The basic science of musculoskeletal tumours

Abstract

The basic science of musculoskeletal tumours is a complex subject and has been historically related to pathological descriptions of the lesions. Our understanding of these conditions has increased rapidly with the advent of genetic sequencing and molecular diagnostic techniques. This article covers the main topics and touches on the relevant research strategies which seek to open up further management options, particularly for the sarcomas.

Introduction

Musculoskeletal tumours encompass a wide variety of entities, and our understanding of them has been historically based on the traditional pathological descriptions of the lesions. These descriptions have evolved into a classification system, of which the World Health Organization (WHO) classification of bone and soft tissue tumours is the essential cornerstone. The histological features of the tumours are now complemented by an array of cytogenetic and molecular diagnostic assays which are increasingly useful for those cases which are equivocal and for further confirmation of a diagnosis. An example of this is cytogenetics to confirm presence of the EWS/FLI1 fusion product in a suspected Ewing’s sarcoma with a histological description of small round blue cells along with immunohistochemical staining that demonstrates high expression of CD99. Another example would be an equivocal case of an active lytic bone lesion that is likely to be benign but with persistent concern that it may actually be a telangiectatic osteosarcoma. The presence of a USP6 rearrangement on cytogenetic testing in such a case would be reassuring that it is an aneurysmal bone cyst, which of course has major implications on the treatment strategy. Therefore it is the progressive understanding of the basic science of these lesions which allows us to improve upon diagnosis and management of this diverse group of musculoskeletal tumours. This section will cover the important basic science features of musculoskeletal tumours including tissue of origin, whether the lesion is benign or malignant, common features and pathophysiology. There will also be a discussion of research strategies in the basic science arena which serves to improve our understanding of these conditions and ultimately leads to advances in diagnosis and management.

Tissues of origin

Musculoskeletal tumours can arise from several main tissue sources. The majority of primary lesions originate from mesenchymal tissue which is analogous to the mesoderm in embryological terms. Neuroectodermal tissue can give rise to primary nerve sheath tumours in the musculoskeletal system and some primary lesions develop from primitive neuroectodermal tissue which is a remnant of embryological neuron precursors. Tumours may be secondary due to spread from carcinomas, with bone being the most common site. These metastatic lesions are therefore of epithelial origin, but have a complex interaction with their host site. Haematological conditions can manifest as musculoskeletal tumours, the main ones encountered by the orthopaedic surgeon being myeloma and lymphoma. Finally, syndromic conditions may give rise to widespread musculoskeletal tumours which are often benign but need to be closely observed for malignant transformation.

Tumours of mesenchymal origin

There are a vast array of primary benign and malignant tumours which arise in the musculoskeletal system. Benign tumours consist of dozens of sub-types based upon histological description. Malignant tumours are mainly the sarcomas of which more than 50 types are described and again, histological description is the mainstay of classification. Broadly, benign tumours are defined by their inability to metastasize but can be locally aggressive and therefore pose significant management problems, as exemplified by fibromatosis. Malignant tumours have the potential to metastasize and cause death and therefore management is complex and multi-modal to optimize outcomes. There are some intermediate tumours which are often locally aggressive but very rarely metastasize such as giant cell tumour of bone. In is important to consider that some benign tumours have the potential to undergo malignant transformation, such as the large atypical lipomas.

Benign versus malignant tumours

The large number of musculoskeletal tumours is too extensive to list but can be placed into groups in to make initial management decisions easier. Figures 1 and 2 show flow diagrams for benign and malignant tissue tumours respectively.

The diagnosis of benign lesions may be achieved with clinical examination and imaging only, but if there is doubt a biopsy, usually in the clinic may be required for confirmation. Management is then dependant on whether the patient is symptomatic or if the lesion has a risk of malignant transformation then excision may be advised.

The largest group of patients with malignant lesions in the musculoskeletal system are patients suffering from metastatic carcinoma or myeloma affecting bone. Many of these patients require surgical intervention prevent an impending pathological fracture or to treat a fracture that has already occurred. It is important to remember that melanoma can metastasize into bone and therefore is there is doubt about the origin of a lesion a biopsy should be performed. The management of bone and soft tissue sarcomas and metastatic disease has been dealt with in chapters 4 and 5.

Finally, there are some locally aggressive bone lesions with a low risk of metastasizing. These are listed in Box 1 . These lesions should be managed by a bone sarcoma centre.

Box 1

Intermediate bone tumours that rarely metastasize

•

Giant cell tumour of bone
•

Chordoma
•

Epithelioid haemangioma
•

Epithelioid haemangioendothelioma
•

Adamantinoma

Benign bone tumours

These lesions will been seen by orthopaedic surgeons in a diverse range of subspecialties and can often be dealt with minimal input from an orthopaedic oncology centre. If there is any concern regarding the diagnosis, it is important that the lesion is discussed with the local oncology team and investigations with the appropriate imaging and biopsy performed. Some benign lesions may require excision by an orthopaedic oncologist if the anatomical location would require an extensive approach with mobilization of neurovascular structures ( Figure 3 ).

It is also important to consider that a benign bone lesion may be related to a syndrome, for example multiple hereditary exostosis (EXT gene mutations) or multiple enchondromatosis, the underlying pathophysiology of which is unclear. Such patients need to be monitored closely for malignant transformation in one of their lesions, particularly if it increases in size or becomes painful.

Enchondromas are commonly referred for further evaluation when they are noted incidentally on an MRI scan for joint pain, typically in the distal femur. It is important to re-scan these lesions to assess for change and in some centres dynamic contrast MRI is used to distinguish between enchondroma and grade 1 chondrosarcoma.

Benign soft tissue tumours

There are a huge range of benign soft tissue lesions encountered by the orthopaedic surgeon. Lipomas and ganglions are the most common. Diagnosis should be confirmed by ultrasound and management is based on symptoms. Deep lipomas (subfascial/intramuscular) may reach impressive sizes. MRI is required to exclude areas of dedifferentiation prior to marginal excision. Many of these large deep lipomas will be given a diagnosis of atypical lipomatous tumour (ALT) by the pathologist based on cellular atypia and positive p16 (tumour suppressor protein), MDM2 (tumour promotor protein) and CDK4 (cell cycle regulator) immunostaining. Loss of p16 activity and MDM2 amplification are postulated to be potential events that may lead to the transformation of ALT into liposarcoma.

Malignant primary bone sarcomas

The three main bone sarcomas are osteosarcoma, Ewing’s sarcoma and chondrosarcoma. Each of these malignancies display unique biological characteristics which impact on medical and surgical management.

Osteosarcoma

The origin of the osteosarcoma cells is likely to be from an osteoblast precursor which undergoes an oncological event during rapid cell division, classically at the physis which is the anatomical site of most lesions. The genetic map of osteosarcoma is complex and despite concerted efforts to identify clear targetable mutations via next generation sequencing, there has been little progress. Mutations and deletions of the TP53 gene which encodes for the p53 tumour suppression protein have been described but this is not directly targetable. Research efforts therefore continue to try and discover novel targets and there are clinical trials running involving a tyrosine kinase inhibitor (Lenvatinib) for relapsed osteosarcoma and an immune check-point antibody pembroluzimab.

Ewing’s sarcoma

This malignancy most often occurs in bone, however there are some soft tissue variants. 85% are driven by the EWS/FLI1 fusion product with the other 15% featuring different translocations. Ewing’s sarcoma is usually very chemosensitive and is also radiosensitive. This may be due to the lack of an extra cellular matrix which provides a barrier to therapy in many solid tumours. Further details on the commonest translocation are described in the histology and diagnostic section below.

Chondrosarcoma

This cartilage-producing bone tumour is resistant to chemotherapy and generally to radiotherapy unless situated in the skull base. The glycosaminoglycan-rich chondroid matrix expressed by the tumour cells may be a factor in mediating resistance to therapy. Surgery is therefore the mainstay of treatment but local recurrence can become a difficult problem with the grade of the sarcoma increasing over time. Potential new therapeutic targets include IDH mutations as identified by next generation sequencing and immunotherapy against neuron glial antigen-2 which is a heavy transmembrane proteoglycan highly expressed on the surface of chondrosarcoma cells.

Malignant primary soft tissue sarcomas

The soft tissue sarcomas (STS) are a diverse range of malignancies which can arise in any site with connective tissue. Most are managed with surgery and radiotherapy. Chemotherapy tends to play a minor role in most cases although can be very effective in certain paediatric types such as rhabdomyosarcoma. The commonest type of STS encountered is the myxofibrosarcoma which is diagnosed on descriptive grounds on the histology. Myxofibrosarcomas display interesting infiltrative behaviour which is the subject of emerging research studies as the pathophysiology is poorly understood. In contrast, synovial sarcoma which is driven by a particular fusion product has been studied in depth with recent findings revealing that the SS18/SSX fusion product causes oncogenesis via the perturbation of BAF complexes which regulate DNA folding. These findings are important as there may be therapies that can be developed to improve the medical management of synovial sarcomas which are often resistant to chemotherapy.

Neuroectodermal tumours

The orthopaedic oncologist will deal with musculoskeletal tumours arising from neuroectodermal tissue on a regular basis because these lesions occur in peripheral nerves. There are benign and malignant forms and there are genetic conditions which lead to multiple lesions. The commonest nerve sheath tumour encountered is the schwannoma. These are benign and most are easily excised. Recently a schwannomatosis disorder has been described which shares some clinical features with neurofibromatosis type 2, but is now recognized to be a distinct condition with a particular driver mutation. Neurofibromatosis type 1 is a condition where patients suffer from a range of neurofibromas many of which may be excised during their lifetime. In patients with neurofibromatosis and schwannomatosis, clinicians must be alert to the possibility of malignant transformation in a lesion. The precise biology leading to malignant change in a lesion involves the dysregulation of tumour suppressor pathways caused by the underlying genetic mutations.

Metastatic and haematological tumours

Malignant bone lesions in the form of metastases from primary carcinoma along with the haematological malignancies myeloma and lymphoma are commonly encountered in orthopaedic practice. Carcinoma cells that metastasize into bone will interact with their host environment and in certain types, lytic lesions are the result which leads to an impending or actual pathological fracture, classically in the proximal femur. The development of these lytic lesions is not from direct bone resorption by the cancer cells, it is via the stimulation of osteoclast formation ( Figure 4 ).