Traditionally, the determination of malignancy and its grade in cartilage tumours has been from the combination of history, radiographic features with or without computed tomography and histologic examination 123. More recently, magnetic resonance imaging has also been employed 456. However, cartilage tumours are recognized for their histologic heterogeneity 789 and bizarre physical features, such that reliance on anatomic imaging and accuracy of biopsy alone for interpretation of state of malignancy or benignity may be misleading. While the recognition of high grade malignancy is not difficult, the differentiation between benign and low grade (grade I) tumours can present a diagnostic dilemma 1011. Such a dilemma may lead inadvertently to under-or over-treatment of cartilage tumours.

Functional nuclear scans employ isotopes that become substrates for various cellular metabolic cycles and therefore, are useful for determining the metabolic activity in these tissues 12. Given that malignant tumours are more metabolically active than benign tumours, and that there is a relationship between grade of malignancy and metabolic activity, functional nuclear scans may help to differentiate between cartilage tumours of varying metabolic activity, which in turn, may shed some light on their state of malignancy.

We now report our experiences with 2 radio-siotopes, Thallium-201 (Tl-201) and pentavalent dimercaptosuccinic acid (DMSAV) for determining the metabolic activity of cartilage tumours, and their value in differentiating between malignant and benign cartilage tumours in 92 consecutive cartilage tumours. We describe their role in the development of our current regimen for treating cartilage tumours.

Anatomic imaging such as computed tomography 13 and magnetic resonance imaging 45614 provide excellent morphologic delineation and localisation of bone tumours. These tests are invaluable in the surgical planning for patients with musculoskeletal tumours However, these tests do not always give an indication of the biologic behaviour of the tumour, particularly if there are subtleties between benign and low grade malignant states 15. Cartilaginous tumours of bone are characterized by radiologic and histologic heterogeneity 78 that may give rise to diagnostic dilemas. Benign tumours such as enchondromas and osteochondromas may appear large and bizarre giving an impression of biologic aggressiveness, particularly those in the hand, while some chondrosarcomas such as a clear cell chondrosarcoma may be small, well defined, slow growing and apart from osteolysis have no other hallmark of malignancy 161718 such as cortical destruction or soft tissue extension to express its malignant phenotype. One of the major difficulties in orthopaedic oncology is the differentiation between enchondroma and grade 1 chondrosarcoma 19.

Conventional technetium monodiphosphonate skeletal scans are employed to identify uni-or multifocal disease when bone tumours are suspected 12. For positivity, this scanning modality relies on the interactions between tumour and host bone that incite an osteoblastic response by adjacent bone and does not necessarily imply malignancy. For example, enchondroma and chondrosarcoma frequently demonstrate a similar uptake of nuclear tracer, without differentiating between benignity and malignanc.

Reliance on preoperative histologic diagnosis for determining the nature of a cartilage lesion can also be difficult. Biopsy of a suspicious cartilage tumour is most helpful when clear malignancy is demonstrated because a benign finding does not necessarily exclude malignancy. The histologic heterogeneity of cartilage tumours, however, is well recognized and unless the biopsy accurately targets the most malignant part of the tumour, there is a risk that the histologic diagnosis may under-report the state of malignancy if this should exist.

Functional nuclear scans reflect the metabolic activity of tumours and may provide important information regarding their biologic behaviour. In this regard, hypermetabolic tumour tissue is likely to be more active than surrounding normal tissue and this difference may be valuable for distinguishing between benign and malignant tumours. Similarly, when dealing with grades of malignancy, a higher level of metabolic activity may be expected from high grade tumours in comparison to lower grade counterparts. Since the late 1970s, thallium (Tl-201) scanning has been used extensively as a safe method to assess ventricular function in patients with myocardial ischaemia and the results have been interpreted as reflecting relative levels of myocardial metabolic activity. As Tl-201 is a potassium analogue, its uptake into cells depends on the sodium potassium ATPase dependent pump. Tl-201 is a readily available, cyclotron produced radionuclide that decays by electron capture with a half-life of approximately 73 hours. The liver, spleen, kidneys, myocardium, thyroid, choroids plexus of the lateral ventricles and testis normally demonstrate avidity for Tl-201, with very minimal uptake in healing surgical wounds. Tl-201 is thought to accumulate less well within connective tissue, which contains inflammatory cells and almost undetectable in necrotic tissue. Localization of Tl-201 within tumours appears to be influenced by tumour vascularity, tumour cellularity, the metabolic rate of the tumour and the histological type of tumour. Thallium uptake studies 20212223 in patients with bone tumours have been used to predict response to preoperative chemotherapy by correlating the histological degree of tumour necrosis to changes in Tl-201 uptake. The correlation between thallium uptake and tumour metabolic activity, thus makes it a good candidate tracer to assess malignancy in chondromatous tumours. 99Tcm-Dimercaptosuccinic acid (DMSA) is another readily available isotope, which was first described as an isotopic agent for investigating the renal parenchyma in a variety of disease entities 242526. Subsequently, the pentavalent form of 99Tcm-dimercaptosuccinic acid (99Tcm-(V)DMSA) developed a recognised role for imaging medullary thyroid carcinoma, 27282930 and this role was further investigated in relation to assessing bone metastases and other neoplastic conditions such as multiple myeloma, osteosarcoma and chondrosarcoma. 313233; 2834. Of note, uptake of DMSA(V) is reported to be absent in vertebral collapse and osteoarthritis 35.

Our study has demonstrated that the combined use of Tl-201 and DMSA(V) scanning may be correlated with the benignity, malignancy and grade of cartilaginous tumours. For a tumour that is hetereogeneous not only on radiologic but also pathologic appearance, the use of functional nuclear scanning may help to differentiate particularly between the low grade and benign lesions. Of note, no malignant lesion had a negative DMSA(V) scan, and only 2 out of 45 benign tumours showed thallium uptake in our study.

While this modality of investigation does not replace the value of combining elements from the clinical presentation, plain radiographic changes and pathology, functional nuclear scanning may increase the confidence of diagnosing a low grade or benign tumour, and the availability of information preoperatively may also be helpful for tumours that are deeply situated and difficult to biopsy. With regard to biopsy, localized thallium or DMSA(V) positivity may be useful for guiding tissue sampling from the most metabolically active site, thus enhancing the procurement of potentially the most aggressive/malignant part of the tumour 12.

Although, the median duration of follow up in this study was limited to 3.7 years, the high proportion of metastases in patients whose sarcomas were thallium positive may suggest a role for thallium scanning as a prognostic indicator for metastasis in chondrosarcoma. Interestingly, the combination of DMSA(V) with thallium scanning did not improve the prognostic value for metastases. This may be attributed to the fact that the spread of DMSA(V) positivity amongst the tumours was greater than thallium positivity, whereas the latter was positive only in patients with grade II and III chondrosarcomas, which are the ones that mainly metastasise.

We cannot explain why 2 out of 45 benign tumours were thallium positive. The specimens were reviewed by a panel of pathologists expert in bone pathology and none conferred a diagnosis of sarcoma. In both of these cases, DMSA(V) positivity was also observed. It is important to note that these tumours occurred in the hand and foot, although not part of the syndrome of enchondromatosis. It is appreciated that small bone enchondromata may behave locally in a very aggressive manner without any cytologic evidence of malignancy 19. However, small bone chondrosarcoma are also know to be fatal and careful inspection of imaging and pathology is required to ensure distinction between benign and malignant lesions which may behave similarly 3637. No conclusion can be drawn about the biologic significance of our finding of 2 benign small bone tumours with thallium uptake, in view of the very small numbers of these in our study. One patient had a small toe amputation and the other had curretage, chemical cautery and cementation of a phalangeal lesion. Neither have represented with local or systemic recurrence of disease.

As a result of this study, we now undertake the following sequence of scanning and treatment (Figure 1). All patients with a suspected chondral tumour would undergo a DMSA(V) scan. If this is negative, no further scanning is performed and the tumour is regarded as benign because our study had indicated that no malignant tumour had a negative DMSA(V) scan. These tumours would then be treated on their individual merits. If there is uptake on the delayed DMSA(V) scans our study had indicated that half of these are likely to be malignant therefore, patients would undergo thallium scanning. If there is no uptake, then based upon our study, the result would be interpreted as benign cartilage tumour or grade 1 chondrosarcoma. Patients may then undergo intralesional curettage with chemical cautery and cementation or wide excision. If there is uptake on the thallium scan, our study demonstrated that there is a very high likelihood that these tumours would be grade II or III and a wide excision would be recommended.

Surgical treatment for cartilage lesions vary widely 38. Intralesional curettage together with local adjuvant treatment is often recommended for benign tumours but the management of chondrosarcoma follows the same principles as espoused for all sarcomas 3940. Wide resection with a cuff of normal tissue radially and axially around the tumour is encouraged. The importance of good margins is highlighted by the predilection for local recurrence of incompletely excised chondrosarcoma 414243, and also because of the risk of chondrosarcomas recurring at a higher maliginancy grade with its associated increased risk of metastasis 44. Inaccurate diagnosis and or grading may thus result in under- or over treatment of cartilage neoplasms that may later manifest as troublesome local recurrence or unnecessary loss of function from ablative surgery.

The management of grade 1 tumours remains controversial. Some authors have recommended intralesional curretage, adjuvant treatment and cementation for these lesions 4546. In a series of 40 enchondromata and low grade chondrosarcomas, Bauer et al. observed a local recurrence of 0.09 over 10 years using this modality of treatment. In all cases, local control was subsequently achieved by repeating the earlier surgery on the recurrence. Neither recurrence occurred as a higher grade of tumour. In contrast, some have recommended wide excision of grade I lesions and so called "borderline" chondrosarcoma for fear of tumour recurrence at a higher grade, which would portend toward a poorer outcome 4748. The relationship between thallium positivity and higher grades of chondrosarcoma in our study suggests that it would be important to review in a prospective manner the outcome of surgery based upon our algorithm of preoperative scanning.

There has been rising interest in studying non-invasive techniques of imaging cartilage tumours to try and determine their biologic aggressiveness prior to definitive surgery. The advantages of functional nuclear scanning with DMSA(V) and thallium are that they are easy to perform in the majority of nuclear medicine departments, the isotopes are easily available and the costs are not prohibitive. We have found that the information derived from our study complements other imaging modalities and apart from improving our understanding of cartilaginous tumours, has also assisted us in developing a strategy for their treatment.

The author(s) declare that they have no competing interests.

TL-201 – Thallium -201

DMSA(V) – Pentavalent dimercaptosuccinic acid

Prof. Peter Choong Surgeon, carried out surgery, participated in clinical and diagnostic practice. Wrote and prepared manuscript

Dr. Toshikunisada Orthopaedic oncology fellow, collected diagnostic data

Dr. Stephen Schlicht Nuclear physician, Participated in manuscript preparation, and conduct of diagnostic tests

Dr. Rodney Hicks Nuclear physician, Participated in manuscript preparation and conduct of diagnostic tests

Dr. John Slavin Pathologists, participated in blinded review of patients histology