical osteosarcoma
Juxtacortical or surface osteosarcoma refers to originating from the surface of bone and accounts for 4% to 10% of all osteosarcomas. It is usually associated with the periosteum and cortex with variable medullary canal involvement. These lesions are further divided into parosteal, periosteal, high grade surface, and intracortical osteosarcomas because of different radiological and histological findings.
Parosteal osteosarcoma
Parosteal osteosarcoma is the most common type of juxtacortical osteosarcoma originates from the outer layer of the periosteum, accounting for 65% of juxtacortical osteosarcomas and typically manifesting in the third and fourth decades [23]. The lesion is slightly more commonly seen in women. The tumor usually occurs in the metaphysis of long bones and posterior aspect of the distal femur is the most frequent site. Pathologically, it is usually a low grade tumour with extensive osteoid matrix and minimal fibroblastic stroma with occasional areas of cartilage are seen. At radiography, the classic appearance is a lobulated, cauliflower like, juxtacortical centrally dense ossific mass, separated by radiolucent cleavage plane with adjacent normal cortex in its early stages (approximately 30% of cases at radiographs and in 65% of cases at MRI) [24, 25]. This cleavage plane refers to the periosteum interposed between the normal cortex and the tumor mass. Cortical thickening with a relative lack of aggressive periosteal reaction may also be seen (Fig.4). The ossified matrix is predominantly low in signal intensity on both T1- and T2-weighted images (Fig.4), while unmineralized soft-tissue mass larger than 1 cm3 is predominantly high in T2 signal intensity. High signal intensity indicates high grade tumour [24]. Medullary cavity invasion may be seen in 8% to 59% of cases on MR imaging, and although the prognosis of these patients of these patients is controversial, knowledge of this invasion helps in complete surgical resection. Prognosis in patients with parosteal osteosarcoma is excellent, with a 10-year survival rate of 80%. High-grade foci warrant adjuvant chemotherapy. The main differential diagnosis includes myositis ossificans, osteochondroma and periosteal chondroma. Apart from trauma history, the gradual ossification of the lesion from the periphery toward the center of the mass and no attachment to the cortex is a characteristic radiographic finding of myositis ossificans [26]. Osteochondroma have corticomedullary continuity between the tumor and the underlying medullary canal which lacks in parosteal osteosarcoma [27].
Periosteal osteosarcoma
Periosteal osteosarcoma is the second most common type of juxtacortical osteosarcoma originates from the inner germinative layer of periosteum, accounts for 25% of juxtacortical osteosarcomas and usually presents in second and third decades with slight male preponderance [28, 29]. Pathologically, it is predominantly cartilaginous with small areas of osteoid, intermediate cytologic grade distinctly lower than that of conventional osteosarcoma but higher than that of parosteal osteosarcoma. Periosteal osteosarcoma characteristically occurs in diaphysis or metadiaphysis and usually involves 50% of the osseous circumference (Fig.5). Common radiographic findings include a broad-based mass on the surface of the bone, with cortical erosions, cortical thickening and periosteal reaction. Though medullary extension can occur, it is still rare and reactive marrow changes can occur in 50% of the cases [28, 29]. Periosteal reaction is seen as perpendicular low signal intensity areas on all MR sequences arising from the inner cortex to the outer margin of the tumor (Fig.5). Pathologically tumours are chondroblastic and they usually appear low attenuation on CT and high signal on T2-weighted images. Perpendicular periosteal reaction is seen as rays of low signal intensity on all MR imaging sequences. Prognosis of patients is better than conventional osteosarcoma but worse than parosteal osteosarcoma. Treatment consists of wide local excision with limb salvage. Perisoteal osteosarcomas are intermediate grade tumors and are staged like high grade osteosarcomas. A wide surgical resection is mandatory but role of chemotherapy is controversial.
High-grade surface osteosarcoma
High-grade surface osteosarcoma is least common type of osteosarcoma and accounts for 10% of juxtacortical osteosarcomas. It usually manifests in second and third decade of life. Pathologically, it is high grade like conventional osteosarcoma. Radiologically, it affects the diaphysis or metadiaphysis of the long bones, involves the entire circumference of the bone and may invade the medullary cavity [30, 31]. These tumors are staged and treated like other high grade osteosarcoma.
Intracortical osteosarcoma
Intracortical osteosarcoma is a rare type of osteosarcoma that arises from the cortex and is most commonly seen in second decade. Radiologically, they affect diaphysis long bones and have a geographic lytic area with variable amounts of mineralized osteoid. The lesions may also have smooth margins and variable cortical thickening with common differential diagnosis for this condition includes osteoid osteoma or osteoblastoma. Medullary invasion is rare.
Secondary osteosarcoma
Although conventional osteosarcoma and secondary osteosarcoma are histologically indistinguishable, diagnosis is made on the basis of typical radiographic appearances in the pre existing lesions such as MFH or paget disease (Fig.7) or secondary to radiation. The prognosis for these patients is usually poor.
Osteosarcomatosis (multifocal osteosarcoma)
Osteosarcomatosis is a condition characterized by multiple intraosseous osteosarcomas believed to represent rapidly progressive multicentric metastatic disease. It accounts for 3% to 4% of all osteosarcomas. Most of these patients have a multiple radiographic lesions and pulmonary metastatic disease. Mean survival for these patients is less than 1 year
Conclusion
Osteosarcoma is the most common primary bony malignancy in children’s. The radiologic appearances vary over a wide spectrum and may be mimicked by various benign and malignant lesions still each subtype have often characteristic radiographic features and are suggestive of the specific diagnosis most of the time. Perhaps more important, additional cross sectional imaging modalities specifically MR imaging, provide vital information for planning biopsies or preoperative staging in surgical management. Recognition of these imaging features is an important guide for the accurate diagnosis which helps our clinical colleagues regarding the often difficult and complex multimodality treatment of patients with osteosarcoma to improve the clinical outcome.
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Emerging role of PET/CT in osteosarcoma
Volume 2 | Issue 1 | Jan-Apr 2016 | Page 19-21 |Nilendu C Purandare1, Venkatesh Rangarajan1
Nilendu C Purandare[1], Venkatesh Rangarajan[1]
Department of Nuclear Medicine and Molecular Imaging, Tata Memorial Hospital, Parel, Mumbai 400012
Address of Correspondence
Dr.Nilendu C Purandare
Department of Nuclear Medicine and Molecular Imaging, Tata Memorial Hospital, Parel, Mumbai 400012
Email: nilpurandare@gmail.com
Abstract
The role of PET/CT in malignant tumors has grown exponentially in the past few years. Newer methods have been investigated and older methods have been refined. This article is a brief review of its current and potential utility in osteosarcoma.
Keywords: PET/CT radioisotope scans, osteosarcoma.
Introduction:
FDG PET/CT has been used to evaluate various malignancies including those of the musculoskeletal system. It is an imaging technique that provides information about the metabolic changes associated with cancer. PET imaging uses molecules that are labelled with radio nuclides. In clinical PET practice the principal radio-isotope used is the positron emitting 18 F-FDG which is a glucose analogue labelled with radionuclide 18 F. FDG is injected intravenously and is transported from the plasma to the cells by glucose transporters (GLUT 1 & GLUT 4). It then undergoes phosphorylation within the cell by the enzyme hexokinase and is converted to FDG-6-phosphate. FDG-6-phosphate does not get further metabolised and gets trapped in the cell. Cancer cells demonstrate increased anaerobic glycolysis (Warburg effect) which is believed to be due to upregulation of glucose transporters and hexokinase and reduced levels of glucose-6-phosphatase thus limiting further metabolism of the tracer in cancer cells [1]. Thus FDG PET provides unique functional information by taking advantage of the propensity of malignant tumors to demonstrate increased glucose utilization (metabolism) as compared with normal tissue. A semiquantitative measure of the metabolic activity (corrected for the amount of radiotracer injected per kilogram of body weight and for blood glucose level) is known as the standard uptake value (SUV) . Although the degree to which both benign and malignant tumors accumulate FDG can be quite variable, malignant tumors tend to have higher SUV values. In general significant difference is noted in the SUV of benign and malignant primary bone tumors. It should be noted that the interpretation of absolute SUV values can be misleading. No cutoff value of SUV can be established in clinical practice to reliably differentiate benign from malignant primary bone tumors. Osteosarcomas (OGS) and Ewings sarcomas tend to be FDG avid whereas chondrosarcomas and soft tissue sarcomas showing a wide range of uptake depending on the histology and grade of the tumor. Since OGS is FDG concentrating tumor, FDG PET can be used for staging and restaging. FDG PET can also be used to monitor response to neo-adjuvant chemotherapy and as a prognostic and predictive marker.
Use of FDG PET in staging:
Effective treatment stratification in patients with musculoskeletal malignancies requires accurate assessment of the extent of primary tumor and evaluation for the presence of metastatic disease. MRI is the modality of choice in assessing the local extent of the primary lesion for surgical planning and PET plays a limited role. However PET may allow the noninvasive estimation of the histologic grade of tumors. The SUV of bone and soft tissue sarcomas has been used as a prognostic marker to predict patient outcomes. It has been shown that the baseline SUVmax is an independent predictor of overall survival [2]. Also FDG accumulation within a large heterogeneous tumor allows identification of the areas with the highest biologic activity. This can allow targeted biopsy from the most metabolically viable portion of the tumor, which can help in ascertaining the accurate histological grade [3]. Since OGS metastasizes to multiple skeletal sites an accurate whole body bone imaging modality is important for accurate staging. Bone scanning using 99m Tc- methylene diphosphonate(MDP) has been for several years the work horse for detection of skeletal metastases in several cancers including OGS. MDP bone scan seems to be well suited to detect skeletal involvement because of the osteoblastic nature of skeletal metastases in OGS which can be detected by a conventional MDP bone scintigraphy with a high degree of sensitivity. However MDP bone scanning can suffer from limited spatial resolution due to planar imaging. In addition the high tracer uptake in the region of the growth plates can also conceal metastatic lesions. Another limitation of bone scanning is the high number of false positives and indeterminate findings which need further confirmation with anatomical imaging. Recent studies have shown a better sensitivity of FDG PET/CT than MDP bone scan primarily due to its greater ability to detect metastases in the region of the growth plate which are often masked on bone scans [4]. Addition of CT information in an integrated PET/CT scan also reduce the number of false positives leading to better accuracy compared to bone scintigraphy. Volker et al in their study in paediatric sarcomas (Ewings, OGS & RMS) showed a higher sensitivity of FDG PET (88%) over conventional imaging (37%) for skeletal metastases from Ewings sarcoma [5]. The sensitivity however was not much different (90% for PET Vs 81% for conventional imaging) for skeletal metastases in OGS. PET was superior to conventional imaging in the correct detection of lymph node involvement (sensitivity, 95% v 25% respectively). With the availability of integrated PET/CT machines, pulmonary metastases can be diagnosed using the CT component of the PET/CT study with same accuracy as that of a chest CT obviating the need for a separate CT examination of the chest. Thus an integrated FDG PET/CT can serve as a single stop shop modality for metastatic work up of OGS patients (figure 1). Various metabolic parameters can be obtained from the FDG PET/CT study that provide valuable prognostic information. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) are indicators of tumor metabolism which are independent prognostic markers and can predict metastases and survival in OGS [6].
Role of FDG PET as a surrogate marker in assessing response to neoadjuvant therapy:
Since functional and biochemical changes in a tumor in response to therapy occur much earlier than morphologic changes, FDG PET has proven to be very useful in looking at tumor viability before the changes are evident on standard morphological imaging techniques. Various studies have found a strong correlation between the degree of tumor necrosis on histology following neo-adjucvant chemotherapy and reduction in FDG concentration in Osteosarcomas [7,8]. In patients classified as having a good response to chemotherapy there is significant reduction in tumor FDG concentration (figure 2). Thus PET using FDG can be potentially used as a non-invasive surrogate to predict response as well for prognostication [9]. A multiparameter analysis technique based on kinetic 18F-FDG data (dynamic PET) of a baseline study and after 2 cycles is helpful for the very early prediction of chemosensitivity in patients with soft-tissue sarcomas receiving neoadjuvant chemotherapy. This can have potential implications on management in the form of whether to change or intensify chemotherapy or to decide whether to salvage or ampute the limb in chemo non-responsive tumors.
Role of FDG PET in detection of disease recurrence:
Conventional imaging modalities such as CT and MR imaging are limited in their ability to differentiate treatment related changes from recurrent tumor. Distortion of normal anatomy, symmetry and tissue planes following surgery or radiation therapy makes detection of tumor recurrence difficult. Also degradation of image quality due to artifiacts produced by metallic prosthesis limits evaluation of local tumor recurrence. The whole body imaging capabilities of FDG PET allow detection of local as well as distant tumor recurrence. FDG PET/CT is useful in detecting recurrence at the primary site and is often complementary to other imaging modalities [9]. It is fairly accurate in detecting sites of distant failure as well. Its potential benefits and limitations compared to conventional imaging modalities will have be studied in larger homogenous patient groups.
18F Sodium fluoride (NaF) PET scan:
18F NaF is a bone seeking radiotracer which was introduced way back in 1962 for skeletal imaging [10]. The availability of integrated PET/CT systems has led to a renewed interest in the use of 18F-NaF for imaging skeletal metastases (Fig. 3). PET/CT imaging allows high-resolution functional imaging of the skeleton with greater sensitivity than that of planar scintigraphy/MDP bone scans. Integrated PET and CT system allows the interpretation of 18FNaF in conjunction with CT images. This enables better morphologic characterization and improved differentiation between benign and malignant lesions reducing the number if false positives and the indeterminate lesions. Studies have shown better accuracy and lesions detectability for 18F NaF PET scans as compared to MDP bone scans in several cancers.(11,12). 18F NaF PET/CT scan can image skeletal as well as lung metastases in a single examination and can be used for metastatic work up of OGS patients. Comparison of the diagnostic accuracy and cost effectiveness of FDG PET/CT and NaF PET/CT in OGS patients has not been investigated in detail and studies addressing the same need to be carried out.
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