Soft tissue sarcomas include all sarcomas except those that arise from bone, the pretext giving the tissue of origin thus: leiomyo-sarcoma (for sarcomas arising from smooth muscle), neurofibro-sarcoma (for those arising from neural sheaths), fibro-sarcoma (for those arising from fibrous cells – and malignant fibrous histiocytoma is a variant of this type), rhabdomyo-sarcoma (for those arising from voluntary muscle cells), lipo-sarcoma (for those arising from fat cells), synovial sarcoma (for those arising from the synovium of joints), angio-saarcoma (for those arising from blood vessel tissue) etc…
It is clear that the group is a very heterogenous one but enough similarity exists for us to consider the group together.
Sarcomas are malignant tumours of the mesenchyme – the background matrix tissues of the body (the third germ layer). Where the sarcoma is resembles the tissue of origin (e.g. long stranded cells, perhaps even demonstrating the cross striations of voluntary muscle and indicating rhabdomyosaarcoma) the diagnosis is easily reached by the histologist.
However, many sarcomas are poorly differentiated and down the microscope it is difficult for the histologist to tell whether such a tumour has a sarcomatous origin. Here the recent explosion of special staining methods and immunocytogenetics has assisted greatly. Thus sarcomas frequently stain for desmin and vimentin (whereas poorly differentiated melanomas stain for melanin and S-100 [although some sarcomas can also stain for S-100], lymphomas stain for leucocyte common antigen – LCA- and carcinomas stain for cytokeratin).
Furthermore, there are well recognised cytogenetic abnormalities such as the expression of t[X;18][p11.2;q11.2] in the tumour cells of synovial sarcoma, t[11:12]]q24;q12] in Ewing’s sarcoma, and t[12;16][q13;p11] in myxoid sarcoma – all of which may help the histologist to identify the tissue of origin of a poorly differentiated tumour.
Overall, the rhabdomyosarcomas predominate in childhood and in adults the distribution of frequency is: Malignant fibrous histiocytoma 20-25%, fibrosarcoma 15%, liposarcoma 15%, leiomyosarcoma 10%, rhabdomyosarcoma 8%, synovial sarcoma 7%, neurofibrosarcoma 7%, others 12%.
Lastly it is now the histologist’s job to grade the sarcoma, as it has been firmly established that the tumour’s grade is strongly related to overall outcome/prognosis.
The grading is based on tumour differentiation (a point we have already alluded to with regard to well differentiated tumours resembling the tissue of origin and poorly differentiated tumours having no such distinguishing foot-prints), pleomorphism, which refers to heterogeneity of appearance of different cells within the sarcoma, cellularity (density of cellular composition within the tumour), number of mitoses (i.e. the number of cells in division when viewed at the moment of preservation of the histological specimen – a modern method of assessing this is by the use of a special stain called the Ki-676 stain which picks up a nuclear antigen that is only present in mitosing cells) and various other factors such as vascular (blood vessel) formation and invasion of such vessels – all to suggest a scoring system which predicts the aggressiveness of behaviour of the tumour. The final score would segregate the sarcoma into a low, intermediate or high grade cancer (sometimes graded 1-4 respectively).
A low grade tumour would resemble the tissue of origin, most of the cells would conform to this picture; it would have a low number of mitoses per high power microscope field and no vascular invasion.
There are established predisposing factors: The condition neurofibromatosis (syn. Von Recklinhausen’s syndrome) predisposes to neurofibrosarcomas as does the multiple endocrine neoplasia syndrome – the former as malignant change in benign neurofibroma.
The syndrome: Gardner’s syndrome predisposes to desmoids (benign fibroid tumours) and occasional sarcomas arise.
Li Fraumeni syndrome is a strongly familial syndrome with an hereditary predisposition to multiple cancers of which sarcomas are but one type – the causative genetic defect is an aberration of the p-53 gene, that has now been recognised as a strongly influential tumour suppressor gene in normal physiological life.
In the hereditary type of retinoblastoma (a childhood malignant eye tumour) the loss or mutation of another tumour suppressor gene called the RB gene leads to predisposition to sarcomas.
There are other predisposing syndromes that are less well elucidated. Radiation exposure predisposes to a higher risk of developing sarcomas (and malignant fibrous histiocytoma is the commonest radiation induced sarcoma type) and to a lesser extent so too does mutagenic cytotoxic chemotherapy.
Sarcomas are cancers that arise from the background supporting cells of the body – the mesenchyme – (in contrast to the more common: carcinomas that arise from lining epithelial cells).
They are less frequent in incidence (perhaps 1% of all cancers) but important in that they often occur in younger ages (there are two age peaks: childhood and past 55 years) and can be curable, if caught early and treated correctly.
As has been said, the incidence is perhaps 1% of cancer overall, and the majority occur without predisposing recognised syndromes.
There is an unequal distribution of anatomic sites from which sarcomas arise: thus, the lower limbs are the commonest site of origin of soft tissue sarcomas in adults, followed by the upper limbs, the torso and then the head and neck region and retroperitoneum.
The disease is slightly more common in males.
This contrasts with the incidence of childhood where the disease accounts for 8% of all childhood cancer and the tumours are very much most commonly rhabdomyosarcomas and the distribution is 1/3 in the genitourinary system, 1/3 in the head and neck region and 1/3 in the rest of the body.
Symptoms & diagnosis: Soft tissue sarcomas
The main initial complaint to the doctor is because of the development of a lump. This is difficult for the doctor as many similar lumps will be benign but the appearance and progression of such a lump should alert physicians to the possibility of a sarcoma.
Of course, when the lump has grown to a large size it causes secondary pressure symptoms that may cause presentation complaints depending on the situation of the growth.
Occasionally, the patient may present with symptoms of metastatic disease; it is noteworthy that sarcomas metastasise to the lungs in the first instance in most cases, although regional node metastatic disease is a feature of some (e.g. synovial sarcoma).
Biopsy (the taking of a piece of the tumour for microscopic analysis) is the key diagnostic test and where the possibility of sarcoma is real, the surgeon will be careful to ensure that the tract of the biopsy needle or knife is through tissue that will be resected at any definitive operation, so as not to contaminate new tissues that will not be resected.
Once the microscopic/histological diagnosis is made (and nowadays this will include sophisticated immunohistochemistry and genomics to ascertain the exact subtype of sarcoma – and possibly give a ‘steer’ to therapeutic options), then there are several staging scans that are performed to establish the extent of the disease. For assessing the extent of the primary tumour, MR imaging is best as it demonstrates the contrast of tumour from background tissues best and allows the surgeon to plan his operation optimally. For assessing the possibility of metastatic disease, then CT scanning of the lungs is important and often PET scanning of the whole body.
By the methods outlined above, the sarcoma is staged as being non-metastatic (localised) or metastatic. If localised, then the tumours less than 5 cm in diameter and confined to the tissue of origin or compartment of muscle/tissue from which they arise, have the best outlook for cure, particularly if they are of low histological grade. Thus the size, situation and histological grade all combine to give prognostically important information.
Staging from 1 (less than 5 cm diameter, low histological grade and no metastases) to 4 (metastatic disease) are recognised with diminishing survival expectations as the stage increases: 90% for stage 1 downwards for increasing stages of the disease.
Treatment & outcomes: Soft tissue sarcomas
Where the tumour is localised, wide excision (which implies that the surgeon cuts cleanly around the tumour, never through it, and with generous margins of safety) is recommended. Sometimes this requires amputation to achieve this goal but nowadays more often than not the requirement can be fulfilled by more conservative, subablative surgery, perhaps supplemented by radiotherapy to the area post-operatively.
Where the sarcoma is localised to one muscle group (e.g. hamstrings of the thigh) such wide excision implies the resection of the whole muscle compartment (operation nicknamed, compartmentectomy), which can be a large and functionally disabling operation. Nevertheless, as an alternative to amputation, it is an advance over what was recommended twenty years ago, and with modern orthopaedic rehabilitation it is often less disabling than initially envisaged.
Where the operation is less than ablative, it is clear that the delivery of high radiotherapy to the region will further lessen the chances of relapse, and most patients will be recommended to receive a five to six week course of fractionated radiotherapy on modern equipment preceded by careful planning.
However, radiotherapy should not substitute a larger operation if the surgeon cannot achieve clear margins (i.e. the histologist is not able to identify any tumour at the edges of the operation specimen) as this does not achieve the good results that can be achieved by a good, clear surgical result before radiotherapy.
For many soft tissue sarcomas of the body, it is not possible to achieve even the modest margins achieved by a compartmentectomy in the limbs; here radiotherapy in the post-operative period is even more important. Sometimes, the radiotherapy precedes the surgery to try to effect shrinkage and facilitate curative resection.
The subject of adjuvant chemotherapy (i.e. the delivery of chemotherapy in the post-operative period in patients who have ostensibly localised disease but are at high risk of subsequent relapse; see breast cancer section) is highly controversial in this disease.
Some trials demonstrate that the delivery of the best agents known against this disease (e.g. doxorubicin/adriamycin and cyclophosphamide/iphosphamide) for a finite number of exposures (e.g. six) immediately after the operation can lead to a reduced risk of subsequent relapse.
However, the risk reduction is not as well validated as for example in node positive breast cancer (see breast cancer section) and many other trials only show a relapse free survival advantage (c.f. an overall survival advantage) or no advantage at all. Thus whilst there is now good evidence to support the routine delivery of adjuvant chemotherapy to children and young adults with resected rhabdomyosarcomas, this practice is less well validated than for some other cancers but is indicated in younger and fitter patients.
Chemotherapy is so much better established in the childhood rhabdomyosarcoma practice that it is common for therapy to commence with chemotherapy here and surgery to come in later when the tumour has shrunk right down.
Where the patient presents with metastatic disease, the use of chemotherapy is more definitely and audited by serial scans. If the Adriamycin/doxorubicin and Iphosphamide regime has failed recently there are other second line drugs such as the combination of gemcitabine and docetaxel or the single agent: trabectadin that can give a second remission and the choice is somewhat dictated by the subtype of sarcoma.
Occasionally, a single metastasis occurs (e.g. in the lungs) and surgery to this and the primary is considered, but this is very much a minority of cases and usually the patient who presents with metastatic disease is treated with chemotherapy to try to contain the disease for as long as possible.
What to do if the sarcoma becomes resistant to all the foregoing therapy?
In cases of soft tissue sarcoma, where the foregoing therapies have failed, then a new biopsy for genomic analysis is warranted – looking for actionable mutations (i.e. those mutations that lead the cancer cells to the ‘drive’ to divide and divide relentlessly and whose effects can be blocked by the new generation of drugs – often Tyrosine Kinase Inhibitors (TKI) – pazopanib currrently looking the most promising. In synovial sarcoma, the cyclin (CDK4) inhibitor palbociclib may cause worthwhile responses, in dermatofibrosarcoma protruberans mutations in the PDGFB gene give rationale to the use of imatinib in therapy – and highly successfully so etc.etc. The genomic profiling of the sarcoma should be performed on a fresh tumour biopsy (as we need to know the genomics of the cancer at this time – as it may substantially differ from earlier in its natural history), or from cell-freeDNA (cfDNA) from the blood (liquid biopsy).
Additionally, the predictive tests for the usefulness of immunotherapy need to be investigated as at lease two big trials have suggested that he checkpoint inhibitors (e.g. pembrolizumab and nivolumab) are useful against metastatic soft tissue sarcoma.
Dr P N Plowman MD, The Oncology Clinic, 20 Harley Street, London W1G 9PH. (Advanced Genomics). Tel: +44-207-631-1632.
Where the sarcoma returns locally after a ‘limb-sparing policy’ and there is no evidence of metastatic relapse on repeat staging, then amputation must be considered or more radical surgery for other body sites. When there is metastatic relapse, then chemotherapy is recommended, using the drugs mentioned above. Metastatic relapse is not a curative proposition.
Overall, this is a rare disease and a population based screening programme is not indicated.