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Distinctive clinicopathologic features of the common myxoid soft-tissue lesions
MINI-SYMPOSIUM: SOFT-TISSUE PATHOLOGY
Distinctive clinicopathologic features of the common myxoid soft-tissue lesions
articular variant may, in fact, be a reactive phenomenon related to injury.3 The intramuscular and cutaneous variants are discussed here. Intramuscular myxoma Intramuscular myxomas are most commonly found in middleaged women in the proximal extremities and limb girdle. They are poorly vascularized and have a water-like character (high T2 signal) on pre-operative MR imaging.4 Although most are sporadic, a percentage of intramuscular myxoma are associated with Mazabraud syndrome (myxomas and fibrous dysplasia) or McuneeAlbright syndrome (myxomas, fibrous dysplasia, cutaneous hyperpigmentation, and endocrine abnormalities). Both sporadic and syndromic intramuscular myxomas have been found to have GNAS mutations.5 On gross examination, intramuscular myxomas are grey, myxoid, and relatively well demarcated. Microscopically, however, the myxoid matrix can infiltrate the surrounding atrophic and oedematous skeletal muscle. This infiltration can be in broad zones or thin strands of myxoid matrix. The lesion itself is classically paucicellular. (Figure 1) Scattered fibroblasts and myofibroblasts are seen in the myxoid matrix. Blood vessels are scant and consist of small capillaries or thicker walled vessels. Collagenous stroma may be focally present. Histiocytes are often numerous and can mimic lipoblasts if foamy; the myxoid matrix may also have “bubbles” that give the appearance of lipoblasts on low power. A subtype of intramuscular myxomas have been termed “cellular myxomas” due to the increase in both cellularity and vascularity6 In this subtype of myxoma, the majority of the lesion may be made up of spindled or stellate cells with only focal areas of paucicellular myxoid matrix. (Figure 2) Nevertheless, nuclear pleomorphism, hyperchromatic nuclei, and necrosis should be absent in any type of intramuscular myxoma. Mitotic figures are very rarely identified.6 The treatment for intramuscular myxoma is simple excision. There is no risk of metastasis, and a low risk of local recurrence even with the cellular variant. The main differential diagnosis for intramuscular myxoma includes two sarcomas that do carry a risk of metastases: myxoid liposarcoma and low grade myxofibrosarcoma. Both of these entities will be described in detail later. Briefly, myxoid liposarcoma has a characteristic delicate capillary network that is lacking in myxoma, while low grade myxofibrosarcoma contains hyperchromatic and pleomorphic nuclei that should not be seen in myxoma. If immunohistochemical stains are used, myxomas show focal positivity for CD34 and SMA, but are nonreactive for S100 or desmin. Myxofibrosarcoma may also be positive for CD34. In contrast, myxoid liposarcomas have focal S100 reactivity and lack CD34.
Meredith E Pittman Elizabeth A Montgomery
Abstract Myxoid change is a nonspecific finding in soft tissue tumours and can be encountered in sarcomas, benign soft tissue neoplasms, and even reactive lesions. For this reason, tumours that are intrinsically myxoid often present a diagnostic dilemma, especially if limited material is available for study. Here we provide a detailed description of four commonly encountered myxoid neoplasms: myxoma, myxoid liposarcoma, myxofibrosarcoma, and low grade fibromyxoid sarcoma. The accompanying differential diagnosis for each will aid the pathologist in the correct classification of myxoid soft tissue tumours.
Keywords low grade fibromyxoid sarcoma; myxofibrosarcoma; myxoid liposarcoma; myxoma; superficial angiomyxoma
Introduction Soft tissue sarcomas are quite rare, estimated to comprise less than 1% of the malignant tumours encountered by pathologists each year.1 Several of these soft tissue sarcomas are characterized by prominent myxoid stroma, a distinguishing feature that can aid in classification of the sarcoma. Benign soft tissue lesions may also have myxoid stroma, however, and the benign lesions are approximately 100-times more common than their malignant counterparts.2 Unsurprisingly, many pathologists are uncomfortable with myxoid lesions. Differentiating the myxoid soft tissue lesions requires knowledge of the clinical, radiologic, and histologic findings. Ancillary studies, including immunohistochemical stains and molecular tests, can be helpful when used in the appropriate setting. In this review, we describe how to distinguish between common benign and malignant myxoid soft tissue lesions so that practicing pathologists will have the tools to do the same.
Myxomas Myxomas are characterized by abundant extracellular mucin in an otherwise hypocellular background of fibroblasts and myofibroblasts. Myxomas may occur in superficial, deep, and organbased sites. While most are thought to be neoplastic, the juxta-
Cutaneous myxoma/superficial angiomyxoma Although histologically similar to intramuscular myxomas, cutaneous myxomas are otherwise different tumours. Often called superficial angiomyxoma, these lesions occur most commonly on the trunk and head and neck area. Sporadic lesions have a slight male predominance and occur in middle age, while syndromic lesions have no gender difference and arise in younger patients.
Meredith E Pittman MD Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Conflicts of interest: none. Elizabeth A Montgomery MD Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Conflicts of interest: none.
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Figure 3 Cutaneous myxoma/Superficial angiomyxoma. This lesion has bland spindled cells, a variable number of blood vessels, and sometimes entrapped adnexal elements that can be mistaken for malignancy.
Figure 1 Intramuscular myxoma with lobules of paucicellular myxoid matrix, unremarkable blood vessels, and oedematous skeletal muscle at the edge of the lesion.
Cutaneous myxomas can be found in the dermis or in the subcutaneous tissues and should present as a painless mass. As with intramuscular myxoma, the histologic appearance is one of abundant extracellular mucin with bland spindled or stellate supporting cells and an increased number of blood vessels. Importantly, entrapped adnexal elements are found in this lesion up to 25% of the time7 (Figure 3). The diagnosis of a cutaneous myxoma will often prompt clinicians to consider Carney complex. The majority of families with Carney complex, which is transmitted in an autosomal dominant fashion, have been found to have mutations in the PRKAR1A gene on chromosome 17q.7 Patients with Carney complex have both cutaneous and cardiac myxomas, characteristic skin pigmentation, and various endocrine abnormalities.8 The importance of making the syndromic diagnosis is in locating and monitoring cardiac myxomas, which may cause intracardiac obstruction or sudden embolization. Cutaneous
myxomas, on the other hand, are merely an irritation to patients, and up to one-third of them locally recur after excision. There is no metastatic potential for these lesions.3 The differential diagnosis for cutaneous myxoma/superficial angiomyxoma is broader than for that of the deep intramuscular myxoma, although the list predominantly consists of other benign lesions. The superficial acral fibromyxoma is a painful lesion found on the palm, sole, or periungual region that also has myxoid matrix and stellate fibroblasts. Besides the characteristic site, microscopic clues to this diagnosis versus a myxoma are increased bland cellularity in a fascicular or storiform pattern, increased vascularity, and prominent mast cells. (Figure 4) The lesional cells are reactive for CD34, but negative for S100 and desmin. Local excision is the treatment, although up to a quarter of superficial acral fibromyxomas recur.9 Another cutaneous lesion with myxoid stroma is the myxoid neurothekeoma. These lesions usually arise in younger patients
Figure 2 Cellular intramuscular myxoma. Although there is increased cellularity, the constituent fibroblasts and myofibroblasts have open chromatin with indistinct stellate or spindled cytoplasm. The blood vessels remain unremarkable, with the exception that the endothelial cells may be more hyperchromatic that the lesional cells (a reassuring finding).
Figure 4 A superficial acral fibromyxoma has increased cellularity, including mast cells (inset), and numerous unremarkable vessels. The lesions are classically found around nails or on the palms/soles.
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(less than 30) on the head and neck or upper extremeties. The lesional cells of neurothekeoma may be spindled or epithelioid and grow in characteristic whorls (Figure 5), quite different from the scattered fibroblasts of a cutanous myxoma. Giant cells are not uncommon. These lesions are positive for CD10 and the marker NKI/C3, but are negative for S100. Local recurrence is rare in neurothekeoma.10 The dermal nerve sheath myxoma is a distinct entity from myxoid neurothekeoma, although the two are often confused in the literature. Dermal nerve sheath myxomas are superficial, multinodular masses found on the distal extremities and fingers. Although this tumour does have a myxoid matrix, the lesional cells are distinctly Schwannian with nuclear psedoinclusions and a tendency to grow in arranged aggregates (Figure 6) unlike any of the lesions discussed thus far, nerve sheath myxoma is diffusely positive for S100 and GFAP. Approximately half recur after excision.11 As with intramuscular myxoma, the differential diagnosis of cutaneous myxoma/superficial angiomyxoma also includes low grade myxofibrosarcoma and myxoid liposarcoma. Myxoid liposarcomas are typically (with rare exceptions) centred in the deep soft tissues rather than in the dermis or subcutis and contain uniform round nuclei. Myxofibrosarcoma is often superficial like myxomas but differs by exhibiting large pleomorphic hyperchromatic nuclei.
Figure 5 Myxoid neurothekeoma. The spindled and epithelial cells of neurothekeoma grow in characteristic whorls.
Myxoid liposarcoma Myxoid liposarcoma (MLS) accounts for 5e10% of all adult soft tissue sarcomas. These are usually painless masses found in the deep soft tissues of the thigh/buttock area of adults in their 30’s and 40’s.12 They are very rarely seen in children or adolescents,13 and for all practical purposes do not occur in the retroperitoneum as a primary neoplasm.14 Approximately 20% of patients develop metastases, often to other soft tissue sites or bone, including the spine.15 Pre-surgical magnetic resonance imaging shows a heterogeneous mass with septations and limited amounts of T1 hyperintense fat. The myxoid component has increased T2 signal intensity.4 Excision specimens of a myxoid liposarcoma show a nodular tumour with enhanced cellularity at the periphery of the nodules. There is often abundant extracellular mucin that can form confluent pools of microcystic or pseudoacinar change. These hypocellular areas are a diagnostic challenge when exclusively sampled by needle biopsy.16 The classic appearance of a myxoid liposarcoma consists of uniform oval cells and small, signet-ring like lipoblasts in myxoid stroma. A characteristic feature is the rich vascular network made up of delicate and arborizing capillaries, often referred to as a “chicken-wire” pattern. (Figure 7) In a low grade myxoid liposarcoma, nuclear pleomorphism, giant cells, and prominent spindling should not be seen. As a myxoid liposarcoma becomes a higher grade lesion, the cells become slightly larger and increase in number resulting in a hypercellular round cell lesion. Still, the cells should be predominately uniform in shape and size. When more than 5% of the lesion consists of this round cell component, the neoplasm is no longer considered low grade.1 (Figure 8). The uniformity of the cells in myxoid liposarcoma is related to its underlying genetic abnormality, a recurrent translocation
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Figure 6 Dermal nerve sheath myxoma. This multilobulated mass is composed of S100 positive cells that have nuclear pseudoinclusions (inset) on routine H&E stained sections.
Figure 7 Myxoid liposarcoma. The myxoid background, uniform cells, and delicate branching capillaries are clues to the diagnosis of myxoid liposarcoma. Lipoblasts with hyperchromatic indented nuclei will be scattered throughout the lesion (inset).
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Figure 8 High grade myxoid liposarcoma. As a myxoid liposarcoma becomes a higher grade lesion, the cellular component transitions from uniform oval cells to a more primitive round cell morphology with vesicular chromatin and decreased stroma (left side of the picture).
Figure 9 Occasionally, well-differentiated liposarcoma may have myxoid features. In excision specimens, this can be worked out by the presence of straightforward well-differentiated component. In needle biopsies, the cells of a well-differentiated liposarcoma should be less uniform, and, while capillaries are present, they should not have the delicate, branching morphology seen in a true myxoid liposarcoma.
t(12;16) (q13;p11) that results in the fusion of FUS-DDIT3 (DDIT3 is also known as CHOP). This translocation accounts for >90% of all myxoid liposarcomas. A second variant translocation has been identified, t(12;22) (q13;q12), which fuses EWSR1 with DDIT3.17 The presence of either translocation is sensitive and specific for the diagnosis of myxoid liposarcoma and can be tested by fluorescence in situ hybridization (FISH) at several reference laboratories. Correct initial diagnosis is very important in myxoid liposarcoma because these lesions respond well to radiation therapy. Although radiotherapy does not impact overall survival, it is significantly associated with decreased local recurrence, overall tumour burden, and preservation of function of large muscle groups.12,15 Distant metastases occur in less than 10% of low grade myxoid liposarcomas; still, the overall metastatic rate is 30 e40%. Histologic features that indicate risk for metastasis include high grade morphology (>5%) and tumoral necrosis.1 Currently, there is no standard chemotherapy regimen for treatment of metastatic disease. A marine derived alkaloid, trabectedin is a newer drug that shows some promise in this area. Now available in both the United States and Europe, this drug blocks binding of certain transcripts from the FUS-DDIT3 and EWSR1DDIT3 gene found in MLS, and studies are ongoing in metastatic disease18 The differential diagnosis for a myxoid liposarcoma includes a benign intramuscular myxoma, previously discussed. Although the extracellular mucin pools of a MLS can mimic a myxoma, myxomas lack the monomorphic cellularity of a MLS and should never have true lipoblasts. This distinction can be very difficult, if not impossible, on small biopsy specimens, making correlation with radiology of utmost importance. A second difficult distinction can be between lipoma-like changes within a myxoid liposarcoma and a well-differentiated liposarcoma (WDLS) with myxoid changes.19 In general, WDLS has more pleomorphism than MLS (Figure 9) and also shows areas of fibrosis/sclerosis. Additionally, WDLS may stain for MDM2 or CDK4,20 while MLS has the characteristic DDIT3 translocation, even in lipoma-like areas.19 The distinction is
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important because WDLS is not radiotherapy sensitive and is more likely to have local recurrence, while MLS benefits from radiation but is more likely to metastasize. Extraskeletal myxoid chondrosarcoma (EMC) is another deep, lobulated, myxoid tumour that is common on the proximal extremities and limb girdle area. Patients with EMC tend to be slightly older than those with MLS. EMC is a hypovascular sarcoma in comparison to the well-vascularized MLS; nevertheless, haemorrhage or hemosiderin are often found within EMC. The cells of EMC are quite monomorphic, due to the recurrent genetic abnormality t(9;22), with eosinophilic cytoplasm and a tendency to grow in nests or cords. (Figure 10) Extracellular myxoid chondrosarcoma is a more aggressive tumour than MLS and needs wide excision and follow-up for predominately pulmonary metastases.21(p-) Finally, myxofibrosarcoma, which will be discussed next, is also in the differential diagnosis for MLS.
Figure 10 Extraskeletal myxoid chondrosarcoma is a mimic of myxoid liposarcoma, especially the presence of a round cell component. The cells of EMC should have eosinophilic cytoplasm. Vessels are not prominent, although hemosiderin can often be found (inset).
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Low grade myxofibrosarcoma
The myxoid variant of dermatofibrosarcoma protuberans (DFSP) can also mimic a myxofibrosarcoma. In general, DFSP has a more “patterened” growth, even with the myxoid background, and the cells are extremely uniform. (Figure 12) Myxoid DFSP is common on the trunk and extremities and should be dermal-based. Finally, the neoplastic cells of DFSP should be strongly CD34 positive.24 As myxofibrosarcoma transitions to a higher grade lesion, it loses the myxoid matrix found in the low grade tumour. If a higher grade area is sampled, dedifferentiated liposarcoma is a reasonable diagnosis to entertain. A tumour that has a WDLS component or that is located in the retroperitoneum should be classified as a dedifferentiated liposarcoma. If the tumour is on the extremity, immunostaining for MDM2, CDK4, or p16 can be very helpful in this situation since a high grade myxofibrosarcoma will be negative for those markers.20
Myxofibrosarcoma is the most common sarcoma to affect the limbs and limb girdles of older adults. It is rare on the trunk, head and neck, or hands/feet, and does not occur in the retroperitoneum or abdomen as a primary site; lesions that have been regarded as retroperitoneal myxofibrosarcomas in the past are essentially all dedifferentiated liposarcomas.22 Myxofibrosarcoma, especially the low-grade form, is usually centred in the dermis and subcutis but some examples extend into the deep soft tissues. The tumours are quite heterogeneous on imaging and extend along fascial planes, particularly in superficial examples, a feature that can be seen on MRI as T2-hyperintense “tails”.4 This infiltration makes it difficult to obtain truly negative surgical margins.23 The cells of a low grade myxofibrosarcoma are fusiform in shape with eosinophilic cytoplasm and indistinct cell borders. The nuclei can be quite pleomorphic with coarsely hyperchromatic chromatin, a key distinguishing feature when considering either myxoma or myxoid liposarcoma. Additionally, multilobated nuclei or multinucleated tumour cells are not uncommon in myxofibrosarcoma. The neoplastic cells are haphazardly arranged in a myxoid matrix with elongated, eyecatching capillaries. The tumour is hypercellular around the blood vessels (“perivascular condensation”). (Figure 11). There is no particular immunohistochemical staining pattern or recurrent genetic abnormality in myxofibrosarcoma. Patients are treated with wide surgical resection because of the tendency to grow beyond grossly visible margins. The size, grade, and margin status of the tumour are all related to overall survival.23 Over half of these sarcomas recur, and both pulmonary and osseus metastases have been reported. The differential diagnoses for low grade myxofibrosarcoma includes myxoid liposarcoma, which lacks significant pleomorphism, hyperchromasia, or perivascular condensation. Additionally, some cells in myxofibrosarcoma contain cytoplasmic deposits of myxoid material, an appearance that superficially resembles that of lipoblasts except that the cytoplasmic droplets are not fat but mucopolysaccharide matrix. This finding leads to misinterpretation as myxoid liposarcoma.
Low-grade fibromyxoid sarcoma The similarly named low grade fibromyxoid sarcoma (LGFMS) is also in the differential diagnosis of lesions with myxoid matrix. Whereas low grade myxofibrosarcomas tend to have more myxoid stroma and occur in older individuals, low grade fibromyxoid sarcoma tends to have a more fibrotic stroma and occur in younger patients. Additionally, low grade fibromyxoid sarcoma is almost always a deep lesion, whereas myxofibrosarcoma tends to be superficial. LGFMS is seen equally in males and females and is usually located on the trunk and proximal extremities. These are slow growing and painless lesions and commonly intramuscular, similar to a myxoid liposarcoma.25 As previously mentioned, low-grade fibromyxoid sarcomas tend to have more collagen than any of the tumours discussed thus far and often resemble fibromatoses. The collagenous regions are hypocellular and alternate with hypercellular zones that have a somewhat myxoid matrix. (Figure 13) This variation in matrix is seen as heterogeneous enhancement on MRI.4 A subset of LGFMS has been reported as “hyalinizing spindle cell tumour with giant rosettes” because of the presence of histologic “rosette” formations seen in the collagenous regions of some examples. (Figure 14) Although blood vessels are prominent in
Figure 11 Low grade myxofibrosarcoma has hyperchromatic, pleomorphic cells and distinctive elongated capillaries. Pseudo-lipoblasts may be seen (inset), but the globules within the cytoplasm are not adipose but rather mucopolysaccharide matrix.
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Figure 12 The uniform growth of a myxoid dermatofibrosarcoma protuberans.
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this lesion, they do not have a characteristic growth pattern. The cells are typically very bland and uniform owing to the underlying t(7;16) (q33;p11) that results in a FUS-CREB3L2 fusion. A variant translocation is FUS-CREB3L1.26 Genetic studies are usually not necessary for definitive diagnosis as the malignant cells are reactive for MUC4.27 Although low-grade fibromyxoid sarcoma appears bland, this sarcoma is notorious for late local recurrence and distant metastases, necessitating wide local excision and very long-term follow-up. In one study, two-thirds of sarcomas had recurred within 15 years, and almost half had distant metastases most commonly to lungs and pleura. The time to metastasis was a median of 5 years, but one patient had a metastatic lesion discovered 45 years after the primary diagnosis.25 High grade fibromyxoid sarcoma (sclerosing epithelioid fibrosarcoma) loses the myxoid stroma that cause diagnostic confusion between the various myxoid lesions. Low-grade fibromyxoid sarcomas, however, can mimic any of the benign and malignant tumours previously discussed. Another important entity in the differential diagnosis is fibromatosis, which occurs
Figure 15 Fibromatosis/Desmoid tumour. The lesional cells of fibromatosis have indistinct stellate cytoplasm, pale chromatin, and a delicate nucleolus. The blood vessels in this lesion are prominent due to the relative hyperchromasia of endothelial cells.
in similar areas in a similar age group. The key to differentiating between LGFMS and fibromatosis is the low power impression. Fibromatosis is classically a pale, relatively hypocellular (but not sclerotic) lesion with blood vessels that stand out because of perivascular oedema and because the endothelial cells are larger and more hyperchromatic than the tumour cells. The lesional cells of a desmoid tumour have cleared chromatin, a delicate nucleolus, and indistinct stellate cytoplasm. (Figure 15) In contrast, LGFMS should have a more zonal pattern of growth, and although the tumour cells are usually bland, hyperchromatic nuclei can be found. Finally, nuclear beta-catenin is common in fibromatosis, while MUC4 is sensitive and specific for LGFMS.
Conclusions Soft tissue neoplasms with myxoid stroma can present a diagnostic challenge for a variety of reasons. If small needle biopsies are taken, the specimen may predominantly consist of myxoid matrix with little defining cellularity. Malignant myxoid tumours can mimic benign lesions, and the nomenclature for myxoid sarcomas is characterized by similar names for completely different lesions. Overall, we hope that this review of common benign and malignant myxoid soft tissue tumours has given practicing pathologists helpful guidelines for distinguishing between these lesions, including key ancillary studies (immunohistochemistry and FISH) that can be helpful in certain situations. In summary, we believe that most myxoid lesions can be accurately classified when pathologists give careful attention to lesion site, depth, patient age, cytologic features, and vascular pattern. A
Figure 13 Low grade fibromyxoid sarcoma shows alternating hypocellular collagen (upper left) and hypercellular myxoid regions (lower right). Although uniform, the cells show nuclear hyperchromasia. MUC 4 is positive in this lesion.
REFERENCES 1 Fletcher CDM, World Health Organization, International Agency for Research on Cancer, eds. WHO classification of tumours of soft tissue and bone. 4th edn. Lyon: IARC Press, 2013. 2 Miettinen M, ed. Modern soft tissue pathology: tumors and nonneoplastic conditions. Cambridge ; New York: Cambridge University Press, 2010.
Figure 14 Hyalinizing spindle cell tumour with giant rosettes is a variant of the low grade fibromyxoid sarcoma.
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3 Allen PW. Myxoma is not a single entity: a review of the concept of myxoma. Ann Diagn Pathol 2000; 4: 99e123. http://dx.doi.org/10. 1016/S1092-9134(00)90019-4. 4 Baheti AD, Tirumani SH, Rosenthal MH, et al. Myxoid soft-tissue neoplasms: comprehensive update of the taxonomy and MRI features. AJR Am J Roentgenol 2015; 204: 374e85. http://dx.doi.org/10. 2214/AJR.14.12888. 5 Delaney D, Diss TC, Presneau N, et al. GNAS1 mutations occur more commonly than previously thought in intramuscular myxoma. Mod Pathol 2009; 22: 718e24. http://dx.doi.org/10.1038/modpathol.2009.32. 6 Nielsen GP, O’Connell JX, Rosenberg AE. Intramuscular myxoma: a clinicopathologic study of 51 cases with emphasis on hypercellular and hypervascular variants. Am J Surg Pathol 1998; 22: 1222e7. 7 Wilkes D, McDermott DA, Basson CT. Clinical phenotypes and molecular genetic mechanisms of Carney complex. Lancet Oncol 2005; 6: 501e8. http://dx.doi.org/10.1016/S1470-2045(05)70244-8. 8 Carney JA. Carney complex: the complex of myxomas, spotty pigmentation, endocrine overactivity, and schwannomas. Semin Dermatol 1995; 14: 90e8. 9 Fetsch JF, Laskin WB, Miettinen M. Superficial acral fibromyxoma: a clinicopathologic and immunohistochemical analysis of 37 cases of a distinctive soft tissue tumor with a predilection for the fingers and toes. Hum Pathol 2001; 32: 704e14. http://dx.doi.org/10.1053/hupa. 2001.25903. 10 Fetsch JF, Laskin WB, Hallman JR, et al. Neurothekeoma: an analysis of 178 tumors with detailed immunohistochemical data and longterm patient follow-up information. Am J Surg Pathol 2007; 31: 1103e14. http://dx.doi.org/10.1097/PAS.0b013e31802d96af. 11 Fetsch JF, Laskin WB, Miettinen M. Nerve sheath myxoma: a clinicopathologic and immunohistochemical analysis of 57 morphologically distinctive, S-100 protein- and GFAP-positive, myxoid peripheral nerve sheath tumors with a predilection for the extremities and a high local recurrence rate. Am J Surg Pathol 2005; 29: 1615e24. 12 Hoffman A, Ghadimi MPH, Demicco EG, et al. Localized and metastatic myxoid/round cell liposarcoma: clinical and molecular observations. Cancer 2013; 119: 1868e77. http://dx.doi.org/10.1002/cncr.27847. 13 Huh WW, Yuen C, Munsell M, et al. Liposarcoma in children and young adults: a multi-institutional experience. Pediatr Blood Cancer 2011; 57: 1142e6. http://dx.doi.org/10.1002/pbc.23095. 14 de Vreeze RS, de Jong D, Tielen IH, et al. Primary retroperitoneal myxoid/round cell liposarcoma is a nonexisting disease: an immunohistochemical and molecular biological analysis. Mod Pathol 2008; 22: 223e31. http://dx.doi.org/10.1038/modpathol.2008.164. 15 Moreau L-C, Turcotte R, Ferguson P, et al. Myxoidyround cell liposarcoma (MRCLS) revisited: an analysis of 418 primarily managed cases. Ann Surg Oncol 2012; 19: 1081e8. http://dx.doi.org/10.1245/ s10434-011-2127-z. 16 Fritchie KJ, Goldblum JR, Tubbs RR, et al. The expanded histologic spectrum of myxoid liposarcoma with an emphasis on newly described patterns: implications for diagnosis on small biopsy specimens. Am J Clin Pathol 2012; 137: 229e39. http://dx.doi.org/10. 1309/AJCP90YNOKBAGCDM. 17 Powers MP, Wang W-L, Hernandez VS, et al. Detection of myxoid liposarcoma-associated FUSeDDIT3 rearrangement variants including a newly identified breakpoint using an optimized RT-PCR assay. Mod Pathol 2010; 23: 1307e15. http://dx.doi.org/10.1038/modpathol.2010.118. 18 Di Giandomenico S, Frapolli R, Bello E, et al. Mode of action of trabectedin in myxoid liposarcomas. Oncogene 2014; 33: 5201e10. http://dx.doi.org/10.1038/onc.2013.462.
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19 Iwasaki H, Ishiguro M, Nishio J, et al. Extensive lipoma-like changes of myxoid liposarcoma: morphologic, immunohistochemical, and molecular cytogenetic analyses. Virchows Arch Int J Pathol 2015; 466: 453e64. http://dx.doi.org/10.1007/s00428-015-1721-z. 20 Thway K, Flora R, Shah C, et al. Diagnostic utility of p16, CDK4, and MDM2 as an immunohistochemical panel in distinguishing welldifferentiated and dedifferentiated liposarcomas from other adipocytic tumors. Am J Surg Pathol 2012; 36: 462e9. http://dx.doi.org/10. 1097/PAS.0b013e3182417330. 21 Meis-Kindblom JM, Bergh P, Gunterberg B, et al. Extraskeletal myxoid chondrosarcoma: a reappraisal of its morphologic spectrum and prognostic factors based on 117 cases. Am J Surg Pathol 1999; 23: 636e50. 22 Hisaoka M, Morimitsu Y, Hashimoto H, et al. Retroperitoneal liposarcoma with combined well-differentiated and myxoid malignant fibrous histiocytoma-like myxoid areas. Am J Surg Pathol 1999; 23: 1480e92. 23 Sanfilippo R, Miceli R, Grosso F, et al. Myxofibrosarcoma: prognostic factors and survival in a series of patients treated at a single institution. Ann Surg Oncol 2010; 18: 720e5. http://dx.doi.org/10.1245/ s10434-010-1341-4. 24 Mentzel T, Sch€arer L, Kazakov DV, et al. Myxoid dermatofibrosarcoma protuberans: clinicopathologic, immunohistochemical, and molecular analysis of eight cases. Am J Dermatopathol 2007; 29: 443e8. http:// dx.doi.org/10.1097/DAD.0b013e318145413c. 25 Evans HL. Low-grade fibromyxoid sarcoma: a clinicopathologic study of 33 cases with long-term follow-up. Am J Surg Pathol 2011; 35: 1450e62. http://dx.doi.org/10.1097/PAS.0b013e31822b3687. 26 Lau PPL, Lui PCW, Lau GTC, et al. EWSR1-CREB3L1 gene fusion: a novel alternative molecular aberration of low-grade fibromyxoid sarcoma. Am J Surg Pathol 2013; 37: 734e8. http://dx.doi.org/10. 1097/PAS.0b013e31827560f8. € ller E, Dal Cin P, et al. MUC4 is a highly sensitive and 27 Doyle LA, Mo specific marker for low-grade fibromyxoid sarcoma. Am J Surg Pathol 2011; 35: 733e41. http://dx.doi.org/10.1097/PAS. 0b013e318210c268.
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Benign myxoid soft tissue lesions are w100 times more common than malignant ones. Attention to cytologic detail in conjunction with key clinical information (age, location, radiology) allows for separation of these similar myxoid lesions. Intramuscular or cutaneous myxomas are paucicellular tumours with bland spindled cells. Simple excision is the treatment of choice. Myxoid liposarcoma can be recognized by its delicate branching capillaries, uniform oval cellularity, and scattered lipoblasts. These lesions respond well to neoadjuvant radiotherapy. Low grade myxofibrosarcoma has elongated capillaries and pseudolipoblasts, but the degree of nuclear pleomorphism and hyperchromasia allows for distinction from myxoid liposarcoma. This is the most common sarcoma in the limbs of older adults. Low grade fibromyxoid sarcoma is likely the least myxoid of these myxoid lesions, as it has areas of hypocellular collagenous stroma. MUC4 immunostaining is a helpful ancillary test when diagnosing this malignancy.
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Distinctive clinicopathologic features of the common myxoid soft-tissue lesions
articular variant may, in fact, be a reactive phenomenon related to injury.3 The intramuscular and cutaneous variants are discussed here. Intramuscular myxoma Intramuscular myxomas are most commonly found in middleaged women in the proximal extremities and limb girdle. They are poorly vascularized and have a water-like character (high T2 signal) on pre-operative MR imaging.4 Although most are sporadic, a percentage of intramuscular myxoma are associated with Mazabraud syndrome (myxomas and fibrous dysplasia) or McuneeAlbright syndrome (myxomas, fibrous dysplasia, cutaneous hyperpigmentation, and endocrine abnormalities). Both sporadic and syndromic intramuscular myxomas have been found to have GNAS mutations.5 On gross examination, intramuscular myxomas are grey, myxoid, and relatively well demarcated. Microscopically, however, the myxoid matrix can infiltrate the surrounding atrophic and oedematous skeletal muscle. This infiltration can be in broad zones or thin strands of myxoid matrix. The lesion itself is classically paucicellular. (Figure 1) Scattered fibroblasts and myofibroblasts are seen in the myxoid matrix. Blood vessels are scant and consist of small capillaries or thicker walled vessels. Collagenous stroma may be focally present. Histiocytes are often numerous and can mimic lipoblasts if foamy; the myxoid matrix may also have “bubbles” that give the appearance of lipoblasts on low power. A subtype of intramuscular myxomas have been termed “cellular myxomas” due to the increase in both cellularity and vascularity6 In this subtype of myxoma, the majority of the lesion may be made up of spindled or stellate cells with only focal areas of paucicellular myxoid matrix. (Figure 2) Nevertheless, nuclear pleomorphism, hyperchromatic nuclei, and necrosis should be absent in any type of intramuscular myxoma. Mitotic figures are very rarely identified.6 The treatment for intramuscular myxoma is simple excision. There is no risk of metastasis, and a low risk of local recurrence even with the cellular variant. The main differential diagnosis for intramuscular myxoma includes two sarcomas that do carry a risk of metastases: myxoid liposarcoma and low grade myxofibrosarcoma. Both of these entities will be described in detail later. Briefly, myxoid liposarcoma has a characteristic delicate capillary network that is lacking in myxoma, while low grade myxofibrosarcoma contains hyperchromatic and pleomorphic nuclei that should not be seen in myxoma. If immunohistochemical stains are used, myxomas show focal positivity for CD34 and SMA, but are nonreactive for S100 or desmin. Myxofibrosarcoma may also be positive for CD34. In contrast, myxoid liposarcomas have focal S100 reactivity and lack CD34.
Meredith E Pittman Elizabeth A Montgomery
Abstract Myxoid change is a nonspecific finding in soft tissue tumours and can be encountered in sarcomas, benign soft tissue neoplasms, and even reactive lesions. For this reason, tumours that are intrinsically myxoid often present a diagnostic dilemma, especially if limited material is available for study. Here we provide a detailed description of four commonly encountered myxoid neoplasms: myxoma, myxoid liposarcoma, myxofibrosarcoma, and low grade fibromyxoid sarcoma. The accompanying differential diagnosis for each will aid the pathologist in the correct classification of myxoid soft tissue tumours.
Keywords low grade fibromyxoid sarcoma; myxofibrosarcoma; myxoid liposarcoma; myxoma; superficial angiomyxoma
Introduction Soft tissue sarcomas are quite rare, estimated to comprise less than 1% of the malignant tumours encountered by pathologists each year.1 Several of these soft tissue sarcomas are characterized by prominent myxoid stroma, a distinguishing feature that can aid in classification of the sarcoma. Benign soft tissue lesions may also have myxoid stroma, however, and the benign lesions are approximately 100-times more common than their malignant counterparts.2 Unsurprisingly, many pathologists are uncomfortable with myxoid lesions. Differentiating the myxoid soft tissue lesions requires knowledge of the clinical, radiologic, and histologic findings. Ancillary studies, including immunohistochemical stains and molecular tests, can be helpful when used in the appropriate setting. In this review, we describe how to distinguish between common benign and malignant myxoid soft tissue lesions so that practicing pathologists will have the tools to do the same.
Myxomas Myxomas are characterized by abundant extracellular mucin in an otherwise hypocellular background of fibroblasts and myofibroblasts. Myxomas may occur in superficial, deep, and organbased sites. While most are thought to be neoplastic, the juxta-
Cutaneous myxoma/superficial angiomyxoma Although histologically similar to intramuscular myxomas, cutaneous myxomas are otherwise different tumours. Often called superficial angiomyxoma, these lesions occur most commonly on the trunk and head and neck area. Sporadic lesions have a slight male predominance and occur in middle age, while syndromic lesions have no gender difference and arise in younger patients.
Meredith E Pittman MD Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Conflicts of interest: none. Elizabeth A Montgomery MD Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Conflicts of interest: none.
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Figure 3 Cutaneous myxoma/Superficial angiomyxoma. This lesion has bland spindled cells, a variable number of blood vessels, and sometimes entrapped adnexal elements that can be mistaken for malignancy.
Figure 1 Intramuscular myxoma with lobules of paucicellular myxoid matrix, unremarkable blood vessels, and oedematous skeletal muscle at the edge of the lesion.
Cutaneous myxomas can be found in the dermis or in the subcutaneous tissues and should present as a painless mass. As with intramuscular myxoma, the histologic appearance is one of abundant extracellular mucin with bland spindled or stellate supporting cells and an increased number of blood vessels. Importantly, entrapped adnexal elements are found in this lesion up to 25% of the time7 (Figure 3). The diagnosis of a cutaneous myxoma will often prompt clinicians to consider Carney complex. The majority of families with Carney complex, which is transmitted in an autosomal dominant fashion, have been found to have mutations in the PRKAR1A gene on chromosome 17q.7 Patients with Carney complex have both cutaneous and cardiac myxomas, characteristic skin pigmentation, and various endocrine abnormalities.8 The importance of making the syndromic diagnosis is in locating and monitoring cardiac myxomas, which may cause intracardiac obstruction or sudden embolization. Cutaneous
myxomas, on the other hand, are merely an irritation to patients, and up to one-third of them locally recur after excision. There is no metastatic potential for these lesions.3 The differential diagnosis for cutaneous myxoma/superficial angiomyxoma is broader than for that of the deep intramuscular myxoma, although the list predominantly consists of other benign lesions. The superficial acral fibromyxoma is a painful lesion found on the palm, sole, or periungual region that also has myxoid matrix and stellate fibroblasts. Besides the characteristic site, microscopic clues to this diagnosis versus a myxoma are increased bland cellularity in a fascicular or storiform pattern, increased vascularity, and prominent mast cells. (Figure 4) The lesional cells are reactive for CD34, but negative for S100 and desmin. Local excision is the treatment, although up to a quarter of superficial acral fibromyxomas recur.9 Another cutaneous lesion with myxoid stroma is the myxoid neurothekeoma. These lesions usually arise in younger patients
Figure 2 Cellular intramuscular myxoma. Although there is increased cellularity, the constituent fibroblasts and myofibroblasts have open chromatin with indistinct stellate or spindled cytoplasm. The blood vessels remain unremarkable, with the exception that the endothelial cells may be more hyperchromatic that the lesional cells (a reassuring finding).
Figure 4 A superficial acral fibromyxoma has increased cellularity, including mast cells (inset), and numerous unremarkable vessels. The lesions are classically found around nails or on the palms/soles.
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(less than 30) on the head and neck or upper extremeties. The lesional cells of neurothekeoma may be spindled or epithelioid and grow in characteristic whorls (Figure 5), quite different from the scattered fibroblasts of a cutanous myxoma. Giant cells are not uncommon. These lesions are positive for CD10 and the marker NKI/C3, but are negative for S100. Local recurrence is rare in neurothekeoma.10 The dermal nerve sheath myxoma is a distinct entity from myxoid neurothekeoma, although the two are often confused in the literature. Dermal nerve sheath myxomas are superficial, multinodular masses found on the distal extremities and fingers. Although this tumour does have a myxoid matrix, the lesional cells are distinctly Schwannian with nuclear psedoinclusions and a tendency to grow in arranged aggregates (Figure 6) unlike any of the lesions discussed thus far, nerve sheath myxoma is diffusely positive for S100 and GFAP. Approximately half recur after excision.11 As with intramuscular myxoma, the differential diagnosis of cutaneous myxoma/superficial angiomyxoma also includes low grade myxofibrosarcoma and myxoid liposarcoma. Myxoid liposarcomas are typically (with rare exceptions) centred in the deep soft tissues rather than in the dermis or subcutis and contain uniform round nuclei. Myxofibrosarcoma is often superficial like myxomas but differs by exhibiting large pleomorphic hyperchromatic nuclei.
Figure 5 Myxoid neurothekeoma. The spindled and epithelial cells of neurothekeoma grow in characteristic whorls.
Myxoid liposarcoma Myxoid liposarcoma (MLS) accounts for 5e10% of all adult soft tissue sarcomas. These are usually painless masses found in the deep soft tissues of the thigh/buttock area of adults in their 30’s and 40’s.12 They are very rarely seen in children or adolescents,13 and for all practical purposes do not occur in the retroperitoneum as a primary neoplasm.14 Approximately 20% of patients develop metastases, often to other soft tissue sites or bone, including the spine.15 Pre-surgical magnetic resonance imaging shows a heterogeneous mass with septations and limited amounts of T1 hyperintense fat. The myxoid component has increased T2 signal intensity.4 Excision specimens of a myxoid liposarcoma show a nodular tumour with enhanced cellularity at the periphery of the nodules. There is often abundant extracellular mucin that can form confluent pools of microcystic or pseudoacinar change. These hypocellular areas are a diagnostic challenge when exclusively sampled by needle biopsy.16 The classic appearance of a myxoid liposarcoma consists of uniform oval cells and small, signet-ring like lipoblasts in myxoid stroma. A characteristic feature is the rich vascular network made up of delicate and arborizing capillaries, often referred to as a “chicken-wire” pattern. (Figure 7) In a low grade myxoid liposarcoma, nuclear pleomorphism, giant cells, and prominent spindling should not be seen. As a myxoid liposarcoma becomes a higher grade lesion, the cells become slightly larger and increase in number resulting in a hypercellular round cell lesion. Still, the cells should be predominately uniform in shape and size. When more than 5% of the lesion consists of this round cell component, the neoplasm is no longer considered low grade.1 (Figure 8). The uniformity of the cells in myxoid liposarcoma is related to its underlying genetic abnormality, a recurrent translocation
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Figure 6 Dermal nerve sheath myxoma. This multilobulated mass is composed of S100 positive cells that have nuclear pseudoinclusions (inset) on routine H&E stained sections.
Figure 7 Myxoid liposarcoma. The myxoid background, uniform cells, and delicate branching capillaries are clues to the diagnosis of myxoid liposarcoma. Lipoblasts with hyperchromatic indented nuclei will be scattered throughout the lesion (inset).
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Figure 8 High grade myxoid liposarcoma. As a myxoid liposarcoma becomes a higher grade lesion, the cellular component transitions from uniform oval cells to a more primitive round cell morphology with vesicular chromatin and decreased stroma (left side of the picture).
Figure 9 Occasionally, well-differentiated liposarcoma may have myxoid features. In excision specimens, this can be worked out by the presence of straightforward well-differentiated component. In needle biopsies, the cells of a well-differentiated liposarcoma should be less uniform, and, while capillaries are present, they should not have the delicate, branching morphology seen in a true myxoid liposarcoma.
t(12;16) (q13;p11) that results in the fusion of FUS-DDIT3 (DDIT3 is also known as CHOP). This translocation accounts for >90% of all myxoid liposarcomas. A second variant translocation has been identified, t(12;22) (q13;q12), which fuses EWSR1 with DDIT3.17 The presence of either translocation is sensitive and specific for the diagnosis of myxoid liposarcoma and can be tested by fluorescence in situ hybridization (FISH) at several reference laboratories. Correct initial diagnosis is very important in myxoid liposarcoma because these lesions respond well to radiation therapy. Although radiotherapy does not impact overall survival, it is significantly associated with decreased local recurrence, overall tumour burden, and preservation of function of large muscle groups.12,15 Distant metastases occur in less than 10% of low grade myxoid liposarcomas; still, the overall metastatic rate is 30 e40%. Histologic features that indicate risk for metastasis include high grade morphology (>5%) and tumoral necrosis.1 Currently, there is no standard chemotherapy regimen for treatment of metastatic disease. A marine derived alkaloid, trabectedin is a newer drug that shows some promise in this area. Now available in both the United States and Europe, this drug blocks binding of certain transcripts from the FUS-DDIT3 and EWSR1DDIT3 gene found in MLS, and studies are ongoing in metastatic disease18 The differential diagnosis for a myxoid liposarcoma includes a benign intramuscular myxoma, previously discussed. Although the extracellular mucin pools of a MLS can mimic a myxoma, myxomas lack the monomorphic cellularity of a MLS and should never have true lipoblasts. This distinction can be very difficult, if not impossible, on small biopsy specimens, making correlation with radiology of utmost importance. A second difficult distinction can be between lipoma-like changes within a myxoid liposarcoma and a well-differentiated liposarcoma (WDLS) with myxoid changes.19 In general, WDLS has more pleomorphism than MLS (Figure 9) and also shows areas of fibrosis/sclerosis. Additionally, WDLS may stain for MDM2 or CDK4,20 while MLS has the characteristic DDIT3 translocation, even in lipoma-like areas.19 The distinction is
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important because WDLS is not radiotherapy sensitive and is more likely to have local recurrence, while MLS benefits from radiation but is more likely to metastasize. Extraskeletal myxoid chondrosarcoma (EMC) is another deep, lobulated, myxoid tumour that is common on the proximal extremities and limb girdle area. Patients with EMC tend to be slightly older than those with MLS. EMC is a hypovascular sarcoma in comparison to the well-vascularized MLS; nevertheless, haemorrhage or hemosiderin are often found within EMC. The cells of EMC are quite monomorphic, due to the recurrent genetic abnormality t(9;22), with eosinophilic cytoplasm and a tendency to grow in nests or cords. (Figure 10) Extracellular myxoid chondrosarcoma is a more aggressive tumour than MLS and needs wide excision and follow-up for predominately pulmonary metastases.21(p-) Finally, myxofibrosarcoma, which will be discussed next, is also in the differential diagnosis for MLS.
Figure 10 Extraskeletal myxoid chondrosarcoma is a mimic of myxoid liposarcoma, especially the presence of a round cell component. The cells of EMC should have eosinophilic cytoplasm. Vessels are not prominent, although hemosiderin can often be found (inset).
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Low grade myxofibrosarcoma
The myxoid variant of dermatofibrosarcoma protuberans (DFSP) can also mimic a myxofibrosarcoma. In general, DFSP has a more “patterened” growth, even with the myxoid background, and the cells are extremely uniform. (Figure 12) Myxoid DFSP is common on the trunk and extremities and should be dermal-based. Finally, the neoplastic cells of DFSP should be strongly CD34 positive.24 As myxofibrosarcoma transitions to a higher grade lesion, it loses the myxoid matrix found in the low grade tumour. If a higher grade area is sampled, dedifferentiated liposarcoma is a reasonable diagnosis to entertain. A tumour that has a WDLS component or that is located in the retroperitoneum should be classified as a dedifferentiated liposarcoma. If the tumour is on the extremity, immunostaining for MDM2, CDK4, or p16 can be very helpful in this situation since a high grade myxofibrosarcoma will be negative for those markers.20
Myxofibrosarcoma is the most common sarcoma to affect the limbs and limb girdles of older adults. It is rare on the trunk, head and neck, or hands/feet, and does not occur in the retroperitoneum or abdomen as a primary site; lesions that have been regarded as retroperitoneal myxofibrosarcomas in the past are essentially all dedifferentiated liposarcomas.22 Myxofibrosarcoma, especially the low-grade form, is usually centred in the dermis and subcutis but some examples extend into the deep soft tissues. The tumours are quite heterogeneous on imaging and extend along fascial planes, particularly in superficial examples, a feature that can be seen on MRI as T2-hyperintense “tails”.4 This infiltration makes it difficult to obtain truly negative surgical margins.23 The cells of a low grade myxofibrosarcoma are fusiform in shape with eosinophilic cytoplasm and indistinct cell borders. The nuclei can be quite pleomorphic with coarsely hyperchromatic chromatin, a key distinguishing feature when considering either myxoma or myxoid liposarcoma. Additionally, multilobated nuclei or multinucleated tumour cells are not uncommon in myxofibrosarcoma. The neoplastic cells are haphazardly arranged in a myxoid matrix with elongated, eyecatching capillaries. The tumour is hypercellular around the blood vessels (“perivascular condensation”). (Figure 11). There is no particular immunohistochemical staining pattern or recurrent genetic abnormality in myxofibrosarcoma. Patients are treated with wide surgical resection because of the tendency to grow beyond grossly visible margins. The size, grade, and margin status of the tumour are all related to overall survival.23 Over half of these sarcomas recur, and both pulmonary and osseus metastases have been reported. The differential diagnoses for low grade myxofibrosarcoma includes myxoid liposarcoma, which lacks significant pleomorphism, hyperchromasia, or perivascular condensation. Additionally, some cells in myxofibrosarcoma contain cytoplasmic deposits of myxoid material, an appearance that superficially resembles that of lipoblasts except that the cytoplasmic droplets are not fat but mucopolysaccharide matrix. This finding leads to misinterpretation as myxoid liposarcoma.
Low-grade fibromyxoid sarcoma The similarly named low grade fibromyxoid sarcoma (LGFMS) is also in the differential diagnosis of lesions with myxoid matrix. Whereas low grade myxofibrosarcomas tend to have more myxoid stroma and occur in older individuals, low grade fibromyxoid sarcoma tends to have a more fibrotic stroma and occur in younger patients. Additionally, low grade fibromyxoid sarcoma is almost always a deep lesion, whereas myxofibrosarcoma tends to be superficial. LGFMS is seen equally in males and females and is usually located on the trunk and proximal extremities. These are slow growing and painless lesions and commonly intramuscular, similar to a myxoid liposarcoma.25 As previously mentioned, low-grade fibromyxoid sarcomas tend to have more collagen than any of the tumours discussed thus far and often resemble fibromatoses. The collagenous regions are hypocellular and alternate with hypercellular zones that have a somewhat myxoid matrix. (Figure 13) This variation in matrix is seen as heterogeneous enhancement on MRI.4 A subset of LGFMS has been reported as “hyalinizing spindle cell tumour with giant rosettes” because of the presence of histologic “rosette” formations seen in the collagenous regions of some examples. (Figure 14) Although blood vessels are prominent in
Figure 11 Low grade myxofibrosarcoma has hyperchromatic, pleomorphic cells and distinctive elongated capillaries. Pseudo-lipoblasts may be seen (inset), but the globules within the cytoplasm are not adipose but rather mucopolysaccharide matrix.
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Figure 12 The uniform growth of a myxoid dermatofibrosarcoma protuberans.
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this lesion, they do not have a characteristic growth pattern. The cells are typically very bland and uniform owing to the underlying t(7;16) (q33;p11) that results in a FUS-CREB3L2 fusion. A variant translocation is FUS-CREB3L1.26 Genetic studies are usually not necessary for definitive diagnosis as the malignant cells are reactive for MUC4.27 Although low-grade fibromyxoid sarcoma appears bland, this sarcoma is notorious for late local recurrence and distant metastases, necessitating wide local excision and very long-term follow-up. In one study, two-thirds of sarcomas had recurred within 15 years, and almost half had distant metastases most commonly to lungs and pleura. The time to metastasis was a median of 5 years, but one patient had a metastatic lesion discovered 45 years after the primary diagnosis.25 High grade fibromyxoid sarcoma (sclerosing epithelioid fibrosarcoma) loses the myxoid stroma that cause diagnostic confusion between the various myxoid lesions. Low-grade fibromyxoid sarcomas, however, can mimic any of the benign and malignant tumours previously discussed. Another important entity in the differential diagnosis is fibromatosis, which occurs
Figure 15 Fibromatosis/Desmoid tumour. The lesional cells of fibromatosis have indistinct stellate cytoplasm, pale chromatin, and a delicate nucleolus. The blood vessels in this lesion are prominent due to the relative hyperchromasia of endothelial cells.
in similar areas in a similar age group. The key to differentiating between LGFMS and fibromatosis is the low power impression. Fibromatosis is classically a pale, relatively hypocellular (but not sclerotic) lesion with blood vessels that stand out because of perivascular oedema and because the endothelial cells are larger and more hyperchromatic than the tumour cells. The lesional cells of a desmoid tumour have cleared chromatin, a delicate nucleolus, and indistinct stellate cytoplasm. (Figure 15) In contrast, LGFMS should have a more zonal pattern of growth, and although the tumour cells are usually bland, hyperchromatic nuclei can be found. Finally, nuclear beta-catenin is common in fibromatosis, while MUC4 is sensitive and specific for LGFMS.
Conclusions Soft tissue neoplasms with myxoid stroma can present a diagnostic challenge for a variety of reasons. If small needle biopsies are taken, the specimen may predominantly consist of myxoid matrix with little defining cellularity. Malignant myxoid tumours can mimic benign lesions, and the nomenclature for myxoid sarcomas is characterized by similar names for completely different lesions. Overall, we hope that this review of common benign and malignant myxoid soft tissue tumours has given practicing pathologists helpful guidelines for distinguishing between these lesions, including key ancillary studies (immunohistochemistry and FISH) that can be helpful in certain situations. In summary, we believe that most myxoid lesions can be accurately classified when pathologists give careful attention to lesion site, depth, patient age, cytologic features, and vascular pattern. A
Figure 13 Low grade fibromyxoid sarcoma shows alternating hypocellular collagen (upper left) and hypercellular myxoid regions (lower right). Although uniform, the cells show nuclear hyperchromasia. MUC 4 is positive in this lesion.
REFERENCES 1 Fletcher CDM, World Health Organization, International Agency for Research on Cancer, eds. WHO classification of tumours of soft tissue and bone. 4th edn. Lyon: IARC Press, 2013. 2 Miettinen M, ed. Modern soft tissue pathology: tumors and nonneoplastic conditions. Cambridge ; New York: Cambridge University Press, 2010.
Figure 14 Hyalinizing spindle cell tumour with giant rosettes is a variant of the low grade fibromyxoid sarcoma.
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3 Allen PW. Myxoma is not a single entity: a review of the concept of myxoma. Ann Diagn Pathol 2000; 4: 99e123. http://dx.doi.org/10. 1016/S1092-9134(00)90019-4. 4 Baheti AD, Tirumani SH, Rosenthal MH, et al. Myxoid soft-tissue neoplasms: comprehensive update of the taxonomy and MRI features. AJR Am J Roentgenol 2015; 204: 374e85. http://dx.doi.org/10. 2214/AJR.14.12888. 5 Delaney D, Diss TC, Presneau N, et al. GNAS1 mutations occur more commonly than previously thought in intramuscular myxoma. Mod Pathol 2009; 22: 718e24. http://dx.doi.org/10.1038/modpathol.2009.32. 6 Nielsen GP, O’Connell JX, Rosenberg AE. Intramuscular myxoma: a clinicopathologic study of 51 cases with emphasis on hypercellular and hypervascular variants. Am J Surg Pathol 1998; 22: 1222e7. 7 Wilkes D, McDermott DA, Basson CT. Clinical phenotypes and molecular genetic mechanisms of Carney complex. Lancet Oncol 2005; 6: 501e8. http://dx.doi.org/10.1016/S1470-2045(05)70244-8. 8 Carney JA. Carney complex: the complex of myxomas, spotty pigmentation, endocrine overactivity, and schwannomas. Semin Dermatol 1995; 14: 90e8. 9 Fetsch JF, Laskin WB, Miettinen M. Superficial acral fibromyxoma: a clinicopathologic and immunohistochemical analysis of 37 cases of a distinctive soft tissue tumor with a predilection for the fingers and toes. Hum Pathol 2001; 32: 704e14. http://dx.doi.org/10.1053/hupa. 2001.25903. 10 Fetsch JF, Laskin WB, Hallman JR, et al. Neurothekeoma: an analysis of 178 tumors with detailed immunohistochemical data and longterm patient follow-up information. Am J Surg Pathol 2007; 31: 1103e14. http://dx.doi.org/10.1097/PAS.0b013e31802d96af. 11 Fetsch JF, Laskin WB, Miettinen M. Nerve sheath myxoma: a clinicopathologic and immunohistochemical analysis of 57 morphologically distinctive, S-100 protein- and GFAP-positive, myxoid peripheral nerve sheath tumors with a predilection for the extremities and a high local recurrence rate. Am J Surg Pathol 2005; 29: 1615e24. 12 Hoffman A, Ghadimi MPH, Demicco EG, et al. Localized and metastatic myxoid/round cell liposarcoma: clinical and molecular observations. Cancer 2013; 119: 1868e77. http://dx.doi.org/10.1002/cncr.27847. 13 Huh WW, Yuen C, Munsell M, et al. Liposarcoma in children and young adults: a multi-institutional experience. Pediatr Blood Cancer 2011; 57: 1142e6. http://dx.doi.org/10.1002/pbc.23095. 14 de Vreeze RS, de Jong D, Tielen IH, et al. Primary retroperitoneal myxoid/round cell liposarcoma is a nonexisting disease: an immunohistochemical and molecular biological analysis. Mod Pathol 2008; 22: 223e31. http://dx.doi.org/10.1038/modpathol.2008.164. 15 Moreau L-C, Turcotte R, Ferguson P, et al. Myxoidyround cell liposarcoma (MRCLS) revisited: an analysis of 418 primarily managed cases. Ann Surg Oncol 2012; 19: 1081e8. http://dx.doi.org/10.1245/ s10434-011-2127-z. 16 Fritchie KJ, Goldblum JR, Tubbs RR, et al. The expanded histologic spectrum of myxoid liposarcoma with an emphasis on newly described patterns: implications for diagnosis on small biopsy specimens. Am J Clin Pathol 2012; 137: 229e39. http://dx.doi.org/10. 1309/AJCP90YNOKBAGCDM. 17 Powers MP, Wang W-L, Hernandez VS, et al. Detection of myxoid liposarcoma-associated FUSeDDIT3 rearrangement variants including a newly identified breakpoint using an optimized RT-PCR assay. Mod Pathol 2010; 23: 1307e15. http://dx.doi.org/10.1038/modpathol.2010.118. 18 Di Giandomenico S, Frapolli R, Bello E, et al. Mode of action of trabectedin in myxoid liposarcomas. Oncogene 2014; 33: 5201e10. http://dx.doi.org/10.1038/onc.2013.462.
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19 Iwasaki H, Ishiguro M, Nishio J, et al. Extensive lipoma-like changes of myxoid liposarcoma: morphologic, immunohistochemical, and molecular cytogenetic analyses. Virchows Arch Int J Pathol 2015; 466: 453e64. http://dx.doi.org/10.1007/s00428-015-1721-z. 20 Thway K, Flora R, Shah C, et al. Diagnostic utility of p16, CDK4, and MDM2 as an immunohistochemical panel in distinguishing welldifferentiated and dedifferentiated liposarcomas from other adipocytic tumors. Am J Surg Pathol 2012; 36: 462e9. http://dx.doi.org/10. 1097/PAS.0b013e3182417330. 21 Meis-Kindblom JM, Bergh P, Gunterberg B, et al. Extraskeletal myxoid chondrosarcoma: a reappraisal of its morphologic spectrum and prognostic factors based on 117 cases. Am J Surg Pathol 1999; 23: 636e50. 22 Hisaoka M, Morimitsu Y, Hashimoto H, et al. Retroperitoneal liposarcoma with combined well-differentiated and myxoid malignant fibrous histiocytoma-like myxoid areas. Am J Surg Pathol 1999; 23: 1480e92. 23 Sanfilippo R, Miceli R, Grosso F, et al. Myxofibrosarcoma: prognostic factors and survival in a series of patients treated at a single institution. Ann Surg Oncol 2010; 18: 720e5. http://dx.doi.org/10.1245/ s10434-010-1341-4. 24 Mentzel T, Sch€arer L, Kazakov DV, et al. Myxoid dermatofibrosarcoma protuberans: clinicopathologic, immunohistochemical, and molecular analysis of eight cases. Am J Dermatopathol 2007; 29: 443e8. http:// dx.doi.org/10.1097/DAD.0b013e318145413c. 25 Evans HL. Low-grade fibromyxoid sarcoma: a clinicopathologic study of 33 cases with long-term follow-up. Am J Surg Pathol 2011; 35: 1450e62. http://dx.doi.org/10.1097/PAS.0b013e31822b3687. 26 Lau PPL, Lui PCW, Lau GTC, et al. EWSR1-CREB3L1 gene fusion: a novel alternative molecular aberration of low-grade fibromyxoid sarcoma. Am J Surg Pathol 2013; 37: 734e8. http://dx.doi.org/10. 1097/PAS.0b013e31827560f8. € ller E, Dal Cin P, et al. MUC4 is a highly sensitive and 27 Doyle LA, Mo specific marker for low-grade fibromyxoid sarcoma. Am J Surg Pathol 2011; 35: 733e41. http://dx.doi.org/10.1097/PAS. 0b013e318210c268.
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Benign myxoid soft tissue lesions are w100 times more common than malignant ones. Attention to cytologic detail in conjunction with key clinical information (age, location, radiology) allows for separation of these similar myxoid lesions. Intramuscular or cutaneous myxomas are paucicellular tumours with bland spindled cells. Simple excision is the treatment of choice. Myxoid liposarcoma can be recognized by its delicate branching capillaries, uniform oval cellularity, and scattered lipoblasts. These lesions respond well to neoadjuvant radiotherapy. Low grade myxofibrosarcoma has elongated capillaries and pseudolipoblasts, but the degree of nuclear pleomorphism and hyperchromasia allows for distinction from myxoid liposarcoma. This is the most common sarcoma in the limbs of older adults. Low grade fibromyxoid sarcoma is likely the least myxoid of these myxoid lesions, as it has areas of hypocellular collagenous stroma. MUC4 immunostaining is a helpful ancillary test when diagnosing this malignancy.
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