Myxoid tumours: A guide to the morphological and immunohistochemical assessment of soft tissue myxoid lesions encountered in general surgical pathology

ARTICLE IN PRESS Current Diagnostic Pathology (2005) 11, 411–425

www.elsevier.com/locate/cdip

MINI-SYMPOSIUM: BONE AND SOFT TISSUE PATHOLOGY

Myxoid tumours: A guide to the morphological and immunohistochemical assessment of soft tissue myxoid lesions encountered in general surgical pathology Peter Hollowaya, Elaine Kayb, Mary Leaderb, a

Department of Pathology, The National Maternity Hospital, Holles St., Dublin 2, Ireland Department of Pathology, Beaumont Hospital, Dublin 9, Ireland

b

KEYWORDS Review; Myxoid; Soft tissue; Histopathology; Immunohistochemistry; Algorithms

Summary Many tumours show a component of stromal myxoid material. While the presence of a prominent myxoid component prompts consideration of a ‘myxoid tumour’ such a designation does not necessarily progress the diagnostic process since myxoid tumours have a broad potential histogenesis and vary in clinical significance from benign to malignant. The presence of a prominent myxoid stroma may obscure characteristic architectural and cytological features and may decrease their density in the material available for assessment. In the light of recent work characterizing many of these entities, this review seeks to provide descriptions of many of the soft tissue myxoid tumours encountered in general surgical pathology and to provide (in the form of algorithms) a suggested approach to the histopathological assessment of them. & 2005 Elsevier Ltd. All rights reserved.

Introduction Myxoid tumours are a heterogeneous group of lesions characterized by marked, abundant mucoid/myxoid extracellular matrix (ECM). Over 60 conditions have been described showing at least focal myxoid change.1 The spectrum of tumours Corresponding author. Tel.: +353 1 809 2541;

fax: +353 1 837 0687. E-mail address: [email protected] (M. Leader).

potentially showing either focal or diffuse myxoid morphology/change is broad and includes soft tissue tumours, many epithelial and mixed tumours and tumours of the central nervous system and eye. It is also important to remember that many soft tissue tumours such as neural and smooth muscle tumours and gastrointestinal stromal tumours (GISTs) can show focal myxoid change. This discussion is limited to the soft tissue myxoid tumours that are likely to be encountered in general surgical pathology. Diffuse cutaneous

0968-6053/$ - see front matter & 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.cdip.2005.08.006

ARTICLE IN PRESS 412 mucinoses, which may enter the histopathological differential diagnosis (particularly where the volume of tissue for assessment is small) and can often be excluded on clinical grounds, lie outside the scope of this article. The purpose of this review is to provide assistance in reaching a correct diagnosis in this group of difficult and often confusing tumours. The aim of this discussion is also to provide descriptions of many of these entities, common and rare and to suggest a systematic approach to the histopathological assessment of these myxoid lesions. This review will not provide prognostic data as that is beyond its remit. For a more in-depth description of the morphology and potential behaviour of soft tissue myxoid tumours the reader is referred to the excellent review by Graadt van Roggen et al.,2 whose useful approach of separating soft tissue tumours into superficial and deep is broadly adhered to in this review.

General considerations The accurate categorization of myxoid lesions is complicated by evolving classifications and the fact that some lesions exist as part of a spectrum of overtly benign and malignant neoplasms separated by lesions of intermediate clinical significance. Soft tissue tumour classification is also confounded by the pathological practice of ‘splitting’. Difficulty arises in the assessment of myxoid tumours for a variety of other reasons including their rarity, morphological overlap, intratumour heterogeneity, mimicry of sarcomas by pseudosarcomas and relatively limited usefulness of immunohistochemistry as a discriminator, particularly in hypocellular myxoid tumours. Diagnosis on inadequate material and overdiagnosis of malignancy on the basis of increased mitoses are other pitfalls. Myxoid soft tissue tumours are rare and some entities may be encountered by a histopathologist only on a few occasions in his or her professional life. There are many overlapping morphological features,1,3 e.g. a hypocellular low vascularity myxoid tumour with ovoid/spindle cells raises a differential diagnosis of a cellular myxoma, juxtaarticular myxoma, angiomyxoma, aggressive angiomyxoma or myxofibrosarcoma. Another example to illustrate overlapping morphological features is myxoid change in a cellular spindle cell tumour that may represent a leiomyosarcoma, a peripheral nerve sheath tumour, a GIST or a synovial sarcoma. Myxoid tumours may show significant intratumoural heterogeneity and the area sampled may not be representative of the tumour. This occurs particu-

P. Holloway et al. larly in needle biopsies or where the periphery or ‘capsule’ of the tumour has been sampled. Radiologists must be advised that the non-necrotic centres of tumours should be sampled when radiologically guided biopsies are taken. One should not be reluctant to ask for additional material in difficult cases. It is inappropriate to render a diagnosis if material is inadequate. We have seen this lead to mistaken diagnoses on a number of occasions. In particular with needle biopsy and aspiration, differential diagnosis may be all that is possible. It is also mandatory to obtain a good clinical history with respect to tumour site, size and duration, history of a preceding non-myxoid lesion and radiological features, if possible. So-called pseudosarcomas can be easily overdiagnosed as malignant if too much reliance is placed on high mitotic indices. Some benign myxoid lesions may have a high mitotic rate, e.g. nodular fasciitis, whilst some bland appearing myxoid tumours with very few mitoses may be malignant, e.g. myxofibrosarcoma. Nodular fasciitis is the most commonly overdiagnosed ‘pseudosarcoma’. Such an overdiagnosis of malignancy can be prevented if attention is paid to the characteristic short history of this entity (less than 3 months) and usually small size (less than 3 cm). Never make a diagnosis of malignancy in a myxoid proliferation of recent onset and small size without asking if the lesion could represent nodular fasciitis. While it is reassuring to find an abnormal mitosis in a malignant tumour that mimics nodular fasciitis, it may not always be possible to do so. Myxoid change may be seen in three broad settings: (1) It may occur in soft tissue entities in which its presence is essential to the diagnosis. (2) It can occur in tumours that often show myxoid change but may not, e.g. myxoid degeneration in a leiomyoma. (3) Myxoid change may occur in a tumour not normally associated with myxoid morphology, e.g. synovial sarcoma. Asking oneself which category the case in question falls into (based on the ratio of myxoid: non-myxoid areas, the presence or absence of specific features in the myxoid and non-myxoid areas or the knowledge of a previous non-myxoid tumour) can prove a useful strategy in the assessment of these lesions. It is wise counsel not to ascribe a diagnosis of benign or malignant to a myxoid tumour until one has arrived at a specific diagnosis. Finally, it is neither a sign of ignorance nor diagnostic weakness

ARTICLE IN PRESS Myxoid tumours to ask a colleague for a second opinion in a difficult soft tissue tumour.

Concerning special stains and techniques Many textbooks cite the value of staining for Alcian blue at critical electrolyte concentrations in myxoid soft tissue tumours.4 In our experience, this is of little value. Myxoid tumours can also cause diagnostic difficulty since immunohistochemistry has a limited role and in many instances molecular studies are of value only in a limited number of cases, e.g. extraskeletal myxoid chondrosarcoma and myxoid liposarcoma. These facilities are also not available routinely in many laboratories. However, immunohistochemistry should be performed in the assessment of all cellular myxoid tumours. The most valuable markers are vimentin, S100P, desmin, actin, cytokeratin and CD34. Immunohistochemical markers must always be performed as part of a panel. Otherwise, lack of specificity of a marker may lead to an incorrect diagnosis. If vimentin is negative, the diagnosis of a mesenchymal tumour is unlikely. However, vimentin is positive in many lymphomas and epithelial tumours. Occasionally, these enter the differential diagnosis of a mesenchymal tumour. Sometimes epithelial markers are also important to exclude a diagnosis of carcinoma. Cytokeratin staining is described in smooth muscle tumours and peripheral nerve sheath tumours as well as in synovial sarcomas and epithelioid sarcomas. A dermal cellular spindle cell myxoid tumour that is S100P positive raises the differential diagnosis of malignant melanoma. In these instances, HMB45 and Melan A should also be performed. Actins are nonspecific but they usually show some positive staining in nodular fasciitis and in myofibroblastic proliferations. Since actin is present in the vast majority of smooth muscle tumours, one should be reluctant to accept this diagnosis in an actinnegative tumour. CD34 was originally regarded as a fairly specific marker of solitary fibrous tumour and vascular tumours. It has now been identified in many other entities including GISTs.

413 The entities discussed below are divided on the basis of whether they characteristically involve cutaneous or subcutaneous tissue or involve more deep-seated areas. However, some entities can involve both sites.

Cutaneous and subcutaneous lesions Hypocellular lesions without a significant vasculature Digital myxoma5 Location: Digital. Duration: Slowly growing. Presentation: Painful cystic lesion. Size: 10–20 mm. Circumscription: Solitary, circumscribed, unencapsulated. Level: Superficial dermis. Cellularity: Variably cellular. Vessels: Avascular. Cell type: Spindle and stellate. Atypia: Bland. Mitoses: No mitoses. Inflammatory infiltrate: No specific infiltrate. Architecture: Cysts if present lack the connective tissue lining of ganglia. Behaviour: Prone to local recurrence. Ganglion6 Location: Around joints and tendons of hands and feet. Dorsum of wrist is a characteristic site. Presentation: Pain and interference with normal function occurring between 25 and 45 years of age. Size: 10–20 mm average. Circumscription: Poor demarcation, unilocular or multilocular cyst. Cellularity: Paucicellular. Atypia: None. Inflammatory infiltrate: May have a chronic inflammatory infiltrate. Architecture: Cyst with a lining of flattened connective tissue cells. Myxoid cellular foci outside cyst wall may be overdiagnosed as malignant if taken out of context. Behaviour: Benign but may recur.

Descriptions In the following descriptions, an attempt has been made to characterize the lesions under fixed clinical and morphological headings. However, in certain cases, where inclusion would give inappropriate weight to non-discriminatory features, they have been omitted.

Hypocellular lesions with a significant vasculature Superficial angiomyxoma, aggressive angiomyxoma, cellular myxoma, juxta-articular myxoma and myxofibrosarcoma (when hypocellular) can all have overlapping morphological features in that the tumours are of low cellularity with a marked

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myxoid stroma and a variable number of blood vessels. Curvilinear vessels are characteristic of myxofibrosarcoma. Smooth muscle condensation around blood vessels is characteristic of aggressive angiomyxoma. The presence of a prominent vasculature virtually excludes an intramuscular myxoma. Superficial angiomyxoma7–9 Location: Head, neck, trunk, genital region. Duration: Slowly growing. Presentation: Non-tender mass, more common in males. Size: Generally less than 4 cm (a 10 cm recurrent lesion has been reported). Circumscription: Lobulated, not circumscribed. Level: Dermis or subcutis. Cellularity: Hypocellular. Vessels: Numerous congested delicate thinwalled vessels of variable size (see Fig. 1(B)). Cell type: Spindle and stellate, scanty eosinophilic cytoplasm. Specific ECM: Fine reticulin network. Atypia: Bland and tissue culture-like with mild atypia at most, may have giant cells and vesicular nuclei. Mitoses: Rare mitoses. Inflammatory infiltrate: Stromal neutrophils. Architecture: There may be an entrapped epithelial component, such as basaloid buds, and keratin cysts especially in recurrent lesions. Immunophenotype: CD34 positive, S100P, SMSA and MSA negative. Behaviour: Prone to local recurrence (30%). Lesions, if multiple, may be associated with Carney complex.10

Figure 1 Characteristic vascular features such as the abnormally thick smooth muscle coat seen in aggressive angiomyxoma (A) and congested delicate thin-walled vessels in superficial angiomyxoma (B) may be very helpful.

Aggressive angiomyxoma11,12 Location: Pelvic and genital. Duration: Slowly growing. Presentation: Painless mass. Predominantly affects women. Size: May be up to 20 cm. Circumscription: Lobulated, not circumscribed, infiltrative margins. Level: Subcutaneous or deeper. Cellularity: Paucicellular/hypocellular, possible foci of increased cellularity. Vessels: Numerous variably sized vessels, some thin walled, some with a ‘collar’ of smooth muscle cells7hyalinization. Cell type: Spindle or stellate. Specific ECM: Possible delicate collagen bands. Atypia: Bland. Mitoses: Infrequent, not atypical. Inflammatory infiltrate: Mast cells frequent.

Architecture: Whorls and clusters of eosinophilic smooth muscle cells surround vessels. There may be red cell extravasation (see Fig. 1(A)). Immunophenotype: Vimentin, desmin, SMSA, MSA positive, S100P negative. Karyotype: May have t(5:12) (q31:p11).13 Behaviour: Locally aggressive with frequent local recurrence (30%). May recur if not fully excised.

Low-grade myxoid neoplasm with recurrent potential/cellular myxoma Recently, it has become apparent that histopathological features do not always allow a definite distinction between benign myxomas and those with some recurrent potential. Therefore, the

ARTICLE IN PRESS Myxoid tumours above category is now used for those with recurrent potential.14 Location: Proximal limbs (less often trunk). Duration: Slowly growing. Presentation: Painless mass. Circumscription: Lobulated but microscopically infiltrative at the margins. Level: May be subcutaneous, but most are deep, subfascial or intramuscular (50%). Cellularity: More cellular than intramuscular myxoma. Vessels: More vascular than intramuscular myxoma. Lacks the perivascular condensation seen in low-grade fibromyxoid sarcoma and myxofibrosarcoma. Cell type: Spindle cells, pseudolipoblasts are common. Atypia: No atypia or pleomorphism, giant cells absent. Mitoses: Scarce. Immunophenotype: CD34 positive (50%). May be actin positive (10%). S100P and desmin negative. Behaviour: May recur locally. No metastatic potential.

415 Mitoses: Present. Numbers determine the histological grade. Usually low mitotic index. More MIB1 positivity than low-grade fibromyxoid sarcoma. Inflammatory infiltrate: Prominent peripheral mixed inflammatory infiltrate. Architecture: Myxoid and fibrous areas. May have architectural features of malignant fibrous histiocytoma. Low-grade lesions have no solid areas. High-grade lesions may be solidly cellular and have areas of necrosis. Immunophenotype: Vimentin positive, 20% CD34 positive. Other markers negative (except focal actin positivity in high-grade lesions). Karyotype: Ring chromosomes may be present. Behaviour: Malignant behaviour is dependent on the histological grade. Local recurrences (66%). Metastasis (30%).

Myxofibrosarcoma/myxoid MFH15–18 The definition of this entity has resulted in much discussion. The current WHO classification requires at least 50% of the entire tumour to display a highly vascularized myxoid stroma with distinctive curvilinear vessels. Location: Extremities. Duration: Slowly growing, painless swelling. Presentation: Older patients. Size: Usually less than 10 cm. Circumscription: Multinodular with ill-defined infiltrative margins particularly if superficial, deeper subfascial variant has more discrete mass. Level: Subcutaneous (70%), intramuscular and subfascial. Cellularity: Overall cellularity dependent on grade, usually low. Vessels: Delicate thin-walled curvilinear vessels with some perivascular tumour cell condensation in myxoid areas. Cell type: Small fusiform to stellate cells with hyperchromatic pleomorphic nuclei and indistinct eosinophilic cytoplasm. Occasional pseudolipoblasts/vacuolated cells may be present (see Fig. 2(A)). Specific ECM: Copious myxoid matrix. Atypia: Dependent on histological grade, usually present.

Figure 2 Features such as occasional ‘bizarre’ cells (arrow) help to differentiate myxofibrosarcoma (lowgrade) in A from low-grade fibromyxoid sarcoma in B.

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Myxoid tumours with spindle cells/ epithelioid cells with relatively inconspicuous vasculature Nodular fasciitis19 This is probably the ‘pseudosarcoma’ that is most commonly misdiagnosed as malignant. Location: Upper extremities and head and neck. Duration: Less than 3 months. Presentation: Children, adolescents and young adults. Tender/painful. Size: Less than 3 cm. Circumscription: Well demarcated but not encapsulated. Level: Subcutaneous (a small proportion is intramuscular). Other sites have been described. Cellularity: Marked cellularity. Vessels: Delicate and thin-walled capillaries. Cell type: Plump fibroblasts and myofibroblasts, plump tapering vesicular nuclei with occasional nucleoli. Specific ECM: Feathery appearance to the ECM. Atypia: None. Mitoses: May be numerous but no abnormal forms. Inflammatory infiltrate: Mild lymphocytic infiltrate with red cell extravasation. Architecture: Short fascicles and untidy bundles, 7cystic change, no necrosis. Immunophenotype: SMSA and MSA positive. Usually desmin negative.20 Behaviour: If excision is adequate, local recurrence is rare.

Dermal nerve sheath myxoma/neurotheceoma Location: Head, neck, upper limb.21,22 Duration: Slowly growing. Presentation: Painless mass in adolescents and young adults. Size: Less than 3 cm. Circumscription: Well circumscribed, lobulated. Level: Dermal more commonly than subcutaneous. Cell type: Spindle cell, occasional epithelioid cells. Specific ECM: Copious myxoid matrix. Atypia: Ovoid nuclei, occasional mild pleomorphism and vesicular chromatin. May have scattered multinucleated cells. Mitoses: Present but scattered. Inflammatory infiltrate: Mast cells. Architecture: Fascicular, whorled, often with connective tissue septation.

P. Holloway et al. Immunophenotype: Cellular areas are strongly S100P positive. Behaviour: Benign. Myxolipoma Location: Often head and neck but can be anywhere on body surface. Duration: Longstanding. Presentation: Solitary. Size: Variable. Circumscription: Thinly encapsulated, well demarcated. Level: Subcutaneous. Cellularity: Variable. Vessels: Delicate vasculature. Cell type: Spindle cells and occasional mature adipocytes. Specific ECM: Ropey collagen bundles. Atypia: Rare atypical vacuolated cells but without nuclear hyperchromasia. Mitoses: Usually absent. Inflammatory infiltrate: Mast cells. Architecture: There may be occasional foci of spindle cells. Immunophenotype: Spindle cells, where present, are usually CD34 positive. Karyotype: May have rearrangements at 13q or 16q. Behaviour: Benign. Myxoid neurofibroma Location: Anywhere on the body surface but often extremities. Duration: Slowly growing. Presentation: Painless mass. May be associated with neurofibromatosis. When sporadic usually present between the ages of 20 and 30 years. Size: Variable size. Circumscription: Well circumscribed but not encapsulated. Level: Sporadic cases are often dermal or subcutaneous. The myxoid variant is often deep. Cellularity: Hypocellular. Cell type: Elongated with bland, tapering, wavy or buckled nuclei, pale indistinct cytoplasm. Specific ECM: Abundant myxoid stroma, little collagen. Atypia: May show ‘ancient’ change, e.g. nuclear pleomorphism. Mitoses: Absent. Architecture: Intralesional nerve fibres or axons. Immunophenotype: S100P patchy but unequivocal. Behaviour: Benign.

ARTICLE IN PRESS Myxoid tumours Myxoid dermatofibrosarcoma protuberans23 Location: Often trunk. Duration: Longstanding, slowly growing. Presentation: Longstanding asymptomatic plaque or nodule. Circumscription: Poorly circumscribed, infiltrative margins. Level: Cutaneous and subcutaneous. Cellularity: Hypocellular myxoid areas. Vessels: May show increased vascularity. Cell type: Small stellate and spindle-shaped cells. Atypia: Mild nuclear hyperchromasia and pleomorphism. Mitoses: Present. Architecture: Haphazard arrangement, may have storiform architecture. Immunophenotype: CD34 positive, S100P negative. Behaviour: Low malignant potential, local recurrence if incompletely excised, infrequently metastasize, possible transformation to high-grade sarcoma. Ossifying fibromyxoid tumour24,25 Location: Upper and lower extremities. Duration: Slowly growing. Presentation: Older adults, firm and painless swelling. Size: Less than 5–10 cm. Circumscription: Well circumscribed and often multinodular, often with a thick acellular pseudocapsule. Level: Subcutaneous or deeper. Cellularity: Variable. Cell type: Monotonous oval or rounded cells moderate amount of eosinophilic or indistinct cytoplasm. Specific ECM: Abundant myxoid or fibrous stroma. Atypia: Usually uniform vesicular nuclei. Atypia and necrosis associated with more aggressive behaviour. Mitoses: Usually infrequent mitoses. If mitotically active then more aggressive. Architecture: Cord- or lace-like arrangement and a rim of mature lamellar bone lined by an attenuated layer of osteoblasts in the fibrous pseudocapsule and sometimes in the septa. Immunophenotype: Around 60% are S100P positive (may be desmin and actin positive). Cytokeratin negative. Behaviour: Local recurrence only after incomplete excision (cellular, atypical subset asso-

417 ciated with more local aggressive behaviour and metastasis).

Deep-seated myxoid soft tissue tumours Intramuscular myxoma26,27 Location: Large muscles of the thigh, gluteal area and arm, not near joints. Duration: Slowly enlarging. Presentation: Painless, slowly enlarging, solitary (may be multiple if associated with fibrous dysplasia) often in middle-aged women. Size: Most are 5–10 cm but they may be larger. Circumscription: Well circumscribed, margin may be infiltrative microscopically. Level: Intramuscular. Cellularity: Paucicellular with, at most, focal hypercellular areas. Vessels: Sparse vessels with patchy increased vascularity. Cell type: Bland spindle cells or small stellate cells, occasional muciphages and small pseudolipoblasts. Specific ECM: Alcian blue positive, hyaluronidase sensitive myxoid matrix, with a delicate meshwork of reticulin fibres. Atypia: Small hyperchromatic nuclei. Mitoses: None. Architecture: There may be microcystic change with mucin pooling. Immunophenotype: Vimentin positive, negative for others. Behaviour: Rare local recurrence. Juxta-articular myxoma28 Location: Soft tissue (particularly subsynovial) around major joints of extremities. Presentation: Older patients. Apparently related to previous trauma or osteoarthritis. Size: Usually less than 5 cm. Circumscription: Lobulated, margin may be infiltrative microscopically. Level: Periarticular tissue and subcutaneous fat. Cellularity: More cellular than intramuscular myxoma. Vessels: More vascular than intramuscular myxoma. Cell type: Scattered small spindle-shaped or stellate fibroblast-like cells. Atypia: Mild pleomorphism. Inflammatory infiltrate: Areas of haemorrhage, haemosiderin deposition and mild chronic inflammatory infiltrate.

ARTICLE IN PRESS 418 Architecture: Thin and thick-walled cystic spaces. Behaviour: Higher risk of local recurrence than intramuscular myxoma possibly due to the inclusion of some low-grade myxofibrosarcomas. Distinction from the latter may be very difficult and is influenced by tumour site. Low-grade fibromyxoid sarcoma29–32 Location: Extremities, trunk and retroperitoneum. Duration: Slowly growing over months or years. Presentation: Painless soft tissue swelling in adults. Size: Marked variation in size. Circumscription: Grossly well circumscribed but unencapsulated with microscopically infiltrative borders. Level: Subfascial soft tissue, infrequently subcutaneous. Cellularity: Variable but generally low. Cell type: Spindle cells with poorly defined pale eosinophilic cytoplasm7stellate cells (see Fig. 2(B)). Atypia: Bland small uniform hyperchromatic oval nuclei, 7minimal nuclear pleomorphism. Mitoses: Scarce. Architecture: Alternating fibrous collagen bands and myxoid areas, whorled and swirling formations, 7infiltration of fat and muscle, 7condensation of tumour cells around vessels, thick collagen bundles, amianthoid fibres, rich network of delicate capillaries. Hyalinizing spindle cell tumour with giant rosettes is a variant of low-grade fibromyxoid sarcoma.33 Immunophenotype: Vimentin positive, with or without actin, desmin, keratin and CD34 positivity. S100P and EMA negative. In the hyalinizing spindle cell tumour with giant rosettes, the rosette cells are positive for S100 and NSE. Karyotype: t(7; 16) (q34; p11). Behaviour: Indolent but ultimately malignant course, multiple recurrences and 50% metastases. This lesion may be misdiagnosed as nodular fasciitis and the correct diagnosis is only made if a recurrence or metastasis occurs.

P. Holloway et al. Circumscription: Circumscribed fusiform mass. Level: Deep seated. Cellularity: Paucicellular myxoid areas with cellular fascicles. Vessels: Accentuation due to perivascular whorling or condensation. Cell type: Ovoid to spindle-shaped cells, pale illdefined cytoplasm, nuclei wavy or buckled rather than cigar shaped. Epithelioid variants and heterologous elements may be seen (see Fig. 3(A)). Atypia: Variable nuclear pleomorphism. Mitoses: Present. Architecture: Fusiform mass, often fascicular arrangement, often with perivascular whorling or condensation, 7heterologous elements. Associated nerve trunk may be identified. Immunophenotype: Only 50% are S100P positive.

Myxoid malignant peripheral nerve sheath tumour34 Location: Deep seated, closely applied to a major nerve trunk. Presentation: Adults, 30% have type 1 neurofibromatosis. Size: Variable, often large, 5 cm.

Figure 3 Residual characteristic cytologic features may be present such as the ‘punched-out’ nuclei and polygonal acidophilic cytoplasm in a malignant peripheral nerve sheath tumour (epithelioid variant) in A and lipoblasts (arrow) in myxoid liposarcoma in B.

ARTICLE IN PRESS Myxoid tumours Behaviour: Significant potential for local recurrence and distant metastases. Extraskeletal myxoid chondrosarcoma35,36 Location: Proximal extremities and limb girdles, often thigh area and around the knee. Duration: Slowly growing. Presentation: Adults (usually males), asymptomatic or painful deep-seated mass. Size: 5–10 cm. Circumscription: Lobulated, well circumscribed, unencapsulated mass. Level: Deep soft tissues, usually subfascial (often intramuscular), occasionally deep subcutis. Cellularity: Cords of cells. Vessels: Few vessels in the myxoid stroma. Cell type: Small and uniform cells with round to oval nuclei. May be spindle shaped. May have variable amounts of pale glycogen-containing eosinophilic cytoplasm. Around 10–20% has rhomboid inclusions. Specific ECM: Abundant hyaluronidase-resistant myxoid stroma, in contrast to most other myxoid soft tissue sarcomas, which are predominantly hyaluronidase sensitive. In practice, this method has been superseded by immunohistochemistry and molecular genetics. Atypia: There may be nuclear pleomorphism, in particular nuclear hyperchromasia. Mitoses: Scarce but may be present. Architecture: Multinodular architecture, tumour lobules in abundant myxoid stroma, connective tissue septation around individual tumour islands, cord or lace-like arrangement with focal, more solid, areas, more cellular peripherally. Overt cartilage formation is seen in less than 5–10%. There may be haemorrhage. Immunophenotype: Vimentin positive; 80% are neurone-specific enolase positive but only 10–20% are S100P positive. Karyotype: Most (70%) cases have t(9; 22) (q22–31:q11–12).37 Behaviour: Slowly growing but high potential for metastasis. Embryonal rhabdomyosarcoma Location: Around 50% arise in the head and neck, most commonly periorbital, auditory canal and oropharynx, while 25% arise in the genitourinary system, most commonly bladder, prostate and paratesticular soft tissues. Duration: Variable depending on site. Presentation: Commonest soft tissue sarcoma in children and adolescents. Uncommon in adult-

419 hood. Clinical presentation depends on the effects of a mass at the particular site of origin. Cellularity: Variably cellular depending on amount of myxoid stroma. Vessels: No specific features. Cell type: Ovoid, spindle, tadpole cells with conspicuous eosinophilic cytoplasm. Cross striations may be evident in a minority of cells. A majority of spindle cells indicates a spindle cell variant of rhabdomyosarcoma. This variant is associated with a better prognosis. The spindle cell variant may have a storiform pattern. The presence of anaplastic cells may indicate an anaplastic variant (with a worse prognosis). The botyroid variant of embryonal rhabdomyosarcoma typically shows a condensation of cells in a subepithelial layer (cambium layer). The cells may show minimal pleomorphism and may closely resemble the cells of a rhabdomyoma. Thorough sampling of such a tumour is required. Atypia: Variable as above. Anaplastic cells may be seen. Mitoses: Variable. Architecture: Botyroid variant as described. Immunophenotype: Almost all are positive for vimentin. Many show positive staining for desmin, SMSA and MSA. Most are positive for myoglobin, myogenin and myoD1. The latter is the most specific marker if staining is nuclear. Cytoplasmic staining may be non-specific and may be related to heat associated antigen retrieval. Aberrant staining for CD20, VS38c, cytokeratin, NSE and S100P may be seen. Karyotype: Allelic loss in region of 11p15. Behaviour: Spindle cell and embryonal rhabdomyosarcomas have a better prognosis than alveolar tumours. Tumours with anaplasia have a worse prognosis within this group. Myxoid liposarcoma38 Location: Extremities, particularly thigh. Size: Variable. Circumscription: Well circumscribed/encapsulated, lobulated mass. Level: Deep seated, subfascial, sometimes subcutaneous. Cellularity: More cellularity at periphery of nodules. Vessels: Delicate, branching, plexiform arrangement of thin-walled capillaries with a chickenwire or crows’ feet distribution. Cell type: Small bland, spindle shape or more rounded cells. Round cells are associated with more aggressive behaviour. There may be univacuolated (signet ring-like) lipoblasts with

ARTICLE IN PRESS 420 small numbers of characteristic multivacuolated lipoblasts often in the more cellular peripheral regions (see Fig. 3(B)). There may be hibernomalike cells. Specific ECM: Abundant hyaluronidase sensitive myxoid matrix. Atypia: There may be sporadic pleomorphic and multinucleate cells. If a round cell component is present it is often associated with larger, rounder, more pleomorphic nuclei than those seen in the myxoid areas. Mitoses: Scarce. Architecture: Pooling of stromal mucin, 7pseudolymphangiomatous appearance. There may be necrosis. There may be heterologous elements. Immunophenotype: Vimentin positive, 30–50% S100 positivity. Other stains generally negative. Karyotype: Majority have t(12:16) (q13:p11),39 minority have t(12:22) (13:p11).40 Behaviour: Roughly 40–90% 5-year survival rate, 10–20% metastases. Myxoid leiomyosarcoma41,42 A detailed assessment of the malignant potential of smooth muscle tumours lies beyond the scope of this article and the reader is referred to work by Hornick and Fletcher.43 Location: Genital tract, perineum, thigh, trunk and retroperitoneum but can occur anywhere and may be associated with vessels and tubular organs. Presentation: Mass effect. If uterine, they may be associated with abnormal PV bleeding. In skin, they may be painful. Cell type: Spindle cells, eosinophilic cytoplasm, bipolar, cigar-shaped nucleus with small to prominent nucleoli. Specific ECM: Copious hyaluronidase sensitive myxoid matrix. Atypia: Variably pleomorphic nuclei. Mitoses: If two or more mitoses/50 high power fields (HPFs) are present, malignancy must be considered. Necrosis that is not surrounded by a ‘collar’ of fibrous tissue or reactive tissue is also an indicator of possible malignancy. In a subcutaneous or dermal location, pleomorphism in the absence of ‘ancient’ features, such as perivascular hyalinization, is also worrying for malignancy and requires the examination of numerous sections in a search for mitoses. Inflammatory infiltrate: Mast cells may be present. Architecture: Areas of interlacing fascicles. Immunophenotype: Actin positive, desmin (70%), 7keratins and EMA. S100P is negative.

P. Holloway et al. Behaviour: Dependent on grade and depth and site, varying from local recurrence to metastasis. Cutaneous and subcutaneous lesions, if excised are most unlikely to metastasize. Retroperitoneal and genital and intramuscular lesions are more likely to behave aggressively. Myxoid change in uterine leiomyoma is common. Similar change in uterine leiomyosarcoma is rare. Myxoid leiomyosarcomata of the uterus exhibit highly aggressive behaviour despite low mitotic index.44 Myxoid synovial sarcoma45 Location: Usually extremities, often around knee and ankle joints. Duration: Variable. Presentation: Juxta-articular mass usually in young adults. Size: 1–10 cm. Circumscription: Circumscribed. Level: Deep soft tissue, occasionally subcutaneous. Cellularity: Variably cellular. Vessels: May have haemangiopericytoma-like ‘stag-horn’ vessels (in 10% of cases). Cell type: Spindle cells with poorly defined cytoplasm and round to oval nuclei with slight hyperchromasia. Specific ECM: Predominantly myxoid Alcian blue positive, hyaluronidase sensitive stroma. Atypia: Slight nuclear hyperchromasia. Mitoses: Often exceeds 10/10 HPFs. Inflammatory infiltrate: Mast cells. Architecture: Lacy, loose fascicular growth pattern with variably (occasionally wiry) collagenized stroma, May have small foci of glandular differentiation and calcification. Mucin pooling is not a feature. Immunophenotype: EMA positive. May be positive for pan-keratin and S100P. Desmin negative. Karyotype: Approximately 90% have t(x:18) (p11.2;q11.2).46 Behaviour: Potential for local recurrence and metastasis but chemosensitive. Soft tissue myxopapillary ependymoma47 Location: Sacral subcutaneous tissue or sacrum proper (dorsal more than ventral). They may be associated with a post-anal pit.48 Duration: Slowly growing. Presentation: Adults (third–fifth decades). Circumscription: Sharply delineated, 7thin fibrous pseudocapsule, microscopically infiltrative edges.

ARTICLE IN PRESS Myxoid tumours Level: Subcutaneous or deeper. Vessels: See architecture (below). Cell type: Cuboidal–elongated cells. Ultrastructural evidence of cilia, microvilli and zonula adherents and blepharoplasts and intracytoplasmic lumen formation. Atypia: If present does not alter prognosis. Mitoses: Modest mitotic activity does not alter prognosis. Architecture: Cuboidal to elongated cells radially arranged in a papillary manner around vascularized stromal cores. A basophilic mucoid matrix material accumulates between tumour cells and blood vessels. There may be pseudo rosettes. Varying proportions of myxomatous (chordoma-like) and spindle cell (schwannoma) components may be present. If longstanding, they may have vascular sclerosis, haemorrhage, haemosiderin or extensive fibrous tissue overgrowth obscuring the neoplastic elements. Immunophenotype: Vimentin, GFAP and S100P positive. Chromogranin, EMA and CEA negative.49 Behaviour: Locally aggressive, 20% metastasis. Chordoma50 Location: Axial, 50% sacrococcygeal, may involve vertebral bodies and/or extend into retroperitoneum. Duration: Slowly growing. Presentation: Commonest in the fifth and sixth decades but can occur at any age. Men more often than women. Invade surrounding tissue. Associated with mass effect (possible spinal cord compression or, in cephalic lesions, cranial nerve involvement) and pain. Circumscription: Lobulated. Cell type: Small round cells and occasional large physaliferous cells with characteristic large intracellular vacuoles (containing glycogen) with vesicular nuclei. Ultrastructure shows peculiar mitochondrial endoplasmic reticulum complexes and desmosomes. If high-grade or pleomorphic spindle cell areas are present, the prognosis is poorer. Specific ECM: Variable but usually extensive amount of myxoid material. Atypia: Pleomorphic cells may be present but do not appear to adversely affect the prognosis. Mitoses: Usually scanty or absent but if highgrade or spindle cell areas are present these show a high proliferative index. Architecture: Cords and lobules of tumour cells separated by mucoid extracellular material. The intracellular vacuoles occasionally line up like

421 beads on a string. There may be fibrous septa. Chondroid and bony elements, if present, are associated with longer survival.51 High-grade or spindle cell ‘dedifferentiated’ components are associated with more aggressive behaviour. Areas resembling renal cell carcinoma may be present. Immunophenotype: S100P, vimentin, cytokeratins 8 and 19 and EMA positive. Galectin-3 75% positive, unlike extraskeletal myxoid chondrosarcoma. Negative for cytokeratins 7 and 20. Rarely CEA positive.52 Behaviour: Locally aggressive with repeated episodes of local recurrence. Possible late metastases (43%) and an often fatal outcome. Myxoma of the jaw53 Location: Affects maxilla and mandible. Duration: Slowly growing. Presentation: Cystic occasionally painful and ulcerated mass associated with local bony destruction. Circumscription: Multilocular non-encapsulated. Vessels: Variable numbers of tiny inconspicuous capillaries. Cell type: Loosely arranged stellate and spindle cells with branching processes that tend to intermesh. Specific ECM: Unlike myxoid malignant fibrous histiocytoma, chondroitin-sulphate-6 and PG-M/ versican are present.54 Atypia: Mild nuclear atypia at most. Mitoses: None. Architecture: May have islands of inactive odontogenic epithelium. Immunophenotype: Vimentin and MSA are positive. S100P is negative.55 Behaviour: Potential for local tissue destruction and recurrence. More aggressive in the maxilla than the mandible. Malignant transformation and metastasis have not been described.

Algorithms for the approach to soft tissue myxoid tumours based on initial assessment of tumour site and architecture (with particular reference to vasculature) The following algorithms have been constructed as an aid to the assessment of myxoid lesions. Since some entities have a characteristic location, an algorithm has been included based on location to

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P. Holloway et al.

prompt consideration of them (see Fig. 4). However, most emphasis has been placed on architectural features as the initial discriminators with subsequent consideration given to the clinical setting and architectural/cytological features which should/ may/may not be present (see Figs 5 and 6). The algorithms are intended as a guide only and exceptions may occur. Having arrived at a putative diagnosis, reference should be made to the preceding descriptions and to the traps and pitfalls section, below.

Potential traps and specific sources of diagnostic error

 

Extensive sampling is required to identify characteristic features occurring sparsely on an abundant myxoid background. The only available evidence of significant cellular atypia may be subtle. In some instances, it may only be present as nuclear hyperchromasia in small otherwise bland nuclei.

The location of the lesion suggests consideration of a specific entity

Around joints and tendons

Finger

Small joints of hands and feet Consider a digital myxoma

Deep-seated in large muscles of thigh, gluteal area and arm

Mandible or maxilla

Consider an intramuscular myxoma

Consider a myxoma of the jaw

Sacral

Knees and ankles

Consider a ganglion cyst

Consider a synovial sarcoma

Consider a juxta-articular myxoma

Consider a myxopapillary ependymoma

Consider a chordoma

Figure 4 Algorithm for the assessment of myxoid lesions based on specific locations.

Specific features are present which are suggestive of a tumour in which myxoid change is not characteristic feature

Elongated cells with wavy/buckled nuclei Deep Consider myxoid peripheral nerve sheath tumour

Focal storiform architecture

Occasional foci of spindle cell lipoma with occasional adipocytes

Spindle cells arranged in fascicles

Consider myxolipoma

Consider a smooth muscle tumour

Cellular tumour with glandular or epithelioid areas

Superficial Consider myxoid neurofibroma

Consider myxoid DFSP

Consider a synovial sarcoma

Figure 5 Algorithm for the assessment of myxoid lesions based on the residual architectural features.architectural features.

A characteristic vascular pattern is present

Rich network of delicate capillaries

Delicate thin walled vessels

Curvilinear

Consider low grade fibromyxoid sarcoma

Consider myxofibrosarcoma

If in skin, consider superficial angiomyxoma

“Tissue-culture” appearance with minimal atypia and mitotic activity+/- red cell extravasation Consider myxoid nodular fasciitis

Delicate branching plexiform arrangement of thin-walled capillaries with a crows’ feet/ chicken wire pattern

Variably sized thick and thin walled vessels, some with thick smooth muscle condensation and occurring in a genital site

Consider myxoid liposarcoma

Consider aggressive angiomyxoma

Figure 6 Algorithm for the assessment of myxoid lesions based on the presence of a characteristic vascular pattern.

ARTICLE IN PRESS Myxoid tumours















The diagnosis of myxoid liposarcoma should not be made on the basis of the apparent presence of lipoblasts alone since lipoblasts may be found in lipoblastomatosis and multivacuolated cells may mimic lipoblasts. Lipoblastoma that occurs subcutaneously in infants and lacks the characteristic translocation, should not be confused with myxoid liposarcoma, which tends to arise in deeper adult tissues.56 Except in the case of nodular fasciitis or an exuberant reactive vascular or fibroblastic repair process, the presence of mitoses at a rate of greater than 3/10 HPFs should make one think twice before diagnosing a benign/indolent process. Immunohistochemistry may be misleading unless a panel of markers is applied, e.g. cytokeratins may be expressed in spindle cell tumours such as smooth muscle tumours and in a small percentage of malignant melanomas. Vimentin is expressed by many spindle cell carcinomas. Unless vimentin and cytokeratin immunostains are both performed, a spindle cell carcinoma may be misdiagnosed as a sarcoma. Vimentin is also expressed in some lymphomas. Myxoid tumours may lack staining for markers that are characteristically seen in their nonmyxoid counterparts, e.g. only 10–20% of extraskeletal myxoid chondrosarcoma and only 35–50% of myxoid liposarcomas are S100P positive. S100P staining is therefore not necessary for the diagnosis of these lesions. When it is low-grade, myxoid fibrosarcoma (MFS) may be hard to differentiate from low-grade fibromyxoid sarcoma. When diagnosing either of these lesions one should attempt to out rule the other. The following features should be borne in mind. Low-grade MFS has elongated curvilinear capillaries and pseudolipoblasts, lacks extensive solid areas, cell cycle regulator expression is higher and the entity tends to occur in older patients. Low-grade fibromyxoid sarcoma is composed of bland spindle cells in a whorled pattern with alternating myxoid and fibrous stroma, has lower cell cycle regulator expression, lacks significant cytological nuclear atypia and tends to occur in a younger patient.57 Aggressive angiomyxoma must be differentiated from angiomyofibroblastoma, which has a much lower risk of local recurrence and is generally more circumscribed, more vascular and usually has plump epithelioid cells showing a perivascular arrangement. Ossifying fibromyxoid tumour may be differentiated from extraskeletal osteosarcoma on the basis of its indolent nature, organoid architec-

423 ture, S100P staining and lack of malignant osteoid.

Practice points

 



 



Various myxoid tumours have clinical significance ranging from benign to malignant Adequate clinicopathological correlation is essential in the assessment of these lesions with particular respect to patient age, tumour site and duration Extensive myxoid stroma may necessitate the assessment of a large percentage of tumour tissue to arrive at the correct diagnosis Vascular architectural clues are helpful in some myxoid lesions Immunohistochemical assessment of the entities using a panel of markers is essential. However, anomalous immunoprofiles occur The presence of specific genetic abnormalities can prove very useful in the diagnosis of a small number of myxoid tumours

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