Clinical Oncology (1992) 4:322-326 © 1992 The Royal College of Radiologists
Clinical Oncology
Current Concepts in Pathology* Soft Tissue Sarcomas C. Fisher Department of Histopathology and Sarcoma Unit, Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK
INTRODUCTION
PATHOLOGY
Soft tissue sarcomas are rare, with some 1200 new cases in the UK each year; clinicians outside specialist centres see no more than a few. They involve principally the soft connective tissues of the limbs, limb girdles and retroperitoneum, and also occur in the head and neck, and abdominal and chest walls. There are now some 50 recognizable histological subtypes [1], but there is generally a uniform clinicopathological approach since sarcomas present common clinical problems, arising out of their natural history. These involve management of primary turnouts by surgery (with or without preoperative irradiation), local control of recurrent disease (principally by surgery and radiotherapy), and the treatment of metastases, usually in the lungs but sometimes in regional lymph nodes (which are particularly likely to be involved by rhabdomyosarcoma, and synovial, epithelioid or clear cell sarcomas). For disseminated disease it is true that, apart from some childhood tumours, specific or effective chemotherapy is not yet available, although pulmonary metastasectomy may have a place. However, in recent years, careful clinicopathological observations, newer histological techniques, and contributions from cytogenetics have delineated the incidences and natural histories of a number of new entities and questioned our concepts of some established tumour types. These advances are valuable in epidemiology, and for better defining subtypes for multicentre therapeutic trials. Most importantly, because many sarcoma subtypes behave in a reasonably consistent fashion, sensible predictions of the potential and likely time course for recurrence and metastasis become possible in individual tumours. Thus, the necessary initial step in management of a soft tissue sarcoma is to make a definite and accurate histological diagnosis.
Essential clinical information for the pathologist includes the patient's age and sex, and site and size of the tumour, the length of the history and knowledge of previous therapy. For example, nodular fasciitis [2], a benign lesion frequently misinterpreted as malignant, typically appears and grows rapidly over a few days, unlike the majority of sarcomas. Some tumours are age- and site-specific, or occur predominantly in one sex. Childhood soft tissue sarcomas have a quite different frequency distribution from those in adults. A family history is also relevant since there is an inherited predisposition to sarcoma, in yon Recklinghausen's neurofibromatosis, familial retinoblastoma and Li-Fraumeni syndrome [3]. Irradiation or chemotherapy can cause marked morphological change, including necrosis, increased nuclear pleomorphism, and, occasionally, maturation of primitive cells. Sarcomas sometimes arise, years later, in fields of radiation therapy for other tumours, such as breast carcinoma.
* Th& bs the first of a new series of articles which will, at regular mtervals, provide updates on various aspects of oncological pathology. Correspondence and offprint requests to" C. Fisher, Department of Histopathology and Sarcoma Unit, Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK.
Classification, Nomenclature and Diagnosis Soft tissue sarcomas, unlike epithelial malignancies have no antecedent dysplastic or in situ component. and the cell of origin is unknown (and perhaps unknowable), so that it is inappropriate to speak of histogenesis; instead, one can regard mesenchymal tumours as differentiating towards one or more types of cell or tissue. These often resemble normal adult or embryonic tissues of the type in which the tumour arises, such as fat or muscle, but with less differentiated neoplasms this resemblance may be apparent only by electron microscopy or by immunohistochemical identification of specific antigens. A few distinctive sarcoma types do not resemble microscopically any normal tissue or cell; for many of these, non-mesenchymal differentiation has been demonstrated. A classification according to differentiation is given in Table 1. The cells of a given tumour type can be variously elongated (spindle cells), polygonal with abundant cytoplasm (epithelioid cells), or of a pleomorphic giant cell morphology, even within the same speci-
323
Soft Tissue Sarcomas Table 1. Sarcoma classificationaccordingto type of differentiation Mesenchymaldifferentiation: adult or embryonic
Other differentiation: consistent pattern
No specificdifferentiation: variable pattern
Liposarcoma (adipose tissue)
Synovialsarcoma (epithelial)
Malignant fibroushistiocytoma (?fibroblastic/histiocytic)
Epithlioid sarcoma (epithelial) Leiomyosarcoma(smooth muscle) Sarcoma NOS (none) Malignant rhabdoid tumour (epithehal) Rhabdomyosarcoma(striated muscle) Clear cell sarcoma (melanocytic/nervesheath) Angiosarcoma (endothelial) Ewing's sarcoma (neural) MPNST (Schwanncell) PNET, Askin turnout (neural) Osteosarcoma (bone) Chondrosarcoma (cartilage) Fibrosarcoma (fibroblastic) Alveolar soft part sarcoma (muscle) MPNST, malignantperipheral nerve sheath tumour; PNET, peripheral primitiveneuroectodermaltumour; NOS, not otherwisespecified.
men. Many tumours can therefore look similar, but, with careful observation, routine immunohistochemistry, and electron microscopy where indicated, a diagnosis can usually be made. Today, open biopsy is rarely necessary, and may prejudice subsequent management; a needle biopsy can usually provide sufficient diagnostic material [4] and should be the first invasive approach. Nonetheless, even when the whole specimen is in experienced hands, up to 10% of sarcomas can remain unclassifiable beyond a simple morphological description; they are undifferentiated according to the techniques presently available [5], although occasionally (e.g. in embryonal rhabdomyosarcoma) these exhibit differentiation in the recurrence or metastases, or following irradiation or chemotherapy. Our concepts of a number of tumours have changed in recent years. These are conveniently considered within the three main morphological groups.
Spindle Cell Sarcomas Tumours of this type undergoing recent re-evaluation include fibrosarcoma, synovial sarcoma, and malignant peripheral nerve sheath tumour. Fibrosarcoma characteristically has a 'herringbone' pattern, and variable collagen fibre production but lacks evidence of more specific differentiation (other sarcomas can produce collagen, and many contain some fibroblasts). Once extremely popular, fibrosarcoma is now one of the least commonly diagnosed sarcomas, for two reasons. Immunohistochemistry and electron microscopy have demonstrated [5] that many such tumours are actually synovial sarcomas, nerve sheath tumours, leiomyosarcomas or even angiosarcomas. This distinction has clinical meaning because a low grade of fibrosarcoma has a good prognosis whereas, for example, the similarly-appearing monophasic synovial sarcoma has a much poorer outlook. Also the concept of malignant fibrous histiocytoma (vide infra) has embraced most of the rest, as well as many of the pleomorphic sarcoma types. Strictly defined, true fibrosarcoma represents 1%-2% of adult soft tissue sarcomas. Synovial sarcoma affects predominantly young adults and arises in soft tissues around large joints, particularly the knee; its occurrence within a joint is
actually very rare. This is typically a distinctive biphasic tumour with spindle cell and epithelial-like (sometimes glandular) areas, in varying proportions. The spindle cells are closely packed and rather uniform with little cytoplasm; when the epithelial component is minimal or lacking, the monophasic spindle cell synovial sarcoma resembles fibrosarcoma. It can, however, be identified, not only by careful light microscopic examination, but by immunohistochemistry for epithelial-type antigens: cytokeratin, intermediate filament proteins [6] and epithelial membrane antigen. Epithelial structures can also be shown with electron microscopy which may be diagnostic in marker-negative cases [7]. The discrete nature of this tumour has been confirmed by the demonstration in most cases so far examined of a specific and consistent chromosomal translocation, t(x;18)(pll.2;qll.2) [8], the detailed mapping of which has begun [9]. Synovial sarcoma has nothing to do with synovium and could be termed 'soft tissue carcinosarcoma' [10]; indeed, it is necessary in some cases to exclude the possibility of a metastatic carcinoma. Its present name is retained since it denotes a clear cut entity. Malignant peripheral nerve sheath tumour (MPNST) is the current term [11] for tumours previously known as neurofibrosarcoma, malignant schwannoma, or neurogenic sarcoma. They differentiate towards the cells of the nerve sheath, principally the Schwann cell. Sporadic cases, occur, but many cases are found in patients with von Recklinghausen's neurofibromatosis (VRN) in whom there is about a 4% chance of malignant change [12]. Typically, MPNST arises from a nerve trunk or named nerve, or from a neurofibroma, but malignant soft tumours without apparent neural connection or antecedent disease sometimes show detectable nerve sheath features [13]. This is a notoriously heterogeneous group of tumours, both histologically and with electron microscopy. Immunohistochemically, $100 protein is the diagnostic marker but is present in only 40%--70% of cases. Ultrastructurally, MPNSTs have variably expressed Schwann cell differentiation, better developed in the S100 positive cases, although a smaller number display some resemblance to the other main component cell of the nerve sheath, the perineurial cell [13]. The outcome is related to tumour grade, but the prognosis is generally worse in VRN-associated cases.
324 Pleomorphic Sarcomas Pleomorphic sarcomas are those with marked cellular variation, including polygonal, spindle and giant cells, and frequently with abnormal mitotic activity and necrosis. Irrespective of any detectable differentiation, they tend to behave as high-grade malignancies, but it may be possible to characterize them further, for example as liposarcoma (by the presence of lipoblasts) or leiomyosarcoma (with desmin and actins). The formerly frequently diagnosed pleomorphic rhabdomyosarcoma is now regarded as extremely rare, and perhaps non-existent over the age of 40 years [14]. Instead, the most common adult sarcoma subtype in recent series has been the malignant fibrous histiocytoma (MFH), a term which, as well as the usual storiform and pleomorphic tumours, includes myxoid, inflammatory, angiomatoid and giant cell variants [1]. Tissue culture studies [15] were originally interpreted as implying that MFH was a tumour of histiocytes which could behave as facultative fibroblasts, and indeed electron microscopy [5] shows cells with characteristics of histiocytes and fibroblasts and their derivatives (giant cells, myofibroblasts) as well as primitive mesenchymal cells. The immunohistochemical detection of alpha-l-antitrypsin [16] supported the hypothesis of histiocytic differentiation but this is now known to be detectable in a variety of other tumours including carcinomas [17]. More specific enzyme histochemical and immunohistochemical investigation [18] indicates that tumour cells in the majority of MFHs are not of histiocytic type. The recent immunohistochemical demonstrations of various intermediate filament types [19], the ultrastructural observations of epithelial or smooth muscle differentiation [20], and the findings of diverse karyotypes [21] all suggest that at least some pleomorphic MFHs represent poorly differentiated examples of specific soft tissue sarcomas (or carcinomas or even lymphomas) which happen to exhibit a common 'end-stage' histological pattern [22]. Nonetheless, there remains a considerable number of such tumours without specific differentiation, many showing a rather consistent histiocytic, fibroblastic and myofibroblastic ultrastructure; the term 'malignant fibrous histiocytoma' should be reserved for these, and 'pleomorphic undifferentiated sarcoma' for the rest. It is likely that the status of the other histological subtypes of M F H will be clarified and that they may become independent entities.
C. Fisher many skeletal and extraskeletal Ewing's sarcomas (as well as the morphologically similar tumour of chest wall, the Askin tumour) exhibit neural differentiation [25]. In addition, the chromosomal translocation t(11:22)(q24:q 12), seen in many examples of Ewing's sarcoma [26], has also been identified in some PNETs, as well as a common antigen [27]. While this subgroup of tumours may be a continuum, at present the term 'Ewing's sarcoma' should perhaps be retained for those clinically appropriate tumours without any detectable differentiation.
CYTOGENETICSAND MOLECULAR GENETICS In addition to the cytogenetic findings already described, consistent karyotypic abnormalities have been reported in other types of sarcoma, such as alveolar rhabdomyosarcoma (t(2;13)(q37;q14))[28], myxoid liposarcoma (t(12;16)(q13;pll))[29], and clear cell sarcoma [30]. Interestingly, consistent translocations have also been detected in benign tumours, notably lipomas [31] and uterine leiomyomas [32]. For some sarcomas these abnormalities appear to be specific enough for diagnostic purposes, and ought to shed light on pathogenesis. Chromosomal translocations in sarcomas might be expected to result in proto-oncogene activation, but so far this has been demonstrated mostly in childhood tumours. Increased expressed and gene amplification of the N-myc oncogene are well known in neuroblastoma, where they have prognostic significance. Point mutations in ras genes have been demonstrated in some embryonal sarcomas [33]. Familial retinoblastoma, in which there is deletion of both alleles of the RB1 tumour suppressor gene (anti-oncogene), is associated with later development of soft tissue or bone sarcoma [3], and RB1 gene structural abnormalities (including deletions) have also been demonstrated in occasional sarcomas in patients without retinoblastoma [34]. Germline p53 mutations have been identified in Li-Fraumeni syndrome [3], and loss of a suppressor gene on chromosome 17p (presumed to be p53) has also been implicated in the MPNST development in neurofibromatosis [35]. It seems likely that other aetiological associations of sarcomas will prove to have a molecular pathological basis.
Small Round Cell Sarcomas Although occurring sporadically in adults, this group of tumours, characterized by darkly haematoxyphilic nuclear staining and scanty cytoplasm, is regularly found in childhood, and includes a number of malignancies with different management strategies. Modern immunohistochemistry [23] has made the separation of neuroblastoma, leukaemia/lymphoma, and embryonal rhabdomyosarcoma relatively easy. The identification of peripheral primitive neuroectodermal tumour (PNET) is enabled by the demonstration within it of neuron-specific enolase and neurofilament [24], and it has now been shown that
GRADING AND PROGNOSIS The prognosis and management of soft tissue sarcomas depends on staging, and staging systems [36] take into account not only the extent of spread at the time of diagnosis, but also the grade of the tumour. For epithelial malignancies it is relatively easy to assess the degree of differentiation, but for sarcomas grading is difficult because the term embraces so many different types of mesenchymal tumour. Some
Soft Tissue Sarcomas
325
Table 2. Behaviour of soft tissue sarcomas
Low metastatic potential
High metastatic potential
Variable metastatic potential (histologically gradable)
Dermatofibrosarcoma protuberans Well differentiated liposarcoma
Alveolar soft part sarcoma Clear cell sarcoma De-differentiated liposarcoma Ewing's sarcoma/PNET Extraskeletal mesenchymal chondrosarcoma Extraskeletal osteosarcoma Malignant rhabdoid tumour Round cell liposarcoma Pleomorphic sarcomas Rhabdomyosarcoma
Angiosarcoma Epithelioid sarcoma Extraskeletal myxoid chondrosarcoma Fibrosarcoma Leiomyosarcoma Malignant fibrous hlstiocytoma Malignant peripheral nerve sheath tumour Myxoid liposarcoma Synovial sarcoma
PNET, primitive neuroectodermal tumour.
resemble adult tissue, such as nerve sheath or smooth muscle tumours; yet may have a poor prognosis even when well differentiated. Others recapitulate normal embryonic tissue but may have a reasonably good prognosis. Additionally, in many sarcomas the concept of differentiation becomes problematic; some types, although readily recognized, are always undifferentiated in the sense that they do not resemble any known normal adult tissue. These principles are illustrated by reference to the subgroups of liposarcoma. Myxoid liposarcoma resembles embryonic fat, yet behaves quite indolently. However, its less differentiated round cell variant is a high-grade aggressive tumour, as is the pleomorphic liposarcoma. The well differentiated liposarcoma, on the other hand, when arising in the limbs or trunk does not metastasize, and it has been suggested that in these extra-abdominal locations the term 'atypical lipomatous tumour [37, 38] is more apt. In some examples, however, an aggressive malignant fibrous histiocytoma-like area occurs (de-differentiated liposarcoma) [39] which redefines its behaviour. A few histological types of sarcoma (Table 2) always have a slow course and low metastatic potential. Others are always aggressive, allowing the histological diagnosis to be used as an initial grading criterion (automatic grading). However, the majority display a wider spectrum of behaviour, which can be related to histological features, and in these a grading system can be applied. There is, unfortunately, no agreed single system for grading soft tissue sarcomas but typically more than two tiers are used with assessment of some or all of mitotic counts, cellularity, differentiation/pleomorphism, and amount of necrosis [40, 41]. One study [42] which graded some cases first by diagnosis, found that the amount of necrosis was the single major predictor for survival among the other tumours. In all series, higher grade tumours form a substantial majority, but with changing concepts of diagnosis, and the use of multivariate analyses, it is becoming clear that the behaviour of some tumours previously always regarded as high grade (e.g. synovial [43] and epithelioid sarcomas) may be better predicted by a twoor three-tier histological grading system. At present, assessment of DNA ploidy and cell proliferation do not offer a significant improvement in predicting the behaviour of sarcomas. Other generally adverse prognostic factors are:
1. Tumour size >5 cm 2. Depth from surface: superficial tumours are less likely to metastasize than those beneath deep fascia or within muscle 3. Location: retroperitoneal tumours, even those of low grade, have a worse outcome, perhaps because of their later presentation, and here, as in the head and neck or thorax, complete surgical removal may not be possible. It should also be noted that some sarcomas, such as epithelioid sarcoma, cause considerable morbidity by relentless local recurrence, even though they may not metastasize until later in the course of the disease. Clearly, as in other areas, proper management of these rare tumours depends on a sound knowledge of the pathology, biology and likely behaviour of the disease; this is best achieved by close collaboration between pathologists and clinicians, and by referral where necessary to specialist centres, preferably even before a biopsy has been performed. References 1. Enzinger FM, Weiss SW. Soft tissue tumors. 2nd ed. St Louis: Mosby, 1988. 2. Bernstein K, Lattes R. Nodular (pseudosarcomatous) fasciitlS, a non-recurrent lesion: clinicopathologlc study of 134 cases. Cancer 1982;49:1668-78. 3. Cooper CS, Stratton MR. Soft tissue tumours: the genetic basis of development. Carcinogenesis 1991 ;12:155-65. 4. Ball AR, Fisher C, Watkins R, et al. Diagnosis of soft tissue tumours by Tru-cut biopsy. Br J Surg 1990;77:756-8. 5. Fisher C. The value of electron microscopy and lmmunohistochemlstry m the diagnosis of soft tissue sarcomas: a study of 200 cases. Histopathology 1990;16:441-55. 6. Corson JM, Weiss LM, Banks-Schlegel SP, et al. Keratin proteins and carcinoembryonic antigen in synovial sarcomas: an irnmunohistochemical study of 24 cases. Hum Pathol 1984;15:615-21. 7. Fisher C. Synovial sarcoma: ultrastructural and immunohistochemlcal features of monophasic and biphasic tumours. Hum Pathol 1986;17:996-1008. 8. Smith S, Reeves BR, Wong L, et al. A consistent chromosome transloeation in synovial sarcoma. Cancer Genet Cytogenet 1987;26:179-80. 9. Reeves BR, Smith S, Fisher C, et al. Characterlsation of the translocation between chromosomes X and 18 in human synovial sarcoma. Oncogene 1989;4:373-8. 10. Miettinen M, Virtanen I. Synovial sarcoma- a misnomer. Am J Pathol 1984;117:18-25. 11. Erlandson RA, Woodruff JM. Peripheral nerve sheath tumors. An electron microscopic study of 43 cases. Cancer 1982;49:273-87
326 12. Rlccardi V. Von Recklinghausen's neurofibromatosis. N Engl J Med 1981;305:1617-26. 13. Fisher C, Carter RL, Ramachandra S, et al. Peripheral nerve sheath differentiation in malignant soft tissue tumours: an ultrastructural and immunohistochemical study. Histopathology 1992:20:115-26. 14. Miettinen M. Rhabdomyosarcoma in patients older than 40 years of age. Cancer 1988;62:2060-5. 15. Ozello L, Stout AP, Murray MR. Cultural characteristics of malignant fibrous histiocytomas and fibrous xanthomas. Cancer 1963;16:331-44 16. Kindblom L-G, Jacobsen GK, Jacobsen M. Immunohistochemical investigations of tumours of supposed fibroblastichistiocytic origin. Hum Pathol 1982;13:834-40. 17. Solni Y, Miettinen M Alpha-l-antitrypsin and lysozyme: their limited significance m fibrohistiocytic tumors. Am J Clin Pathol 1989;91:515-21. 18. Wood GS, Beckstead JH, Turner RR, et al. Malignant fibrous hlstiocytoma tumor cells resemble fibroblasts. Am J Surg Pathol 1986:10:323-35. 19. Lawson CW, Fisher C, Gatter KC. An immunohistochemical study of differentiation in malignant fibrous histiocytoma. Histopathology 1987;11:375-83. 20. Hirose T, Kudo E, Hasegawa T, et al. Expression of intermediate filaments in malignant fibrous histiocytomas. Hum Pathol 1989;20:871-77. 21. Molenaar WM, DeJong B, Buist J, et al. Chromosomal analysis and the classification of soft tissue sarcomas. Lab Invest 1989:60:266-74. 22. Brooks JJ. The significance of double phenotypic patterns and markers in human sarcomas. A new model of mesenchymal differentiation. Am J Pathol 1986;125:113-23. 23. Leong AS-Y, Kan AE, Milios J. Small round cell tumors in childhood: immunohistochemcal studies in rhabdomyosarcoma, neuroblastoma, Ewing's sarcoma, and lymphoblastic lymphoma. Surg Pathol 1989;2:5-17. 24. Ushigome S, Shimoda T, Takaki K, et al. Immunocytochemical and ultrastructural studies of the histogenesis of Ewing's sarcoma and putatively related tumors. Cancer 1989;64:5262. 25. Lizard-Nacol S, Lizard G, Justrabo E, et al. Immunologic characterization of Ewing's sarcoma using mesenchymal and neural markers. Am J Pathol 1989;135:847-55. 26. Whang-Peng J, Triche TJ, Knutsen T, et al. Cytogenetic characterization of selected small round cell tumors of childhood. Cancer Genet Cytogenet 1986;21:185-208. 27. Ambros IM, Ambros PF, Strehl S, et al. MIC2 is a specific marker for Ewing's sarcoma and peripheral primitive neuroectodermal tumors. Evidence for a common histogenesis of Ewing's sarcoma and peripheral primitive neuroectodermal tumors from MIC2 expression and specific chromosome aberration. Cancer 1991;67:1886-93. 28. Seidal T, Hagmar MB, Angervall L. Alveolar rhabdomyo-
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sarcoma: a cytogenetlc and correlated cytological and histological study. Acta Pathol Microbiol Immunol Scand 1982;90A:345-54. Smith S, Reeves B, Wong L. Translocation t(12;16) in a case of myxoid liposarcoma. Cancer Genet Cytogenet 1987;26:185-6. Bridge JA, Borek DA, Neff JR, et al. Chromosomal abnormalities in clear cell sarcoma. Implications for histogenesis. Am J Clin Pathol 1990;93:26-31. Sreekantaiah C, Leong SPL, Karakousis CP, et al. Cytogenetic profile of 109 lipomas. Cancer Res 1991;51:422-33. Arheden K, Nilbert M, Helm S, et al. No amplification or rearrangement of INT1, GL1 or COL2A1 in uterine lelomyomas with t(12;14)(q14-15;q23-24). Cancer Genet Cytogenet 1989;39:195-201. Stratton MR, Fisher C, Gusterson B, et al. Human embryonal rhabdomyosarcomas: detection of point mutations in N-ras and K-ras genes using oligonuceotide probes and the polymerase chain reaction. Cancer Res 1989;49:6324-7. Stratton MR, Williams S, Fisher C, et al. Structural alteration of the RB1 gene in human soft tissue turnouts. Br J Cancer 1989;60:202-5. Menon AG, Anderson KM, Rlccardi VM, et al. Chromosome 17p deletions and p53 gene mutations associated with the formation of malignant neurofibrosarcomas in yon Recklinghausen neurofibromatosis Proc Natl Acad Sci USA 1990;87:5435-9. Suit HD, Mankin HJ, Schiller AL, et al. Staging systems for sarcoma of soft tissue and bone. Cancer Treat Symp 1985 ;3:29-36. Azumi N, Curtin J, Kempson RL, et al. Atypical and malignant neoplasms showing lipomatous differentiation. A study of 111 cases. Am J Surg Pathol 1987;11:161-83. Evans H. Liposarcomas and atypical hpomatous tumors: a study of 66 cases following for a minimum of 10 years. Surg Pathol 1988;1:41-54. Brooks J J, Connor AM. Atypical hpoma of the extremities and peripheral soft tissues with dedifferentiation: implications for management. Surg Pathol 1990;3:169-78, Myhre-Jensen O, H0gh J, Ostgaard SE, et al. Histopathological grading of soft tissue tumours. Prognostic significance in a prospective study of 278 consecutive cases. J Pathol 1991;163:19-24. Trojani M, Contesso G, Coindre JM, et al. Soft tissue sarcomas of adults:study of pathologic prognostic variables and definition of a histopathological grading system. Int J Cancer 1984:33:37-42. Costa J, Wesley RA, Glatstein E, et al. The grading of soft tissue sarcomas: results of a clinicohlstopathologic correlation in a series of 163 cases. Cancer 1984;53:530.41. Cagle L, Mirra J, Storm F, et al. Histologic features relating to prognosis in synovial sarcoma. Cancer 1987;59:1810-4.
Clinical Oncology
Current Concepts in Pathology* Soft Tissue Sarcomas C. Fisher Department of Histopathology and Sarcoma Unit, Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK
INTRODUCTION
PATHOLOGY
Soft tissue sarcomas are rare, with some 1200 new cases in the UK each year; clinicians outside specialist centres see no more than a few. They involve principally the soft connective tissues of the limbs, limb girdles and retroperitoneum, and also occur in the head and neck, and abdominal and chest walls. There are now some 50 recognizable histological subtypes [1], but there is generally a uniform clinicopathological approach since sarcomas present common clinical problems, arising out of their natural history. These involve management of primary turnouts by surgery (with or without preoperative irradiation), local control of recurrent disease (principally by surgery and radiotherapy), and the treatment of metastases, usually in the lungs but sometimes in regional lymph nodes (which are particularly likely to be involved by rhabdomyosarcoma, and synovial, epithelioid or clear cell sarcomas). For disseminated disease it is true that, apart from some childhood tumours, specific or effective chemotherapy is not yet available, although pulmonary metastasectomy may have a place. However, in recent years, careful clinicopathological observations, newer histological techniques, and contributions from cytogenetics have delineated the incidences and natural histories of a number of new entities and questioned our concepts of some established tumour types. These advances are valuable in epidemiology, and for better defining subtypes for multicentre therapeutic trials. Most importantly, because many sarcoma subtypes behave in a reasonably consistent fashion, sensible predictions of the potential and likely time course for recurrence and metastasis become possible in individual tumours. Thus, the necessary initial step in management of a soft tissue sarcoma is to make a definite and accurate histological diagnosis.
Essential clinical information for the pathologist includes the patient's age and sex, and site and size of the tumour, the length of the history and knowledge of previous therapy. For example, nodular fasciitis [2], a benign lesion frequently misinterpreted as malignant, typically appears and grows rapidly over a few days, unlike the majority of sarcomas. Some tumours are age- and site-specific, or occur predominantly in one sex. Childhood soft tissue sarcomas have a quite different frequency distribution from those in adults. A family history is also relevant since there is an inherited predisposition to sarcoma, in yon Recklinghausen's neurofibromatosis, familial retinoblastoma and Li-Fraumeni syndrome [3]. Irradiation or chemotherapy can cause marked morphological change, including necrosis, increased nuclear pleomorphism, and, occasionally, maturation of primitive cells. Sarcomas sometimes arise, years later, in fields of radiation therapy for other tumours, such as breast carcinoma.
* Th& bs the first of a new series of articles which will, at regular mtervals, provide updates on various aspects of oncological pathology. Correspondence and offprint requests to" C. Fisher, Department of Histopathology and Sarcoma Unit, Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK.
Classification, Nomenclature and Diagnosis Soft tissue sarcomas, unlike epithelial malignancies have no antecedent dysplastic or in situ component. and the cell of origin is unknown (and perhaps unknowable), so that it is inappropriate to speak of histogenesis; instead, one can regard mesenchymal tumours as differentiating towards one or more types of cell or tissue. These often resemble normal adult or embryonic tissues of the type in which the tumour arises, such as fat or muscle, but with less differentiated neoplasms this resemblance may be apparent only by electron microscopy or by immunohistochemical identification of specific antigens. A few distinctive sarcoma types do not resemble microscopically any normal tissue or cell; for many of these, non-mesenchymal differentiation has been demonstrated. A classification according to differentiation is given in Table 1. The cells of a given tumour type can be variously elongated (spindle cells), polygonal with abundant cytoplasm (epithelioid cells), or of a pleomorphic giant cell morphology, even within the same speci-
323
Soft Tissue Sarcomas Table 1. Sarcoma classificationaccordingto type of differentiation Mesenchymaldifferentiation: adult or embryonic
Other differentiation: consistent pattern
No specificdifferentiation: variable pattern
Liposarcoma (adipose tissue)
Synovialsarcoma (epithelial)
Malignant fibroushistiocytoma (?fibroblastic/histiocytic)
Epithlioid sarcoma (epithelial) Leiomyosarcoma(smooth muscle) Sarcoma NOS (none) Malignant rhabdoid tumour (epithehal) Rhabdomyosarcoma(striated muscle) Clear cell sarcoma (melanocytic/nervesheath) Angiosarcoma (endothelial) Ewing's sarcoma (neural) MPNST (Schwanncell) PNET, Askin turnout (neural) Osteosarcoma (bone) Chondrosarcoma (cartilage) Fibrosarcoma (fibroblastic) Alveolar soft part sarcoma (muscle) MPNST, malignantperipheral nerve sheath tumour; PNET, peripheral primitiveneuroectodermaltumour; NOS, not otherwisespecified.
men. Many tumours can therefore look similar, but, with careful observation, routine immunohistochemistry, and electron microscopy where indicated, a diagnosis can usually be made. Today, open biopsy is rarely necessary, and may prejudice subsequent management; a needle biopsy can usually provide sufficient diagnostic material [4] and should be the first invasive approach. Nonetheless, even when the whole specimen is in experienced hands, up to 10% of sarcomas can remain unclassifiable beyond a simple morphological description; they are undifferentiated according to the techniques presently available [5], although occasionally (e.g. in embryonal rhabdomyosarcoma) these exhibit differentiation in the recurrence or metastases, or following irradiation or chemotherapy. Our concepts of a number of tumours have changed in recent years. These are conveniently considered within the three main morphological groups.
Spindle Cell Sarcomas Tumours of this type undergoing recent re-evaluation include fibrosarcoma, synovial sarcoma, and malignant peripheral nerve sheath tumour. Fibrosarcoma characteristically has a 'herringbone' pattern, and variable collagen fibre production but lacks evidence of more specific differentiation (other sarcomas can produce collagen, and many contain some fibroblasts). Once extremely popular, fibrosarcoma is now one of the least commonly diagnosed sarcomas, for two reasons. Immunohistochemistry and electron microscopy have demonstrated [5] that many such tumours are actually synovial sarcomas, nerve sheath tumours, leiomyosarcomas or even angiosarcomas. This distinction has clinical meaning because a low grade of fibrosarcoma has a good prognosis whereas, for example, the similarly-appearing monophasic synovial sarcoma has a much poorer outlook. Also the concept of malignant fibrous histiocytoma (vide infra) has embraced most of the rest, as well as many of the pleomorphic sarcoma types. Strictly defined, true fibrosarcoma represents 1%-2% of adult soft tissue sarcomas. Synovial sarcoma affects predominantly young adults and arises in soft tissues around large joints, particularly the knee; its occurrence within a joint is
actually very rare. This is typically a distinctive biphasic tumour with spindle cell and epithelial-like (sometimes glandular) areas, in varying proportions. The spindle cells are closely packed and rather uniform with little cytoplasm; when the epithelial component is minimal or lacking, the monophasic spindle cell synovial sarcoma resembles fibrosarcoma. It can, however, be identified, not only by careful light microscopic examination, but by immunohistochemistry for epithelial-type antigens: cytokeratin, intermediate filament proteins [6] and epithelial membrane antigen. Epithelial structures can also be shown with electron microscopy which may be diagnostic in marker-negative cases [7]. The discrete nature of this tumour has been confirmed by the demonstration in most cases so far examined of a specific and consistent chromosomal translocation, t(x;18)(pll.2;qll.2) [8], the detailed mapping of which has begun [9]. Synovial sarcoma has nothing to do with synovium and could be termed 'soft tissue carcinosarcoma' [10]; indeed, it is necessary in some cases to exclude the possibility of a metastatic carcinoma. Its present name is retained since it denotes a clear cut entity. Malignant peripheral nerve sheath tumour (MPNST) is the current term [11] for tumours previously known as neurofibrosarcoma, malignant schwannoma, or neurogenic sarcoma. They differentiate towards the cells of the nerve sheath, principally the Schwann cell. Sporadic cases, occur, but many cases are found in patients with von Recklinghausen's neurofibromatosis (VRN) in whom there is about a 4% chance of malignant change [12]. Typically, MPNST arises from a nerve trunk or named nerve, or from a neurofibroma, but malignant soft tumours without apparent neural connection or antecedent disease sometimes show detectable nerve sheath features [13]. This is a notoriously heterogeneous group of tumours, both histologically and with electron microscopy. Immunohistochemically, $100 protein is the diagnostic marker but is present in only 40%--70% of cases. Ultrastructurally, MPNSTs have variably expressed Schwann cell differentiation, better developed in the S100 positive cases, although a smaller number display some resemblance to the other main component cell of the nerve sheath, the perineurial cell [13]. The outcome is related to tumour grade, but the prognosis is generally worse in VRN-associated cases.
324 Pleomorphic Sarcomas Pleomorphic sarcomas are those with marked cellular variation, including polygonal, spindle and giant cells, and frequently with abnormal mitotic activity and necrosis. Irrespective of any detectable differentiation, they tend to behave as high-grade malignancies, but it may be possible to characterize them further, for example as liposarcoma (by the presence of lipoblasts) or leiomyosarcoma (with desmin and actins). The formerly frequently diagnosed pleomorphic rhabdomyosarcoma is now regarded as extremely rare, and perhaps non-existent over the age of 40 years [14]. Instead, the most common adult sarcoma subtype in recent series has been the malignant fibrous histiocytoma (MFH), a term which, as well as the usual storiform and pleomorphic tumours, includes myxoid, inflammatory, angiomatoid and giant cell variants [1]. Tissue culture studies [15] were originally interpreted as implying that MFH was a tumour of histiocytes which could behave as facultative fibroblasts, and indeed electron microscopy [5] shows cells with characteristics of histiocytes and fibroblasts and their derivatives (giant cells, myofibroblasts) as well as primitive mesenchymal cells. The immunohistochemical detection of alpha-l-antitrypsin [16] supported the hypothesis of histiocytic differentiation but this is now known to be detectable in a variety of other tumours including carcinomas [17]. More specific enzyme histochemical and immunohistochemical investigation [18] indicates that tumour cells in the majority of MFHs are not of histiocytic type. The recent immunohistochemical demonstrations of various intermediate filament types [19], the ultrastructural observations of epithelial or smooth muscle differentiation [20], and the findings of diverse karyotypes [21] all suggest that at least some pleomorphic MFHs represent poorly differentiated examples of specific soft tissue sarcomas (or carcinomas or even lymphomas) which happen to exhibit a common 'end-stage' histological pattern [22]. Nonetheless, there remains a considerable number of such tumours without specific differentiation, many showing a rather consistent histiocytic, fibroblastic and myofibroblastic ultrastructure; the term 'malignant fibrous histiocytoma' should be reserved for these, and 'pleomorphic undifferentiated sarcoma' for the rest. It is likely that the status of the other histological subtypes of M F H will be clarified and that they may become independent entities.
C. Fisher many skeletal and extraskeletal Ewing's sarcomas (as well as the morphologically similar tumour of chest wall, the Askin tumour) exhibit neural differentiation [25]. In addition, the chromosomal translocation t(11:22)(q24:q 12), seen in many examples of Ewing's sarcoma [26], has also been identified in some PNETs, as well as a common antigen [27]. While this subgroup of tumours may be a continuum, at present the term 'Ewing's sarcoma' should perhaps be retained for those clinically appropriate tumours without any detectable differentiation.
CYTOGENETICSAND MOLECULAR GENETICS In addition to the cytogenetic findings already described, consistent karyotypic abnormalities have been reported in other types of sarcoma, such as alveolar rhabdomyosarcoma (t(2;13)(q37;q14))[28], myxoid liposarcoma (t(12;16)(q13;pll))[29], and clear cell sarcoma [30]. Interestingly, consistent translocations have also been detected in benign tumours, notably lipomas [31] and uterine leiomyomas [32]. For some sarcomas these abnormalities appear to be specific enough for diagnostic purposes, and ought to shed light on pathogenesis. Chromosomal translocations in sarcomas might be expected to result in proto-oncogene activation, but so far this has been demonstrated mostly in childhood tumours. Increased expressed and gene amplification of the N-myc oncogene are well known in neuroblastoma, where they have prognostic significance. Point mutations in ras genes have been demonstrated in some embryonal sarcomas [33]. Familial retinoblastoma, in which there is deletion of both alleles of the RB1 tumour suppressor gene (anti-oncogene), is associated with later development of soft tissue or bone sarcoma [3], and RB1 gene structural abnormalities (including deletions) have also been demonstrated in occasional sarcomas in patients without retinoblastoma [34]. Germline p53 mutations have been identified in Li-Fraumeni syndrome [3], and loss of a suppressor gene on chromosome 17p (presumed to be p53) has also been implicated in the MPNST development in neurofibromatosis [35]. It seems likely that other aetiological associations of sarcomas will prove to have a molecular pathological basis.
Small Round Cell Sarcomas Although occurring sporadically in adults, this group of tumours, characterized by darkly haematoxyphilic nuclear staining and scanty cytoplasm, is regularly found in childhood, and includes a number of malignancies with different management strategies. Modern immunohistochemistry [23] has made the separation of neuroblastoma, leukaemia/lymphoma, and embryonal rhabdomyosarcoma relatively easy. The identification of peripheral primitive neuroectodermal tumour (PNET) is enabled by the demonstration within it of neuron-specific enolase and neurofilament [24], and it has now been shown that
GRADING AND PROGNOSIS The prognosis and management of soft tissue sarcomas depends on staging, and staging systems [36] take into account not only the extent of spread at the time of diagnosis, but also the grade of the tumour. For epithelial malignancies it is relatively easy to assess the degree of differentiation, but for sarcomas grading is difficult because the term embraces so many different types of mesenchymal tumour. Some
Soft Tissue Sarcomas
325
Table 2. Behaviour of soft tissue sarcomas
Low metastatic potential
High metastatic potential
Variable metastatic potential (histologically gradable)
Dermatofibrosarcoma protuberans Well differentiated liposarcoma
Alveolar soft part sarcoma Clear cell sarcoma De-differentiated liposarcoma Ewing's sarcoma/PNET Extraskeletal mesenchymal chondrosarcoma Extraskeletal osteosarcoma Malignant rhabdoid tumour Round cell liposarcoma Pleomorphic sarcomas Rhabdomyosarcoma
Angiosarcoma Epithelioid sarcoma Extraskeletal myxoid chondrosarcoma Fibrosarcoma Leiomyosarcoma Malignant fibrous hlstiocytoma Malignant peripheral nerve sheath tumour Myxoid liposarcoma Synovial sarcoma
PNET, primitive neuroectodermal tumour.
resemble adult tissue, such as nerve sheath or smooth muscle tumours; yet may have a poor prognosis even when well differentiated. Others recapitulate normal embryonic tissue but may have a reasonably good prognosis. Additionally, in many sarcomas the concept of differentiation becomes problematic; some types, although readily recognized, are always undifferentiated in the sense that they do not resemble any known normal adult tissue. These principles are illustrated by reference to the subgroups of liposarcoma. Myxoid liposarcoma resembles embryonic fat, yet behaves quite indolently. However, its less differentiated round cell variant is a high-grade aggressive tumour, as is the pleomorphic liposarcoma. The well differentiated liposarcoma, on the other hand, when arising in the limbs or trunk does not metastasize, and it has been suggested that in these extra-abdominal locations the term 'atypical lipomatous tumour [37, 38] is more apt. In some examples, however, an aggressive malignant fibrous histiocytoma-like area occurs (de-differentiated liposarcoma) [39] which redefines its behaviour. A few histological types of sarcoma (Table 2) always have a slow course and low metastatic potential. Others are always aggressive, allowing the histological diagnosis to be used as an initial grading criterion (automatic grading). However, the majority display a wider spectrum of behaviour, which can be related to histological features, and in these a grading system can be applied. There is, unfortunately, no agreed single system for grading soft tissue sarcomas but typically more than two tiers are used with assessment of some or all of mitotic counts, cellularity, differentiation/pleomorphism, and amount of necrosis [40, 41]. One study [42] which graded some cases first by diagnosis, found that the amount of necrosis was the single major predictor for survival among the other tumours. In all series, higher grade tumours form a substantial majority, but with changing concepts of diagnosis, and the use of multivariate analyses, it is becoming clear that the behaviour of some tumours previously always regarded as high grade (e.g. synovial [43] and epithelioid sarcomas) may be better predicted by a twoor three-tier histological grading system. At present, assessment of DNA ploidy and cell proliferation do not offer a significant improvement in predicting the behaviour of sarcomas. Other generally adverse prognostic factors are:
1. Tumour size >5 cm 2. Depth from surface: superficial tumours are less likely to metastasize than those beneath deep fascia or within muscle 3. Location: retroperitoneal tumours, even those of low grade, have a worse outcome, perhaps because of their later presentation, and here, as in the head and neck or thorax, complete surgical removal may not be possible. It should also be noted that some sarcomas, such as epithelioid sarcoma, cause considerable morbidity by relentless local recurrence, even though they may not metastasize until later in the course of the disease. Clearly, as in other areas, proper management of these rare tumours depends on a sound knowledge of the pathology, biology and likely behaviour of the disease; this is best achieved by close collaboration between pathologists and clinicians, and by referral where necessary to specialist centres, preferably even before a biopsy has been performed. References 1. Enzinger FM, Weiss SW. Soft tissue tumors. 2nd ed. St Louis: Mosby, 1988. 2. Bernstein K, Lattes R. Nodular (pseudosarcomatous) fasciitlS, a non-recurrent lesion: clinicopathologlc study of 134 cases. Cancer 1982;49:1668-78. 3. Cooper CS, Stratton MR. Soft tissue tumours: the genetic basis of development. Carcinogenesis 1991 ;12:155-65. 4. Ball AR, Fisher C, Watkins R, et al. Diagnosis of soft tissue tumours by Tru-cut biopsy. Br J Surg 1990;77:756-8. 5. Fisher C. The value of electron microscopy and lmmunohistochemlstry m the diagnosis of soft tissue sarcomas: a study of 200 cases. Histopathology 1990;16:441-55. 6. Corson JM, Weiss LM, Banks-Schlegel SP, et al. Keratin proteins and carcinoembryonic antigen in synovial sarcomas: an irnmunohistochemical study of 24 cases. Hum Pathol 1984;15:615-21. 7. Fisher C. Synovial sarcoma: ultrastructural and immunohistochemlcal features of monophasic and biphasic tumours. Hum Pathol 1986;17:996-1008. 8. Smith S, Reeves BR, Wong L, et al. A consistent chromosome transloeation in synovial sarcoma. Cancer Genet Cytogenet 1987;26:179-80. 9. Reeves BR, Smith S, Fisher C, et al. Characterlsation of the translocation between chromosomes X and 18 in human synovial sarcoma. Oncogene 1989;4:373-8. 10. Miettinen M, Virtanen I. Synovial sarcoma- a misnomer. Am J Pathol 1984;117:18-25. 11. Erlandson RA, Woodruff JM. Peripheral nerve sheath tumors. An electron microscopic study of 43 cases. Cancer 1982;49:273-87
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