MYXOID SOFT TISSUE TUMOURS
Professor Mary Leader, Royal College of Surgeons in Ireland/Beaumont Hospital.
Myxoid soft tissue tumours are a difficult group of tumours from the diagnostic viewpoint. There are a number of reasons for this. Many common tumours show myxoid change. There is also a significant histological overlap as many spindle cell tumours with myxoid change have only a limited repertoire of morphological patterns. Furthermore, myxoid tumours of certain types are very uncommon and may only rarely be seen by a histopathologist during his/her career. Yet another reason for the confusion in the diagnosis of this type of tumour is the similar and confounding nomenclature used in some of these entities. For example amongst spindle cell malignant myxoid tumours the following entities are included namely, myxofibrosarcoma, low grade fibromyxoid sarcoma, inflammatory myofibroblastic tumours and myxoinflammatory fibroblastic sarcoma. That is a lost of myxos and fibros! For all of these reasons a good clinical history and awareness of the different entities is essential in the differential diagnosis of myxoid soft tissue tumours.
When attempting to form a differential diagnosis in a myxoid soft tissue tumour it is best to first divide them into two categories namely, spindle cell and round cell. The spindle cell myxoid group can be further divided into those tumours which are common but which rarely show myxoid change in what is otherwise a recognisable spindle cell sarcoma, e.g. myxoid change in a leiomyosarcoma, malignant schwannoma, gastrointestinal stromal tumour (GIST) and synovial sarcoma. These tumours can be readily recognised with the use of immunohistochemistry. There is more diagnostic difficulty in the remaining myxoid spindle cell soft tissue sarcomas where myxoid change is an expected integral part of the tumour e.g. the myxofibrosarcoma, low grade fibromyxoid sarcoma, inflammatory myofibroblastic tumour and myxoinflammatory fibroblastic sarcoma.
It is worth briefly describing each of these latter entities. The myxofibrosarcoma is the term now used for myxoid malignant fibrous histiocytoma (MFH). The cellular myxofibrosarcoma presents little diagnostic difficulty as it has a storiform pattern and is composed of spindle and histiocyte like cells. It is generally negative with antibodies against Desmin and S100P but it may be focally positive with SMSA. The major diagnostic difficulty resides in the low grade hypocellular myxofibrosarcoma. This is a hypocellular tumour composed of spindle cells with minimum pleomorphism, very occasional mitoses, characteristic vacuolated cells and with characteristic curvy linear vessels. The main differential diagnosis for this tumour when hypocellular is a myxoma. By contrast a myxoma shows very few vessels, is less cellular and does not show mitoses. Myxomas also occur in rather restricted sites e.g. intramuscular, the jaw and juxta articular.
The entity low grade fibromyxoid sarcoma is also termed hyalinising spindle cell tumour with giant rosettes when this tumour shows giant rosettes. This occurs in about 40% of these tumours. This is now regarded as a low grade malignant tumour whereas previously it was regarded as an aggressive neoplasm. With the increased recognition of this condition it is now being recognised at an earlier stage, hence the improved prognosis. Microscopically this tumour has a “two tone” appearance. There are areas of collagen with adjacent cellular nodules composed of spindle cells in a myxoid stromoa. Mitoses are scarce and the spindle cells are deceptively bland. Forty percent of cases show collagen rosettes and these are numerous in 10%. Immunohistochemistry is not of value in this tumour except to exclude other spindle cell sarcomas such as a malignant schwannoma, a solitary fibrous tumour with myxoid change and a leiomyosarcoma.
The inflammatory myofibroblastic tumour was previously called a plasma cell granuloma or an inflammatory pseudotumour. This is generally found in children and young adults and may be associated with fever, malaise, weight loss and anaemia. This tumour is now regarded as a true neoplasm and all are potentially capable of metastases. Microscopically this has a “three tone” appearance composed of areas with inflammatory cells in a myxoid stroma, areas with a fibromatosis type of appearance composed of plumped myofibroblasts and also areas suggestive of a scar characterised by the presence of collagen. Occasionally these tumours show large cells with a prominent nucleolus and are occasionally positive for ALK1 antibodies. Given the systemic clinical symptoms a potential pitfall is misdiagnosis as a Hodgkin’s lymphoma or an anaplastic large cell lymphoma if only a small tissue biopsy is available.
Myxoinflammatory fibroblastic sarcoma is a very rare but easily recognised entity. It has also been called inflammatory myxohyaline tumour of distal extremities with virocyte or Reed Sternberg like cells and also called acral myxoinflammatory fibroblastic sarcoma. It typically occurs in the hands and feet but has been reported rarely in other sites, usually in the middle aged or elderly patients. This tumour was previously considered to be a benign reactive lesion. It is now clasified as a neoplasm. Some studies have shown a 50% recurrence rate and a 6% metastatic rate. Limited molecular studies suggest it is a neoplasm. It is composed of bland spindle cells, admixed with inflammatory cells. It has characteristic Virocyte like or Reed Sternberg like cells with large nuclei and some with nucleoli and with abundant eospinophilic cytoplasm which may have vacuolated spaces. The latter may resemble lipoblasts. These are negative with immunostains for viruses.
The myxoid tumours with round cells are more easy to diagnose as immunohistochemistry is of significant value. These round cell myxoid soft tissue sarcomas are best separated from each other initially by the use of immunohistochemistry. The S100P positive tumours (extraskeletal myxoid chondrosarcoma, chordoma, myxoid liposarcoma and myxoid epithelioid malignant peripheral nerve sheath tumour) are then further subdivided by the use of cytokeratin. Cytokeratin may be positive in extraskeletal myxoid chondrosarcoma and is usually positive in a chordoma. It is negative in myxoid liposarcoma and in myxoid malignant epithelioid peripheral nerve sheath tumour.
The chordoma can be readily identified as the history is of a tumour attached to either the sacrococcygeal region or the sphenooccipital region. The characteristic physalliferous cells are readily identified. S100P is usually positive in these tumours as is cytokeratin. The embryonal rhabdomyosarcoma is a tumour which occurs in children and young adults. The sites usually include the head and neck in 50% of cases and the genitourinary tract in 25% of cases. A cambium layer may be present. Nuclear staining for myoD1 is a specific marker. Cytoplasmic staining is not regarded as being specific. Other skeletal muscle markers and desmin are also positive. In difficult cases molecular studies will show alleic loss in the region of chromosome 11p15. Myxoid liposarcoma is a tumour with a characteristic pattern of small thin blood vessels in a characteristic so called “chicken wire” appearance. The cells may be round and quite bland. The prognosis is related to the percentage of round cells and the percentage of necrosis. These tumours may have numerous lipoblasts or alternatively lipoblasts may be difficult to find. Mitoses may be very scanty and difficult to locate.
The distinction of extraskeletal myxoid chrondrosarcoma (ESMCS) and malignant epithelioid myxoid peripheral nerve sheath tumour may be more difficult as these tumours can be very similar. If cytokeratin staining is seen it favours a diagnosis of ESMCS. In difficult cases molecular analysis may be necessary.
The benign myxoid tumours include the myxoma, three tumours with a myxoid and vascular pattern, namely aggressive angiomyxoma, superficial angiomyxoma and cellular angiofibroma. These three may all occur in the genital/perineal area of men or women and therefore need to be distinguished from each other. The other two tumours in this category include the myxoid schwannoma which is strongly S100P positive and a nodular fasciitis. The latter can be overdiagnosed as malignant as mitoses may be numerous. It shows spindle cell proliferation with a “tissue culture” type of appearance and perhaps a sprinkling of inflammatory cells, and extavasation blood cells in a myxoid stroma. Mitoses may be numerous but no abnormal mitosis is present. If one pays attention to the clinical history such a tumour will not be called malignant. Nodular fasciits typically has a history of less than 3 months and it rarely exceeds 3cm in size.
The myxoma typically occurs in either a large muscle, the jaw or in a juxta articular position. Typically these are very hypocellular tumours with very scanty cells and very scanty blood vessels. The juxta articular tumour may be more cellular than the myxoma in the other two sites. For this reason it may be difficult to differentiate from a low cellularity low grade myxofibrosarcoma.
The aggressive angiomyxoma can be differentiated from superficial angiomyxoma and cellular angiofibroma as it has low cellularity and spindle cells scattered in abundant myxoid material. The periphery is poorly defined and characteristic vessels are found with either a thick layer of muscle around the vessel wall or collagen. The cellular angiofibroma if much more cellular, shows less myxoid change and shows vessels of varying sizes. Inflammatory cells may also be seen within this tumour. The superficial angiomyxoma typically occurs in a cutaneous site and this is a helpful differentiating feature. Furthermore, it is generally much smaller than the other two entities. These tumours may in 30% of cases show epithelial buds of squamous epithelium. Another poorly defined entity the angiomyofibroblastoma is a myxoid tumour in the perineal region. It is probably part of the spectrum of cellular angiofibroma.
In summary, myxoid malignant soft tissue tumours are challenging. They should initially be divided into those with a spindle cell pattern and a round cell pattern. The spindle cell pattern should be divided into those where immunohistochemistry shows a definite lineage e.g. malignant schwannoma, leiomyosarcoma, gastrointestinal stromal tumour or solitary fibrous tumour. The remaining myxoid entities amongst the spindle cell sarcomas can be separated from each other by careful attention to clinical details and to the histological features. A hypocellular myxofibrosarcoma shows ovoid spindle cells in a myxoid stroma with curlilinear vessels. The low grade fibromyxoid sarcoma shows a “two tone” appearance and may show hyalinising giant rosettes. The inflammatory myxohyaline tumour has a “three tone” appearance i.e. inflammatory/myxoid, fibromatosis like and scar like. The myxoinflammatory fibroblastic sarcoma is again largely composed of inflammatory cells and shows characteristic virocyte type cells or Reed Sternberg like cells.
The myxoid round cell sarcomas are diagnostically less difficult due to the helpful phenotypes demonstrated by immunohistochemistry.
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