Evaluation of Osteogenic Sarcoma

Volume 2 | Issue 1 | Jan-Apr 2016 | Page 8-12 | Mandip Shah, Chetan Anchan.

Authors: Mandip Shah[1], Chetan Anchan[2]

[1] SPARSH orthopedic Oncology Clinic, 9th floor, Medicare building, Ellisbridge, Ahmedabad. India
[2]Bombay Hospital & Medical Research Centre, Mumbai, India

Address of Correspondence
Dr. Mandip C Shah (M.S Ortho)
SPARSH orthopedic Oncology Clinic
9th floor, Medicare building, Ellisbridge, Ahmedabad, 380006
Email: drmandip@gmail.com


Primary malignant bone tumors are very rare diseases and the initial symptoms and signs can be vague and nonspecific resulting in such patients receiving, at best, some symptomatic care, with the expectation that the problem would resolve naturally. Often the patient may wait out a period of weeks or months hoping that the problem would settle on its own with some home remedy. The foundation of optimal outcome in the treatment of any malignant disease is early detection and correct diagnosis. Osteosarcoma (also called as osteogenic sarcoma) is a high grade malignant disease which is fatal unless treated in time. Early detection and correct diagnosis can make a big difference in the outcome of treatment of these diseases. Awareness of these conditions and the knowledge of vulnerable age groups is the perfect start for achieving this goal. A detailed history of the presenting complaints and a thorough clinical evaluation of the patient will provide vital clues that should alert the clinician to a possible bone tumor. Radiographs and MRI form the mainstay of radiological investigation of bone tumors. Besides aiding in detection of the bone tumor, radiographs are of vital diagnostic value; whereas MRI provides very detailed anatomical information of the extent of the disease. No diagnosis of a malignant bone tumor is complete without histological confirmation of the disease and therefore biopsy is the final step in the diagnostic evaluation of a suspected malignant bone tumor. As for all malignant tumors, staging investigations must be done before starting treatment for osteosarcoma.
Keywords: Osteogenic Sarcoma, diagnosis, evaluation.


Osteosarcoma is a malignant tumor of mesodermal origin where the tumor cells produce bone or osteoid [1]. It is the most common primary malignant bone tumor, excluding hematopoietic bone tumors [1, 2]. Despite the simple and clear definition of this disease, the term osteosarcoma represents a family of tumors with significant diversity in its histological features, grade and clinical behavior [1]. However, it is a very rare disease and represents less than 1% of all cancers diagnosed in the United States [4]. It is seen most frequently in children and adolescents peaking in the second decade, which coincides with the growth spurt [3]. In these young patients, it chiefly affects the metaphysis of long bones. The most commonly involved region is the knee with the distal femur being the most affected, followed by the proximal tibia [3]. Besides the appendicular skeleton, osteosarcoma can affect other bones too; including the skull, axial, and very rarely, the acral bones. Although the majority of osteosarcomas occur in children and adolescents, there is a second spike in its incidence which is seen in the elderly – above the age of 60 years [5]. Unlike in the younger patients where most of the osteosarcomas arise de novo, a large number of osteosarcomas in the elderly arise in preexisting bone pathologies like Paget’s disease, fibrous dysplasia and in areas previously treated with radiation for some other cause [6, 7]. Males are more frequently affected than females. The overall world male to female ratio of osteosarcoma, in the age group of 0-24 years is 1.43:1 [8]. This difference steadily decreases with increasing age [8]. Osteosarcoma is a high grade malignant tumor which is fatal unless detected and diagnosed in time, and treated appropriately. Due to the rarity of this disease and lack of very obvious early clinical diagnostic features, there is often a delay in its detection and diagnosis; adversely affecting the outcome of treatment. Early detection and correct diagnosis gives the patient the best start to a long and difficult fight. In this article we describe a simple, logical and practical approach to evaluating a patient for a suspected bone tumor.

Evaluation of Osteosarcoma
A systematic approach is involved in the evaluation of any suspected bone neoplasm so as to reach a correct diagnosis, following which optimal treatment can be planned. As for most bone tumors, in cases of suspected osteosarcoma, this involves detailed clinical, radiological and histological evaluation.

Clinical evaluation
The three chief presenting symptoms of any bone tumor are pain, swelling and disability (Fig 1). Of these, pain is the most common presenting complaint in osteosarcoma, which, to begin with, may be experienced during activity that loads the affected bone. The pain may be in the form of a dull ache or such non-specific nature which could be attributed to more common causes like bone/muscle/ligament injury, articular pathologies etc. The duration of this pain may range from days to months. Special attention must be paid to patients in the vulnerable age group, especially when the complaint is unilateral, localized, persistent or progressive. Some individuals may associate the onset of the disease with some past injury. However, there is no evidence to substantiate that injury can lead to genesis of osteosarcoma.
Unexplained musculoskeletal pain should be taken very seriously, especially in children and adolescents, and should not be dismissed without proper investigation. In general, one must rule out a neoplastic cause for the musculoskeletal pain if one or more of the points mentioned below are noted.
1) Unilateral and localized extremity pain without a known cause
2) Pain intensity/duration/evolution in conflict with assumed routine cause
3) Pain with swelling
4) Pain since weeks/months
5) Persistent or progressively increasing pain
6) Pain, only temporarily / not relieved – with conservative care (rest and analgesics)
7) Pain causing disability, or affecting activity which is considered normal for the patient
8) Pain aggravated/triggered with activity
9) Rest/night pain

Figure 1

The next common presenting complaint is swelling in the affected region. This swelling may be visible or/and palpable – depending on the size and location of the tumor. It is unusual for a patient of osteosarcoma to present with a painless swelling, with the possible exception of parosteal osteosarcoma. Unlike pain, which is far more likely to be due to some injury or many such routine causes, a swelling is clearly an indication of a pathology, the significance of which should be investigated without further delay. Again, one must be aware that there are many causes of bony swelling ranging from infection to various types of benign and malignant tumors, and tumor like conditions. It is useful to get answers to the following questions when a patient presents with a bony swelling.
1) Location and size of swelling?
2) Is the swelling painful or painless?
3) Did the pain lead to discovery of the swelling or an existing swelling became painful?
4) Duration – Days/weeks/months/years?
5) Rate of growth?
6) Solitary or multiple?
Pain or/and swelling may result in some form of disability. Pain in the lower limb may affect ambulation or cause limitation of range or function across the adjacent joint. Rarely, patients with osteosarcoma may present with a pathological fracture. Pathological fracture is uncommon in osteosarcoma as majority of these patients would have sought medical attention before such an event occurred [9]. The risk of pathological fracture is higher in telangiectatic variant of osteosarcoma as it is a lytic expansile disease. Pathological fracture in children and adolescents is far more likely to be due to benign conditions like simple bone cyst, fibrous dysplasia, aneurysmal bone cyst, etc. Nevertheless, an occasional telangiectatic osteosarcoma can present in a similar way. Therefore, it becomes essential that a clear diagnosis of the cause of the fracture is established before deciding on the treatment. To identify a pathological fracture, one must rely a lot on the circumstances of the fracture rather than the X-ray alone. One must seek answers to the following questions:
1) How did the fracture occur? Was the cause significant or trivial?
2) Did the patient have complaints of pain/swelling/disability in the affected region prior to the fracture?
3) Has the patient suffered similar fractures in the past in the same location or in other bones?

There are generally no systemic or constitutional symptoms due to osteosarcoma, unless the disease is very advanced with extensive metastases. Lungs are the most common site for metastasis and these patients mainly present with breathlessness [10]. Some patients may present with bone metastases, which is the most common site for extra-pulmonary metastasis [10]. Regional nodal metastases and systemic metastasis to other organs/tissue is rare [10].

Clinical Evaluation
A detailed clinical examination is the next step in the evaluation of a patient with suspected bone tumor. A detailed local examination assessing the exact location, size and extent of the lesion should be done. The findings could range from subtle signs like raised local temperature/deep tenderness/vague swelling, to a very obvious painful, tender and large bony swelling with stretched hypervascular overlying skin and restriction of associated joint function. One must also make a note of the function of the adjacent joint and any distal neuro-vascular deficit. Although nodal metastasis is very rare in osteosarcoma, as a routine practice, regional draining nodes should be examined.

Blood investigations
There are no specific serum markers for osteosarcoma. Patients with high pre-treatment Lactate Dehydrogenase (LDH) levels have been reported to have 20% lower disease free survival as compared to those with normal LDH levels [12]. Similarly, a high pretreatment level of serum Alkaline Phosphatase has been reported to be an independent adverse prognostic marker in the outcome of treatment of non-metastatic osteosarcoma of extremities [13].

Radiological Evaluation
The next logical step in the work-up of a suspected bone tumor is imaging. MRI and CT scan have revolutionized medical imaging of human body and have contributed hugely to the success in the treatment of musculoskeletal tumors. However, when it comes to diagnosing bone tumors, the imaging modality that matters the most is the plain radiograph. With few exceptions, all other imaging modalities help mainly in understanding the anatomical extent of the disease and are of limited/selective diagnostic value.

A good quality plain radiograph in two perpendicular planes screening the entire bone should be taken. Conventional osteosarcoma can have varying appearance on the plain X-ray. It appears like an ill-defined cloudy/fluffy radiodensity in the bone which may show a mixture of lytic and sclerotic areas. The borders of this lesion are ill-defined and it appears to permeate through the normal bone around. It does not have a precisely identifiable border on the X-ray and there is a wide zone where the disease merges with the normal bone. This is described as a “wide zone of transition” and is a sign of an aggressive disease. Once the disease breaches the cortex, it lifts up the periosteum which elicits a periosteal reaction which may have varying appearances described as a sunburst /spiculated/lamellated reaction or as a Codman triangle. All such patterns of periosteal reaction, which is described as an interrupted periosteal reaction, are a very important sign of a potentially malignant disease. Large osteosarcomas can have soft tissue extension of the disease which appears as a soft tissue shadow on the X-ray and which may show cloudy/fluffy radiodensities within it. Besides these classic X-ray findings of a conventional osteosarcoma, many of the rare variants of osteosarcoma have X-ray characteristics which are unique to that particular sub-type and could help in suspecting/identifying them [11] (Fig 2).

Figure 2

MRI is the investigation of choice in suspected case of osteosarcoma for local staging [14, 15]. One must insist on a contrast study screening of whole involved bone to rule out any skip lesion [16]. MRI must ideally be done before the biopsy as it helps in planning the biopsy approach and also in targeting representative areas within the lesion, avoiding areas of tumor necrosis. Also, doing an invasive procedure before the MRI may alter the MRI findings by causing procedure related artifacts and edema. MRI gives useful information on intra medullary and extramedullary extent of disease, presence of any skip lesion, proximity of the tumor to the neurovascular structures and involvement of joint / physeal plate etc (Fig. 3,4,5). An additional MRI study is usually advised after the completion of neoadjuvant chemotherapy, just prior to the surgery for local management of the osteosarcoma, Post chemotherapy response prediction can be assisted with MRI as well. Reduction in the size of the soft tissue mass/vascularity/reactive zone and intramedullary edema, thickening of the peritumoral capsule and presence of necrosis are some of the signs of good response to chemotherapy. Assessment of chemotherapy response is best done by contrast enhanced, diffusion weighted study [17,18].

Figure 3, 4, 5, 6

Histopathological Evaluation
Although, the diagnosis of osteosarcoma can be assumed with a fair degree of certainty based on the clinical and radiological findings, under no circumstances the treatment can be started without histological confirmation. Osteomyelitis, osteoblastoma, bone metastasis, lymphoma, GCT, ABC, are the radiological differentials to osteosarcoma. On the other hand, one cannot rely only on biopsy alone for diagnosis of osteosarcoma – the classic example is of callus which can be indistinguishable from osteosarcoma on histology. Hence it is very important to correlate clinical, radiological and histological information to reach a diagnosis of any bone tumor. Biopsy is a procedure where a representative sample of the disease tissue is procured for histological studies. There are many ways this sample can be obtained. The routine procedures are open biopsy, needle biopsy and fine needle aspiration cytology (FNAC). Before doing a biopsy, it is advisable to complete all the radiological imaging studies. The most important step in planning a biopsy of any bone tumor is to decide on the approach. This is very important because, during the definitive surgery of a malignant bone tumor, the entire biopsy tract including the skin scar is excised en masse with the tumor. Therefore, it is very essential that the biopsy incision is placed in the line of the incision of the future surgery [19]. Open biopsy is a surgical procedure where tissue samples are obtained through a minor surgical procedure. The incision should be just adequate to obtain the deeper tissue and should be parallel to the long axis of the limb, in a location that would allow its easy excision along with the tumor at the time of definitive surgery. Needle biopsy is a procedure where tissue samples are obtained using a bone biopsy needle through a small stab incision. There are several advantages of needle biopsy over open biopsy. It causes limited contamination of the biopsy tract as it has a small footprint, which makes excision of the biopsy tract much easier during definitive surgery and also results in much less loss of skin as a result of the same. Besides this, it has several advantages like faster recovery, less hospital stay, lower cost etc. Also, the longer reach of the needle makes it easier to sample different regions of the tumor. As with open biopsy, the placement of the biopsy incision is important. Also, sampling of different regions of the lesion should be done through the same incision by just changing the angle of the needle and not through another skin incision. The only relative disadvantage of this procedure as compared to open biopsy is perhaps the smaller quantity of tissue sample that may be obtained, which could prove challenging to the pathologist to work on. However, in experienced hands this is generally not a problem. Frozen section may be used to confirm that the tissue sample obtained is representative. However, it should not be relied on to make a definitive diagnosis of bone tumors. FNAC as a procedure has many advantages, being minimally invasive and practically without morbidity, and with the least risk of tumor seeding along the biopsy tract. There are many reports of bone tumor diagnosis using FNAC. However, it has some limitations especially related to adequate representative tissue sampling and hence is not ideal for a definitive diagnosis of bone tumors like osteosarcoma [20].

Staging in Osteosarcoma
Cancer staging is a process to know the magnitude of the primary tumor and possible spread of the disease in a particular patient. It helps to understand the severity of the disease and hence the prognosis and thus aids in optimal treatment planning. Staging any cancer is therefore mandatory before starting its treatment. The most common site for metastasis in osteosarcoma is lung, followed by the skeletal system. At presentation, the reported incidence of lung metastasis is 15-20% whereas for skeletal metastasis it is 4%. Staging investigations includes High Resolution CT scan of thorax (plain) + Tc-99m methylene diphosphonate (Tc-99m MDP) Bone scan. Nowadays, 18 Fluoro Deoxy Glucose PET-CT scan is showing great promise as an alternative staging investigation. Plain chest radiograph can only detect large lung metastasis. For detection of early smaller lung lesions, a high resolution CT scan of thorax without contrast is recommended [21]. Typically metastases appear of soft tissue attenuation, dull, well circumscribed rounded lesions, more often in the periphery of the lung. Patients who present with metastatic pulmonary disease have a poorer prognosis. However, cure can be achieved in a small number of patients who respond well to chemotherapy and undergo pulmonary metastatectomy [22, 23]. (Tc-99m MDP) Triple-phase, whole-body bone scintigraphy still remains standard of care for determining the sites of metastatic disease in the skeletal system [24]. It may also detect skip lesions, although MRI is more accurate for this purpose. Whole-body turbo STIR MRI is also a reliable method for screening patients with suspected skeletal metastases. It is more specific than bone scan. This technique is also advantageous in that it reveals extraskeletal organ and soft tissue metastases [25]. Longer study time and cost are the limiting factors. Functional or metabolic imaging in form of 18 Fluoro Deoxy Glucose PET-CT scan is much more sensitive and specific than Tc-99m MDP bone scan in picking up the skeletal metastasis in osteosarcoma [26]. Moreover it gives valuable information on viable disease representation in proposed site for biopsy and some idea of the grade of the sarcoma. As it remains unaffected by presence of metallic prosthesis and radiation beam hardening artifacts, it is extremely valuable in detecting and defining a suspected recurrence [27]. However its scarce availability and prohibitive cost at present, makes it a difficult investigation to recommend in every case. Most popular staging system for bone and soft tissue sarcomas has been the Enneking’s staging system (Table 1). It is based on histological grade of sarcoma, local extent of disease i.e. intra or extra- compartmental involvement and presence or absence of metastasis [28]. American Joint committee on Cancer (AJCC) has also developed a staging system for sarcomas. (Table 2) It takes into the consideration the size of sarcoma, tumor grade, presence, and location of metastases [29].

Table 1


Osteosarcoma is a high grade malignant disease which is fatal unless treated appropriately, in time. Effective treatment is available for this disease with a high cure rate. However, despite the availability of such treatment in developing countries, the cure rates for osteosarcoma are much lower as compared to the western population. One of the most significant points of failure is timely detection and diagnosis of this condition. Awareness of this disease and the knowledge of the vulnerable age group can go a long way in improving the prospects for osteosarcoma patients in developing countries. Time tested clinical skills along with readily available radiological imaging modalities and histopathology will help us reach accurate diagnosis and staging in most cases of osteosarcoma.


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How to Cite this article: Shah M, Anchan C. Evaluation of Osteogenic Sarcoma. Journal of  Bone and Soft Tissue Tumors Jan-Apr 2016;2(1):8-12.

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Osteosarcoma – A Clandestine Enigma

Vol 2 | Issue 1 | Jan – Apr 2016 | page:6-7 | Ashish Gulia.

Author: Ashish Gulia[1]

[1] Orthopaedic Oncology, Tata Memorial Hospital, Mumbai, India.

Address of Correspondence
Dr. Ashish Gulia MS (Ortho), Mch – Surgical Oncology
Fellowship – Musculoskeletal Oncology (TMH – HBNI)
Asst. Professor – Orthopaedic Oncology, Tata Memorial Hospital, Mumbai, India

 Osteosarcoma – A Clandestine Enigma

Bone tumors form a small part of all human cancers. As per the SEER data about 2570 new cases of bone sarcomas were diagnosed in the United States in the year 2005. Osteosarcoma, earlier called as “Osteogenic Sarcoma” is the most common primary bone tumor in humans, which has a predilection for metaphysis of long bones in children, adolescents, and young adults and most commonly involves the bones around the knee joint in about 65% of cases. The earliest published literature takes us to 1879, where in his publication, Gross advocated early amputation as the only treatment modality for extremity osteosarcoma with dismal survival outcomes. Since then the overall outcome of osteosarcoma has seen a sea change. This journey of evolution of treatment of osteosarcoma has been a roller coaster ride with its ups and downs. The world has seen remarkable survival improvements with some rapid strides in 1970s and 1980s. Introduction of multi-agent chemotherapy improved the 5 year survival from a dismal 20% to almost 70%. This fast paced growth reached a stagnant phase with no further improvements in the survival in almost last three decades. Though multiple agents have been tested in both phase II and phase III randomized controlled trials, none has been significant enough to be incorporated in clinical practice. Similar to the oncological outcomes, functional outcomes have also seen a dramatic improvement over last half a century. Limb salvage has become a norm in today’s orthopedic oncology practice, which wasn’t so in 1970s. Advent of neo-adjuvant chemotherapy, refinements in surgical skills, availability of durable metallic endo-prosthesis have led to a “limb salvage revolution” where about 85% to 90% of extremity osteosarcoma patients use their own extremity at the end of the treatment. The exponential growth in function preservation still continues with more technology driven innovations and solutions making the commonly encountered implant related complications like aseptic loosening and frequent breakage, a thing of the past. The current standards of care warrant a multi-disciplinary approach in the management of osteosarcoma. The approach is not only required in treatment phase involving a multi-agent neo adjuvant chemotherapy followed by optimal surgical resection & reconstruction and adjuvant chemotherapy, but also in evaluation, diagnosis and staging process. A seamless integration between musculoskeletal surgeon, musculoskeletal radiologist and sarcoma pathologist can achieve higher levels of accuracy in diagnosis in order to initiate the optimum line of treatment within an ideal time frame. The presence of metastatic disease at presentation is one of the most significant negative prognostic factors. Western data have shown that about 15% to 20% of patients will have clinically detectable metastases at presentation with lung being the most common site of metastasis in about 85% of cases followed by bone as the second most common site. These figures may be higher in developing countries as patients typically present with large volume disease. Lack of awareness, belief in alternative medicine and poor socio economic status are some of the factors contributing to higher percentages in these countries. Delay in diagnosis due to lack of suspicion and inappropriate initial evaluation as well as management has also led to dismal outcomes. The present symposium on Osteosarcoma tries to address the above issues and provide evidence based robust data, which will help the clinicians to understand the principles for evaluation and management of extremity osteosarcoma. The importance of understanding the presenting symptomatology and clinical evaluation is well scripted in the first article [1]. This article also stresses the importance of multi disciplinary strategy to diagnose a suspected bone lesion correctly. It discusses in depth the role of sequential radiological and histopathological evaluation of a suspected case of osteosarcoma. Staging of osteosarcoma is also discussed, which eventually helps clinicians to plan the treatment and estimate the prognosis. Radiological evaluation, whether it is with radiographs or with high end cross sectional imaging, has been the cornerstone for diagnosis and the local staging of the disease. Osteosarcoma exhibits various radiological and histological forms, which have deep implications on their treatment. These varied radiological presentations are discussed in the second article, which gives a tabulated comparison of various characteristics and their differentials [2]. The modern era is dominated by technology driven tools and this surge is quite evident in evaluation of bone tumors too. Emergence of PET scan as a “one stop shop” for the evaluation of bone tumors has created some whirlpools, leading to unending debates in recent era. Though more data is being collected to prove its worth in osteosarcoma, it is now being used to replace invasive investigations in other tumors like Ewing sarcoma and chondrosarcoma. The third article discusses the use of PET scan as a single modality to stage as well as to assess the chemo response evaluation in osteosarcoma [3]. The recent advances of this bio-imaging tools and the probable futuristic avenues are addressed in the third article. Complete surgical resection has been the single most important criteria to achieve adequate local control. Local relapses are associated with very poor overall survivals. The surgeons need to work to achieve a fine balance between complete tumor resection and retaining function. Over the years this has been addressed by “concept of margins” which was first popularized by the godfather of musculoskeletal oncology, Dr. W.F. Enneking. The concept was further revisited and modified by Kawaguchi, who gave the concept of “barrier effects” and challenged the traditionally propagated concept of “quantitative margins” and replaced it with a new concept of “qualitative margins”. The fourth article in the symposium address the similar issues regarding the adequacy of margins in the resection of osteosarcoma [4]. The article also explains the relationship of local failures with respect to resection margins and tumor necrosis. As discussed earlier multi-agent chemotherapy forms an integral part of management of osteosarcoma. The next article details the evolution of various chemotherapy protocols and current standards of chemotherapy for osteosarcoma [5]. Osteosarcoma is considered as a radio-resistant tumor, thus radiotherapy had a limited role in the management of osteosarcoma. Similar to the other specialties of medicine, radiation oncology has seen major changes in understanding the mechanism of radio tumor kill and also in the development of the delivery system. The advent of high-end technique like carbon ion and proton beam radiotherapy with their high accuracy, ability to give very high focused dosage and reduced side effects have made radiotherapy a new tool in the armamentarium for local control in osteosarcoma. Though these techniques are more useful in non-resectable lesions of axial skeleton, these are becoming increasingly popular in margin positive cases to avoid amputations. The latest updates regarding the use of this modality are explained in the last article of the symposium [6]. This symposium on osteosarcoma has been divided in to two sets, this first set encompasses articles related to evaluation and overall management of extremity osteosarcoma. Next issue will contain the second half of the symposium which will have articles on surgical management and advances in the management of osteosarcoma.


1. Shah M, Anchan C. Evaluation of Osteogenic Sarcoma. Journal of Bone and Soft Tissue Tumors Jan-Apr 2016;2(1):8-12.
2. .Janu A, Jain N, Juvekar S, Gulia A. Radiological Review of Extremity Osteosarcoma. Journal of Bone and Soft Tissue Tumors Jan-Apr
3. Purandare NC, Rangarajan V. Emerging role of PET/CT in osteosarcoma. Journal of Bone and Soft Tissue Tumors Jan-Apr 2016;2(1):19-21.
4. Cloake T, Jeys L.How important are surgical margins in Osteosarcoma? . Journal of Bone and Soft Tissue Tumors Jan-Apr 2016;2(1):22-26
5. Jain S, Kapoor G. Chemotherapy in Osteosarcoma: Current Strategies. Journal of Bone and Soft Tissue Tumors Jan-Apr 2016;2(1):27-32.
6. Kakoti S, Khanna N, Laskar S. The Current Role of Radiation Therapy for Osteogenic Sarcoma. Journal of Bone and Soft Tissue Tumors Jan-Apr

How to Cite this article: Gulia A. Osteosarcoma – A Clandestine Enigma. Journal of  Bone and Soft Tissue Tumors Jan-Apr 2016;2(1): 6-7.


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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


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.


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.

Figure 1, 2, 3

Figure 4, 5

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.

Figure 6, 7

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.


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,
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.

How to Cite this article:Biradar S, Joshi S, Panchwagh Y, Ghanekar V, Kothadiya P. Extraskeletal Myxoid Chondrosarcoma- Rare ‘Non-chondroid’ soft tissue Sarcoma!!!. Journal of  Bone and Soft Tissue Tumors Jan-Apr 2016;2(1):36-38 .


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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


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.

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].

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].

Table 1
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].

Table 2

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].

Figure 1, 2
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].

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].

Figure 3
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]


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.


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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
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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.
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15. Ruggieri P, Sim FH, Bond JR, et al. Malignancies in fibrous dysplasia. Cancer 1994;73:1411–24.
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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.
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How to Cite this article: Gulia A, Panda PK. Fibrous Dysplasia – an Update. Journal of  Bone and Soft Tissue Tumors Jan-Apr 2016;2(1): 39-43.


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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.


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.

How to Cite this article: Kumta SM. Osteosarcoma – Has it really been a Success Story? Journal of  Bone and Soft Tissue Tumors Jan-Apr 2016;2(1): 3-5.

Prof. Shekhar M. Kumta

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

How to Cite this article: Panchwagh Y, Shyam AK. Tata Memorial Centre – Torch bearer for Care of Cancer in India.  Journal of  Bone and Soft Tissue Tumors Jan- April 2016; 2(1):1-2.


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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


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.

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.

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%.

Figure 1, 2

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.

Figure 3, 4

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.

Figure 5

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

Figure 6, 7


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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27.Lin J, Yao L, Mirra JM, Bahk WJ. Osteochondromalike parosteal osteosarcoma: a report of six cases of a new entity. AJR Am J Roentgenol 1998;170(6): 1571–1577.
28. Murphey MD, Jelinek JS, Temple HT, Flemming DJ, Gannon FH. Imaging of periosteal osteosarcoma: radiologic-pathologic comparison. Radiology 2004;233(1):129–138. 19.
29.Revell MP, Deshmukh N, Grimer RJ, Carter SR, Tillman RM. Periosteal osteosarcoma: a review of 17 cases with mean follow-up of 52 months. Sarcoma 2002;6(4):123–130.
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How to Cite this article:.Janu A, Jain N, Juvekar S, Gulia A. Radiological Review of Extremity Osteosarcoma. Journal of  Bone and Soft Tissue Tumors Jan-Apr 2016;2(1): 13-18.


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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


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.

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].

Figures 1, 2

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.

Figure 3


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2. Brenner W, Bohuslavizki KH, Eary JF. PET imaging of osteosarcoma. J Nucl Med 2003;44:930–942.
3. Eary JF, Conrad EU, Bruckner JD, et al. Quantitative[F-18] fluorodeoxyglucose positron emission tomography in pretreatment and grading of sarcoma. Clin Cancer Res 1998;4:1215–1220.
4. Byun BH, Kong CB, Lim I et al. Comparison of (18)F-FDG PET/CT and (99 m)Tc-MDP bone scintigraphy for detection of bone metastasis in osteosarcoma. Skeletal Radiol. 2013;42(12):1673-81.
5.Volker T, Denecke T, Steffen I et al. Positron Emission Tomography for Staging of Pediatric Sarcoma Patients: Results of a Prospective Multicenter Trial. J Clin Oncol. 2007; 25:5435-41
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SY, Lim SM. Initial metabolic tumor volume measured by 18F-FDG PET/CT can predict
the outcome of osteosarcoma of the extremities. J Nucl Med. 2013 Oct;54:1725-32.
6.Hawkins DS, Schuetze SM, Butrynski JE, et al. [18F] Fluorodeoxyglucose positron emission tomography predicts outcome for Ewing sarcoma family of tumors. J Clin Oncol 2005;23:8828–8834.
7.Im HJ, Kim TS, Park SY, et al. Prediction of tumour necrosis fractions using metabolic and volumetric18F-FDG PET/CT indices, after one course and at the completion of neoadjuvant chemotherapy, in children and young adults with osteosarcoma. Eur J Nucl Med Mol Imaging. 2012;39:39–49.
8. Cheon GJ, Kim MS, Lee JA, et al. Prediction model of chemotherapy response in osteosarcoma by 18F-FDG PET and MR imaging. J Nucl Med. 2009;50:1435–1440.
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12. Schirrmeister H, Guhlmann A, Elsner K, et al. Sensitivity in detecting osseous lesions depends on anatomic localization: planar bone scintigraphy versus 18F PET. J Nucl Med 1999;40:1623–1629.

How to Cite this article:Purandare NC, Rangarajan V. EPurandare NC, Rangarajan V. Emerging role of PET/CT in osteosarcoma. Journal of  Bone and Soft Tissue Tumors Jan-Apr 2016;2(1):19-21 .


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How important are surgical margins in Osteosarcoma?

 Volume 2 | Issue 1 | Jan-Apr 2016 | Page 22-26 |Thomas P Cloake, Lee M Jeys.

Authors: Thomas P Cloake[1], Lee M Jeys[2].

[1]The Royal Orthopaedic Hospital, Bristol Road South, Birmingham, B31 2AP, UK.
[2]School of Health and Life Sciences, Aston University, Aston Triangle, Birmingham, B4 7ET, UK.

Address of Correspondence
Professor Lee M. Jeys
Professor of Health and Life Sciences
Aston University, Aston Triangle, Birmingham, B4 7ET, UK.
E-mail: lee.jeys@nhs.net


Surgical resection combined with chemotherapy is the mainstay of treatment of osteosarcoma. Traditionally, surgical margins were based upon tumour grade and classified into marginal, wide or radical resection. The definition of these margins, however, remains subjective and recent research has questioned the need for wide or radical margins. Advances in surgical technique and the use of neo-adjuvant chemotherapy have led to an improvement in outcome. By reducing tumour burden, chemotherapy has provided surgeons with the option of limb salvage surgery rather than radical resection. Surgical margins and response to chemotherapy are now considered the two most important predictors of outcome in osteosarcoma. This review focuses on surgical margins with respect to limb salvage surgery and discusses the importance of response to chemotherapy.
Keywords: osteogenic sarcoma, osteosarcoma, surgical margins, chemotherapy, limb salvage surgery.

Osteosarcoma is a high grade, primary tumour of bone in which the tumour cells produce osteoid [1]. It is the most common primary bone tumour, with an annual incidence rate of 5.0 per million [2]. Osteosarcoma is predominantly a disease of the young with a peak incidence in the second decade and displays a male predominance which is most pronounced at a younger age [3]. The treatment of osteosarcoma is challenging. The use of neo-adjuvant chemotherapy regimes combined with surgical resection has led to an improvement in outcome. Nevertheless, despite recent advances in surgical technique and chemotherapy agents, the survival rate has plateaued over the last 30 years [4]. There has been much research into prognostic factors that may help predict outcome in osteosarcoma, a number of these have been identified (see Table 1). Authors have suggested the most important, independent risk factors are the response to adjuvant chemotherapy and resection margins [5-7]. This review considers the impact of resection margins with a focus on limb salvage surgery and discusses the significance of response to chemotherapy.

Table 1

Resection margins
There has been much debate around the margin of clearance required for surgical treatment of osteosarcoma.  Enneking et al. were the first group to formally stage osteosarcoma into three distinct grades according to biologic aggressiveness, tumour site and distant metastases [8].  The authors suggested this system be used in surgical planning and inform the use of marginal, wide or radical resection margins. Nonetheless the definition of marginal or wide resection remains subjective and may vary between surgeons or units and has never been objectively defined (Fig 1).  Kawaguchi et al. developed this concept by giving distinct numerical values for desired resection margin according to the grade to tumour suggesting a 2cm margin was required for low-grade tumours and a 3cm margin was needed for high-grade neoplasms such as osteosarcoma [9].More contemporary studies have failed to reach a consensus on a numerical value for an adequate resection margin. Li et al. reported there was no difference in local recurrence when wide (>5mm) margins and close (<5mm) margins were used [10]. Bispo et al. failed to detect a difference in local recurrence using a margin of 2mm [11]. Betrand et al. found surgical margin to be the only independent risk factor for local recurrence and suggested a margin of 1mm may be adequate [12].  These papers suggest resection does not require a strict numerical margin, however efforts should be made to ensure no margins are intralesional. However, international consensus is in equipoise regarding margins, and this has made interpreting research articles very difficult. Even within units, tumour clear margins and ‘wide’ margins have become interchangeable when in reality they may be completely different and may lead to inappropriate treatment for patients. In the oncological world, the concept of patient specific treatment or ‘personalised medicine’ is gaining popularity and what is correct for one patient, may not be suitable for another patient, even with the same tumour type.

Figure 1

Limb salvage surgery

Prior to the advent of effective chemotherapy, the surgical treatment for osteosarcoma involved early radical amputation or disarticulation of the affected limb. Whilst ensuring complete removal of the tumour, performing this radical surgery on young patients caused loss of function and permanent disability, without improving patient survival. Limb salvage surgery (LSS) aims to resect the tumour, whilst maintaining function of the preserved limb, all with minimal risk to the patient (Fig 2).

Figure 2 Figure 3


The emergence of efficacious chemotherapy regimes, which acted to reduce tumour burden and reduce metastatic spread, and enhanced imaging techniques such as CT and MRI have led to the increased use of LSS [13-15]. By definition, the use of LSS requires preservation of limb neurovascular structures and narrower surgical margins when compared to amputation. Preservation of tissue during tumour resection has led to the inevitable decrease in resection margins, which potentially risks causing an increase in local recurrence (Fig 3). There are conflicting reports on the rate of local recurrence in LSS with some studies reporting an increase [15-17] and others a decrease [18], when compared to amputation. Considering local recurrence is associated with poor outcome, much work has been done to examine the impact of LSS on survival. Simon et al. were one of the first groups to investigate outcomes following LSS in a multi-centre retrospective review of 227 patients. They reported LSS had a comparable survival rate with amputation at 5 years follow up [19] and provided the impetus for increased uptake of LSS amongst surgeons. A large study by Bacci et al. retrospectively compared the outcome in patients who underwent LSS to amputation. The authors report that whilst LSS was associated with reduced resection margins, local recurrence and 5-year disease free survival were comparable to amputation [20]. These results are confirmed by a number of other groups, with each describing a survival rate equal to or better than that of amputation [15,17,18,21-27].It is important to consider, however, these studies are limited by their retrospective nature. Without robust methods of randomisation, treatment decisions have been based on individual patient and tumour characteristics, local practice and patient choice, leaving them open to the influence of selection bias. Postoperative quality of life is an important outcome measure in osteosarcoma. As patients with osteosarcoma are young and can expect a prolonged period of survival following treatment, the demands put upon a salvaged limb or prosthesis can be great. It is essential, therefore to ensure there is minimal risk of technical failure, the limb provides adequate function for the individual patient and has an acceptable cosmesis for both the patient and their care givers. Measurement of quality of life in children is difficult and there have been relatively few studies assessing this outcome measure. Using objective quality of life scores, LSS and amputation groups report reduced quality of life compared to population norms [29,30]. A meta-analysis comparing quality of life in patients who underwent LSS and amputation found there was no significant difference between the 2 groups. Taking into consideration all the above evidence LSS remains a safe and effective management option and when used in combination with adjuvant chemotherapy offers a good survival outcome.


The introduction of chemotherapy regimes alongside surgical resection has led to a dramatic improvement in survival. The use of chemotherapy in the treatment of osteosarcoma began in the 1970s with the use of doxorubicin and high dose methotrexate regimens [31]. Administration of chemotherapy agents before surgical resection as neo-adjuvant therapy enhanced survival from10 – 20% to 70% [32].Current modern chemotherapy regimes are based on combination therapy using methotrexate, adriamycin/doxirubicin and cisplatin. Poor response to chemotherapy has been identified as an important independent risk factor for poor prognosis. Histological evaluation of surgical resection specimens permits the classification of response to chemotherapy as good (>90% tumour necrosis) and poor (<90% tumour necrosis). Patients who display poor response are consistently reported to have worse outcome [33,34]. A number of strategies have been employed to improve results in poor responders. Evidence suggests modification of chemotherapy regime may improve results. Several groups have showed intensification of pre-operative chemotherapy enhances tumour response [35-37] and may improve survival [38-40]. This benefit however, is limited and intensification of chemotherapy beyond a certain level does not improve outcome [36,41-43]. The use of high dose, intensive treatment to induce a good response early in the disease process has also been shown not to convey overall survival benefit [38,42-44]. Further work is therefore required to optimize tumour response and improve outcome in patients with poor chemotherapy response. A recent, large, multi-national study EURAMOS-1 investigated the effect of adding the additional agents, ifosfamide and etoposide, to salvage poor response to chemotherapy, as well as evaluating the addition of pegylated interferon for good responding tumours [45]. The published initial results suggest that the addition of interferon for good responding tumours appears beneficial, however, it was poorly tolerated and frequently refused by patients. Current practice involves assessing tumour response using resection specimens following surgery, after the completion of neo-adjuvant chemotherapy, to advise further treatment[45]. Considering tumour response to chemotherapy is such a significant prognostic factor, measuring response early in the disease process may inform further management choices. Non-invasive imaging techniques such as CT [46], MRI [47-49] and F-FDG PET [50,51] have all be used to investigate response to neo-adjuvant chemotherapy. A combination of F-FDG PET and CT (F-FDG PET-CT) scanning is widely used for the detection of many cancers. Meta-analysis of the current evidence for its use in osteosarcoma has shown F-FDG PET-CT to be a valuable modality to assess chemotherapy-induced necrosis [52]. Newer techniques for evaluating response to chemotherapy prior to surgery, such as functional MRI (fMRI) are also promising and may inform surgeon’s decisions in planning surgical margins.
Patients with poor response to chemotherapy present a complex management challenge. There have been few studies presenting evidence to guide the surgical management of these patients. Bacci et al. suggested that amputation should be considered in the setting of poor response to chemotherapy due to its significant correlation with local recurrence rates [20]. Recent work in Birmingham investigated the influence of resection margins on survival in patients with poor response to chemotherapy [28]. The authors showed there was no survival benefit gained from amputation when compared to LSS with close margins, irrespective of the risk of developing local recurrence [28]. These data demonstrate resection with preservation of the limb to be a safe surgical option even in patients with poor chemonecrosis.

Predicting outcome
The current classification systems used to grade osteosarcoma, pioneered by Enneking, incorporate tumour characteristics including the presence of metastases to guide surgical management and predict prognosis [8]. However, despite the widely accepted importance of response to chemotherapy in prognosis, the current classification fails to reflect this.  In a recent presentation at International Society of Limb Salvage (ISOLS 2015), Jeys et al introduced The Birmingham Classification, which uses numerically defined tumour margins and response to chemotherapy to predict both local recurrence and survival. In this series, chemotherapy response was reported to show a significant effect on the rate of local recurrence and overall survival. It was also reported that a margin of 2mm was a statistically significant cut off value for predicting local recurrence.  Furthermore, combining resection margins (greater or lesser then 2mm) with response to chemotherapy (good, >90% or poor, <90%) was more effective in predicting local recurrence and survival than other staging systems.  This classification, however, requires further validation on a multi-centre basis.


Osteosarcoma continues to present a number to treatment challenges. Although surgical resection margins are an important predictor of outcome, limb salvage surgery with close margins has been shown to be a safe and effective surgical option.  Response to chemotherapy is an important independent predictor of survival.  A distinct group of poor responders exist, who despite modification to chemotherapy regimes and complete surgical excision of the tumour continue to have a poor outcome.  Current classification systems have so far failed to reflect important prognostic indicators, the Birmingham Classification represents a new, robust system for classifying osteosarcoma and predicting outcome.


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30. Eiser C, Darlington AS, Stride CB, Grimer R. Quality of life implications as a consequence of surgery: limb salvage, primary and secondary amputation. Sarcoma 2001;5(4):189-195.
31. Rosen G, Murphy ML, Huvos AG, Gutierrez M, Marcove RC. Chemotherapy, en bloc resection, and prosthetic bone replacement in the treatment of osteogenic sarcoma. Cancer 1976 Jan;37(1):1-11.
32. Anninga JK, Gelderblom H, Fiocco M, Kroep JR, Taminiau AH, Hogendoorn PC, et al. Chemotherapeutic adjuvant treatment for osteosarcoma: where do we stand? Eur J Cancer 2011 Nov;47(16):2431-2445.
33. Winkler K, Beron G, Delling G, Heise U, Kabisch H, Purfurst C, et al. Neoadjuvant chemotherapy of osteosarcoma: results of a randomized cooperative trial (COSS-82) with salvage chemotherapy based on histological tumor response. J Clin Oncol 1988 Feb;6(2):329-337.
34. Goorin AM, Schwartzentruber DJ, Devidas M, Gebhardt MC, Ayala AG, Harris MB, et al. Presurgical chemotherapy compared with immediate surgery and adjuvant chemotherapy for nonmetastatic osteosarcoma: Pediatric Oncology Group Study POG-8651. J Clin Oncol 2003 Apr 15;21(8):1574-1580.
35. Fuchs N, Bielack SS, Epler D, Bieling P, Delling G, Korholz D, et al. Long-term results of the co-operative German-Austrian-Swiss osteosarcoma study group’s protocol COSS-86 of intensive multidrug chemotherapy and surgery for osteosarcoma of the limbs. Ann Oncol 1998 Aug;9(8):893-899
36. Smeland S, Muller C, Alvegard TA, Wiklund T, Wiebe T, Bjork O, et al. Scandinavian Sarcoma Group Osteosarcoma Study SSG VIII: prognostic factors for outcome and the role of replacement salvage chemotherapy for poor histological responders. Eur J Cancer 2003 Mar;39(4):488-494.
37. Winkler K, Bielack SS, Delling G, Jurgens H, Kotz R, Salzer-Kuntschik M. Treatment of osteosarcoma: experience of the Cooperative Osteosarcoma Study Group (COSS). Cancer Treat Res 1993;62:269-277.
38. Fuchs N, Bielack SS, Epler D, Bieling P, Delling G, Korholz D, et al. Long-term results of the co-operative German-Austrian-Swiss osteosarcoma study group’s protocol COSS-86 of intensive multidrug chemotherapy and surgery for osteosarcoma of the limbs. Ann Oncol 1998 Aug;9(8):893-899
39. Ferrari S, Mercuri M, Picci P, Bertoni F, Brach del Prever A, Tienghi A, et al. Nonmetastatic osteosarcoma of the extremity: results of a neoadjuvant chemotherapy protocol (IOR/OS-3) with high-dose methotrexate, intraarterial or intravenous cisplatin, doxorubicin, and salvage chemotherapy based on histologic tumor response. Tumori 1999 Nov-Dec;85(6):458-464.
40. Bacci G, Ferrari S, Bertoni F, Ruggieri P, Picci P, Longhi A, et al. Long-term outcome for patients with nonmetastatic osteosarcoma of the extremity treated at the istituto ortopedico rizzoli according to the istituto ortopedico rizzoli/osteosarcoma-2 protocol: an updated report.J Clin Oncol 2000 Dec 15;18(24):4016-4027.
41. Ferrari S, Smeland S, Mercuri M, Bertoni F, Longhi A, Ruggieri P, et al. Neoadjuvant chemotherapy with high-dose Ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity: a joint study by the Italian and ScandinavianSarcoma Groups. J Clin Oncol 2005 Dec 1;23(34):8845-8852.
42. Lewis IJ, Nooij MA, Whelan J, Sydes MR, Grimer R, Hogendoorn PC, et al. Improvement in histologic response but not survival in osteosarcoma patients treated with intensified chemotherapy: a randomized phase III trial of the European Osteosarcoma Intergroup. J Natl Cancer Inst 2007Jan 17;99(2):112-128.
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How to Cite this article: Cloake T, Jeys L.How important are surgical margins in Osteosarcoma? . Journal of  Bone and Soft Tissue Tumors Jan-Apr 2016;2(1):22-26.

Dr. Thomas P Cloake

Dr. Thomas P Cloake

Prof Lee M Jeys

Prof Lee M Jeys

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Chemotherapy in Osteosarcoma: Current Strategies

Volume 2 | Issue 1 | Jan-Apr 2016 | Page 27-32 | Sandeep Jain, Gauri Kapoor.

Authers: Sandeep Jain[1], Gauri Kapoor[1]

[1]Department of Pediatric Hematology and Oncology, Rajiv Gandhi Cancer Institute & Research Centre, Delhi.

Address of Correspondence
Dr. Gauri Kapoor MD, PhD
Director Department of Pediatric Hematology and Oncology,
Rajiv Gandhi Cancer Institute & Research Centre, Delhi.
Email: kapoor.gauri@gmail.com


Incorporation of chemotherapy to multi-modality management of high grade osteosarcoma has led to remarkable improvement in survival rates. Its use in the neoadjuvant setting is now accepted as standard of care and has the added advantage of providing important information on histologic response. Survival rates for non-metastatic disease are nearly 70%. Outcome of patients with poor histological response and those with metastatic and recurrent disease continues to be unsatisfactory and an ongoing challenge. Therefore, there is a need to develop novel agents and biologically driven strategies to target these disease subgroups. The current review focusses on evolution of chemotherapy, controversies in its use and current standard of care for osteosarcoma.
Keywords: Osteosarcoma, chemotherapy, neoadjuvant chemotherapy.

Osteosarcoma is the most common primary malignant bone tumor in children and adolescents accounting for 4% of all pediatric malignancies. Approximately 20% of children present with metastatic disease at diagnosis and it remains, unquestionably the most important factor affecting long term survival. Prior to 1970, the prognosis of patients with osteosarcoma was dismal, with a 10–20 % overall survival despite being treated with radical surgeries [1-3]. Outcome of patients with osteosarcoma has improved in the past three decades with the addition of effective systemic polychemotherapy and advances in surgical resection. These have led to improvements in overall survival of patients with localized disease to the tune of 70% [4-5]. Various well coordinated systemic trials by different co-operative groups in North America and Europe have identified high-dose methotrexate (HD-MTX), cisplatin, doxorubicin, ifosfamide and etoposide as active cytotoxic agents and combinations of these drugs make up the cornerstone of treatment. Chemotherapy not only takes care of micrometastatic disease at diagnosis but also facilitates limb salvage surgery. The choice of regimen and optimal schedule of chemotherapy is somewhat controversial. In this review we focus on evolution of chemotherapy, controversies in chemotherapy use and current standard of care.

Evolution of chemotherapy
Before the introduction of chemotherapy, the outcome of patients with osteosarcoma was only 15-20%, despite adequate local control. Most patients succumbed to metastatic lung disease. These findings led to the conclusion that patients with osteosarcoma have microscopic metastatic disease at the time of diagnosis and this prompted investigators to identify active agents to target it. Initial studies to demonstrate chemosensitivity of osteosarcoma were done in the early 1970s by Sutow et al [6]. He developed a regimen called “Conpadri”which included cyclophosphamide, Oncovin (vincristine), doxorubicin (adriamycin), and L-phenylalaninemustard. Later on with the inclusion of HD-MTX, the acronym was changed to “Compadri’ [6-7]. These regimes were the first rational attempt at confirming the role of adjuvant combination chemotherapy using drugs with non-overlapping toxicities in osteosarcoma. Compadri I–III yielded a 41% 18-month disease-free survival [8]. These results suggested that addition of chemotherapy improved survival in patients with osteosarcoma. However, in the absence of randomized trials, it was not clear, to what extent improvement in surgical techniques and radiological studies contributed to achieving these results. These observations were further supported by the first randomized trial from Mayo clinic wherein patients were randomized to receive adjuvant vincristine and HD-MTX versus surgery alone[9]. This trial did not show any difference between the two arms. All these concerns were put to rest by two subsequent randomized controlled trials from North America that clearly established the survival benefit of adjuvant chemotherapy. In both these trials patients receiving no adjuvant treatment had a 2 year event free survival of just 20% compared to 66% and 55% in patients who received adjuvant chemotherapy [10-11]. These trials also established adriamycin, cisplatin, HD-MTX and alkylating drugs like ifosfamide and etoposide as active agents in the treatment of osteosarcoma. The various trials showing benefit of chemotherapy in osteosarcoma are listed in Table 1[12-22].

Table 1

Role of neoadjuvant chemotherapy
The concept of neoadjuvant chemotherapy (NACT) was first introduced at Memorial Sloan-Kettering Cancer Center (MSKCC) in their T-10 protocol [23]. Preoperative chemotherapy was administered in an effort to increase the number of patients who could undergo limb salvage as the surgeons needed time to order the prosthetic devices. Administration of NACT also had the theoretical advantage of treating presumed microscopic metastatic disease. The outcome of the T-10 trial was similar to that of the Multi Institutional Osteosarcoma Study (MIOS), with a 65% survival rate at 5 years. Importantly, the results of this trial laid the foundation for the subsequent important association between histologic necrosis and prognosis. However, there were concerns regarding the impact of delayed surgery among patients with chemo-resistant disease as well as the probability of development of resistant clone in those with high volume disease. To answer this concern Pediatric Oncology Group conducted a randomized clinical trial (POG 8651) between 1986 and 1993, comparing NACT with adjuvant chemotherapy. This trial compared immediate surgery followed by postoperative adjuvant chemotherapy with 10 weeks of the NACT (same drugs) followed by surgery in 100 patients under the age of 30 years with non-metastatic,high grade osteosarcoma. Chemotherapy consisted of alternating courses of HD-MTX with leucovorin rescue, cisplatin, doxorubicin, and bleomycin, cyclophosphamide,dactinomycin (BCD). The five-year relapse-free survival rates were similar between the two groups, 65% versus 61% for adjuvant and neoadjuvant arms respectively. There was also no difference in the number of patients who underwent limb salvage procedures (55% and 50 % for immediate and delayed surgery, respectively) [24]. On the basis of these results, the use of preoperative chemotherapy has become standard of care, given its advantages, as it allows sufficient time for surgical planning, potentially facilitates tumor removal, and permits evaluation of response to therapy. Several investigators in single and multi-institutional studies in the United States and across Europe, support this general strategy [13,14,16,18].

Histological response to chemotherapy
Most trials reveal that patients with greater than 90% necrosis following NACT have significantly better event free survival (EFS) compared to those with less than 90% necrosis. Several grading systems have been developed for assessing the effect of preoperative chemotherapy on the tumor. The two most commonly used classification systems are the Picci and Huvos classifications[Table 2]. The Institute of Rizzoli (IOR) reviewed data on localized extremity osteosarcoma in more than 1000 patients over the 19-year period from 1983 to 2002 [25]. Fifty-nine percent of all patients had good response to chemotherapy (Picci), and had a 5-year survival of 76%, compared to 56% for poor responders. The Cooperative Osteosarcoma Study group (COSS) database analyzed 1,700 patients between 1980 and 1998 that included all sites, ages, and presence or absence of metastases [26]. The data revealed that 55.6% of patients had good response to therapy. The 5-year survival rate for good and poor responders was 77.8% and 55.5% respectively. The European Osteosarcoma Intergroup (EOI) analyzed data of two consecutive studies between 1983 and 1986 and 1986 and 1991 [27]. A total of 570 patients were analyzed in the report. This analysis is notable for several differences compared to the COSS and IOR analyses. Only 28% of patients had a good histologic response, whereas 72% of patients had a poor histologic response. Their 5-year survival rate was 75% and 45% respectively. Interestingly, many of the patients included in the analysis did not receive HD-MTX as they were randomized to receive either doxorubicin and cisplatin or more intensive therapy including doxorubicin and HD-MTX. This data clearly established that histological response to chemotherapy is an important prognostic factor.

Table 2

Intensification of neoadjuvant and adjuvant chemotherapy
As it became clear that the degree of histological necrosis after pre-operative chemotherapy predicts survival, efforts were directed to intensify chemotherapy so as to achieve maximum therapeutic response. This strategy of preoperative chemotherapy intensification has been tested in COSS-86 and MSKCC T-12 study [14,28]. Although this strategy resulted in increased proportion of good responders achieving >90% necrosis, it did not translate into improved overall survival (OS) or EFS rates. Till date only INT-0133 study has shown benefit of NACT intensification [19]. The next group of trials focused to alter or intensify chemotherapy for patients with sub-optimal response to preoperative chemotherapy. In the early 1980s at Memorial Sloan-Kettering Cancer Center, poor responders had cisplatin substituted for HD-MTX in addition to continuing BCD (bleomycin, cyclophosphamide, and dactinomycin) and doxorubicin [13]. Survival of patients with intensified adjuvant treatment was similar to others. Several other reports have also failed to demonstrate benefit of intensification of therapy for poor responders[20,29]. Thus, till date it has not been possible to improve the outcome of poor responders by altering postoperative chemotherapy. An explanation for this may be that the NACT response is a surrogate measure of chemo-sensitivity of tumor and an inherently biologic unresponsive tumor is not modifiable by currently available therapies.

Table 3

Role of intra-arterial chemotherapy
The intra-arterial route was introduced in an attempt to enhance the efficacy of drugs by increasing the local concentration of chemotherapy. Alkylating agents like ifosfamide and cyclophosphamide could not be used as they required phosphorylation in liver for activation. Doxorubicin was not a suitable agent as it is associated with skin and subcutaneous necrosis. MTX achieved high tumoricidal concentrations intra-arterially but similar concentrations could also be attained via the intravenous route. Intra-arterial cisplatin was therefore, selected and found to be highly effective. Response rates with the intra-arterial route were better when compared to the intravenous route[30]. It has been used extensively at the MD Anderson Cancer Center in the TIOS pediatric trials. It was highly effective in patients with pathological fractures and neurovascular involvement. Unfortunately, intra-arterial route is labor intensive and requires general anaesthesia or conscious sedation in a radiological suite. It also requires intensive monitoring of the distal arterial vascular status during and after the infusion. Moreover, similar results could be achieved with multiple courses of combination chemotherapy administered by the intravenous route over a more prolonged period. Therefore, intra-arterial route is generally not preferred.

High Dose Methotrexate
High dose methotrexate is one of the oldest drugs used in the treatment of osteosarcoma. It is generally administered over 4-6 hours and requires aggressive hydration, leucovorin rescue, serum level monitoring and adequate infrastructure to safeguard delivery and manage toxicity. Moreover, it adds substantially to the overall cost of treatment. In addition, there are no randomized studies to compare the efficacy of higher versus intermediate doses of HD-MTX plus doxorubicin and cisplatin versus doxorubicin/cisplatin alone. Furthermore, investigators at St. Jude Children’s Research Hospital have demonstrated good outcomes with five-year EFS and OS of 66% and 75% respectively with non-methotrexate-containing chemotherapy regimen consisting of carboplatin, ifosfamide and doxorubicin [31]. All of this has led to considerable controversy regarding the optimum role of HD-MTX. Methotrexate is the only active agent that has been subjected to a comparative trial of efficacy with another active agent i.e. cisplatin. Compared to 5-20% survival of historical controls in pre-chemotherapy era, HD-MTX increased survival to 40% – 60% as a single agent. When combined with other active agents like cisplatin and doxorubicin the long term survival of 65% – 75% was reported [12-15]. Many studies have shown a favorable correlation between peak serum levels and outcome [19,32-33]. Therefore, optimum doses and administration schedule is crucial to derive optimum benefit from HD-MTX therapy. Chemotherapy regimes devoid of HD-MTX were considered, among the “major poor prognostic factors” in the treatment of osteosarcoma by Graf et al. [33]. Despite the absence of randomized trials evaluating osteosarcoma treatment with and without HD-MTX, it is generally acknowledged that methotrexate is a standard component of almost all contemporary osteosarcoma protocols in children and adolescents.

Current standard of care for patients with osteosarcoma
It is well established that chemotherapy is an integral component of osteosarcoma treatment and is essential in addition to local surgery in order to achieve a reasonable expectation of cure. Therefore, optimum treatment for osteosarcoma demands a multidisciplinary strategy. The treatment generally consists of three stages: initial cytoreduction with chemotherapy to eradicate micro metastatic disease and facilitate effective local control measures with wide negative margins; and consolidation therapy for eradication of occult residual disease to reduce the likelihood of tumor recurrence. Importantly, NACT not only helps to achieve optimal cytoreduction in facilitating limb salvage procedures but also provides a chance to assess the histologic response to chemotherapy. Most treatment protocols include cisplatin, doxorubicin and HD-MTX with or without ifosfamide plus etoposide(IE). In the recently concluded EURAMOS study, all patients received NACT: 2 blocks of MAP (methotrexate, doxorubicin and cisplatin) chemotherapy for 10 weeks followed by surgery (wide excision). Surgical excision of tumor with oncologically safe margins was the best means of local control. Post surgery, poor responders were randomized to receive MAP for 28 weeks with or without IE. All good responders continued on MAP for 28 weeks and then were randomized to no further therapy and maintenance therapy with pegylated interferon. This is the largest international trial in the history of osteosarcoma treatment and its results show that intensification of adjuvant chemotherapy by addition of IE in poor responders did not improve survival. Furthermore, in good responders addition of pegylated interferon maintenance was not useful [22]. Schema of this treatment is shown in [Figure 1] and most of the study groups endorse this strategy as current standard of care.

Figure 1

Non-methotrexate based chemotherapy for countries with limited resources
There is paucity of published data on osteosarcoma from India. Historically, the role of high dose methotrexate in the treatment of osteosarcoma has always been debatable. From the practical perspective, it requires rigorous pharmacokinetic monitoring and often the infrastructure required for monitoring is not available in many centers with limited resources. Therefore, most of the centers in India use cispaltin, doxorubicin and ifosfamide based chemotherapy. Pathak et al have reported relapse-free survival was 72% nonmetastatic osteogenic sarcoma of the extremities using cisplatin and doxorubicin as adjuvant therapy [35]. Recently, results from a single center study from India have revealed 2yr progression free survival of 70 % for patients with non-metastatic osteosarcoma [36]. In light of these results use of non methotrexate based therapy in resource constraint setting seems justified. In addition, it is desirable to focus on developing infrastructure to provide limb salvage procedures and direct resources to develop indigenous affordable prosthesis.

Treatment of relapsed osteosarcoma
Treatment of relapsed osteosarcoma has not been tested in randomized clinical trials, and thus, there is no single standard approach. Prognosis of patients with relapse depends on duration of off therapy and site of relapse. In a large database of 565 osteosarcoma patients who relapsed after being treated with one of three different NACT protocols within the European Osteosarcoma Intergroup, five year survival post relapse in those whose disease recurred after two years versus within two years of randomization was 35 versus 14 percent, respectively[37]. There is no reasonable chance of cure without complete surgical resection of all sites of disease. Choice of chemotherapy depends on agents used in front line therapy. In most of contemporary studies, most of the patients receive cisplatin and doxorubicin in front line therapy. Therefore, ifosfamide, etoposide and HD-MTX are the most commonly used drugs in relapse setting. In general, patients should be treated with any of the four most active agents that were not included in front line therapy. The use of high-dose chemotherapy with autologous hematopoietic stem cell rescue has been applied to salvage therapy. However, at least two small pilot studies failed to demonstrate significant advantage of standard salvage therapy approaches [38-39].

Newer therapies
There has been significant progress in the management of patients with osteosarcoma from 1970 to 1990. However, thereafter, progress has been stalled due to limited options available for patients with poor histologic response and those with metastatic and recurrent disease. It is clear that intensification of available chemotherapeutic agents has not translated into survival benefit for these group of patients and novel agents are required. Some of the agents being tested include mTOR inhibitor (ridaforolimus), inhibitors of insulin-like growth factor I receptor, tyrosine kinase inhibitor (sorafenib), microtubule inhibitor (oferibulin), human monoclonal antibody against RANKL (Denosumab) and anti-disialoganglioside antibody (theuseofan) [40-44]. Some of these agents have demonstrated promising results in preclinical data and may offer a potential role in adjuvant therapy in the future.

Acute toxicities and Late Effects
The most frequent acute toxicities due to chemotherapy are infections secondary to myelosuppression and mucositis. Renal dysfunction may lead to hypomagnesemia and other electrolyte abnormalities from tubular and glomerular damage induced by ifosfamide and cisplatin respectively. Ototoxicity from cisplatin and cardiac dysfunction related to anthracyclines are the other commonly observed side effects. Late effects in osteosarcoma may be attributed to local therapy i.e. surgery or to systemic chemotherapy. Those related to chemotherapy are usually agent specific. Doxorubicin is known to cause chronic cardiomyopathy which is dependent on the total cumulative dose. Longhi et al reported 2% incidence of symptomatic cardiomyoathy at a median follow up of 10 years [45]. In general, cumulative dose of doxorubicin is usually limited to less than 450 mg/m2. Anthracycline and alkylating agents may also result in second malignant neoplasm (SMN). The same authors report a 10-year and 20-year cumulative incidence of SMN of 4.9% and 6.1% respectively in osteosarcoma survivors. The alkylating agent, ifosfamide is associated with infertility, especially male infertility, so sperm cryopreservation should be offered to postpubertal boys if treatment plan includes alkylating agents. In addition, ifosfamide can cause a persistent renal tubular electrolyte loss and, less commonly, a decrease in glomerular function, in a dose-dependent fashion.


Inclusion of chemotherapy in the multimodality treatment of osteosarcoma has undoubtedly improved survival from a dismal 20% to the present 60%. NACT has enabled limb salvage rates to the tune of 90-95% in most advanced centers. Outcome of patients with poor histological response and those with metastatic and recurrent disease continues to be unsatisfactory and an ongoing challenge. Therefore, there is a need to develop novel agents and biologically driven strategies to target these disease subgroups.


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How to Cite this article:Jain S, Kapoor G. Chemotherapy in Osteosarcoma: Current Strategies. Journal of  Bone and Soft Tissue Tumors Jan-Apr 2016;2(1):27-32 .


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