Non-Vascularised Ipsilateral Fibular strut – A Modality to Treat Giant cell tumor of lower end radius using Anterior Approach.

Vol 1 | Issue 1 | May – August 2015 | page:45-47 | Ninad Godghate[1], Vikram V Kadu[1], K  A Saindane[1], Neha N Godghate[1].

Author: Ninad Godghate[1], Vikram V Kadu[1], K A Saindane[1], Neha N Godghate[1].

[1]ACPM Medical College, Dhule – 424001, Maharashtra, India

Address of Correspondence
Dr. Vikram V. Kadu
ACPM Medical College, Dhule – 424001, Maharashtra India
Email :


Introduction: Giant cell tumor is a benign bone tumor, locally aggressive with low malignant potential. The goal of treatment of this tumor at the distal radius is complete removal of the tumor and reconstruction of the bone defect in order to preserve maximum function of the wrist joint.
Case Series: This is a retrospective study conducted in 5 consecutive patients of GCT of distal radius. All patients presented with pain and swelling over distal end radius and were assessed clinically and radiographically. X-ray showed lytic lesion at lower end of radius suggestive of GCT. Histopathological examination and FNAC was done to confirm the diagnosis. Once the patient was fit for Surgery, wide excision of tumor and reconstruction with ipsilateral non-vascularised proximal fibula was performed. DCP plating was done to secure the fibular graft to the radius. 2 K – wires, 1 transverse through the fibula and ulna and 1 through fibula into the carpals were used for additional fixation and to help maintain the fibula and ulna in close approximation.
Results: At final follow up of minimum 1 year, all cases had good graft union with no recurrence. The range of motion of the wrist was near normal with no instability and good grip strength. Although this is an early follow up no graft collapse and no arthritic changes were noted. There were no complications both at donor and recipient graft sites.
Conclusion: Autogenous non-vascularised fibular graft for reconstruction of distal radius GCTcan be considered as a reasonable option for treating such conditions. Long term follow up will be needed to assess temporal complications and long term survival of the graft.
Keywords: Distal radius, fibula, GCT, ipsilateral.


Juxta-articular giant cell tumors of the lower end radius are common and present a special problem of reconstruction after tumor excision. Various reconstructive procedures described, non-vascularised fibular autograft has been widely used with satisfactory functional results. Giant cell tumors (GCT) of the bone are aggressive and are recognised for variable clinical behaviour, which is not always related to radiographic or histological appearance [1]. Complete excision of the tumor offers the best chance of cure but sacrifices the articular surface and presents complex reconstructive problems. Giant cell tumor (GCT) of bone is a benign but locally aggressive tumor with tendency for local recurrence [2]. Distal radius is the third most commonly involved site of skeletal GCTs (10% cases) next to distal femur and proximal tibia [3,4]. Goals of treatment are to achieve satisfactory removal of the tumor, lessen the chance of local recurrence and to preserve as much wrist function as possible.

Case Series
This is a retrospective study conducted between 2004-2014. We studied 5 consecutive cases of GCT involving the distal radius operated by en-bloc resection of tumor followed by reconstruction with ipsilateral non-vascularized fibular graft with a minimum 1 year follow-up. Informed consent from the patient was taken and approval from the institutional review board was obtained for the study. Of the 5 cases studied, 3 were males and 2 were females. 3 right sided and 2 left sided. Mean age group was 22 yrs (14 – 30 yrs). Campanacci’s staging system for giant cell tumour of the bone [5] was used for cortical breach. According to this system, 2 tumours were classified as Stage I and 3 tumours as Stage II. Once the patient was medically fit, surgery (ORIF with resection of distal end of radius and reconstruction with ipsilateral non vascularised proximal fibula along with plate and 2 k-wires) was performed.

Surgical Technique
Patient supine on the operating table, with the arm on an arm board. Tourniquet on the arm was applied without exsanguinating the limb. Incision taken from the distal flexor crease of the wrist proximally upwards. The plane between the brachioradialis and flexor carpi radialis longus was used to reach upto the bone. The distal end of the radius was resected and measured. According to the measurement, the ipsilateral proximal fibula was resected and was reconstructed after giving thorough wash to the reconstruction site. The fibula was then fixed to the radius with a 6 hole DCP plate and 2 transverse k-wires at the distal end to stabilize the distal DRUJ. The path of common peroneal nerve was encased in soft tissue which was attached to proximal tibia. Closure was done and drain was kept. Below elbow slab was provided post-operatively.

Case Study
28 yrs old male presented to our OPD with complaints of pain and swelling over distal radius, moreover on the lateral side since 3 months. The swelling was initially small (Pea shaped) and gradually increased. On clinical examination, skin over the swelling was normal, swelling was diffuse and was fixed to the bone. The movements at the wrist joint was painless but the patient had tenderness on deep palpation. The egg shell crackling sign was absent on palpation. X-ray (Fig 1a) showed lytic lesion at the distal end of the radius. It was characteristic of soap bubble appearance. FNAC was done which revealed GCT. Further histopathology (Fig 1b) was done which confirmed GCT. Once the patient was medically fit, surgery (ORIF with resection of distal end of radius (Fig 1c) and reconstruction with ipsilateral non-vascularised proximal fibula along with plate and 2 k-wires) was performed. 6 hole DCP plate was used for reconstruction of the fibula to radius and 2 k-wires for additional stability to distal radio-ulnar joint. The patient was given below elbow slab post-operatively for 4 weeks and then below elbow cast for another 2 months. The arm was protected in corset for 1 yr. The 2 k-wires were removed at 3 months follow-up (Fig 1d). At 5 months follow-up (Fig 1e), patient was clinically and radiologically assessed and physiotherapy was started. At 1 yr follow-up (Fig 1f), The patient had gained acceptable range of movement with excellent grip strength, without any complication and returned to his previous work. All patients completed one year follow up and were called for final assessment. Bone graft had united in all cases with acceptable range of motion when compared to opposite side. There were no obvious complications, arthritis or recurrence.

Giant cell tumor is an aggressive lesion with a high rate of recurrence [6]. There are reports that giant cell tumors in the lower end of the radius are more aggressive and metastasize more often to the lungs(1). Non-vascularised fibular autograft was first used in 1945 for congenital absence of radius(7). Later, fibular transplants were used by various authors for tumours of the lower end radius(8). This reconstruction technique has yielded good functional results for giant cell tumour of the lower end of the radius in various series, although large series with longer follow-ups are few(9).
In our study, we treated 5 patients with giant cell tumour of the distal radius by resection and ipsilateral non-vascularised fibular graft. Non-vascularised proximal fibular graft is reasonably congruous with distal radius and incorporated more rapidly. The graft is easily accessible without donor site morbidity. No allograft was used in our study. The patients we studied belonged to young generation in which limb salvage along with functional range of motion is the demand. The aim of treatment is to remove the tumor, reduce the chances of recurrence and preserve the joint function.
Resection of distal radius and reconstruction with ipsilateral non-vascularized fibula offers several advantages like more congruency of carpal joint, rapid incorporation as autograft and easy accessibility without significant donor site morbidity. Structural change is also minimal. Moreover, immunogenic reactions are absent. Case reports of joint preservation using vascularized fibula or prosthesis are found to be few and inconclusive(10,11]. Vascularised fibula has advantages of speeding up the healing time and early mobilization but at the same time its disadvantages includes; prolonged surgery time, need to sacrifice the arteries, skilled surgeon, not possible by an average orthopaedic surgeon.
The most commonly encountered complication in such cases are non-union, delayed union, wrist joint subluxation, subluxation of DRUJ. In our study we didn’t encounter any of the complications. Moreover, reconstruction with ipsilateral non-vascularised fibular graft is less time consuming, comparatively easy, can be done by any average orthopaedic surgeon and does not require any microvascular surgery. A proper length of fibular graft is a must to maintain the radial height and to prevent subluxation of the wrist joint. We ensured this by harvesting the fibula 2-3 mm more than the required length, which is the resected tumor length plus the safe margin. This 2-3 mm allowed us to achieve compression at the host-graft junction during fixation with DCP. A longer fibular graft will lead to subluxation of the wrist whereas 2 k-wires fixed in the distal fibula-ulnar joint further helps in stabilization of the wrist joint. There is a chance of stiffness of the wrist with relatively longer duration of immobilization and consequently decrease in the hand grip strength.
GCT of the distal radius is best treated with excision of the distal radius and reconstruction by non-vascularized fibula with good functional results[12].Our method of resection and reconstruction with non-vascularized fibular graft, internal fixation with DCP with primary bone grafting, use of stabilizing K-wires across the newly formed wrist joint and ligament reconstruction has been advocated by many other authors[13,14,15].

Figure 1

Clinical Message

ORIF with resection of distal end of radius and reconstruction with ipsilateral non-vascularised proximal fibula along with plate and 2 k-wires is a novel method for treating giant cell tumors of distal end of radius with all good results, excellent grip strength and  with minimal complications. It also preserves the functional movement and stability with normal appearance of the wrist. Further, this procedure eliminates the need for microvascular surgery. Moreover, the anterior approach used in our study offers excellent and safe exposure of the radius.

Editor’s Note

The surgical treatment of a giant cell tumor located in the distal radius is dictated mainly by the Campanacci grading. It is accepted that the distal radius is one site where giant cell tumors have a very high rate of local recurrence. It is mainly because of the anatomical constraints and difficulty in achieving a complete intra lesional clearance. However, whenever possible, salvaging the wrist by intra lesional curettage and reconstruction has always shown much better functional outcomes as compared by the M.S.T.S. scoring system. This is possible when the disease is not involving the radio-carpal joint, the soft tissue extension is in only one plain and the residual bone stock is adequate. Campanacci grade 1 and 2 lesions and some grade 3 lesions may still be amenable to intra lesional curettage, though with a higher risk of local recurrence. This is compensated by the much better functional outcomes as compared with en bloc resections. The success of fibular reconstruction modality with wrist salvage would largely depend on regaining the wrist ligamentous and capsular stability, failure of which will result in stiff, painful wrist and carpal subluxation. Such a reconstructive modality may not be the preferred choice in very large Campanacci grade 3 lesions, wherein wrist arthrodesis either by bone graft or ulnar translocation technique gives excellent functional outcome with minimum risk of local recurrence.


1. Szendroi M. Giant cell tumor of bone. J Bone Joint Surg Br 2004;86:5-12.
2. Eckardt JJ, Grogan TJ. Giant cell tumour of bone. Clin Orthop. 1986;204:45–58.
3. Dahlin DC, Cupps RE, Johnson EW., Jr Giant cell tumour: A study of 195 cases. Cancer. 1970;25:1061–70.
4. Goldenberg RR, Campbell CJ, Bonfiglio M. Giant cell tumour of bone. An analysis two hundred and eighty cases. J Bone Joint Surg Am. 1970;52:619–64.
5. Campanacci M. Giant cell tumor and chondrosarcoma: grading, treatment and results. Cancer Res 1976;54:257-61.
6. Smith RJ, Mankin HJ. Allograft replacement of distal radius for giant cell tumor. J Hand Surg Am 1977;2:299-308.
7. Starr DE. Congenital absence of radius; method of surgical correction. J Bone Joint Surg 1945;27:572.
8. Parrish FF. Treatment of bone tumors by total excision and replacement with massive autologous and homologous grafts. J Bone Joint Surg Am 1966;48:968-90.
9. Murray JA, Schlafly B. Giant cell tumors in the distal end of the radius. Treatment by resection and fi bular autograft interpositional arthroplasties. J Bone Joint Surg Am 1986;68:687-94.
10. Pho RW. Malignant giant cell tumour of distal end of the radius treated by a free vascularized fibular transplant.J Bone Joint Surg Am. 1981;63:877–84.
11. Ihara K, Doi K, Sakai K, Yamamoto M, Kanchiku T, Kawai S. Vascularized fibular graft after excision of giant cell tumour of the distal radius.a case report. J Surg Oncol. 1998;68:100–3.
12. Goni V, Gill SS, Dhillon MS, Nagi ON. Reconstruction of massive skeletal defects after tumour resection. Ind J Orthop. 1992;26:13–6.
13. Deb HK, Das NK. Resection and reconstructive surgery in giant cell tumour of bone. Ind J Orthop.1992;26:13–6.
14. Dhamni IK, Jain AK, Maheswari AV, Singh MP. Giant cell tumours of the lower end of radius:problems and solutions. Ind J Orthop. 2005;39:201–5.
15. Saraf SK, Goel SC. Complications of resection and reconstruction in giant cell tumour of distal end of radius- An analysis. Ind J Orthop. 2005;39:206–11..

How to Cite this article: Godghate N, Kadu VV, Saindane KA, Godghate NN. Non-Vascularised Ipsilateral Fibular strut – A Modality to Treat Giant cell tumor of lower end radius using Anterior Approach. Journal of  Bone and Soft Tissue Tumors May-Aug 2015; 1(1):45-47.

Dr. Ninad Godghate

Dr. Ninad Godghate


Dr. Vikram V. Kadu

Dr. Vikram V. Kadu


Dr. K. A. Saindane

Dr. K. A. Saindane


Dr. Neha N Godghate

Dr. Neha N Godghate


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Ewing Sarcoma: What’s in a name?

Vol 1 | Issue 1 | May – August 2015 | page:6-7 | Ashok K Shyam[1,2*]

Author: Ashok K Shyam[1,2*].

[1]Department of Orthopaedics, Sancheti Institute for Orthopaedics and Rehabilitation, Pune India.
[2]Indian Orthopaedic Research Group, Thane, India.

Address of Correspondence
Dr. Ashok K Shyam MS Orth.
Department of Orthopaedics, Sancheti Institute for Orthopaedicsand Rehabilitation, Pune India.


There appears to be some ambiguity surrounding interpretation of collaborating disciplines on how ‘Ewing sarcoma’ is named, written or spoken. And they mostly are pretty sure about their version (or probably unaware of any other version!). The article will focus on the issue of how Ewing sarcoma is quoted in literature and shed some light on origin of the term. This will also serve as an introduction to our symposium on Management of Ewing Sarcoma.
Keywords: Ewing Sarcoma, Name.


Ewing sarcoma was first described by Dr James Ewing in 1921 in his paper read at New York Pathological society proceedings [1]. In his paper he described a 14 year old girl with a bone tumor arising from radius shaft which was diagnosed to be osteosarcoma. Although osteosarcomas were known to be radioresistent, this particular patient underwent radiotherapy and to everyone’s surprise had a ‘miraculous’ response both clinically and radiographically. The tumor did recur but biopsy done this time revealed it to be distinct form osteosarcoma. Ewing described the cells as round using the loose term ’round cell sarcoma’. To him the cells appeared similar to cells of endothelium of the blood vessels of the bone and thus he described the tumor as ‘Endothelioma of the bone’. He further described 6 such similar patients. This tumor was named as ‘Ewing sarcoma’ few years later by Ernest Codman [Ewing sarcoma is the most common differential of Codman Triangle] [2]. Although Dr James Ewing has contributed a lot to medicine his contributions in estabilishing oncology as an independent science is noted by naming him as ‘The Cancer Man’ or ‘Mr Cancer’ by his colleagues and media. He is still best known to every student of medicine by the eponym of ‘Ewing Sarcoma’.

What’s in the Name?

Ewing sarcoma has been reported to be written as ‘Ewing sarcoma’, Ewing’s Sarcoma’, ‘Ewings’ Sarcoma’ or simply ‘Ewings sarcoma’. Which is the correct version? I came across this issue rather accidently on preparing and reviewing for this particular symposium. We have three articles in the symposium [3,4,5], one on radiotherapy, one on medical management and one on surgical aspect. There was difference in how these three manuscripts spelled Ewing sarcoma. The non surgical articles insisted the name to be ‘Ewing Sarcoma’ while the surgical article insisted on ‘Ewing’s Sarcoma’. So what is the correct nomenclature? On site I found this description “The tumor which bears his name is generally referred to as Ewing’s sarcoma when spoken and either Ewing’s sarcoma or Ewing sarcoma when written [6].” I reviewed the policies about the eponymus words and found an interesting fact about them. A cold war is been fought between US and Europe with US wishing to phase out use of eponyms and is against creating any new ones [7]. The argument is that the disease is not ‘Owned’ by a person. They called the eponymus use with an apostrophe as a possessive case of the word that indicates that the person either had the disease or owned the disease. By that example Ewing’s sarcoma indicates that Ewing had the sarcoma! They advocated a non possessive use of the eponyms like ‘Ewing sarcoma’. Following the rule the AMA Manual of Style: a guide to authors and editors recommends use of non-possessive case for writing eponyms. Even if we ask word nerds in true grammatical sense an apostrophe does indicate possessive nature of the noun to which it is attached. On the other hand the European literature holds the eponyms in high regards as historical testaments to physicians who first described the diseases and advice to write eponyms with an apostrophe as in Ewing’s sarcoma. To support this there remains arguments regarding using non possessive case in certain diseases like replacing ‘Down’s Syndrome’ with ‘Down syndrome’ which will then imply that there is an ‘Up Syndrome’! The controversy still rages and anyone interested should read these two articles published in British Medical Journal [8,9].
But what about our question about Ewing Sarcoma? Searching pubmed, I could find 1021 article with Ewing sarcoma , 2147 articles with Ewing’s Sarcoma , 17 article with Ewings sarcoma and 9 articles with Ewings’ sarcoma respectively in their titles (Fig 1 a-d). Thus most of them were divided into either possessive case or non-possessive case and possibly it depends on journal policy and geographical preference. Search of MESH (Medical Subject Heading) in pubmed identifies Ewing sarcoma as Mesh Major Subject Heading. I too would personally agree with non-possessive case [also as per AMA Style and Pubmed MESH term] in form of ‘Ewing Sarcoma’ although authors may choose other versions too. However when one of the version is used, authors should use the same version consistently throughout the manuscript. In this symposium we have used the non-possessive version in medical management and radiotherapy articles while a possessive version is used by the surgical focussed article. We hope the symposium is informative and any queries that remain in readers mind are welcomed as ‘Letter to Editor’ and will be answered by the respective authors.

Figure 1


1. Ewing J: Diffuse endothelioma of bone, Proc NY Pathol Soc 1921;21:17.
2. Timothy P. Cripe, “Ewing Sarcoma: An Eponym Window to History,” Sarcoma, vol. 2011, Article ID 457532
3. Valvi S & Kellie SJ. Ewing Sarcoma: Focus on Medical Management. Journal of Bone and Soft Tissue Tumors May-Aug 2015; 1(1):4-6
4. Irukulla MM, Joseph DM. Management of Ewing Sarcoma: Current Management and the Role of Radiation Therapy. Journal of Bone and Soft Tissue Tumors May-Aug 2015; 1(1):4-6
5. Panchwagh Y. Ewing Sarcoma: Focus on Surgical Management. Journal of Bone and Soft Tissue Tumors May-Aug 2015;1(1):4-6
7. Jana N, Barik S, Arora N. Current use of medical eponyms–a need for global uniformity in scientific publications. BMC Med Res Methodol. 2009 Mar 9;9:18.
8. Woywodt A, Matteson E. Should eponyms be abandoned? Yes. BMJ. 2007;335:424
9. Whitworth JA. Should eponyms be abandoned? No. BMJ. 2007;335:425.

How to Cite this article: Shyam AK. Ewing Sarcoma: What’s in a name? Journal of  Bone and Soft Tissue Tumors May-Aug 2015;1(1):6-7.

Dr.Ashok Shyam

Dr.Ashok Shyam

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Current role of FDG-PET in Bone and Soft tissue tumors

Vol 1 | Issue 1 | May – August 2015 | page:29-36 | Junaid Ansari[1], Reinhold Munker[1], Amol Takalkar[2,3*].

Author: Junaid Ansari[1], Reinhold Munker[1], Amol Takalkar[2,3*].

[1]Feist Weiller Cancer Center, Shreveport, Louisiana.
[2]Center for Molecular Imaging & Therapy, Biomedical Research Foundation of Northwest Louisiana.
[3]Dept. of Radiology, LSU Health, Shreveport, Louisiana.

Address of Correspondence
Dr. Amol Takalkar MD.
Dept. of Radiology, Louisiana State University Health Sciences Center – Shreveport, 1505 Kings Highway, Shreveport, LA 71103


FDG-PET/CT imaging is an established modality for the workup of several malignancies; it is now considered standard for the initial as well as a subsequent treatment strategy in the management of most malignancies. The focus of this article is to discuss the role of FDG-PET/CT imaging in the workup and management of malignant bone and soft tissue tumors in conjunction with standard imaging techniques like MRI and CT scanning. The article also briefly touches upon the potential role of emerging PET-MRI modality.
Keywords: FDG-PET, Musculoskeletal tumors, Bone tumors, CT, MRI, Ewing Tumors, Osteosarcoma, GIST.


Positron emission tomography (PET) is a non-invasive nuclear imaging technique which relies on the detection of positrons emitted during the decay of a radionuclide and maps the biodistribution of the administered radiopharmaceutical. Compounds of interest are labelled with a positron-emitting radiotracer and infused and distributed according to the in vivo biologic behavior of the tagged compound. 18F-fluorodeoxyglucose (FDG) is the most commonly used PET radiopharmaceutical for oncology. FDG is a glucose analog in which the hydroxyl group is replaced by positron-emitting fluorine isotope (18F) and FDG-PET or FDG-PET/CT (when PET is combined with computed tomography) provides a map of glucose metabolism in the body. In contrast to anatomical and morphological approaches, FDG-PET provides more metabolic and functional information about the disease and can be an important imaging tool to non-invasively understand cancer biology [1]. FDG is actively taken up by cancer cells and remains metabolically trapped intracellularly. Otto Warburg, a German physiologist in the 1920’s, had shown that most tumor cells generate energy by non-oxidative breakdown of glucose and are hypermetabolic compared to the normal cells (The Warburg Effect). FDG-PET exploits this effect as cancer cells take up more FDG than normal cells and are hence detected on imaging as regions of increased FDG uptake. The concept of FDG-PET was developed in the 1970’s when it was used for functional brain imaging and then in the 1980’s to assess the cardiac metabolism. However, over the past 15 to 20 years, oncologic indications have become the predominant use for FDG-PET imaging and along with technological advances, it has now evolved to integrated PET/CT systems that provide highly sophisticated information with implementation of further hybrid imaging technologies, like combined PET/MRI, on the horizon [2].
With notable exceptions (such as prostate cancer), FDG PET/CT is routinely used for the initial treatment strategy (formerly encompassing diagnosis and staging) as well as a subsequent treatment strategy (formerly encompassing restaging and assessing treatment response as well as disease status) for most cancers, such as: lymphomas, lung cancer, colorectal cancer, melanomas, head and neck cancer, breast cancer, and musculoskeletal tumors and other malignancies. PET has largely been replaced by PET/CT scanners (at least in the Western nations) and this article will largely focus on PET/CT imaging instead of stand-alone PET imaging. Since MRI plays an important role in the evaluation of bone lesions, this article will briefly discuss the potential for combined PET/MRI hybrid imaging in the setting of bone and musculoskeletal tumors.

Musculoskeletal tumors
Malignant musculoskeletal tumors, also known as sarcomas, are rare and account for about 1% of cancer deaths in the United States [3]. They are a heterogeneous group of mesenchymal malignancies arising from bone and soft tissues. Primary bone tumors are seen more commonly in adolescents and younger adults, while primary soft tissue sarcomas are seen more commonly in adolescents with a second peak in the fifth decade. However, these sarcomas can affect all age groups. The World Health Organization’s classification of soft tissue sarcomas is based on the tissue of origin which continues to evolve with the discovery of new molecular genetic abnormalities [4]. The majority of soft tissue sarcomas are sporadic and only a few are linked to environmental factors like exposure to radiation, burns, toxins, viruses like HHV-8 causing Kaposi sarcoma in HIV patients, immunodeficiency syndromes, and germline mutations in Li-Fraumeni syndrome, neurofibromatosis 1, and Gardner syndrome. The common examples of soft tissue sarcomas include liposarcoma, synovial sarcoma, leiomyosarcoma (LMS), rhabdomyosarcoma (RMS), fibrosarcoma, and angiosarcoma. The patients usually present with an asymptomatic mass. The primary diagnosis is made by a tissue biopsy and imaging studies like plain radiograph, CT and MRI. Lungs are the most common site of metastases, and hence a plain radiograph and CT scan of the chest is also advisable. Treatment is based on AJCC staging. Stage IA (T1a-1b,N0,M0,G1,GX) and Stage IB (T2a-2b,N0,M0,G1,GX), low grade patients are usually managed by surgery by obtaining adequate oncologic margins. Stage IIA (T1a-b,N0,M0,G2,G3) can be managed with surgery alone, or surgery followed by radiotherapy or preoperative radiotherapy followed by surgery. Stage IIB (T2a-b,N0,M0,G2,G3) and Stage III (T2a,T2b,N0.M0,G3 and any T,N1,M0, Any G) if resectable with acceptable functional outcomes are managed with surgery followed by radiotherapy and adjuvant chemotherapy, or preoperative chemo-radiotherapy followed by surgery followed by adjuvant chemo-radiotherapy. Unresectable and resectable with adverse functional outcomes Stage II and III are managed with radiotherapy, chemotherapy, chemo-radiotherapy, or palliative surgery, alone or in combination. Synchronous Stage IV with single organ involvement or limited tumor bulk that are amenable to local therapy are managed primarily like Stage II and III tumors. Disseminated metastases are managed with palliative options. Accurate staging is critical for determining the appropriate treatment.
Gastrointestinal stromal tumors (GISTs) are discrete forms of sarcomas and are the most common abdominal mesenchymal tumors. They can arise anywhere in the gastrointestinal tract with the stomach being the most common site. Due to identification of driver mutations in the c-KIT and platelet-derived growth factor alpha genes encoding tyrosine kinase receptors, the treatment of GIST has been a role model of targeted therapy with Imatinib mesilate, a tyrosine kinase inhibitor [5, 6]. Surgery is still the main stay of management in resectable non-metastatic lesions with Imatinib playing an adjuvant role [7]. GISTs have variable clinical behavior with some presenting with nonspecific symptoms and some detected incidentally.
Bone sarcomas occur less commonly than soft tissue sarcomas and will account for 0.18% of all new malignancies, with 2970 estimated new cases and 1490 estimated deaths in the US in 2015 [3]. They are classified by Musculoskeletal Tumor Society Staging System based on grade and compartment localization. Osteosarcoma accounts for almost half of the bone sarcomas and is seen mainly in children and adolescent males in the metaphysis of long bones, especially the femur, the proximal tibia and the proximal humerus. Most of the cases are sporadic in nature with few cases arising from inherited genetic diseases like hereditary retinoblastoma and Li-Fraumeni syndrome. The patients usually present with pain and swelling of the affected area. Osteosarcomas are usually detected on imaging studies. The diagnosis is made by tissue sampling and pathology and can be suggested by imaging studies. These are usually high grade tumors with aggressive biological features and are found in or adjacent to areas with high bone growth, with subdetectable tumor spread elsewhere in majority of the cases [8, 9]. They are managed by neoadjuvant chemotherapy, which shrinks the tumor and targets micrometastatic tumor cells, followed by limb sparing surgery and adjuvant chemotherapy [9]. The prognosis is based on the response to chemotherapy. Radiation therapy generally has a limited role in the management of these tumors and is used mainly for unresectable and relapsed lesions [10]. Chondrosarcomas account for almost 25% of all bone sarcomas and are seen mainly in adult and old patients with predilection for flat bones. They have variable clinical behavior with an indolent nature and low metastatic potential [11]. Surgical resection is the standard of treatment. Radiation therapy is given in unresectable lesions. Chemotherapy is the primary therapy for systemic recurrence[10]. Ewing sarcoma constitutes approximately 10-15% of all bone sarcomas and is mainly seen in the second decade of life involving the diaphyseal region of the long bones, mostly in the lower extremity. These sarcomas present with localized pain or swelling of short duration. Constitutional symptoms are seen in small percentage of patients on presentation. They belong to a family of tumors known as PNETs (Primitive neuroectodermal tumors) and are associated with t(11;22) translocation[12]. The disease is aggressive and the presence of widespread metastasis is a sign of poor prognosis. It is primarily treated by multiagent chemotherapy and based on the response, is subsequently managed with radiotherapy, surgery or chemotherapy [10].
Improved diagnostic imaging has changed the primary management of musculoskeletal tumors. MRI is still the primary imaging technique used in detecting lesions and local staging due to its pluridirectional capabilities and superior contrast resolution. MRI thus plays an essential role in surgical planning by providing detailed information about the local extent of the disease and involvement of locoregional structures. MRIs are not, however, able to determine the subtypes of soft tissue sarcomas or differentiate between benign and malignant lesions. The regional nature of MRI also precludes identification of lymph nodes outside of the imaginary plane. Imaging distant metastatic disease is also not practical with routine MRI imaging studies. CT scans are not very sensitive for osseous pathology. Although CT has excellent spatial resolution, it is suboptimal to MRI when it comes to contrast resolution and soft tissue differentiation. CT scans are mainly used to assess pulmonary metastases and for staging of disease in the lungs in such patients [13]. Although used for assessing response to treatment based on shrinkage of the primary lesion, this approach may not be the best in the era of molecular imaging. Both CT and MRI have limitations in assessing local recurrence with altered anatomy and presence of post-therapy changes.
FDG PET/CT is not the optimal modality to assess the T-stage of these lesions. Although it can provide metabolic and functional information related to tumor biology, it has lower spatial resolution compared to morphologic imaging modalities and does not provide the intimate details about the local extent and invasiveness of the tumor. However, the intensity of FDG uptake can aid diagnosis by providing better targets for biopsy and increase the yield from biopsies. FDG PET imaging can also overcome some of the limitations of MRI, by separating high- from low-grade tumors, in determining the biological activity of a tumor, and by allowing the detection of abnormal lymph nodes and occult distant metastases, including pulmonary metastases, especially by virtue of almost whole body imaging [13]. However few studies have demonstrated that PET is less sensitive than CT scanning in the detection of pulmonary metastases and a significant number of known pulmonary metastases greater than 1.0 cm on CT, are PET negative (micro-metastases) [14]. Evolution of hybrid PET/MR may be a more efficient diagnostic modality in the future. It can provide additional information regarding soft-tissue analysis, tumor detection, tissue characterization, functional imaging and biological landscape at the same time.

Specific role of PET in musculoskeletal tumors
MRI and CT scanning are still the most commonly used imaging techniques to evaluate bone and soft tissue tumors with known limitations as discussed above. FDG-PET/CT imaging is now routine for cancer workup and the addition of a CT component in integrated PET/CT scanners have made this quite a reliable tool that can provide additional information about the biological behavior of the tumor and can aid in the management of these tumors.
Most soft and bone tumors are FDG-avid and the degree of avidity is usually associated with their clinical outcomes. In soft tissue sarcomas, FDG-PET is able to detect intermediate and high-grade lesions due to their high FDG uptake, but is not able to differentiate between benign and low-grade sarcomas since both of them tend to show low FDG uptake. Dual phase/delayed PET imaging can help in differentiating benign from malignant lesions in some cases as malignant lesions show increasing uptake on delayed images [15]. In bone tumors, low FDG uptake is usually seen in a benign lesion, with high FDG uptake in a malignant lesion. However, the highest FDG uptake is seen in metastases [16]. There are few exceptions to this rule; malignant tumors like plasmacytoma and low-grade chondrosarcoma can have low uptake, and benign tumors with either involvement of giant cells (giant cell tumor of bone) or histiocytic cells (Langerhans cells histiocytosis) can have high uptake. Using a TBR (tumor-to-background ratio) of 3.0 as a positive for malignant bone lesions, FDG PET has a specificity of 67% and a sensitivity of 93% in bone tumors [17]. The latest imaging guidelines set by Children’s Oncology Group Bone Tumor Committee highly recommend FDG-PET as a part of functional imaging in osteosarcoma and Ewing sarcomas at presentation and prior to surgery/local control. It also maintains use of FDG-PET for surveillance during and post chemotherapy [18].

Initial Treatment Strategy
Diagnosis of musculoskeletal tumors is usually established on the basis of directed biopsies after the detection of a mass on clinical exam and/or imaging. As discussed above, they are staged per the AJCC system using the TNM staging criteria. Along with clinical evaluation, contrast enhanced CT and MRI are extremely useful for optimal assessment of the “T” stage as they provide further structural information regarding tumor extension and involvement of adjacent structures. FDG-PET imaging lacks the spatial resolution to provide such exquisite structural details necessary for adequate “T” staging. However, FDG-PET can still play a role in the diagnosis of these tumors. Many of these lesions can be heterogenous and initial biopsy can be “non-diagnostic”. (Figure 1 demonstrates the value of FDG-PET in a patient with a negative/non-contributory biopsy). Since FDG PET relies on the biologic characteristics of the tumor and provides metabolic and functional information, it can be suited in such difficult cases to direct biopsies to the appropriate target site and improve the yield from biopsies. In addition, it can play an important role in the detection of locoregional metastatic lymphadenopathy and distant metastatic disease. Traditional anatomical evaluation of nodal involvement in the malignancies is sub-optimal since nodes may be enlarged as a result of infection/inflammation (that is not uncommon in the groin region), and normal sized nodes can frequently be involved with metastatic disease leading to inaccurate upstaging or downstaging of the disease with conventional imaging methods. FDG-PET (and especially PET/CT) imaging can have a tremendous impact in improving the nodal staging of sarcomas cancers compared to CT/MR (sensitivity: 87-90% versus 61-90% and specificity: 80-93% versus 21-100%) [19]. FDG-PET imaging frequently detects metastatic disease in normal-sized lymph nodes. However, caution is recommended in N0 disease per PET as micrometastases cannot be detected by FDG-PET imaging and hence the management of such patients should not solely be determined by FDG-PET findings; other techniques like surgical lymph node dissection should be employed for optimal “N” staging in such patients. Also, sometimes malignant lymph nodes with large extensive central necrosis can be falsely negative on FDG-PET with only mild FDG uptake at the periphery or no uptake at all. However, the most important added value of FDG-PET imaging is the detection of unsuspected distant metastases that can lead to dramatic changes in patient management. By virtue of its near whole body imaging and reliance on metabolic information, it has the potential to detect unsuspected occult metastases and change the management significantly. Moreover, FDG PET imaging is useful in therapy planning for patients undergoing radiation therapy with a curative or palliative intent or as neoadjuvant therapy. The increasing implementation of intensity modulated radiation therapy (IMRT) is well complemented by the additional functional/metabolic information provided by the FDG imaging, as it allows delivery of maximal radiation dose to the most metabolically active areas of the tumor and more complete inclusion of loco-regional disease with sparing of the uninvolved areas.

Figure 1      Fig 2

Subsequent Treatment Strategy
In addition to the above, FDG-PET imaging probably has an important benefit in assessing response to therapy and restaging of musculoskeletal tumors [20-23]. Following surgery or radiation therapy, it is extremely difficult to assess the treated area with conventional imaging modalities like CT/MRI due to inflammatory changes with fibrosis, edema and alteration of normal structures. Determining whether residual neoplasm is present in the postsurgical/postradiated tumor bed is one of the most daunting tasks facing radiologists. When compared to conventional radiological examination, FDG-PET has a better diagnostic accuracy in the assessment of residual or recurrent malignant disease in the post-therapeutic region, including avoidance of unnecessary planned surgery in patients with negative PET. Lack of any significant FDG uptake in the treated area generally indicates no active residual/recurrent disease. There may be some mild to modest irregular FDG uptake related to post-therapy changes, but generally there should be no gross intense focal abnormalities. Dual-phase PET imaging/delayed PET imaging may help in distinguishing post-therapeutic inflammatory changes from cancerous tissue. It may also help in the prediction of PFS (Progression free survival) and OS (overall survival). Focal intense FDG uptake within the area of post-surgical change is worrisome and needs further workup. A negative tissue biopsy after a strongly positive post-treatment PET scan can be caused by sampling error and warrants a closer follow-up rather than routine surveillance. Decrease in the intensity of uptake on the follow-up scan confirms a false positive post-treatment PET scan, usually due to inflammatory changes. However, persistence of a focally intense lesion or increase in the intensity of uptake warrants invasive evaluation. The timing of the post-treatment PET scan is very crucial, especially after radiation therapy. Although there are no specific recommendations in this regards, generally a 3-month interval after completing radiation therapy is felt to be adequate to assess response to therapy. The superior assessment of response to therapy with FDG-PET imaging may facilitate a more conservative approach in management, as patients undergoing combined chemo-radiation therapy with a complete response on the post-treatment FDG-PET scan can be followed with a more watchful approach.
There are several limitations of FDG-PET imaging in the evaluation of musculoskeletal tumors. Although it may detect tumors that may be missed by anatomic imaging (especially in-transit metastases as in Figure 2), the sub-optimal spatial resolution of PET imaging (compared to CT/MRI) limits the evaluation of local extent and invasiveness of the tumor. Also, low-grade tumors may be missed on PET if there is significant intense physiologic FDG uptake in an adjacent structure (like muscle). Conditions like joint inflammation, muscle contraction, radiation induced inflammation and osteoradionecrosis need to be kept in mind when interpreting FDG-PET studies in musculoskeletal pathology. The added information from CT images in a dedicated PET/CT scan can further help to discern this uptake as benign/physiologic.

After the advent of neo-adjuvant chemotherapy in osteosarcoma, which has dramatically improved the prognosis, there has been a need for better imaging modality for tumor staging and grading, pre- and post-treatment evaluation, and detection of tumor recurrence (Figure 3 demonstrates FDG uptake may be quite heterogeneous and intense in osteosarcoma).

Figure 3      Figure 4     Figure 5

Initial Treatment Strategy
FDG-PET/CT imaging has a limited role in the initial workup of osteosarcoma. It is limited in its ability to diagnose osteosarcoma (which definitely requires tissue sampling) and is suboptimal to CT/MRI in delineating the local extent and invasiveness. The correlation between the histological grading and the FDG avidity has been well documented by several studies [24]. However, FDG-PET/CT imaging cannot obviate the need for the tumor biopsy to differentiate between a benign and a malignant lesion and establish the underlying pathology. The highest SUV values are seen in bone metastases. MRI and plain radiographs are still the first line diagnostic tools in staging the disease. In children, there may be an indication of FDG-PET in cases of unequivocal MRI findings due to physiological red blood marrow distribution to detect interosseous skip metastases. Lymph node metastasis is a rare phenomenon in osteosarcoma and hence the need of PET is limited. About 80% of metastases in osteosarcoma involve the lungs and early detection is important. The method of choice for detecting lung metastases is spiral high-resolution CT as PET can miss smaller lung lesions [25] However, whole body imaging in PET has an advantage of finding other sites of occult metastases, which cannot be seen with CT or MRI due to limited field of scanning and so should be employed in situations where clinical suspicion for metastatic disease is high. Infrequently, it may be used to guide biopsies if clinically necessary.
SUVmax and TLG (Total lesion glycolysis) are both strong prognostic factors that can predict progression-free survival, overall survival, and tumor necrosis in osteosarcoma [26].

Subsequent Treatment Strategy
FDG-PET plays a more established role in assessing therapy response and detecting recurrence. It has also been able to predict the tumor response as it relies on functional and metabolic parameters rather than structural changes. Tumor metabolic changes detected by FDG-PET precede morphological changes on anatomic imaging and early evaluation of tumor response allows treatment to be tailored to the individual. In two different studies, FDG-PET was found to be superior to MRI in the assessment of response [20, 21]. There is a direct correlation between SUV and histological grade. SUVmax reduction after therapy is the biggest indicator of whether the patient is responding to therapy or not, and based on this, the therapy can be modulated accordingly. SUVmax > 5 after neoadjuvant therapy is arbitrarily defined as a histological nonresponder and ≤ 2 as a responder [20-22, 27]. Byun et al suggested that the combination of FDG-PET/CT and MRI may be the best way to determine histological response of osteosarcoma after neoadjuvant chemotherapy [23]. The availability of combined PET/MRI imaging in the future may facilitate this.
FDG-PET has also a significant role in the assessment of tumor recurrence and restaging of high risk osteosarcoma patients. (28) It is also more accurate than other imaging studies in differentiating post-therapeutic fibrosis or inflammatory changes from local recurrence [25].

These sarcomas have less FDG uptake than other sarcomas owing to their high level of acellular gelatinous matrix and lower mitotic rates. Average FDG uptake of chondrosarcoma is as high as Ewing sarcoma but lower than osteosarcoma [29]. The role of PET in the diagnosis and management of chondrosarcoma is almost the same as with other malignant bone lesions. The biological activity helps to assess the tumor grade and to differentiate between benign and malignant tissue, and the whole body imaging helps to identify any occult metastases. Grade II and III chondrosarcomas have higher glucose metabolism and can be easily distinguished from a benign tumor; Grade I chondrosarcomas/atypical cartilaginous tumors cannot be so easily distinguished because of apparently similar metabolism rates [30]. (Figure 4 demonstrates the heterogeneous nature of FDG uptake in chondrosarcoma; intense FDG uptake site can help in guiding the biopsy in such patients)

Ewing sarcomas
Ewing sarcomas are high-grade malignancies and high SUVs are usually seen. PET is very sensitive in the detection of primary and recurrent lesions. PET is also superior to bone scan in detecting bone metastases and is used as a part of metastatic workup. PET has low sensitivity for smaller lesions, especially in lungs which are a common site of metastases for Ewing sarcomas and a CT scan is a superior imaging modality in such cases. PET can also be used for monitoring the tumor response to chemotherapy and radiotherapy and the possibility of a recurrence post-operatively. PET has a limitation in differentiating malignant from inflammatory lesions and cannot be used as a non-invasive diagnostic tool between Ewing sarcoma and osteomyelitis, which are frequently indistinguishable [31].

Fibrosarcomas arising from polyostotic fibrous dysplasia have intense FDG uptake indicating sarcomatous transformation. Fibrous dysplasia sarcomas are well known to have intense FDG uptake despite their benign nature [32]. Fibrous synovial sarcomas originate from the mesenchymal tissue and their histological appearance resembles the synovium. FDG-PET can also be used for the staging of these malignant tumors. (Figure 5 demonstrates intensely FDG avid soft tissue mass)

  Figure 6

Gastrointestinal stromal tumors
Metabolic imaging with FDG-PET in GIST has proven to be an effective tool to evaluate the treatment response with tyrosine kinase inhibitors like imatinib. The functional imaging with FDG-PET provides earlier evidence of response in comparison to morphological changes seen with a CT scan. Jager et al observed that changes in tumor metabolism were seen as early as 1 week after the start of the treatment, which helped in delineating responders from non-responders in 14/15 cases [33]. Studies done by Stroobants et al and Goerres et al showed that PET responders had a better progression free survival and better prognosis than PET non-responders with residual FDG activity.(34, 35) However a recent study done by Chacon et al showed the early metabolic response (EMR) does not correlate with the progression-free survival or overall survival in patients with metastatic GIST. (36) GIST-specific molecular tracers are also in the making which can provide more accurate prognosis and development of treatment resistance. (37) FDG negativity however does not preclude the diagnosis of a GIST [38] (Figure 6 demonstrates the value of FDG-PET as a prognostic tool in the management of GIST)

Benign Tumors
FDG-PET has a limited role in the management of benign musculoskeletal tumors. Benign soft tissue lesions usually do not have substantial FDG uptake. Fibrous dysplasia can have variable FDG uptake, and in some cases intense FDG activity. In such situations, it is important to differentiate benign tumors from any possibility of a sarcomatous changes [39]. Hemangiomas can also be a site of intense FDG activity which can sometimes mimic metastasis. Lipomas have the lowest uptake. Careful history, physical examinations and other imaging tests like CT and MRI should help in the accurate diagnosis.


The evolution of PET in the recent years has changed the previous paradigm in the management of malignancies. In general, it is not the primary diagnostic modality for workup of musculoskeletal tumors but can play a role in certain clinical scenarios. Along with other imaging techniques, FDG PET/CT plays an important role in musculoskeletal tumors by guiding biopsies in heterogeneous tumors, predicting tumor response to preoperative neo-adjuvant chemotherapy, detecting skip metastases and reflecting risk of recurrence and prognosis. It also plays a more robust role in subsequent treatment strategy. Overall, it is more useful in evaluating primary soft tissue tumors relative to primary osseous lesions. However, the potential availability of integrated PET/MRI may allow for a more robust role for FDG-PET imaging in the workup of primary osseous tumors as well. FDG-avidity correlates negatively with survival and positively with disease progression. It can be used to tailor treatment, surgical versus chemo-radiotherapy. More prospective trials are needed to develop new tracers that can be more specific and lead to higher signal to noise ratio (SNR), which may help in establishing the response to treatment with newer agents and can set guidelines. Suboptimal T-stage and heterogeneous uptake in some cases, insufficient topography, radiation exposure and higher costs are a few of the limitations of using FDG-PET. In the current times, its role is still considered as an adjunct and has not replaced MRI and CT scanning. The combined PET-MRI multimodality imaging systems can provide adequate information about the morphology as well as the metabolic status of the lesion in a single imaging session and may potentially become the standard of imaging for musculoskeletal tumors in the near future. Precision medicine (prevention and treatment strategies that take individual variability into account) is the way to the future. Adopting global disease assessment, radiotherapy fractionation, imaging hypoxia, adaptive radiotherapy as part of quantifiable methodologies and standardization of FDG-PET, it can become a powerful tool for the diagnosis, individual treatment planning and subsequent treatment strategy. The absolute potential of FDG-PET in various malignancies including musculoskeletal tumors is still a work in progress and is evolving at a rapid pace with the recent development of radiopharmaceuticals and technological advancements..


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How to Cite this article: Ansari J, Munker R, Takalkar A. Current role of FDG-PET in Bone and Soft tissue tumors. Journal of  Bone and Soft Tissue Tumors May-Aug 2015; 1(1):29-36.

Dr. Junaid Ansari
Dr. Junaid Ansari
Dr. Reinhold Munker
Dr. Reinhold Munker
Dr. Amol Takalkar
Dr. Amol Takalkar

(Abstract)      (Full Text HTML)      (Download PDF)

Re implantation of Sterilised tumour bone by Extra Corporeal Radiotherapy

Vol 1 | Issue 1 | May – August 2015 | page:37-39 | Subin Sugath[1*].

Author: Subin Sugath[1*].

[1]Department of Aster Orthopaedics, Aster DM Healthcare Pvt Ltd., Kochi 682 027, Kerala, India.

Address of Correspondence
Dr. Subin Sugath MS Orth.
Department of Ortho Oncology. Aster DM Healthcare Pvt Ltd. Kuttisahib Road, Near Kothad Bridge, South Chittoor PO, Cheranallor, Kochi 682 027, Kerala, India.


With the use of potent chemotherapeutic drugs, newer imaging modalities and improved surgical techniques limb preserving surgeries for malignant bone tumours have become the norm. Endoprosthesis still remains the commonest method of reconstruction after tumour resection. But when one is able to an oncologically safe intercalary resection for malignant bone tumours one method of reconstruction is reimplanting the resected tumour bone after sterilisation. Radiation given outside the body to sterilise the tumour bone is called Extra Corporeal Radiotherapy (ECRT). After resection the bone is cleaned of all its soft tissue and marrow contents and sent in a plastic container to the Radiotherapy department where it is subjected to 50 Gy of radiation which kills all cells including the tumour cells. The bone is brought back to the theatre and reimplanted after augmenting it with either bone cement or fibular grafts and stabilised by appropriate fixation devices. The advantage of reimplanting the same bone is that you get an exact match to the resected bone which is tumour free. Post operatively the joint is mobilised immediately and weight bearing started as appropriate to the fixation used. The diaphyseal end takes more time to unite than the metaphyseal end. In our series of 16 patients who had undergone ECRT and reimplantation for malignant bone tumours of the extremity and had completed two year follow up, the metaphyseal end took an average of 6.2 months (4 – 12 months) for union while the diaphyseal end united in 10.6 months (5 – 15 months). If the tumour has caused extensive destruction of the bone or has a pathological fracture, it may be mechanically not sound to reimplant it after ECRT. ECRT is an oncologically safe and mechanically stable procedure in biologically reconstructing bony defects after tumour resection.
Keywords: Extra Corporeal Radiotherapy, Bone tumour, intercalary resection.


With the use of potent chemotherapeutic drugs, newer imaging modalities and improved surgical techniques limb preserving surgeries for malignant bone tumours have become the norm. Endoprosthetic replacement is the most commonest method used to bridge the bone defect after tumour resection [1]. Such resection commonly involve resection of the growth physis across the joint leading to limb length disparity as the child grows. To overcome this, one will have to use a growing prosthesis which can be lengthened post operatively either by invasive or non invasive techniques to compensate for the growth of the normal limb [2] These implants are expensive and are not affordable to majority of patients who undergo limb salvage surgery in our country
At times, especially in young children where the open physis can be taken as a wide margin the tumour can be resected with wide margins sparing the joint ant the physis. The bone defects after these resection can be bridged by intercalary implants or size matched allografts if one has access to good tissue bank. Biological method of reconstruction has the advantage that once it incorporates with the host bone it is a life long procedure and is not associated with the complications of using a prosthesis [3,4]. Alternative technique of biological reconstruction if one does not have access to a tissue bank would be to use a vacularised or non vascularised autograft like fibula. But at times it would be impossible to harvest enough autografts to bridge large bony defects [5]. Sterilising and reimplanting the resected tumour bone is a viable option in these situations.
The advantage of reimplanting the same bone is that you get an exact match to the resected bone which is tumour free. The different methods used to sterilise tumour bone are autoclaving, pasteurisation, liquid nitrogen and radiotherapy [6]. Autoclaving involves sterilising the bone at 1210 C for 20 minutes which kills all tumour cells. But it has got the disadvantage that it reduces the bone strength as well as destroys the Bone Morphogenic Protein (BMP) [7]. Sterilising the specimen in a water bath at 650 C for 30 minutes is called pasteurisation. It has the advantage it retains the bone strength and BMP but has the practical difficulty of maintain the sterility during the procedure [6,8]. The most common method of sterilisation technique used is radiotherapy. 50 Gy of single shot high dose radiotherapy is used to sterilise the tumor bone. The procedure of giving radiotherapy outside the human body is called Extra Corporeal Radiotherapy (ECRT). The dose of radiotherapy given is so high that it destroys all cells including the tumour cells which necessitates this dose to be given outside the human body. The mechanical strength of the bone is least affected by this procedure and there are enough publications in literature which show this to be an oncological safe procedure in sterilising tumour bone. 50 Gy of radiotherapy is sufficient in attain tumour kill [9,10,11] and any higher dose of radiation decreases the mechanical strength and revascularisation and delays graft union and incorporation. The resection is made as per the pre operative imagings (Fig 1a). Marrow curettings from both the proximal and distal cut ends are send for frozen study to ensure adequacy of tumour clearance. Intercalary resected specimen with soft tissue cover over the tumour. Now the bone is completely stripped of all its soft tissue, periosteum and medullary contents (Fig 1b). The soft tissue removed is oriented with suture tags so that adequacy of tumour clearance can be assessed by histopathological examination. The bone is thoroughly washed with Vacomycin saline using a pulse lavage (Fig 1c).

Figure 1The vancomycin which gets absorbed by the graft is eluded over a period of time when it is reimplanted. The cleaned specimen is put in a plastic container and sent for radiotherapy (Fig 2a).

Care is taken to eliminate free space in the container with saline and cotton pads to eliminate air as air causes dispersion of radiation. Specimen is taken to the radiotherapy department and as described earlier 50 Gy of single shot radiotherapy is given to the specimen after planning CT scan (Fig 2b,2c). This procedure takes between 30 – 90 minutes depending on the radiation machine used. The specimen is then brought back to the theatre and cleaned and washed with Vancomycin saline (Fig 2d).

Figure 2
The medullary canal of the sterilised bone can either be filled with bone cement or fibular graft to add on to the osteoconductive property (Fig 3a). The graft is re-implanted and stabilised by appropriate plate and screw fixation (Fig 3b). Care must be taken to put only minimal screws in the re-implanted graft during fixation. In case of tibial lesions an additional medial gastrocnemius flap may be needed for covering the sub cutaneous implants (Fig 3c). Post operatively the joint is mobilised immediately and weight bearing started as appropriate to the the fixation used. Patients are followed up at the routine frequency practised for malignant bone tumours. Radiological, oncological and functional assessment are done at each visit. The diaphyseal end takes more time to unite than the metaphyseal end. In our series of 16 patients who had undergone ECRT and reimplantation for malignant bone tumours of the extremity and had completed two year follow up, the metaphyseal end took an average of 6.2 months (4 – 12 months) for union while the diaphyseal end united in 10.6 months ( 5 – 15 months) (Fig 3c, 3d).

Figure 3

There were two cases of non union at the diaphyseal end for which subsequent bone grafting was required to attain union.
ECRT can also be used in reconstruction of bony defects after Internal Hemipelvectomy for malignant tumours of the pelvis. Here like in the long bones the tumour can be resected with margins as per the pre chemotherapy imagings and reimplanted after ECRT and fixed with appropriate plate and screw fixation (Fig 4a-d).

Figure 4

ECRT and reimplantation is an inexpensive method of reconstruction which can be carried out even in hospitals without radiation facility. The specimen after resection can be transported to the nearby centre having radiation facility where ECRT can be done and brought back and reimplanted. This method eliminates the need to have a tissue bank in hospital for doing biological reconstruction and also is not associated with the complications of using massive allografts. This technique also has the advantage that it provides an exact size matched graft for reconstruction.
If the tumour has caused extensive destruction of the bone or has a pathological fracture, it may be mechanically not sound to reimplant it after ECRT and alternative methods of reconstruction like intercalary implants or allografts would be ideal. Graft fracture is one complication that can occur in this procedure. This can be reduced by using appropriate fixation devices which bridge the whole length of the graft and also augmenting the graft with bone cement or fibular graft.
ECRT is an oncologically safe and mechanically stable procedure in biologically reconstructing bony defects after tumour resection. But the success of the procedure depends on appropriate patient selection, meticulous preoperative planning, implementing these plans intra operatively and the infrastructure backup to support it.


1. Gosheger, G.; Gebert, C.; Ahrens, H.; Streitbuerger, A.; Winkelmann, W.; Hardes, J. Endoprosthetic reconstruction in 250 patients with sarcoma. Clin. Orthop. Relat. Res. 2006, 450, 164–171.
2. Kotz, R.I.; Windhager, R.; Dominkus, M.; Robioneck, B.; Muller-Daniels, H. A self-extending paediatric leg implant. Nature 2000, 406, 143–144.
3. Tsuchiya H, Tomita K, Minematsu K, et al. Limb salvage using distraction osteogenesis: a classification of the technique: J Bone Joint Surg [Br] 1997;79-B:403–11.
4. Plotz W, Rechl H, Burgkart R, et al. Limb salvage with tumor endoprostheses for malignant tumors of the knee: Clin Orthop 2002;405:207–15.
5. Ceruso M, Falcone C, Innocenti M, Delcroix L et al. Reconstruction with a free vascularized fibula graft associated to bone allograft after resection of malignant bone tumor of limbs. Handchir. Mikrochir. Plast. Chir. 2001, 33, 277–282.
6. Singh VA, Nagalingam J, Saad M, Pailoor J: Which is the best method of sterilization of tumour bone for reimplantation? A biomechanical and histopathological study : Biomed Engineering OnLine 2010, 9:48.
7.Kok Long Pan, Wai Hoong Chan, Gek Bee Ong, Shanmugam Premsenthil et al. Limb salvage in osteosarcoma using autoclaved tumor-bearing bone: Pan et al. World Journal of Surgical Oncology 2012,10:105
8.Jyoti Kode, Prasad Taur, Ashish Gulia, Nirmala Jambhekar, Manish Agarwal, and Ajay Puri. Pasteurization of bone for tumour eradication prior to reimplantation – An in vitro & pre-clinical efficacy study; Indian J Med Res. 2014 Apr; 139(4): 585–597.
9.Mondelaers W, Van Laere K, Uyttendaele D. Treatment of primary tumours ofbone and cartilage by extracorporeal irradiation with a low energy high power electron linac; Nuclear Instruments Methods in Physics Res 1993;70-B:898-900.
10.Hong A, Stevens G, Stalley P, et al. Extracorporeal irradiation for malignant bone tumours. Int J Radiat Oncol Biol Phys 2001;50:441-7
11.Sharma D N, Rastogi S, Bakhshi S, Rath G K, Julka P K, Laviraj M A, Khan S A, Kumar A. Role of extracorporeal irradiation in malignant bone tumors. Indian J Cancer 2013;50:306-9.

How to Cite this article: Sugath S. Re implantation of Sterilised tumour bone by Extra Corporeal Radiotherapy. Journal of  Bone and Soft Tissue Tumors May-Aug 2015; 1(1):37-39.

Dr.Subin Sugath

Dr.Subin Sugath

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Management of Ewing Sarcoma: Current Management and the Role of Radiation Therapy

Vol 1 | Issue 1 | May – August 2015 | page:18-22 | Monica Malik Irukulla[1,*], Deepa M Joseph[1].

Author: Monica Malik Irukulla[1,*], Deepa M Joseph[1].

[1]Department of Radiation Oncology, Nizam’s Institute of Medical Sciences, Hyderabad. India

Address of Correspondence
Dr. Monica Malik Irukulla, MD.
Department of Radiation Oncology, Nizam’s Institute of Medical Sciences, Hyderabad. India.


The management of Ewing sarcoma has evolved over the last few decades with successive improvement in survival rates. Multidisciplinary management is the key to successful outcomes. Dose intensity of chemotherapy is of vital importance. Local control can be effectively achieved with surgery, radiation therapy or a combination of the two. The choice of appropriate local therapy should be individualized and depends on various factors such as site, size, resectability, expected morbidity, long term effects etc. Metastatic disease remains a significant challenge and optimal therapeutic strategies still need to be defined. Current management and the role of radiation therapy in Ewing sarcoma are reviewed.
Keywords: Ewing sarcoma, radiation therapy, management.


Ewing sarcoma family of tumors (ESFT) are a group of small round cell tumors showing varying degrees of neuroectodermal differentiation with Ewing sarcoma being the least differentiated. Primitive neuroectodermal tumors (PNET) show neuroectodermal differentiation by light microscopy, immune histochemistry (IHC) or electron microscopy [1]. According to WHO classification of bone and soft tissue tumors, Ewings sarcoma/PNET is synonymous with Ewing tumor, peripheral neuroepithelioma, peripheral neuroblastoma and Askin tumor [1]. In most of the patients, a chromosomal translocation leads to the expression of the EWS-FLI1 chimeric transcription factor which is the major oncogene in this pathology [2].

Ewing sarcoma is the second most common primary bone tumor of childhood and it most commonly occurs in the second decade of life with a slight male preponderance. The incidence of Ewing sarcoma has been reported to be low in Asian population as compared to Caucasians[3]. Data from Indian population show that it is not so uncommon[4]. The common sites of primary Ewing sarcoma are the long bones of the lower extremities (41%), pelvic bones (26%), and bones of the chest wall (16%)[5]. Extraosseous Ewing sarcoma is more commonly axial in location involving the trunk (32%), extremities (26%), head and neck (18%), the retroperitoneum (16%) etc[6]. Approximately 20-25% of patients present with metastasis at diagnosis. Common sites of metastases include lungs, bones and bone marrow.

Diagnostic Evaluation
Typical presenting symptoms include pain and swelling with occasional constitutional symptoms like fever, fatigue and loss of weight. Patients should be evaluated and managed by a multidisciplinary team of experts including pediatric oncologists, orthopedic surgeons, radiologists, pathologists and rehabilitation specialists. A biopsy should be performed in a way such that the track and scar can be included in the subsequent resection or radiation portal. Biopsy should be from soft tissue as often as possible to avoid increasing the risk of fracture and should be through rather than between muscle compartments avoiding the neurovascular bundles. A skilled pathologist should be available onsite to confirm adequacy of the material and review the frozen sections. A needle biopsy may be adequate if sufficient tissue can be obtained for histological, cytogenetic and molecular studies. The risk of diagnostic errors and complications increases by as much as 12-fold when the biopsy is improperly done [7]. Ewing sarcoma/PNETs usually strongly express the cell surface glycoprotein MIC2 (CD99) and this can be helpful in diagnosis of small blue round cell tumors. CD99 is however not exclusively specific for ES/PNET and is found in other tumors such as synovial sarcoma, NHL, GIST etc [8]. Approximately 85% patients have expression of EWS-FLI1 chimeric transcription factor resulting from translocation between EWS and FLI-1 gene t(11;22)(q24;q12) [9]. In most of the remaining patients, alternative translocations between EWS and another ETS- family member (ERG, FEV, ETV1, E1AF) are detected [2]. Molecular analysis for EWS-FLI 1 should be considered. The prognostic value of the same remains inconclusive until now[10]. This is being evaluated as potential therapeutic target [11]. Local imaging with MRI with or without CT scan is recommended. Conventional staging evaluation includes bilateral bone marrow aspiration and biopsy or MRI of spine and pelvis, bone scan and CT scan of the chest. Serum LDH is an important prognostic marker. Positron emission tomography (PET) combined with conventional imaging is a valuable tool in staging and restaging ESFT with a sensitivity of 96% and specificity of 92% [12]. FDG-PET can also serve as a non-invasive method to predict response to chemotherapy which is a useful prognostic marker.13 Whole-body MRI can be a useful radiation-free modality to detect metastatic lesions with a higher sensitivity than bone scintigraphy [14,15]. Fertility consultation should be done for patients desiring future child bearing before starting therapy.

Prognostic factors
5-year event free survival approaches around 70% with standard multimodality approach in localized disease [16]. Favorable prognostic factors include extremity tumors, tumor volume <100ml, normal LDH and absence of metastases at presentation. Common adverse prognostic factors include metastatic disease at presentation, extra skeletal presentation, pelvis as the primary site and poor response to induction chemotherapy. Metastatic disease is the most significant adverse prognostic factor. Those with isolated pulmonary metastasis have a slightly better outcome than those with bone or bone marrow metastasis [17]. Survival depends on the site and number of metastases and the tumor burden with 5 year survival rates ranging from approximately 30% with isolated lung metastasis to less than 20% with multiple bone metastases. Older patients do worse than patients younger than 15 years.18 Poor histologic response to chemotherapy is associated with worse outcomes in patients with localized disease [19].

Treatment of Ewing sarcoma has evolved following evidence from large multinational trials over the past few decades with successive improvement in outcomes. Multimodality approach is the key in the management of nonmetastatic Ewing sarcoma.

The prognosis in Ewing sarcoma remained very poor until 1960s in spite of good initial response to local treatment. The introduction of chemotherapy into the treatment regimen dramatically improved the response rates and thus the cure rates. Patients are started on induction chemotherapy for 3-4 cycles followed by local therapy at 12weeks. Restaging should be done with a chest imaging and MRI of the local part before local therapy. Further adjuvant chemotherapy is continued for total treatment duration of about 10-12 months. Chemotherapy with Vincristine, Adriamycin/Actinomycin D, cyclophosphamide, (VAC) alternating with Ifosfamide and Etoposide (IE) administered at a three weekly fashion is the standard regimen. Maintaining adequate dose intensity of chemotherapy is of utmost importance. Interval compressed or dose dense chemotherapy improves DFS and has the potential to improve overall survival [20].

Local therapy
Local therapy is delivered at the completion of 3-4 cycles of chemotherapy at 12 weeks and comprises of surgery or radiotherapy or both. There are no randomized trials comparing the two modalities. The choice of local therapy depends on the site of the disease, age of the patient, expected functional outcomes and concern over the late morbidities. Although retrospective institutional series suggest superior local control and survival with surgery rather than radiation therapy, most of these studies are compromised by selection bias. A North American intergroup trial showed no difference in local control or survival based on local treatment modality – surgery, radiation therapy, or both [21]. In patients with localized Ewing sarcoma treated in cooperative intergroup studies there was no significant effect of local control modality (surgery, RT, or surgery plus RT) on OS or EFS rates. In the CESS 86 trial, although radical surgery and resection plus RT resulted in better local control rates (100% and 95%, respectively) than definitive RT (86%), there was no improvement in relapse free survival and overall survival [22]. Preoperative radiation therapy can achieve tumor shrinkage and surgical resection with negative margins in cases with borderline resectability and can potentially allow smaller fields and lower radiation doses [23].

Definitive Radiotherapy
Ewing sarcoma was described by James Ewing in 1921 as “diffuse endothelioma of bone”, a distinct entity from osteosarcoma due to its high response to radiation therapy. In the current scenario, definitive radiotherapy remains an effective local therapy strategy for patients with tumors in sites not amenable for surgical resection and in cases where resection is likely to result in unacceptable morbidity. Advances in imaging, tumor delineation, treatment planning and delivery is now allowing greater precision and sparing of normal tissues. Historically, patients were treated with whole bone irradiation. With the POG 8346 trial, adequate involved field RT with MRI based planning became the standard. Current guidelines recommend 1.5 to 2 cm margin from the gross tumor volume. A randomized study of 40 patients with Ewing sarcoma using 55.8 Gy to the prechemotherapy tumor extent with a 2 cm margin compared with the same total-tumor dose after 39.6 Gy to the entire bone showed no difference in local control or EFS [24]. Initial treatment volume include the pre-chemotherapy volume with margin up to a dose of 45Gy, further boost is delivered to the post chemotherapy volume upto a total dose of 55.8Gy to 60Gy. Tumor size and RT dose have been shown to be predictive of local control rates in patients with non-metastatic Ewing sarcoma treated with chemotherapy and definitive RT [25]. Role of hyperfractionated radiotherapy in management of Ewing sarcoma has been evaluated in the CESS 86 trial [22]. No significant advantage has been demonstrated over the standard fractionation and dose. Recent reports suggest that Proton beam therapy can potentially spare more amount of normal tissue but longer follow up is needed to determine its impact on morbidity and cure rates [26]. Radiation therapy is associated with the development of second malignant neoplasms. In a retrospective analysis, the incidence of second malignancy was 20% in patients who received doses of 60 Gy or more and 5% in those who received 48 Gy to 60 Gy. Those who received < 48 Gy did not develop a second malignancy [27]

Postoperative RT
Postoperative radiation (PORT) is recommended in cases of intralesional or marginal resection, intraoperative spill and poor pathological response to chemotherapy and is usually initiated at 6-8 weeks following surgery. Current Children’s Oncology Group (COG) protocols have more specifically defined adequate margin status. Complete resection is defined as a minimum of 1 cm margin and ideally 2–5 cm around the involved bone. The minimum soft tissue margin for fat or muscle planes is at least 5 mm and for fascial planes at least 2 mm. The Intergroup Ewing Sarcoma Study (INT-0091) recommends 45 Gy to the original disease site plus a 10.8 Gy boost for patients with gross residual disease and 45 Gy plus a 5.4 Gy boost for patients with microscopic residual disease. In the absence of gross residual disease there seems to be no clear benefit to doses over 45 Gy [28]. No radiation therapy is recommended for those who have no evidence of microscopic residual disease following surgical resection. Although not statistically significant, local relapse was least in the combined arm (10.5%) compared with 25% for either surgery or radiotherapy alone [21]. EICESS 92 evaluated the role of postoperative RT in patients with poor pathological response to induction chemotherapy (<90% necrosis). In their analysis there was reduction in local failures (5% vs.12%) in the poor responders if they received PORT [29 In the CESS and EICESS trials, the local failure rate for central primaries was reduced by 50% with PORT. However the role of adjuvant radiotherapy in poor responders and central tumors needs to be clearly defined and the benefits need to be balanced against potential risks of long term effects and second malignancies. For extraskeletal ES, PORT is generally recommended except in good prognosis superficial tumors [30].

Management of metastatic disease
Standard treatment guidelines for metastatic Ewing sarcoma recommend treatment similar to localized disease [30]. Different chemotherapy agents used are Vincristine, Adriamycin, Cyclophosphamide, Ifosphamide and Etoposide. Addition of IE to VAC does not seem to have additional benefit in this subset of patients [31]. Dose-intense treatment approach with high dose chemotherapy and autologous stem cell transplantation (HDT/SCT) was evaluated in the nonrandomized Euro-EWING 99 R3 study [32]. Even though this may have a potential to improve outcome, it has not become the standard of therapy.
Following induction chemotherapy, patients are reassessed with local and chest imaging and previously abnormal investigations are repeated. A progressive disease is treated with palliative intent and the good responders are managed with treatment of primary disease and metastatic sites. Timing of local therapy for both primary site and metastatic sites remain unclear.

Radiotherapy in metastatic disease
Whole lung irradiation (WLI) in patients with lung-only metastases has shown improved disease free and overall survival in various trials. Patients with lung metastasis should be considered for whole lung irradiation even after complete resolution following chemotherapy [33] Doses of 12 to 21 Gy have been used and are usually well tolerated [34]. Hemithoracic irradiation is recommended in patients with chest wall tumor with pleural nodules, pleural effusion or positive pleural cytology.
Bone metastases in Ewing sarcoma should be treated with similar doses as the primary site. They may be treated simultaneously or following completion of chemotherapy depending on the risk of marrow suppression. In the phase II POG/CCG trial which evaluated the role of intensive chemotherapy, local treatment for primary disease was done after completion of 21weeks of chemotherapy and that of metastatic disease was done after week 39 chemotherapy [35]. With the emergence of stereotactic body radiotherapy (SBRT), it is now possible to deliver ablative doses to sites of bone metastases with excellent sparing of normal tissues. SBRT delivered in one to five fractions can also minimize interruptions of systemic therapy.

Treatment of relapse
Outlook of patients who relapse remain unfavorable. Late onset relapse (>2years) and strictly localized disease has a favorable outcome [36]. Chemotherapy regimens in relapse settings are not standard. Two phase II studies have demonstrated upto 33% partial responses in relapsed refractory Ewing’s sarcoma with the combination of Topotecan and Cyclophosphamide [37]. The combination of Irinotecan and Temozolomide has demonstrated clinical responses.38 Gemcitabine in combination with Docetaxel has shown modest activity [39]. Newer drugs and targeted therapies are being evaluated. Radiotherapy and/or surgery may play a role in improving control rates.

Indian Data
There is paucity of data from Indian population. In a retrospective analysis, symptom duration >4 months, tumor diameter >8cm and baseline WBC >11×10(9)/L were predictive of poorer outcomes [40]. Optimal surgical margin in extra skeletal Ewing sarcoma in children was evaluated by Laskar et al who concluded that clear margins of resection correlated with local control irrespective of margin size[41] Survival rates in India remain dismal in spite of the advancement seen in the western world [42]. Patients tend to present with advanced stage disease and often default treatment due to socioeconomic factors.


The management of Ewing sarcoma has significantly evolved over the last few decades with consequent improvements in survival and functional outcomes. Treatment mandates multidisciplinary co-ordination involving Medical, Surgical and Radiation Oncologists, Orthopedic surgeons, Rehabilitation specialists, Pediatricians and others. Dose intensity of chemotherapy and optimal timing and modality of local therapy appear to significantly influence outcomes and survival rates. Metastatic disease represents a major challenge and optimal treatment strategies still need to be defined.


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2.Stoll G, Surdez D, Tirode F, et al. Systems biology of Ewing sarcoma: a network model of EWS-FLI1 effect on proliferation and apoptosis. Nucleic acids research 2013;41:8853-71.
3.Parkin DM, Stiller CA, Nectoux J. International variations in the incidence of childhood bone tumours. International journal of cancer Journal international du cancer 1993;53:371-6.
4.Rao VS, Pai MR, Rao RC, Adhikary MM. Incidence of primary bone tumours and tumour like lesions in and around Dakshina Kannada district of Karnataka. Journal of the Indian Medical Association 1996;94:103-4, 21.
5.Bernstein M, Kovar H, Paulussen M, et al. Ewing’s sarcoma family of tumors: current management. The oncologist 2006;11:503-19.
6.Applebaum MA, Worch J, Matthay KK, et al. Clinical features and outcomes in patients with extraskeletal Ewing sarcoma. Cancer 2011;117:3027-32.
7. Mankin HJ, Mankin CJ, Simon MA. The hazards of the biopsy, revisited. Members of the Musculoskeletal Tumor Society. The Journal of bone and joint surgery American volume 1996;78:656-63.
8. Perlman EJ, Dickman PS, Askin FB, Grier HE, Miser JS, Link MP. Ewing’s sarcoma–routine diagnostic utilization of MIC2 analysis: a Pediatric Oncology Group/Children’s Cancer Group Intergroup Study. Human pathology 1994;25:304-7.
9. Delattre O, Zucman J, Plougastel B, et al. Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours. Nature 1992;359:162-5.
10. Le Deley MC, Delattre O, Schaefer KL, et al. Impact of EWS-ETS fusion type on disease progression in Ewing’s sarcoma/peripheral primitive neuroectodermal tumor: prospective results from the cooperative Euro-E.W.I.N.G. 99 trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2010;28:1982-8.
11. Herrero-Martin D, Fourtouna A, Niedan S, Riedmann LT, Schwentner R, Aryee DN. Factors Affecting EWS-FLI1 Activity in Ewing’s Sarcoma. Sarcoma 2011;2011:352580.
12. Volker T, Denecke T, Steffen I, et al. Positron emission tomography for staging of pediatric sarcoma patients: results of a prospective multicenter trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2007;25:5435-41.
13. Dimitrakopoulou-Strauss A, Strauss LG, Egerer G, et al. Impact of dynamic 18F-FDG PET on the early prediction of therapy outcome in patients with high-risk soft-tissue sarcomas after neoadjuvant chemotherapy: a feasibility study. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 2010;51:551-8.
14. Mentzel HJ, Kentouche K, Sauner D, et al. Comparison of whole-body STIR-MRI and 99mTc-methylene-diphosphonate scintigraphy in children with suspected multifocal bone lesions. European radiology 2004;14:2297-302.
15. Burdach S, Thiel U, Schoniger M, et al. Total body MRI-governed involved compartment irradiation combined with high-dose chemotherapy and stem cell rescue improves long-term survival in Ewing tumor patients with multiple primary bone metastases. Bone marrow transplantation 2010;45:483-9.
16. Grier HE, Krailo MD, Tarbell NJ, et al. Addition of Ifosfamide and Etoposide to Standard Chemotherapy for Ewing’s Sarcoma and Primitive Neuroectodermal Tumor of Bone. New England Journal of Medicine 2003;348:694-701.
17. Cotterill SJ, Ahrens S, Paulussen M, et al. Prognostic factors in Ewing’s tumor of bone: analysis of 975 patients from the European Intergroup Cooperative Ewing’s Sarcoma Study Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2000;18:3108-14.
18. Ladenstein R, Potschger U, Le Deley MC, et al. Primary disseminated multifocal Ewing sarcoma: results of the Euro-EWING 99 trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2010;28:3284-91.
19. Paulussen M, Ahrens S, Dunst J, et al. Localized Ewing tumor of bone: final results of the cooperative Ewing’s Sarcoma Study CESS 86. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2001;19:1818-29.
20. Womer RB, West DC, Krailo MD, et al. Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the Children’s Oncology Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2012;30:4148-54.
21. Yock TI, Krailo M, Fryer CJ, et al. Local control in pelvic Ewing sarcoma: analysis from INT-0091–a report from the Children’s Oncology Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2006;24:3838-43.
22. Dunst J, Jurgens H, Sauer R, et al. Radiation therapy in Ewing’s sarcoma: an update of the CESS 86 trial. International journal of radiation oncology, biology, physics 1995;32:919-30.
23. Wagner TD, Kobayashi W, Dean S, et al. Combination short-course preoperative irradiation, surgical resection, and reduced-field high-dose postoperative irradiation in the treatment of tumors involving the bone. International journal of radiation oncology, biology, physics 2009;73:259-66.
24. Craft A, Cotterill S, Malcolm A, et al. Ifosfamide-containing chemotherapy in Ewing’s sarcoma: The Second United Kingdom Children’s Cancer Study Group and the Medical Research Council Ewing’s Tumor Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 1998;16:3628-33.
25. Krasin MJ, Rodriguez-Galindo C, Billups CA, et al. Definitive irradiation in multidisciplinary management of localized Ewing sarcoma family of tumors in pediatric patients: outcome and prognostic factors. International journal of radiation oncology, biology, physics 2004;60:830-8.
26. Rombi B, DeLaney TF, MacDonald SM, et al. Proton radiotherapy for pediatric Ewing’s sarcoma: initial clinical outcomes. International journal of radiation oncology, biology, physics 2012;82:1142-8.
27. Kuttesch JF, Jr., Wexler LH, Marcus RB, et al. Second malignancies after Ewing’s sarcoma: radiation dose-dependency of secondary sarcomas. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 1996;14:2818-25.
28. Donaldson SS. Ewing sarcoma: radiation dose and target volume. Pediatric blood & cancer 2004;42:471-6.
29. Schuck A, Ahrens S, Paulussen M, et al. Local therapy in localized Ewing tumors: results of 1058 patients treated in the CESS 81, CESS 86, and EICESS 92 trials. International journal of radiation oncology, biology, physics 2003;55:168-77.
30. Group TEESNW. Bone sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 2014;25:iii113-iii23.
31. Grier HE, Krailo MD, Tarbell NJ, et al. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing’s sarcoma and primitive neuroectodermal tumor of bone. The New England journal of medicine 2003;348:694-701.
32. Ladenstein R, Pötschger U, Le Deley MC, et al. Primary Disseminated Multifocal Ewing Sarcoma: Results of the Euro-EWING 99 Trial. Journal of Clinical Oncology 2010;28:3284-91.
33. Paulussen M, Ahrens S, Burdach S, et al. Primary metastatic (stage IV) Ewing tumor: survival analysis of 171 patients from the EICESS studies. European Intergroup Cooperative Ewing Sarcoma Studies. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO 1998;9:275-81.
34. Bolling T, Schuck A, Paulussen M, et al. Whole lung irradiation in patients with exclusively pulmonary metastases of Ewing tumors. Toxicity analysis and treatment results of the EICESS-92 trial. Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft [et al] 2008;184:193-7.
35. Bernstein ML, Devidas M, Lafreniere D, et al. Intensive therapy with growth factor support for patients with Ewing tumor metastatic at diagnosis: Pediatric Oncology Group/Children’s Cancer Group Phase II Study 9457–a report from the Children’s Oncology Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2006;24:152-9.
36. Stahl M, Ranft A, Paulussen M, et al. Risk of recurrence and survival after relapse in patients with Ewing sarcoma. Pediatric blood & cancer 2011;57:549-53.
37. Saylors RL, 3rd, Stine KC, Sullivan J, et al. Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2001;19:3463-9.
38. Wagner LM, McAllister N, Goldsby RE, et al. Temozolomide and intravenous irinotecan for treatment of advanced Ewing sarcoma. Pediatric blood & cancer 2007;48:132-9.
39. Mora J, Cruz CO, Parareda A, de Torres C. Treatment of relapsed/refractory pediatric sarcomas with gemcitabine and docetaxel. Journal of pediatric hematology/oncology 2009;31:723-9.
40. Biswas B, Rastogi S, Khan SA, et al. Developing a prognostic model for localized Ewing sarcoma family of tumors: A single institutional experience of 224 cases treated with uniform chemotherapy protocol. Journal of surgical oncology 2015;111:683-9.
41. Qureshi S, Laskar S, Kembhavi S, et al. Extraskeletal Ewing sarcoma in children and adolescents: impact of narrow but negative surgical margin. Pediatr Surg Int 2013;29:1303-9.
42. Tiwari A, Gupta H, Jain S, Kapoor G. Outcome of multimodality treatment of Ewing’s sarcoma of the extremities. Indian journal of orthopaedics 2010;44:378-83.

How to Cite this article: Irukulla MM, Joseph DM. Management of Ewing Sarcoma: Current Management and the Role of Radiation Therapy. Journal of  Bone and Soft Tissue Tumors May-Aug 2015;1(1):18-22.

Dr. Monica M. Irukulla
Dr. Monica M. Irukulla
Dr. Deepa M Joseph
Dr. Deepa M Joseph

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From TMH-NICE to ResTOR: An Eventful Journey A Treatise of developing a Tumor Megaprosthesis

Vol 1 | Issue 1 | May – August 2015 | page:40-44 | Ravi Sarangapani[1*].

Author: Ravi Sarangapani[1*].

[1]Development & Quality Director Adler Mediequip Pvt. Ltd, Pune, India.

Address of Correspondence
Mr. Ravi Sarangapani
Development & Quality Director, Adler Mediequip Pvt. Ltd., Sushrut House, Survey 288,
Next to MIDC Hinjewadi Phase II, At. Mann, Tal. Mulshi, Pune 411057, Maharashtra, India.


The primary option for patients with osteosarcoma for many decades was an amputation to save life. A review in 1986 demonstrated that limb salvage surgery was as safe as an amputation and provided the evidence to change the surgical management of these patients to limb salvage surgery and megaprosthetic reconstruction. International developments since the 1990s formed the backdrop for the evolution of limb salvage surgery in India. Initial obstacles faced in India were that of patient affordability. In the late nineties, Dr. Ajay Puri and Dr. Manish Agarwal from the orthopaedic oncology department of Tata Memorial Hospital (Mumbai) in association with Sushrut-Adler initiated development of an indigenous limb salvage megaprosthesis (the TMH-NICE). This had to be a low-cost prosthesis by all means. This surgeon industry partnership over time led to overcoming many challenges and failures and continuous learning both on the clinical and engineering fronts resulting in the evolution of the ResTOR modular resection prosthesis system. This journey continues with improvements and modernization of the system contributing to cost-effective limb salvage surgery to patients in India and a number of other countries.
Keywords: Bone Tumor, Osteosarcoma, Limb Salvage, TMH-NICE, ResTOR.


Although bone tumours form less than 1% of cancers in adults, they account for 3-5% of cancers in children with osteosarcoma being the most commonly diagnosed form of primary malignant bone tumours, followed by Ewing’s sarcoma [1]. These tumours represent the fourth most common type of cancer in patients under the age of 25.
The primary recourse for these patients for many decades was an amputation with an emphasis on sacrifice of the limb to save life. It was a landmark retrospective review by Simon et al in 1986 that demonstrated that limb salvage surgery was as safe as an amputation and provided the evidence that enabled surgeons to change the surgical management of these patients to limb salvage surgery and megaprosthetic reconstruction [2]. Enneking’s work related to staging of the disease [3] and the importance of surgical margins [4] significantly contributed to the development of limb-salvage surgery.
Not unlike most modern developments in the medical field, the clinical research and evolution of this treatment modality originated in the western world and resulted in limb salvage surgery with a megaprosthetic reconstruction slowly acquiring the status of “standard of care” for the majority of bone tumour patients through the 1990s. These International developments form the backdrop for what can aptly be termed the evolution of limb salvage surgery in India.

Indian Perspective
In late 1999, the Tata Memorial Hospital which is a pioneering initiative in the field of cancer care and research, originally commissioned in 1941, decided to augment their orthopaedic oncology service by bringing in a specialist orthopaedic surgeon to work with Dr. Badhwar, the then surgical oncologist who was also handling bone tumours. This resulted in Dr. Ajay Puri joining the oncology service of Tata Memorial in November 1999. Fate perhaps conspired in creating what would turn out to be a great team as Dr. Badhwar unfortunately took ill and the Tata Memorial management decided to recruit a second orthopaedic surgeon in the form of Dr. Manish Agarwal who came on board in January 2000. (read all about these happenings in the guest editorial by Dr A. Puri in this very issue [5]). Thus, two young and enthusiastic orthopaedic surgeons, well recognized in Mumbai for the contribution to the trauma service at major public hospitals, came on board to develop the orthopaedic oncology service at the Tata Memorial Hospital.
What Dr. Puri and Dr. Agarwal lacked in formal oncology training, they more than made up with their eagerness to learn, their obvious intelligence and most of all their dedication and commitment to make a difference to the lives of patients’ afflicted with this dreaded disease. The challenges they faced were numerous and perhaps too many to enlist; a gigantic workload of patients, a general lack of awareness of bone tumours and their management in the community, patient expectations, sometimes unrealistic to save limbs considering the social stigma attached to amputation considering the general difficulties faced by amputees in a developing country like India [6] and above all fast-advancing international developments in the management of bone tumours and perhaps frustration at not being able to offer the best standard of care to their patients. What they had in their favour was the backing and belief of the Institution, excellent infrastructure and the potential to form a world-class multi-disciplinary team.
As the development of the orthopaedic oncology service in Tata Memorial Hospital in the last fifteen years amply demonstrates, the selection panel which included Prof. Laud and Prof. Bawdekar and Dr. Dinshaw, the then Director of the Institution who also created these positions, did well. The young team, not fazed by the enormity of the challenges confronting them, set about tackling the problems they saw in a methodical and systematic manner.
One of their first priorities was to bring themselves up to date with the current international standard of care which involved offering their patients the option of limb salvage surgery with megaprosthetic reconstruction. As they started efforts to implement this initiative, they were faced with an obstacle not uncommon to the developing world, that of patient affordability. As so eloquently described by Dr. Agarwal and Dr. Puri, “Though all these exciting developments occurred in the West, in our own country limb salvage was still a difficult proposition. Chemotherapeutic drugs were very expensive, endoprosthesis unaffordable, ignorance widespread and the patients poor” [7]. This situation resulted in the team not being able to effectively offer the option of a good quality mega-prosthetic replacement to even ten patients of the approximately 200 new cases [7] or primary malignant bone tumours presenting to the hospital at that time.
It is said that experience can sometimes be a hindrance and the enthusiasm of youth goes a long way in surmounting seemingly impossible hurdles. The young team refused to be dismayed with these setbacks and set about convincing the management of the Sushrut-Adler Group (currently Adler Mediequip Pvt. Ltd., a Smith & Nephew subsidiary) of their mission to save limbs and improve the quality of life of these patients. It is testimony to their eloquence and persuasive skills that the Sushrut-Adler management adopted the surgeons’ goals as their own and agreed to invest the time and resources needed in the service of these patients, in a situation where a financially viable business was nowhere in sight. Thus began the evolutionary journey which took this Indian designed, Made-in-India implant from the early hesitant efforts of the TMH-NICE to the modular resection system, the ResTOR.
The Sushrut-Adler team commenced work, fabricating implants to patient dimensions in a surgeon-led design effort that was blessed by the Institutional Review Board of the Tata Memorial Hospital. In keeping with the objectives defined by Dr. Puri and Dr. Agarwal, the primary consideration was their estimate of what patient’s would be able to afford based on their understanding of the financial situation of these patients. This resulted in certain choices of material and fabrication methods which in hindsight were incorrect choices driven by the early “cost” objectives.
The early period between the years 2000 to 2002 featured implants that were almost entirely fabricated in a custom-basis to patient specific dimensions specified by the surgeon team. The rather crude initial design without femoral condyles (Fig.1a) quickly evolved into a more refined femoral shape (Fig. 1b) under the guidance of the surgeons. These implants were manufactured from 316L stainless steel, the material choice dictated by easy availability, ease of fabrication and cost considerations. The condylar region with the patient specific resection length was welded to the straight intramedullary stem which featured a male thread screwed into the resection shaft. Longitudinal grooves were machined into the stem to inter-digitate with bone cement and a valgus angle of 7 degrees was incorporated. The hinge pin was locked into place using a simple slotted screw.
In a first hint of problems to be faced in the future near the level of the resection or the intramedullary stem junction, a case of failure was encountered in the implant at the location close to the resection level which was fabricated as a threaded junction (Fig.2). This failure was similar to the failure of a humeral implant reported by Bos et al with a fracture at the base of a threaded stem [8] due to stress concentration and a structural weakness.
As the number of operated patients increased, the surgeons began to note certain repetitive dimensions that could be standardized. These were the Antero-posterior and Medio-lateral dimensions of the femoral and tibial condyles. Later on as the project progressed, other dimensions including stem diameters, lengths and types, lengths of resection segments and spacers would get standardized to enable modularity. The standardized condylar dimensions in 2002 enabled the femoral condylar section of the implant to be “cast” in 316L stainless steel, a development that featured in the implants manufactured in the period 2002-2004. The adoption of casting enabled some reduction in lead time by reducing the rather extensive condylar machining that was required earlier. As anatomical understanding grew, intramedullary stems evolved from a straight design to including an option with an anatomical curvature (Fig. 3).

Fig 1
It was also in this period that the first instrument set (Fig. 4) was created. Notably, nearly all surgeries performed by the surgeon team till that time had been carried out by using general orthopaedic instrumentation. With increasing experience came the realization that specifically designed instrumentation would be needed. Also contributing to this development was the fledgling thought in the minds of the surgeons that this system might go out of Tata Memorial Hospital some day in the future and it was important to create instrumentation that would enable easier use of this system by average surgeons. In late 2004, a circumferential groove oriented transversely (Fig. 5a) was added to the stem with the thought of improving cement fixation. This change resulted in early failure at the location of the groove (Fig.5b) and was quickly abandoned.

Fig 2
It was in early 2004 that the project began to face what would turn out to be its most major challenge, the incidence of mechanical failure predominantly located at the intramedullary stem-bone junction (Fig. 6). As subsequently reported in 2010 by Dr. Agarwal and Dr. Puri, there were 22 mechanical failures in 183 patients (12.02%) predominantly at the stem-collar junction with an average time to failure of 38 months [9]. While these failures initially unnerved the team working on the project, reviews of literature reveal that such failures were by no means uncommon and had been faced and continue to be faced by each such group of surgeons and engineers working in the field of limb salvage. Biau et al reported mechanical failures including stem fractures and hinge pin failures in 7 out of 91 patients (7.7%) operated between 1972 and 1994 [10]. More recently in 2013, Nakamura et al [11] reporting on the Japanese early experience with the Kyocera limb salvage system revealed mechanical failures in 7 out of 82 distal femur resections (8.53%) including predominantly stem failures and one tibial tray breakage.
While the stem failures were beginning to present themselves and were being investigated, a number of refinements continued to be made in the period since 2004. The tibial baseplate acquired its rounded geometry (Fig. 7a) conforming to the tibial plateau. The important alignment mark on the stem was added (Fig. 7b) to enable correct rotational alignment of the implant. In mid-2005, bushes and a bumper manufactured from UHMWPE were introduced into the design (Fig. 7c) to minimize metal on metal articulation.
In early 2006, based on initial investigations into the failure location which was centered near the stem-bone junction, a decision was made to introduce a gradual change of diameter in the region and reduce stress concentration by introducing a fillet (Fig. 7d) with a liberal radius of curvature. This change was done based on standard good design principles and was perhaps the first engineering input to what had essentially been a surgeon-led project from inception.

Fig 3
With all the changes and refinements that had taken place over the years (Fig. 8a,b), the system in mid-2006 was fairly standardized based on a large patient experience of nearly 260 cases, standard condylar and intra-medullary dimensions, UHMWPE bushes and bumpers and a reliable hinge locking mechanism.
What however concerned the entire team was that the intramedullary stems continued to fail at the stem-bone junction and even the reduced stress concentration with the filleted design did not seem to work (Fig. 8c).
It was at this point that the engineering team at Sushrut-Adler brought in a new level of seriousness and application to understanding this problem better. Literature was extensively reviewed [12,13,14] to develop a better appreciation of the forces the implant was being subjected to. Resultant stresses on the implant cross sections were calculated and analyzed with reference to the materials being used. Based on the analytical work, it was clear that the stainless steel being used for these implants did not have the capability to withstand the continuous stresses being imposed on this implant in normal patient activities in the medium to long term. Better materials were needed.Fig 4The team opted for titanium alloy as the material of choice for the ramedullary stems as a material with no biocompatibility issues given its long history of successful clinical use, the ability of the material to withstand the imposed stresses in this application with an adequate factor of safety and the lower modulus of elasticity which was perceived as a possible advantage.
Titanium alloy is known to have its own difficulties in processing and is not an easy material from a manufacturing standpoint. Fortunately, the engineering and manufacturing teams at Sushrut-Adler had developed strong experience in working with this alloy due to their previous history with successful development and commercialization of spine implants manufactured from titanium alloy and these challenges were not difficult to overcome.
The change of materials and the expected solution to the difficult stem failure issue thus opened the way for the team of surgeons and the Sushrut-Adler engineers to take the next step of modularizing the system paving the way for more widespread use. The difficulties of custom-manufacturing implants by this time were well understood and the constraint imposed on an operating surgeon working with an implant of fixed size was not desirable. Modularity enabled a surgeon to intra-operatively select the most optimum surgical margin for the excision with no concerns about having an implant size that would adapt to the length of the resection.
The surgeons’ need for modularity resulted in many months of manufacturing trials at Sushrut-Adler as the necessary self-locking tapers for the modular components were designed and proven through the manufacturing process.
The final standardized condylar dimensions enabled the team to opt for superior Cobalt Chrome alloy investment castings for the condylar components thus gaining better articulation properties with the UHMWPE components.
The culmination of all these efforts resulted in the first patient implanted with the ResTOR modular resection prosthesis in a limb salvage procedure in late 2006. The modular system was commercialized in early 2007 for distal femur and proximal tibia resections. The addition of an upper limb system and a proximal femur resection system over the next few years enabled a complete portfolio of solutions.
It may be argued, with hindsight, that the inception of this project in 1999-2000 was with a compromised implant. However, as cogently argued by Dr. Agarwal ten years later [9], many patients benefited even with these compromised implants, the failure rate of around 15% was not viewed as catastrophic and was considered acceptable in a situation where an expensive implant was not an option and where amputation or rotationplasty would have been the only alternatives for the patient. The limb salvage procedure allowed many children to continue with education and adults to remain employed. Icing on the cake came in the form of the prestigious Golden Peacock Innovation Award in 2010 which recognized this as a major health-care initiative.
The ResTOR modular resection prosthesis system since 2007 has contributed to cost-effective limb salvage surgery of more than 2000 patients in India and a number of other countries [17] with prosthesis survivorship rates comparable to those reported in literature [15,16]. As a case in point, the Tata Memorial experience of 88% implant survivorship at five years with total femoral replacement [16], a specially challenging procedure with extensive resection does great credit to the team of surgeons and engineers who worked on this project. As implant survivorship improves and a greater number of patients experience disease-free survivorship with continuously improving surgeon experience, the ResTOR team continues to face newer challenges related to the increased demands on the implant.
While many improvements have been made and will continue to be made, as global experience with limb salvage implants has shown, the demands placed on these implants are immense and the way forward promises an abundance of challenges to be faced and problems to be solved.


The author was privileged to be associated with this program right from inception till date and will remain forever grateful for the opportunities this program has provided to learn, develop and evolve. The team of engineers who have contributed at various stages are too numerous to name and their efforts will always be remembered and recognized by the surgeons who care for patients with these difficult conditions..


1. Mirabello L, Troisi RJ, Savage SA. International osteosarcoma incidence patterns in children and adolescents, middle ages and elderly persons. Int J Cancer. 2009 Jul 1;125(1):229-34..
2. Simon MA, Aschliman MA, Thomas N, Mankin HJ. Limb-salvage treatment versus amputation for osteosarcoma of the distal end of the femur. J Bone Joint Surg Am. 1986 Dec;68(9):1331-7.
3. Enneking WF, Spanier SS, Goodman MA. A System for the surgical staging of musculo-skeletal sarcoma. Clin. Orthop., 153;106-120, 1980.
4. Springfield DS, Schmidt R, Graham-Pole J, Marcus RB Jr, Spanier SS, Enneking WF. Surgical treatment for osteosarcoma. J Bone Joint Surg Am. 1988 Sep;70(8):1124-30.
5. Puri A. The “ODYSSEY”: “Orthopaedic Oncology” – My journey thus far! Journal of Bone and Soft Tissue Tumors May-Aug 2015; 1(1):3-5
6. Agarwal M, Anchan C, Shah M, Puri A, Pai S. Limb salvage surgery for osteosarcoma: effective low-cost treatment. Clin Orthop Relat Res. 2007 Jun;459:82-91.
7. Agarwal M, Puri A. Limb Salvage for malignant primary bone tumours: current status with a review of literature. Indian J Surg 2003;65:354-60.
8. Bos G, Sim F, Pritchard D, Shives T, Rock M, Askew L, Chao E. Prosthetic replacement of the proximal humerus. Clin Orthop Relat Res. 1987 Nov;(224):178-91.
9. Agarwal M, Gulia A, Ravi B, Ghyar R, Puri A. Revision of broken knee megaprostheses: new solution to old problems. Clin Orthop Relat Res. 2010 Nov;468(11):2904-13..
10. Biau D, Faure F, Katsahian S, Jeanrot C, Tomeno B, Anract P. Survival of total knee replacement with a megaprosthesis after bone tumor resection. J Bone Joint Surg Am. 2006 Jun;88(6):1285-93.
11. Nakamura T, Matsumine A, Uchida A, Kawai A, Nishida Y, Kunisada T, Araki N, Sugiura H, Tomita M, Yokouchi M, Ueda T, Sudo A. Clinical outcomes of Kyocera Modular Limb Salvage system after resection of bone sarcoma of the distal part of the femur: the Japanese Musculoskeletal Oncology Group study. Int Orthop. 2014 Apr;38(4):825-30.
12. Perry J, Antonelli D, Ford W. Analysis of knee-joint forces during flexed-knee stance. J Bone Joint Surg Am. 1975 Oct;57(7):961-7.
13. Paul JP. Approaches to Design – Force actions transmitted by joints in the human body. Proc. R. Soc. Lond. B. 1976; 192: 163-172.
14. Taylor SJ, Walker PS, Perry JS, Cannon SR, Woledge R. The forces in the distal femur and the knee during walking and other activities measured by telemetry. J Arthroplasty. 1998 Jun;13(4):428-37..
15. Puri A, Gulia A. The results of total humeral replacement following excision for primary bone tumour. J Bone Joint Surg Br. 2012 Sep;94(9):1277-81..
16. Puri A, Gulia A, Chan WH. Functional and oncologic outcomes after excision of the total femur in primary bone tumors: Results with a low cost total femur prosthesis. Indian J Orthop. 2012 Jul;46(4):470-4.
17. Data on file at Adler.

How to Cite this article: Sarangapani R. From TMH-NICE to ResTOR: An Eventful Journey. Journal of  Bone and Soft Tissue Tumors May-Aug 2015; 1(1):40-44.

Dr. Ravi Sarangapani
Dr. Ravi Sarangapani

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The “ODYSSEY”: “Orthopaedic Oncology” My journey thus far!

Vol 1 | Issue 1 | May – August 2015 | page:3-5 | Dr Ajay Puri.

Author: Dr Ajay Puri.

Chief – Orthopaedic Oncology.
Professor & Head – Surgical Oncology, Tata Memorial Centre.
President – Indian Musculo Skeletal Oncology Society,
Chairman – Indian Orthopaedic Association (Oncology)
President Elect – Asia Pacific Musculo Skeletal Oncology Society.

Address of Correspondence
Dr. Ajay Puri.

Guest Editorial:The “ODYSSEY”: “Orthopaedic Oncology”  My journey thus far!

“The Odyssey is one of two major ancient Greek epic poems attributed to Homer. It centres on Odysseus and describes his journey home after the fall of Troy. It takes Odysseus ten years and multiple trials and tribulations as he seeks to return after the ten-year Trojan War.”

Circa 1999. Well ensconced as Associate Professor in one of Mumbai’s premier teaching University Hospitals living life in my “comfort zone” I was unaware of the cosmic forces building up that were soon to bring about a major upheaval in my professional career. An advertisement brought to my notice by a colleague for an “orthopaedic oncologist” in India’s premier oncology centre triggered a chain of events that I could have little foreseen. To most of us “routine” orthopaedic surgeons, orthopaedic oncology in the last millennium was a dark and forbidding battleground littered with countless mines all waiting to explode in the faces of those who were foolish enough to walk down that path. Besides the occasional giant cell tumor seen infrequently, the little I knew of this “unexplored specialty” was from the lectures heard at meetings where the wise man from the North propounded the theory of “God’s foresight that gave us two fibulae for reconstruction”, equally forcefully countered by the “mega” surgeon from the South who emphatically put forward the benefits of huge metallic monsters for reconstruction that functioned in lieu of our God given bones. [1, 2] To me as a youngster all this was as fascinating and farfetched as “Star Wars” because I never expected to walk down this road where “few men had gone before”.
Having had this “fateful” advertisement brought to my notice and more for lack of an alternate opportunity at adventure rather than a belief in choosing this as “the” career option I ventured to appear for this interview. Sports psychologists will go blue in the face trying to drill into their wards theories about “just enjoy the game” and “don’t let the pressure get to you and you will perform better”. With no pressure to perform, secure in the knowledge that I had a faculty position already and buoyed by the cockiness that was inherent in most young orthopaedic surgeons of my generation, the “enjoyable” interview went like a breeze. Lo and behold, “unexpectedly” I had an appointment letter in my hand to venture into this minefield.
Then is when the “pressure” set in. Should I leave my “comfort” zone to try and navigate this minefield? “Fools rush in – where angels fear to tread”. Angel I definitely was not, but a fool…….?
…………And I became the first orthopaedic oncologist to be appointed as full time faculty by Tata Memorial Hospital. I was joined a few months later by a colleague, a lecturer from the adjoining KEM hospital – Dr. MG Agarwal and together we set about navigating these stormy seas. Apart from the complexity of these “first time” surgeries one of the main obstacles that we encountered was the lack of a credible prosthesis for reconstructing large defects after resection. Though individual surgeons earlier had their prosthesis manufactured by local fabricators no national implant company had envisaged interest in these previously, either because of lack of numbers or the absence of an opportunity to develop a prosthesis with surgeon inputs. Armed with little more than the enthusiasm of the “new convert” we set up a collaboration with Sushrut, an implant manufacturer with whom I had the opportunity earlier to help develop their spine and trauma implants while working at “Sion” hospital. The absence of stringent regulatory requirements facilitated rapid development which would otherwise have been a lot slower in today’s era. The TMH –NICE (Tata Memorial Hospital – New Indigenous Customised Endoprosthesis) a custom prosthesis, individually manufactured for each patient was the result of this collaboration.[3] Over a decade, based on our clinical experience and increasing understanding of biomechanics the TMH –NICE metamorphosed into the “ResTOR”. This “off the shelf” modular prosthesis can now reconstruct whole bones and offers a cost effective alternative in many Asian and African countries.[4, 5] Along the way we also practised and refined numerous biological reconstructions.[6, 7] These offered alternative options that were more durable, universally applicable and easier to implement in financially constrained situations. The adrenaline pumping pelvis surgeries; fearful bloodbaths initially, gradually transformed into more controlled battles. We learned to reconstruct these large pelvic resections with options more suited for squatting and sitting cross legged, “activities of daily living” inherent to our patients.[8] Yes, there were complications and disasters. While we hopefully learned from these we did not allow them to overshadow our enthusiasm and possibly were the first believers of the “acche din aayenge” philosophy which encouraged us to keep moving ahead. While benefiting from the published experience of “western” literature we learned to innovate and develop methods and techniques more suited to our own our local socio-economic milieu.
We were fortunate that the environment of the institution we worked in was steeped in the culture of “multi-disciplinary” management, the essence of successful treatment of any cancer. We were easily able to implement “joint clinics” where patients benefited from a “one stop window” where all specialties pooled in their expertise to decide the optimum treatment of a particular case. The concept of our weekly ORP “ortho – radio – path” diagnostic meeting to discuss difficult diagnostic lesions has been the genesis of the hugely popular musculo skeletal oncology ORP gatherings that have been organised all across the country over the last decade or so.
Besides service, “education” has been a core component of the philosophy of the institute that gave me this opportunity to practise the art and science of musculoskeletal oncology. We began by training post M.S. “fellows”. As there was no formal program or rigid curriculum they spent varying amounts of time with us based on their endurance and ability to last the course and tolerate my idiosyncrasies. It is a matter of great pride now to see most of them as well established proponents of “orthopaedic oncology” in various parts of the country. Publishing our results in international peer reviewed journals and presentations at various international meetings helped establish the unit as a credible centre for bone and soft tissue tumors. This drew various international visitors all keen to experience the “large volumes” unlikely to be seen in most other global centres, further enhancing the exposure of the Indian musculoskeletal oncology fraternity on a global platform.[9] The earlier informal training has now formalised into a 2 year recognised “orthopaedic oncology fellowship” program, the only one of its kind in the country.
In ancient Roman religion and myth, Janus is the god of beginnings and transitions. He is usually depicted as having two faces, since he looks to the past and to the future. While certainly no Janus I think this is an appropriate moment to dwell on the future challenges we as a specialty must now try and overcome?[10] We must embrace the responsibility of increasing awareness about these uncommon lesions both in the public and professional domain. We must enhance our ability to disseminate and propagate current information and techniques, continue to train surgeons in larger numbers and help set up collaborative networks to gain further insight into these rare lesions. There is increasing pressure for medical technology assessment to include cost-effectiveness analyses to help determine difficult resource allocation decisions.[11] While the importance of clinical expertise and experience is unquestionable we do need to combine this with the judicious integration of best available scientific evidence to facilitate rational “informed” clinical decision making and help develop evidence based protocols that would be both effective and applicable in our settings.
The Indian Musculo Skeletal Oncology Society (IMSOS) is a step in this direction.[12] It aims to “promote scientific, evidence based, comprehensive multidisciplinary management of bone and soft tissue sarcomas and encourage basic and clinical research.” IMSOS seeks to provide a common forum for interaction and mutual collaboration between different specialists and institutes involved in the treatment of sarcomas. It will help foster training and education opportunities, promote dissemination of knowledge and aid in the development of treatment guidelines suitable for our socio cultural environment. Together we must strive to develop this society to ultimately provide the best possible care to the maximum number of patients. The launch of the “Journal of Bone and Soft Tissue Tumors” cannot have come at a more opportune time. It will provide a fillip to surgeons seeking to share their experience who may have otherwise been intimidated by the “established” journals which currently look askance at individual case reports and series with relatively small numbers.
The “Odyssey” continues…….. , Indian orthopaedic oncology while having successfully navigated its nascent and adolescent period is successfully maturing into a vibrant specialty seeking to stamp its own unique impression globally. It is heartening to see an ever increasing number of practitioners venturing into these seas, now armed with navigational aids and charts that could help make the journey less turbulent, yet as exciting and exhilarating as it has always been.

Ajay Puri.


1. Natarajan MV, Sivaseelam A, Ayyappan S, Bose JC, Sampath Kumar M. Distal femoral tumours treated by resection and custom mega-prosthetic replacement. Int Orthop 2005;29: 309-13.
2. Yadav SS. Dual-fibular grafting for massive bone gaps in the lower extremity. J Bone Joint Surg Am 1990;72: 486-94.
3. Agarwal M, Anchan C, Shah M, Puri A, Pai S. Limb salvage surgery for osteosarcoma: effective low-cost treatment. Clin Orthop Relat Res. 2007 Jun;459:82-91.
4. Puri A, Gulia A. The results of total humeral replacement following excision for primary bone tumour. J Bone Joint Surg Br 2012;94: 1277-81.
5. Puri A, Gulia A, Chan WH. Functional and oncologic outcomes after excision of the total femur in primary bone tumors: Results with a low cost total femur prosthesis. Indian J Orthop 2012;46: 470-4.
6. Puri A, Subin BS, Agarwal MG. Fibular centralisation for the reconstruction of defects of the tibial diaphysis and distal metaphysis after excision of bone tumours. J Bone Joint Surg Br 2009;91: 234-9.
7. Puri A, Gulia A, Jambhekar N, Laskar S. The outcome of the treatment of diaphyseal primary bone sarcoma by resection, irradiation and re-implantation of the host bone: extracorporeal irradiation as an option for reconstruction in diaphyseal bone sarcomas. J Bone Joint Surg Br 2012;94: 982-8.
8. Puri A, Pruthi M, Gulia A. Outcomes after limb sparing resection in primary malignant pelvic tumors. Eur J Surg Oncol 2014;40: 27-33.
10. Puri A. Orthopedic oncology – “the challenges ahead”. Front Surg 2014;1: 27.
11. Brauer CA, Neumann PJ, Rosen AB. Trends in cost effectiveness analyses in orthopaedic surgery. Clin Orthop Relat Res 2007;457: 42-8.

How to Cite this article: Puri A. The “ODYSSEY”: “Orthopaedic Oncology” – My journey thus far! Journal of  Bone and Soft Tissue Tumors May-Aug 2015;1(1):3-5

Dr Ajay Puri

Dr Ajay Puri

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Intractable Knee pain….it could be Glomus!

Vol 1 | Issue 1 | May – August 2015 | page:48-50 | Umesh M Kulkarni[1], Vijay Zavar[2], Sudhir Sankalecha[3], Ameya Kulkarni[1].

Author: Umesh M Kulkarni[1], Vijay Zavar[2], Sudhir Sankalecha[3], Ameya Kulkarni[1].

[1]Sanjivan Hospital, India Security Press Hospital, Nashik, Maharashtra, India.
[2]Skin Diseases Center, Nashik, Maharashtra, India.
[3]Sankalecha Labs, Nashik, Maharashtra, India.

Address of Correspondence
Dr. Umesh M Kulkarni
Sanjivan Hospital, India Security Press Hospital, Nashik, Maharashtra, India.
Email :


Introduction: Glomus tumors are areteriovenous anastomoses mostly found on flexor surfaces of fingers and nail beds. Occurrences in lower extremity is rarity and requires high index of suspicion.
Case Report: Thirty eight year old housewife presented with severe knee pain and swelling on the medial side of the knee since last two years. She had taken multiple opinions and was on analgesics and anti inflammatory medications for an extended duration. On examination an ill defined tender nodule was palpable on superolateral aspect of patella. MRI showed hypointense nodule with uniform contrast uptake. Excision biopsy was done to remove the lesion in total. Patient has complete relief of symptoms. Histopathology confirmed the diagnosis of glomus tumor
Conclusion: Glomus tumors can rarely occur in unusual locations. Clinical presentation and MRI help to narrow down the diagnosis. Excision leads to complete relief of symptoms.
Keywords: Glomus tumor, Knee, excision biopsy.


The glomus body is a specialised form of arteriovenous anastomosis localised in the dermal soft tissue and acts as a thermoregulator. A glomus tumour (glomangioma, tumors of Popoff, or Barré-Masson syndrome) is a benign mesenchymal neoplasm composed of cells which resemble the modified smooth muscle cells of the normal glomus body (glomocytes) [1]. Extra-digital location of glomus tumour is uncommon [2]. Considering the rarity of this site, we present this case of Glomus tumour (GT) of the knee.

Case Report
A 38-yr-old housewife presented with severe right knee pains, supero-laterally to the patella, progressive since 2 years. Even the gentle touch would result in disproportionate shooting or stabbing type of pains, sometimes associated with paraesthesia. At times, the touch of clothing was unbearable. There was no seasonal exacerbation of the pains, which increased on extreme flexion of the knee or sitting cross-legged, compromising her daily work. She had abnormal apprehensive behaviour towards any person or object near her knee. There was no history of trauma or any inflammatory episode of the knee. She had received a number of analgesics, anti-inflammatory and anti-psychotic agents without much relief. She was even advised a psychiatric consultation prior to coming to us. On examination, an ill-defined soft nodule was palpable at the point of maximum tenderness only on extreme flexion of the knee (Fig.1). It was exquisitely tender on deep palpation. Movements of knee were painful in terminal flexion. There was no increase in local temperature. Swelling was mobile in the transverse direction, indicating adherence to deeper fibrous layers.

Figure 1 and 2
MRI revealed a hypointense nodule with in supero-lateral area of right knee on T1(Fig 2a). Gadolinium contrast showing enhanced and uniform uptake of the contrast (Fig. 2b). This confirmed the vascular nature of the lesion. The authors had earlier treated a similar case of GT of the knee joint and thus a high index of suspicion was present for GT. Excision biopsy was planned for the lesion. Open mini- excision biopsy of the lesion was preferred over arthroscopic shaving so that the lesion could be obtained in toto. The discrete lesion was found to be arising from the capsule of the suprapatellar region of the right knee and was fully excised. The patient had a miraculous recovery from the pain and unusual behaviour pattern. Histological examination revealed a well-circumscribed benign lesion with several vascular spaces (Fig. 3a) and solid aggregates of regular round glomus cells with darkly staining basophilic nucleus in a hyaline stroma.(Fig. 3b). On follow up the patient was completely relieved of all her symptoms. A consent for publication was taken before submitting the case report

Figure 3

Histologically GT arises from glomus bodies that are specialised form of arteriovenous anastomosis involved in temperature regulation. Structurally plump endothelial cells line a centrally coiled canal which is surrounded by longitudinal and circular muscle fibres containing rounded epithelial appearing glomus cells (glomocytes) [1,2]. Histologically, GT are divided into 3 subtypes: The classical glomus tumour, glomangiomas and glomangiomyomas, the last being least common. Rarely, glomus tumours may have a malignant potential [3].
Though GT occur more commonly on digits below the nails, they may appear in other anatomical areas. Cutaneous lesions appear as small bluish-red tender nodules in the dermis or sub dermal skin. Pinpoint exquisite tenderness is characteristic. Pain from GT is so severe that at times a patient may even demand an amputation of the limb. The symptoms are generally worse in winter. Extra-digital GT commonly get misdiagnosed for a significant time period before the final diagnosis.4,5,6 In our case too there was a delay of more than a year in diagnosis. GT around the knee are reported infrequently [2,4-22]. In a review of cases GT of mayo clinic, tumors around the knee were 17.8% of all the cases of extradigital GT [2]. The structures around the knee that may be involved can be varied and GT is reported to arise from patellar ligament [9,22], quadriceps muscle [10], vastus lateralis [11], hoffa’s fat pad [13-18], plica synovialis [17]. In our case the lesion was arising from the joint capsule and did not involve muscles or tendons.
We had a very high index of suspicion of GT because of our earlier experience in treating such patients of GT along the knee joint. Often the tumour may not appear for a long time after the pain has begun [23] or may be neglected by the patient [8] or delayed diagnosed [6]. In our case the patient had taken medications from multiple consultants and presented to us with no specific diagnosis. According to Shugart et al, “almost diagnostic is the fact that the patient is reluctant, and often refuses palpation during examination [24]. In our case there was tenderness on deep palpation on complete flexion. This may be because the lesion was deep seated in the capsule and was covered laterally by vastus musculature. The clinical diagnosis needs to be confirmed with MRI and histopathology of the excised tissue. It is important to diagnose glomus tumour because the condition is potentially curable by surgical excision [2,3,4,5]. It however remains intriguing as to why a glomus appeared at this uncommon location.
In conclusion, intractable knee pain with focal exquisite tenderness may be due to glomus tumour and should be suspected early to minimize painful endurance by the patient.


1. GombosZ, ZhangPJ. Glomus tumor. Arch Pathol Lab Med 2008;132:1448-52.
2. Schiefer TK, Parker WL, Anakwenze OA, Amadio PC, Inwards CY, Spinner RJ. Extradigital glomus tumors: a 20-year experience. Mayo Clin Proc. 2006 Oct;81(10):1337-44
3. Hiruta N, Kameda N, Tokudome T, Tsuchiya K, Nonaka H, Hatori T, Akima M, Miura M. Malignant glomus tumor: a case report and review of the literature. Am J Surg Pathol. 1997 Sep;21(9):1096-103..
4. Clark ML, O’Hara C, Dobson PJ, Smith AL. Glomus tumour and knee pain: a report of four cases. Knee. 2009; 16: 231-4.
5. Puchala M, Kruczynski J, Szukalski J, Lianeri M. Glomangioma as a rare cause of knee pain. J Bone Joint Surg Am. 2008; 90: 2505-8.
6. Panagiotopoulos E, Maraziotis T, Karageorgos A, Dimopoulos P, Koumoundourou D. A twenty-year delay in diagnosing a glomus knee tumor. Orthopedics. 2006 May;29(5):451-2.
7. Caughey DE, Highton TC. Glomus tumour of the knee. Report of a case. J Bone Joint Surg Br. 1966 Feb;48(1):134-7.
8. Davenport D, Colaco HB, Edwards MR. The 30-year wait for treatment of an acutely painful knee. BMJ Case Rep. 2014 Sep 29;2014.
9.Mabit C, Pecout C, Araud JP. Glomus tumour in the patellar ligament: A case report. J Bone Joint Surg [Am] 1995; 77: 140-141.
10.Negri G, Schulte M, Mohr W. Glomus tumour with diffuse infiltration of the quadriceps muscle: A case report. Hum Path 1997; 28: 750-752.
11.Amillo S, Arriola FJ, Munoz, G. Extradigital glomus tumour causing thigh pain. J Bone Joint Surg [Br] 1997; 79B: 104-106.
12.Oztekin HH. Popliteal glomangioma mimicking baker’s cyst in a 9-year-old child: an unusual location of a glomus tumour. Arthroscopy 2003; 19(7); 1-5.
13.Hardy P, Muller GP, Got C. Glomus tumour of the fat pad. Arthroscopy 1998; 14: 325-328.
14.Waseem S, Jari S, Paton R. Glomus tumour, a rare cause of knee pain: a case report. Knee 2002; 9:161-163.
15. Clark ML, O’Hara C, Dobson PJ, Smith AL. Glomus tumor and knee pain: a report of four cases. Knee. 2009 Jun;16(3):231-4.
16. Gholve PA, Hosalkar HS, Finstein JL, Lackman RD, Fox EJ. Popliteal mass with knee pain in a 57-year-old woman. Clin Orthop Relat Res. 2007 Apr;457:253-9.
17. Kato S, Fujii H, Yoshida A, Hinoki S. Glomus tumor beneath the plica synovialis in the knee: a case report. Knee. 2007 Mar;14(2):164-6.
18. Prabhakar S, Dhillon MS, Vasishtha RK, Bali K. Glomus tumor of Hoffa’s fat pad and its management by arthroscopic excision. Clin Orthop Surg. 2013 Dec;5(4):334-7.
19. Gonçalves R, Lopes A, Júlio C, Durão C, de Mello RA. Knee glomangioma: a rare location for a glomus tumor. Rare Tumors. 2014 Dec 18;6(4):5588.
20. Sraj SA, Khoury NJ, Afeiche NE, Abdelnoor J. Thigh pain of 5 years’ duration in a 48-year-old man. Clin Orthop Relat Res. 2008 Sep;466(9):2291-5.
21. Okahashi K, Sugimoto K, Iwai M, Kaneko K, Samma M, Fujisawa Y, Takakura Y. Glomus tumor of the lateral aspect of the knee joint. Arch Orthop Trauma Surg. 2004 Nov;124(9):636-8.
22. Akgün RC, Güler UÖ, Onay U. A glomus tumor anterior to the patellar tendon: a case report. Acta Orthop Traumatol Turc. 2010;44(3):250-3.
23. King ESJ. Glomus Tumour. Australian and New Zealand Journal of Surgery, 1954:23(4); 280-295.
24. Shugart RR, Soule EH, Johnson EW. Glomus tumor. Surgery, Gynecology & Obstetrics. 1963;117:334–340.

How to Cite this article: Kulkarni UM, Zavar V, Sankalecha S, Kulkarni A. Intractable Knee pain….it could be Glomus! Journal of  Bone and Soft Tissue Tumors May-Aug 2015; 1(1):48-50.

Dr.Umesh M Kulkarni

Dr.Umesh M Kulkarni

Dr.Vijay Zavar

Dr.Vijay Zavar

Dr.Sudhir Sankalecha

Dr.Sudhir Sankalecha

Dr.Ameya Kulkarni

Dr.Ameya Kulkarni

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Ewing Sarcoma: Focus on Medical Management

Vol 1 | Issue 1 | May – August 2015 | page:1-2 | Santosh Valvi, Stewart J Kellie

Author: Santosh Valvi [1,2*], Stewart J Kellie [3,4]

[1]Kids Cancer Centre, Sydney Children’s Hospital, Randwick 2031, New South Wales, Australia
[2] Children’s Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick 2031, New South Wales, Australia
[3] Oncology Unit, The Children’s Hospital at Westmead, Westmead 2145, New South Wales, Australia
[4] Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney, Westmead 2145, New South Wales, Australia

Address of Correspondence
Dr. Santosh Valvi FRACP
Kids Cancer Centre, Sydney Children’s Hospital, Randwick 2031, New South Wales, Australia


The management of Ewing sarcoma has evolved over the last few decades with successive improvement in survival rates. Multidisciplinary management is the key to successful outcomes. Dose intensity of chemotherapy is of vital importance. Local control can be effectively achieved with surgery, radiation therapy or a combination of the two. The choice of appropriate local therapy should be individualized and depends on various factors such as site, size, respectability, expected morbidity, long term effects etc. Metastatic disease remains a significant challenge and optimal therapeutic strategies still need to be defined. Current management and the role of radiation therapy in Ewing sarcoma are reviewed.
Keywords: Ewing sarcoma, radiation therapy, management

In 1921, James Ewing reported a group of primary radiosensitive tumors as diffuse endothelioma of bone, believing they arose from the blood vessels of bone tissue [1]. A few years later the noted Boston surgeon, Ernest Codman, referred to this new entity as Ewing sarcoma (EWS) [2]. EWS, a rare malignancy with a strong pediatric predilection, typically presents as a bone tumor [3]. It is the second most common primary malignant bone tumor in children and young adults, following osteosarcoma and accounts for approximately 3% of all childhood malignancies [4].

Over the last 30 years, the incidence of EWS has remained unchanged at around 3 cases per million per year [5]. With a median age of 15 years, it most commonly occurs in the second decade of life (Fig 1) [6]. There is a slight male predilection (male: female 1.2:1) and Caucasians are much more frequently affected than Asians and Africans [7,8]. Lower extremities are the most common site of bone disease (43%) while extraosseous primary tumors mostly occur in the trunk (32%) (Fig 2). Metastatic disease is present at diagnosis in about 20-25% of patients and affects the lungs, other bones or multiple systems [5,9].

Biology & Pathology
The World Health Organisation (WHO) classification uses EWS/primitive neuroectodermal tumor (PNET) as an inclusive term which encompasses classic EWS, Askin tumor of the thoracic wall, Ewing tumor, peripheral neuroepithelioma, peripheral neuroblastoma, Ewing family of tumors and Ewing sarcoma family of tumors [10]. EWS is derived from a primordial bone marrow-derived mesenchymal stem cell [11,12]. Histologically, EWS is characterised by a monotonous population of small round blue cells with a low mitotic activity of 15-20%. Cytoplasmic glycogen is abundant which gives periodic acid-Schiff (PAS) positivity [13]. The MIC2 gene product, CD99, a surface membrane glycoprotein is overexpressed [14] but it is not specific for EWS. Neural differentiation is evident in the form of positive vimentin in approximately one third of cases.
A reciprocal chromosomal translocation involving the EWSR1 gene on chromosome 22 band q12 combined with any of a number of partner chromosomes is pathognomonic of the diagnosis of EWS. The breakpoint was first cloned in the 1990s [12,15]. Although abnormalities of chromosome 11 are involved in 95% of cases [16], the translocation may involve chromosomes 21, 7 and 17 uncommonly [17,18]. The fusion protein resulting from this chromosomal rearrangement is a potent transcriptional factor which inappropriately activates the target genes, thereby exerting the oncogenic activity.
Other numerical and structural alterations seen in EWS are gains of chromosomes 2, 5, 8, 9, 12, and 15; deletions on the short arm of chromosome 6; the nonreciprocal translocation t(1;16)(q12;q11.2); and trisomy 20 [19,20].

Figure 1: Investigation Workflow for a newly diagnosed Patient with EWS
Figure 1: Investigation Workflow for a newly diagnosed Patient with EWS

EWS is defined by clinical and imaging techniques as localized when there is no spread beyond the primary site or metastatic when the tumor has disseminated to distant organs. Of all imaging modalities, 18FDG PET-CT has the highest specificity (96%) and sensitivity (92%) [21] and is superior to the traditionally used 99mTc-MDP bone scan for detection of bone metastases except for skull lesions [22]. Current recommendations for staging work-up include CT and/or MRI of the primary tumor, chest CT to detect lung metastases and 18FDG PET-CT for identification of distant metastases [23]. As bone marrow involvement is an independent risk factor [24], marrow biopsy has been an integral part of the initial work-up and is still recommended in ongoing clinical trials [25] (26). But recent studies have questioned the utility of bone marrow biopsy in localized [22,27] and metastatic disease [23].

fig 2

The 5 year survival rate for EWS was less than 10% before the advent of modern chemotherapy [28,29]. Currently, the survival rates are 70% for the patients with localized disease [30] and 30% for the patients with metastatic disease [9]. Among patients with refractory or recurrent disease, fewer than 20% of patients can expect to be long term survivors [31,32].
The presence of metastatic disease at diagnosis remains the most important adverse prognostic factor in EWS [33,34,35,36]. In patients with metastatic disease the site(s) of metastases can have an impact on the outcome. Patients with only lung metastases fare better (event free survival, EFS 29% to 52%) than patients with bone and/or bone marrow involvement (EFS 19%) [37,38] or combined bones and lungs involvement (EFS 8%) (34). Unilateral lung involvement has a better outcome compared with bilateral lung lesions [39].
Younger age (<15 years old) [5,40,41], female gender [42], tumor site (distal extremity better than proximal extremity and pelvis) [9], tumor size (volume less than 200 ml and single dimension less than 8 cm) [43], normal serum lactate dehydrogenase (LDH) levels at diagnosis [44], and decreased metabolic activity on 18FDG PET scan after presurgical chemotherapy [45,46] are associated with a more favourable prognosis.
Complex karyotypic abnormalities or chromosome number less than 50 in tumor cells at diagnosis [19], detection of fusion transcripts by polymerase chain reaction (PCR) in morphologically normal bone marrow [47], p53 protein overexpression, Ki67 expression, loss of 16q [48,49], overexpression of microsomal glutathione S-transferase (associated with doxorubicin resistance [50] may be associated with inferior outcome. Patients with secondary Ewing sarcoma [51] or with a poor response to presurgical chemotherapy [52,53] and patients relapsing less than two years after diagnosis (early) have a poorer prognosis [54].


Treatment options
Chemotherapy for a total of 10-12 months before and after local control is common practice [33,55]. Initial chemotherapy aims to shrink the tumor to increase to probability of effective local control. Alkylating agents, mainly ifosfamide and cyclophosphamide and anthracyclines form the chemotherapeutic backbone Etoposide, vincristine and actinomycin-D make up the remainder of the four-to five-drug combination chemotherapy.

Chemotherapy for newly diagnosed patients:
Clinical trials in the early years (pre-1990)
Before 1960s, radiation therapy and surgery were used for the treatment of EWS which provided adequate control of the primary disease but patients invariably died of metastatic disease [56]. Chemotherapy was added based on the hypothesis that, in most cases of apparently localized disease, tumor cells were already disseminated without clinical manifestations. Single chemotherapy agents including cyclophosphamide [57,58,59], vincristine [60], daunorubicin [61] and actinomycin-D [62] were trialled in 1960s with promising results.
From two- to as many as six-drug combinations have been used in various randomized and non-randomized trials for the treatment of EWS. Hustu et al [63] used a first ever combination with vincristine and cyclophosphamide with 80% overall survival. In Europe, the French Society of Pediatric Oncology (SFOP) [64,65,66], the United Kingdom Children’s Cancer Study Group (UKCCSG) [35,67], the Scandinavian Study Group (SSG) [68, 69] and the German/Austrian Cooperative Ewing Sarcoma Study Group (CESS) [70,71] performed early clinical trials. Subsequently, the European Intergroup Cooperative Ewing Sarcoma Study group (EICESS) and the European Ewing Tumor Working Initiative of National Groups (EURO-EWING) continued the trials. In the United States, initially the Intergroup Ewing Sarcoma Study (IESS) group [72,73,74], the Children’s Cancer Group (CCG), the Pediatric Oncology Group (POG) and subsequently the Children’s Oncology Group (COG) conducted trials for EWS.
Four-drug combination chemotherapy including vincristine, actinomycin-D, cyclophosphamide and doxorubicin was universally accepted for the treatment by the early 1980s [75] with survival rates between 36-60%. Ifosfamide and etoposide were identified as effective single agents [76,77] and subsequent studies established a survival benefit of their addition to VACD [78]. National Cancer Institute protocol INT0091 was a randomized trial conducted by the Children’s Cancer Group (CCG) and Pediatric Oncology Group (POG) from 1988 through 1992. Patients were assigned to receive VACD or VACD plus ifosfamide and etoposide (VACD-IE). In patients without metastatic disease, the five-year EFS for the VACD group was 54% while the same for the VACD-IE group was 69%. These results established VACD-IE as the gold standard for the treatment of localised Ewing sarcoma [30].
Clinical trials for standard risk (SR) and high risk (HR) EWS since 1990
The disease risk stratification into SR and HR has varied depending on the trial but in general SR means localized small tumors (<200 mL), or tumors with a good histological response to preoperative chemotherapy (<10% cells). HR tumors include metastatic tumors, or large localized tumors (>200 mL).
The trials for SR EWS have tried to address the important questions like the superiority of one alkylating agent over the other (cyclophosphamide and ifosfamide) and survival advantage by dose intensification or addition newer chemotherapy agents.


Cyclophosphamide vs Ifosfamide
Historically, cyclophosphamide was used for the treatment of EWS. Promising results were seen with ifosfamide in relapsed patients who did not respond to cyclophosphamide [83]. It was postulated that 9 g/m2 of ifosfamide was equimyelotoxic to 2.1 g/m2 of cyclophosphamide [84]. With the potential for less myelotoxicity and high-dose administration, cyclophosphamide was replaced with ifosfamide in the 1980s. But the results of these non-randomized, single-arm studies were mixed, with one study showing no benefit [66] while others proving superiority of ifosfamide over cyclophosphamide [71,67,69]. With this uncertainty of greater efficacy and long-term renal tubular damage with the cumulative dose of ifosfamide [85], its role in the consolidation treatment of EWS was debated. Two large randomized trials, EICESS-92 [79] and its successor Euro-Ewing99-R1 [80] investigated if cyclophosphamide can replace ifosfamide in the consolidation treatment of standard-risk EWS. The results of these studies confirmed that both the drugs had similar efficacy and though cyclophosphamide was associated with more haematological toxicity, the incidence of renal toxicity was much less as compared to ifosfamide. But the question of superiority of one drug over the other is far from resolved and needs further investigation in light of their efficacy to improve the survival [75].

Standard dose vs dose intensification
To improve the outcome, intensification of chemotherapy drug doses was investigated. One way of achieving dose intensification is by escalating the doses of chemotherapy agents while keeping the interval stable. National Cancer Institute protocol INT0154 used VDC+IE chemotherapy and randomized patients to standard (17 cycles over 48 weeks) or intensified (11 cycles over 30 weeks) arms. This study showed no improvement in the outcome of patients with nonmetastatic disease by dose escalation of alkylating agents (81) which was in contrast to an earlier similar study, IESS-II [74].
AEWS0031 trial investigated the feasibility of dose intensification by interval compression (increased dose density) in patients with localized disease [82]. Patients treated every two weeks (intensified arm) had an improved five-year EFS (73%) compared with the standard arm group receiving chemotherapy every 3 weeks (65%) with no increase in toxicity. Due to its superiority, interval compression is used in many ongoing trials.
The Children’s Oncology Group is currently conducting a phase III randomized trial of adding vincristine, topotecan and cyclophosphamide to standard chemotherapy for patients with localized EWS in an attempt to improve the outcome further [25].
The EICESS-92 study recruited 492 high risk patients of which 157 had metastatic disease at diagnosis. These patients were randomized to receive either VAID or etoposide in addition to VAID (EVAID). Although there was evidence that etoposide had a more pronounced effect in localized HR group, there was no benefit for the patients with metastatic disease with a three-year EFS of 30% [79].
The EURO-EWING99-R3 study enrolled 281 patients with primary disseminated multifocal EWS. 169 patients received the high dose therapy (HDT)/stem cell transplant (SCT) post completion of chemotherapy and local therapy. 3-year EFS for whole cohort was 27% and for patients receiving HDT was 37% [24].

Local therapy
The goal of local therapy is to maximize the local control with minimal morbidity. Surgery and radiation therapy are the two local control modalities employed for EWS. No randomized trials have compared these and as such their relative roles remain controversial [13].
Surgical resection provides information about the amount of tumor necrosis and may be less morbid in the younger patients. Radiation therapy is also associated with the development of second malignant neoplasms in a dose and time dependent manner [86]. A retrospective analysis of patients treated on three consecutive clinical trials for localized EWS showed that the risk of local failure was greater for patients receiving definitive radiotherapy but the EFS and OS were comparable for both surgery and radiation as local control modalities [87]. Microscopically complete surgical resection of localised disease remains the goal of neoadjuvant (or upfront) chemotherapy. Large bone defects after the surgery may be reconstructed using autogenous or allogenic bone grafts and endoprosthetic replacements [13]. Radiation therapy may be used as the main modality of primary disease control in patients with axial or unresectable primary disease. Careful consideration about the use of radiation, dose and volume is required, particularly in younger patients.
In patients with lung metastases, upfront whole-lung radiation may be used irrespective of the radiographic response following chemotherapy [88]. The results of the recently concluded Euro-EWING99 R2 pulmonary (AEWS0331) study which compared the HDT and peripheral blood stem cell (PBSC) rescue with the standard chemotherapy and whole lung irradiation are awaited. A multivariate analysis of the R3 arm of this trial including patients with metastatic disease emphasized the importance of aggressive local control of primary and metastatic sites. The EFS was higher with combined surgery and radiation compared to either modality alone or no local control [89].

High-dose therapy (HDT) and stem cell transplantation (SCT)
Despite advances in multimodal therapy of EWS, there remains a group of patients with high risk of treatment failure. These are primarily the patients with metastatic disease or with extensive unresectable localized disease and patients with a poor response to chemotherapy. This group has a poor 20%-30% disease free survival (DFS) [90,91]. Although conventional chemotherapy regimens induce remission, patients with metastatic disease relapse after a median of one to two years after completion of therapy owing to minimal residual or metastatic disease (MRD/MMD). In the 1980s trials investigating the role of SCT to consolidate remission by reduction of MRD/MMD began. The results of the initial National Cancer Institute (NCI) studies investigating total body irradiation (TBI) with autologous bone marrow transplant (ABMT) showed no improvement in survival [92]. Since then multiple reports have been published of consolidation using HDT followed by SCT but its role in the treatment of EWS has yet to be conclusively determined [93].

Melphalan vs busulfan-based conditioning regimens
Response to melphalan-based HDT has been variable. Some studies showed no additional benefit with poor survival rates between 5%-27% [34,90,94,95] while others [96,97,98] reported improved survival rates of 45%-50%. As use of high-dose busulfan combined with melphalan or other agents has shown promising results with survival rates between 36%-60% [99,100,101,102,103,104], these regimens have been widely used in high-risk patients.

Role of total-body irradiation (TBI)
Use of TBI during the consolidation phase had no survival advantage but increased the incidence of toxicity [92,94]. Two Meta European Intergroup Cooperative Ewing Sarcoma Studies (MetaEICESS) assessed the role of TBI in consolidation treatment. Patients received systemic consolidation in the form of hyperfractionated TBI with melphalan/etoposide in the first HyperME study or two times the melphalan/etoposide in the second TandemME study. EFS were similar in both studies while TBI containing regimen was associated with a higher incidence of toxicity [105]. In conclusion, although EWS is a radiosensitive tumor, there is limited role of TBI in its treatment because of poor efficacy and increased toxicity.

Autologous vs allogenic BMT
Allogeneic transplant may overcome the concerns with tumor cell contamination of stem cell products during autologous transplant [106] and have a potential of graft-versus-tumor (GVT) effect with improved survival. A retrospective analysis of the MetaEICESS study data showed that the EFS was 25% after autologous and 20% after allogeneic transplant [54]. As there was increased incidence of toxicity and no evidence of GVT effect after allogeneic transplant, there seems to be no advantage of allogeneic over autologous transplant.

Chemotherapy for recurrent EWS
Although around 80% of relapses occur within 2 years of initial diagnosis [107], late relapses occurring more than five years from the initial diagnosis are more common in EWS than any other pediatric solid tumors. The Childhood Cancer Survivor Study (108) retrospectively assessed more than 12,700 childhood cancer survivors and concluded that survivors with EWS were at a higher risk of late recurrence, 5-20 years after the diagnosis, than survivors with acute lymphoblastic leukemia. Time to relapse is an important prognostic factor with recurrences occurring within two years of initial diagnosis having worse five-year survival of 7% compared to 30% for patients relapsing after two years [32,107]. Number of recurrences also impacts the outcome with multiple metastatic recurrences having worse prognosis than isolated local or metastatic recurrence [107]. There is no established treatment for these patients and the preferred approach is to combine multi-agent chemotherapy with local modality of surgery and/or radiotherapy [109,110].
High dose Ifosfamide alone [111] or with carboplatin and etoposide (ICE) has been commonly used with survival rates between 29%-33% [112,113]. Cyclophosphamide and topotecan combination achieved response rates of 23%-44% with low toxicity and an added advantage of outpatient administration [114,115] but with a small median duration of response of 8 months [116]. Response rates of 29% to 68% and median time to progression of 3 to 8.5 months were seen with irinotecan and temozolomide [117,118,119,120]. Diarrhea was a troublesome complication which was managed effectively with oral cephalosporins. The combination was otherwise well tolerated. Although gemcitabine and docetaxel showed activity in one study [121], the results were not confirmed by subsequent studies. [122].
In case of recurrent EWS, the addition of HDT to salvage regimens is controversial. Some studies showed a good response in specific groups of patients who responded to relapse therapy and underwent HDT with OS rates of 53 to 66% [123,124], but most of the reports indicate HDT does not improve prognosis [54,125,126].

Targeted therapy for EWS
Tyrosine kinase (TK) inhibitors
TKs are important modulators of growth factor signaling and play a critical role in tumor growth. TK inhibitors are used alone or in combination with conventional chemotherapy agents in treatment of various cancers (127). A number of TK inhibitors have been tried in EWS with variable response.

Insulin-like growth factor 1 receptor (IGF1R) inhibitors
IGF1R is necessary for growth and development of normal as well as cancer cells [128]. With promising pre-clinical results showing IGF1R inhibition in EWS cell lines and xenografts [129], more than 25 agents inhibiting IGF1R are currently under investigation [130].
IGF1R monoclonal antibodies including R1507 (131), figitumumab [132], ganitumab (AMG479) [133], cixutumumab [134,135], and robatumumab (SCH-717454) [136] have shown activity in early phase clinical trials with response rates ranging from 6-14% and a favourable safety profile. But the results of the phase II studies were less impressive compared with the promising preclinical and early clinical data [137]. Small-molecule inhibitors of IGF1R such as GSK1838705A [138], GSK1904529A [139], BMS-754807 [140], and INSM-18 [141] are also in preclinical and clinical development.
Phase II clinical trials of imatinib, a TK inhibitor of the BCR-ABL fusion protein [142,143,144] and dasatinib, a multitargeted TK inhibitor [145] showed no efficacy in EWS.

Biologic agents
Angiogenesis inhibitors
Neovascularization plays a critical role in the pathogenesis of EWS [146] and targeting vascular endothelial growth factor (VEGF) may interfere with vasculogenesis, providing a novel therapeutic approach [147]. A phase I study [148] and a randomized phase II trial [149] conducted by the Children’s Oncology Group have shown the feasibility and tolerability of bevacizumab in EWS patients. Another phase II study investigated the role of vinblastine and celecoxib as angiogenesis inhibitors in combination with the standard chemotherapy (150). Although the feasiblity of this combination was established, there were significant pulmonary and bladder toxicities.

Histone deacetylase (HDAC) inhibitors
HDAC inhibition suppresses EWS-FLI1 expression and may represent a novel therapeutic target for EWS (151).

Mammalian target of rapamycin (mTOR) inhibitors
MTOR is a serine/threonine kinase with critical role in protein synthesis, cell growth and proliferation regulation. mTOR inhibitors have shown activity in preclinical models. A phase I study of temsirolimus, irinotecan and temozolomide demonstrated efficacy and tolerability [152]. But another phase II study of temsirolimus with cixutumumab did not show any objective response despite the encouraging preclinical data [153]. Ridaforolimus was associated with a statistically significant but clinically small benefit on PFS [154].

Aurora A kinase inhibitors
Although alisertib (MLN8237), an Aurora A kinase inhibitor produced promising results in the Pediatric Preclinical Testing Program [155], a recently concluded Children’s Oncology Group phase II trial failed to establish its efficacy in EWS [156].

Hedgehog pathway modulation
Arsenic trioxide was effective in inhibiting EWS growth in preclinical cell culture models by targeting p38(MAPK) and c-Jun N-terminal kinase [157]. These observations warrant further investigation.

Zoledronic acid acts by inducing apoptosis by upregulating osteoprotegerin which was the basis of activity seen in EWS pre-clinical models [158,159]. However, confirmatory clinical trials have not been performed.

Immune therapy
Interleukin-15-activated natural killer (NK) cells combined with HDAC inhibitors improve immune recognition of therapy-sensitive and –resistant EWS and sensitize for NK cell cytotoxicity [160]. Allogenic NK cells have shown activity against EWS cells on their own [161].

EWS-FLI1 targeting
Targeting the EWS-FLI1 fusion protein or its key signalling pathway is another attractive approach [162]. YK-4279, a small molecule inhibitor of EWS-FLI1 protein activity [163,164], mithramycin, a chemotherapy drug [165] and midostaurin (PKC412), a multikinase inhibitor [166] have shown activity in preclinical models.


Many advances have been made in the management of EWS since its first description almost 100 years ago. Molecular and imaging techniques are progressing at a rapid pace allowing for newer insights into the biology of this disease. From radiation therapy alone, the treatment has evolved to include multiple modalities. The outcome for localized disease has improved dramatically but more needs to be done for patients with metastatic or recurrent EWS. Targeted therapies may offer some hope for the latter group.


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How to Cite this article: Valvi S & Kellie SJ. Ewing Sarcoma: Focus on Medical Management. Journal of  Bone and Soft Tissue Tumors May-Aug 2015;1(1):8-17.

Dr. Santosh Valvi
Dr. Santosh Valvi
Dr. Stewart J Kellie
Dr. Stewart J Kellie

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Journal of Bone and Soft Tissue Tumors: A New Beginning

Vol 1 | Issue 1 | May – August 2015 | 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.

Editorial: Journal of Bone and Soft Tissue Tumors: A New Beginning

The faculty of bone and soft tissue tumors has seen tremendous growth in terms of recognition and advancement in recent years. As pointed out by Dr Ajay Puri [1] the field is fairly new in India but has shown great promise both in terms of patient care and education. The aspects of education on which the Journal of Bone and Soft Tissue Tumors (JBST) will focus is on inter disciplinary collaborations and providing platform for publication of relevant research and clinical studies from all over the world and specially from Asia. The journal also aims to provide the most relevant and practice based information to everyone involved in care of bone and soft tissue tumors.
Cancers on a whole and bone tumors specifically require multidisciplinary approach towards managing patients. Orthopaedic Oncology as it is termed is not simply a surgical branch but requires inputs from various different faculties including orthopaedic oncologist, radiologist, pathologist, medical oncologist, radiation oncologist, pediatric medical oncologist, surgical oncologist, plastic surgeons and micro-vascular surgeons. In fact the first symposium published in JBST is written by pediatric oncologists, radiation oncologist and orthopaedic oncologist which say a lot about how important this interdisciplinary collaboration is to JBST[2,3,4]. JBST specifically aims to provide a platform where multiple faculties can come together and interact. We have inter disciplinary members on the editorial board and in coming months we will be expanding this further to include many more faculties like biomechanics, genetics, basic sciences and Prosthetics. This will help us understand the viewpoints of each other and also help us provide better patient care.
The other aim of the journal is promotion of research activities and publication of clinically relevant articles not only from the western world but also from Africa and Asia. Although research has been increasingly seen as gaining importance in our country but there exists a lot of research apathy and research lethargy. JBST aims to provide a platform for publication and will also provide assistance in manuscript preparation which will be useful for new researchers and writers. This assistance will be provided through the writers club of the orthopaedic research group which is also involved in conception and publication of the Journal. Thus the authors will be supported at every stage of publication and best quality articles will be made available to readers
The main focus of the Journal will be to provide clinically relevant articles that will be directly applicable to treating patients in real world and not only on paper with statistics. We urge our authors to keep statistics to minimal and to use only basic statistics in their articles and focus on bringing out the clinically relevant points in their articles. The reviewers too are advised to focus on the clinical relevance of the article and on the paradigm in which the particular article will be useful in treating patients. The journal will focus both on Evidence based medicine and on Practice based medicine and will try to find a balance between the two. With this in mind features like expert reviews, narrative reviews will be published along with systematic reviews. Technical notes and case reports, case studies will be regular features and will have specific focus on case based approach to particular clinical scenario.
With these aims we have embarked on a journey toward excellence in treatment of bone and soft tissue tumors. We would like to thank all the editorial board members who encouraged us and helped us in every way to start this venture. We thank all our authors who provided us with excellent articles and lastly we thank our reviewers who did rapid reviews and corrections in the articles. We thank the Orthopaedic Research Group for supporting this venture and helping at every step of the publication process. The future of JBST looks very promising specially with the support from the editorial board. We as a team are committed to JBST and aim to make this journal a landmark publication in years to come.
With this we leave you to enjoy the First issue of the Journal of Bone and Soft Tissue Tumors.

Yogesh Panchwagh & Ashok Shyam


1. Puri A. The “ODYSSEY”: “Orthopaedic Oncology” – My journey thus far! Journal of Bone and Soft Tissue Tumors May- Aug 2015;1(1):3-5
2. Valvi S & Kellie SJ. Ewing Sarcoma: Focus on Medical Management. Journal of Bone and Soft Tissue Tumors May-Aug 2015;1(1):8-17
3. Irukulla MM, Joseph DM. Management of Ewing Sarcoma: Current Management and the Role of Radiation Therapy. Journal of Bone and Soft Tissue Tumors May-Aug 2015;1(1):18-22
4. Panchwagh Y. Ewing Sarcoma: Focus on Surgical Management. Journal of Bone and Soft Tissue Tumors May-Aug 2015;1(1):23-28

How to Cite this article: Panchwagh Y, Shyam AK. Journal of Bone and Soft Tissue Tumors: A New Beginning Journal of  Bone and Soft Tissue Tumors May-Aug 2015; 1(1):1-2

Dr Yogesh Panchwagh
Dr Yogesh Panchwagh
Dr Ashok Shyam
Dr Ashok Shyam

(Abstract)      (Full Text HTML)      (Download PDF)