This chapter discusses a heterogeneous group of myxoid soft tissue tumors, spanning a clinicopathological spectrum from benign tumors (or pseudotumors), to tumors of borderline malignancy, and low-grade myxoid sarcomas. It also discusses pleomorphic hyalinizing angiectatic tumor, which while not a myxoid neoplasm per se, is closely related to hemosiderotic fibrolipomatous tumor, a myxoid tumor of borderline malignancy.
Intramuscular Myxoma
A dizzying array of benign mesenchymal lesions is characterized by abundant myxoid matrix, inconspicuous stellate- or spindle-shaped cells, and a poorly developed vascular pattern. Most are composed of modified fibroblasts that produce excessive amounts of glycosaminoglycans rich in hyaluronic acid and with little collagen. Intramuscular myxoma, a benign mesenchymal lesion, is of particular importance because it is almost always cured by local excision, yet is easily mistaken for a low-grade myxoid sarcoma.
Clinical Findings
Intramuscular myxoma is a tumor of adult life that occurs primarily in patients 40–70 years old. It is rare in young adults and virtually nonexistent in children and adolescents. About two-thirds of the patients are women. , There is no evidence of increased familial incidence.
The clinical manifestations are nonspecific, and it is difficult to diagnose this tumor before biopsy and microscopic examination. In most patients, the sole presenting sign is a painless, palpable mass that is slightly movable and often fluctuant. As one would expect, pain and occasional numbness, paresthesia, and muscle weakness distal to the lesion are mostly associated with tumors of large size. Because of the relative lack of symptoms, most lesions are present for several months or even years before they are excised. A history of trauma is rarely given, and the tumor is not etiologically related to thyroid dysfunction, as in myxedema.
By far the most common sites of the tumor are the large muscles of the thigh, shoulder, buttocks, and upper arm ( Fig. 32.1A ). Unusual examples have been reported in the muscles of the head and neck, the forearm, scrotum, and small muscles of the hand. The exact location in the musculature varies; some tumors are completely surrounded by skeletal muscle tissue, whereas others are firmly attached on one side to muscle fascia. There are also myxomas of identical appearance that arise from the periosteum, subchondral epiphysis, and joint capsule, discussed later. Angiographic examination reveals a poorly vascularized soft tissue mass surrounded by well-vascularized muscle tissue. Magnetic resonance imaging (MRI) reveals a well-defined, usually homogeneous tumor exhibiting low signal intensity relative to skeletal muscle on T1-weighted images and a hyperintense appearance relative to muscle on T2-weighted images ( Fig. 32.1B ). , In most cases, intramuscular myxomas have characteristic imaging features, and correlation with radiologic studies is often quite helpful in limited biopsies where the differential diagnosis includes myxoid sarcoma.
Intramuscular myxoma showing a uniform, yellowish white cut surface. The tumor characteristically appears well circumscribed ( A ). MRI studies typically show a well-circumscribed mass with very bright T2 signal (“lightbulb sign”) ( B ).
Multiple Intramuscular Myxomas and Fibrous Dysplasia
Although most intramuscular myxomas are solitary, there are occasional patients in whom two or more myxomas are present, usually in the same region of the body. Microscopically, these tumors are no different from the solitary myxomas. Almost all are associated with monostotic or polyostotic fibrous dysplasia of bone, generally in the same anatomic region where the myxomas are located ( Mazabraud syndrome ) ( Fig. 32.2 ). In this setting, females are affected much more frequently than males, even more so than in solitary cases. Often there is a long interval between the appearances of the two processes. In most cases, the fibrous dysplasia is noted during the growth period, whereas the multiple myxomas, as with their solitary counterparts, become apparent many years later during adult life. On occasion, multiple intramuscular myxomas are detected before the osseous lesions. If specifically sought, radiologically evident bone abnormalities are seen in many patients with intramuscular myxomas. In the case originally reported by Mazabraud et al., an osteosarcoma developed in a patient with fibrous dysplasia and multiple myxomas, a phenomenon that others have noted.
Patient with multiple intramuscular myxomas and fibrous dysplasia. ( A ) Characteristic radiographic features of fibrous dysplasia involving the humerus show a shepherd’s crook deformity. ( B ) Histologic appearance of fibrous dysplasia. An intramuscular myxoma was found in the soft tissues adjacent to the humerus.
Gross and Microscopic Findings
The gross appearance is characteristic and varies little from case to case. Most tumors are ovoid or globular and have a glistening gray–white or white appearance, depending on the relative amounts of collagen and myxoid material ( Fig. 32.3 ). They consist of a mass of stringy, gelatinous material with occasional small, fluid-filled, cyst-like spaces, often covered by bundles of skeletal muscle or fascial tissue. Although on gross examination most tumors appear to be well circumscribed, many infiltrate the adjacent musculature or are surrounded by edematous muscle tissue, which may serve as a natural cleavage plane for the surgeon. The size varies greatly; the majority measure 5–10 cm in greatest diameter, but some lesions are 20 cm or larger.
Gross appearance of intramuscular myxoma. Tumor has a mucoid, gelatinous cut surface with thin fibrous septa.
Histologically, intramuscular myxomas vary little. One of the most characteristic features is peripheral splaying apart of skeletal muscle ( Fig. 32.4 ), wherein individual skeletal muscle fibers are separated by bland spindled cells and myxoid matrix. Condensation of tumor cells adjacent to the muscle is also commonly present ( Fig. 32.5 ). A multilobular growth pattern is often present ( Fig. 32.6 ), as well as multifocal microcystic change ( Fig. 32.7 ). Although occasional blood vessels may be present, a well-developed, arborizing, thick-walled vasculature (as seen in myxofibrosarcoma) is absent ( Figs. 32.8 and 32.9 ). The constituent cells have small, hyperchromatic, pyknotic-appearing nuclei and scanty cytoplasm that sometimes extends along the reticulin fibers with multiple processes, giving the cell a stellate appearance ( Figs. 32.10 and 32.11 ). Pleomorphism and tumor giant cells are absent. Pseudolipoblasts with distended endoplasmic reticulum containing myxoid matrix are absent or very sparse in myxomas, in contrast to low-grade myxoid sarcomas. In some cases, there are also scattered macrophages with small intracellular droplets of lipid material. The small size of these droplets and the absence of nuclear deformation or scalloping afford their distinction from lipoblasts. At the periphery, where the tumor merges with the surrounding muscle, fat cells and atrophic muscle fibers are occasionally scattered in the mucoid substance.
Intramuscular myxoma. ( A ) Although grossly well circumscribed, tumor involves surrounding skeletal muscle. ( B ) Higher-magnification appearance of peripheral portion of intramuscular myxoma showing splaying and atrophy of surrounding skeletal muscle.
Condensation of cells in peripheral portion of intramuscular myxoma.
Fibrous septa within intramuscular myxoma creating a multinodular pattern.
( A ) and ( B ) Cystic changes within intramuscular myxoma.
Intramuscular myxoma showing bland spindled cells within relatively avascular myxoid backdrop.
Intramuscular myxoma showing cells widely separated by abundant mucoid material.
( A ) Bland spindled cells of intramuscular myxoma. ( B ) Note occasional presence of histiocytes within the lesion.
Cells of intramuscular myxoma with high nuclear/cytoplasmic ratio and small, darkly staining nuclei.
Some intramuscular myxomas show focal areas of hypercellularity and hypervascularity, which may cause further confusion with a low-grade myxoid sarcoma ( cellular myxoma ) , ( Fig. 32.12 ). Nielsen et al. found that 38 of 51 (76%) cases of intramuscular myxoma had hypercellular zones that comprised 10%–80% of the tumor. However, even in these hypercellular zones, the cells lack nuclear atypia, and there is a paucity of mitotic figures and an absence of necrosis. Areas of more typical hypocellular intramuscular myxoma are always present and allow their definitive recognition.
Cellular variant of myxoma. ( A and B ) Lesions have increased cellularity, but there is no qualitative difference in the nature of cells or matrix.
Immunohistochemical Findings
By immunohistochemistry, the cells may stain for actins consistent with focal myofibroblastic differentiation. The macrophages containing lipid droplets are negative for S-100 protein, unlike true lipoblasts. The cells are suspended in large amounts of mucoid material that stains positively with Alcian blue and colloidal iron stains and is depolymerized by prior treatment of the sections with hyaluronidase, although this is of little practical diagnostic value. Ultrastructurally, the cells show evidence of fibroblastic differentiation.
Genetic Findings
Activating missense mutations in the Arg201 codon of the gene encoding the alpha subunit of G S ( GNAS ), the G protein that stimulates cAMP formation, have been recognized in fibrous dysplasia of bone and McCune-Albright syndrome , consisting of polyostotic fibrous dysplasia, sexual precocity, and café au lait spots. , Subsequently, these same mutations were identified in sporadic intramuscular myxomas and fibrous dysplasias. Delaney et al. found that 8 of 28 (29%) sporadic intramuscular myxomas had GNAS mutations, using a conventional polymerase chain reaction (PCR) technique. However, using a more sensitive COLD ( co amplification at l ower d enaturation temperature) PCR technique, 17 of 28 (61%) sporadic lesions harbored this mutation, which was not detected in any of the low-grade myxofibrosarcomas. More recently, Hatchett et al., using both Sanger sequencing and Ion Ampliseq technology, have identified codon 201 or codon 227 GNAS mutations in 19 of 22 (86%) studied myxomas, most often the p.R201C variant. Gains of chromosomes 7 and 9 were also noted in a subset of cases. Similar findings were noted in a very recent study by Henzinger and colleagues, who also found cellular myxomas to form a distinct methylation cluster, apart from myxofibrosarcomas.
Outcome
Despite their frequently large size and prominent myxoid appearance, intramuscular myxomas are benign and rarely recur locally, even when incompletely excised. In the series by Nielsen et al., none of the 32 patients for whom follow-up was available developed a local recurrence, including those with hypercellular lesions. In the rare examples that do recur, reexcision is typically curative.
Differential Diagnosis
Numerous benign and low-grade malignant myxoid neoplasms are apt to be confused with intramuscular myxoma. At times, the tumor is difficult to distinguish from myxoid lipoma, myxoid neurofibroma, nerve sheath myxoma, chondroma with myxoid change, and nodular fasciitis, conditions discussed in previous chapters. More important, intramuscular myxoma may be confused with low-grade myxoid sarcomas of various types. Low-grade myxofibrosarcoma, similar to intramuscular myxoma, predominantly affects adults and most often arises as an irregular infiltrating subcutaneous mass, although it can arise in deeper soft tissues. At the low end of the histologic spectrum, myxofibrosarcoma is a hypocellular neoplasm composed of spindle-shaped cells deposited in an abundant myxoid stroma. However, the cells always demonstrate a greater degree of nuclear hyperchromasia and cytologic atypia than those of intramuscular myxoma. Many of these neoplasms also have prominent curvilinear blood vessels, often with perivascular tumoral condensation, although this latter feature is frequently not seen at the low-grade end of the spectrum. Pseudolipoblasts are commonly present in low-grade myxoid sarcomas, but are not generally found in myxomas. Myxoid liposarcoma is characterized by a regular plexiform (“chicken-wire”) vasculature with spindle-shaped or stellate cells with mild cytologic atypia deposited in a myxoid stroma. In addition, the identification of cells with adipocytic differentiation, including well-formed lipoblasts, is useful for this distinction. Immunohistochemical or molecular genetic demonstration of DDIT3 expression/rearrangement is confirmatory. Extraskeletal myxoid chondrosarcoma is a multinodular tumor composed of nests and cords of cells with densely eosinophilic cytoplasm deposited in a chondroitin sulfate–rich stroma. Although blood vessels are often not conspicuous, these lesions frequently show areas of hemorrhage and hemosiderin deposition at the periphery of the nodules. Perhaps the most difficult distinction is from a low-grade fibromyxoid sarcoma (Evans tumor) , especially when dealing with a cellular intramuscular myxoma or a small biopsy specimen. Low-grade fibromyxoid sarcoma arises in the deep soft tissues of young adults. Histologically, this tumor is composed of cytologically uniform, spindle-shaped cells deposited in a variably collagenous and myxoid matrix, often with a swirling arrangement of tumor cells around thin-walled capillaries. The transition between fibrous and myxoid zones is often abrupt. In most instances, low-grade fibromyxoid sarcomas are predominantly fibrous tumors, showing myxoid change only in relatively small nodules. In difficult cases, MUC4 immunohistochemistry, positive in low-grade fibromyxoid sarcoma but not myxoma, can also be helpful. At the genetic level, low-grade fibromyxoid sarcomas are characterized by FUS/EWSR1::CREB3L2/CREB3L1 fusions, rather than GNAS mutations.
Juxtaarticular Myxoma
Juxtaarticular myxoma is an uncommon lesion marked by the accumulation of mucinous material in the vicinity of the large joints, most often the knee (almost 90% of cases) but occasionally near the shoulder, elbow, hip, or ankle ( Fig. 32.13A ). , It almost always arises in adults, particularly men, with a predilection for the third through fifth decades of life. In the largest series to date, the patients ranged in age from 16 to 83 years (median: 43 years). The growth typically presents as a swelling or mass that is sometimes rapidly enlarging and can be associated with pain or tenderness. These lesions may be associated with antecedent trauma and can arise adjacent to a joint with osteoarthritis; some lesions are discovered incidentally during total knee or hip arthroplasty. When in the region of the knee, they are frequently referred to as parameniscal cyst , cystic myxomatous tumor , or periarticular myxoma . The radiologic features are similar to those found with intramuscular myxoma.
Juxtaarticular myxoma, occurring adjacent to the synovium of the hip joint ( A ). The lesion is composed of hypocellular proliferation of bland spindled cells evenly deposited in myxoid stroma, similar to intramuscular myxoma ( B ).
Grossly, most lesions are 2–6 cm, but some are as large as 12 cm at excision. They typically have a mucoid, cystic, or multicystic appearance on cut section. Histologically, juxtaarticular myxoma closely resembles intramuscular myxoma and is composed of scattered small, spindled, or stellate-shaped fibroblast-like cells deposited in a richly myxoid matrix that often contains variably sized, thin- or thick-walled cystic spaces ( Fig. 32.13B ). Occasionally, there are hypercellular areas with slight cellular pleomorphism, features that may arouse suspicion of a low-grade myxoid sarcoma. The process involves not only the periarticular soft tissues and overlying cutaneous fat, but also the joint capsule, tendons, and rarely skeletal muscle. Some lesions have areas of hemorrhage and hemosiderin deposition with mild chronic inflammation and reactive fibroblastic proliferation. This lesion has the same immunohistochemical and ultrastructural features as its intramuscular counterpart.
Juxtaarticular myxomas are benign but are apt to recur after incomplete excision. In the series by Meis and Enzinger, recurrences appeared in 10 of the 29 patients for whom follow-up was available, including one lesion that recurred four times.
The pathogenesis of this condition is not clear, but it may represent an exuberant reactive fibroblastic proliferation with overproduction of mucin, thereby lying on a spectrum with ganglion cyst. Interestingly, Sciot et al. described a case with clonal chromosomal changes, including trisomy 7 and a translocation between chromosomes 8 and 22. Unlike intramuscular myxoma, juxtaarticular myxoma does not have mutations in the GNAS gene.
Cutaneous Myxoma (Superficial Angiomyxoma)
Cutaneous myxoma, also known as superficial angiomyxoma, was first described by Carney et al. in their 1986 study of the superficial myxoid tumors occurring in the setting of Carney complex (which had been described 1 year earlier). This lesion was later more fully characterized by Allen et al. in 1988 and Calonje et al. in 1999. Cutaneous myxoma should be distinguished from the other cutaneous myxoid lesions with which it may be confused (discussed later) because it has a propensity for local recurrence.
Cutaneous myxoma arises slightly more often in males, predominantly middle-aged adults, with a peak incidence between 20 and 40 years. , These lesions can arise essentially anywhere in the superficial tissues, but there is a predilection for the trunk, lower extremities, and head and neck; some arise in the genital region (vulva, mons pubis, scrotum/inguinal) of both males and females. A recent series of 54 cutaneous myxomas, reported by Sharma et al., found a median patient age of 55 years (range 7–91 years), a slight female predominance, and most frequent involvement of the back/trunk, followed by the lower extremities, head/neck, and upper extremities. Histologically, identical lesions may arise in the setting of Carney complex, particularly those that are multiple and arise in the eyelids and external ear. , Clinically, most appear as slowly growing, polypoid or papulonodular cutaneous lesions that may be confused with a cyst, skin tag, or neurofibroma.
Gross and Microscopic Findings
Grossly, cutaneous myxomas are usually well circumscribed, but some are poorly demarcated. The majority are between 1 and 5 cm and have a gray to white, glistening, gelatinous cut surface. Thin fibrous septa traverse the neoplasm, resulting in a vaguely multinodular tumor. Cysts that are sometimes filled with keratinous debris may be identified grossly.
Cutaneous myxomas have a lobular or multinodular appearance at low magnification ( Figs. 32.14 and 32.15 ). Most are histologically poorly circumscribed with extension into the underlying subcutaneous tissue and rarely skeletal muscle. A sparse proliferation of spindled to stellate-shaped cells is deposited in an extensive myxoid stroma, sometimes forming cysts or irregular clefts ( Fig. 32.16 ). The cells have indistinct cell borders and oval nuclei with inconspicuous nucleoli; mitotic figures are rare. Binucleated or multinucleated cells may be seen, as are scattered cells with intranuclear cytoplasmic pseudoinclusions. There is often a prominent vasculature that is focally arborizing, reminiscent of that seen in myxoid liposarcoma ( Fig. 32.17 ). Other vascular alterations may be seen, including perivascular hyalinization, perivascular lymphocytes, and fibrin thrombi. A mixed inflammatory infiltrate is common, particularly stromal neutrophils, a feature unique to this tumor compared to other cutaneous myxoid lesions ( Fig. 32.18 ). The percentage of cutaneous myxomas reported to contain stromal neutrophils varies from study to study, but has been reported in up to 88% of tumors. Up to one-quarter of these tumors have epithelial structures consisting of basaloid buds, epithelial strands, or epidermoid (keratin-filled) cysts, possibly as a result of entrapment of adnexal structures by the neoplasm , , ( Figs. 32.19–32.21 ).
Cutaneous myxoma (superficial angiomyxoma). At low magnification, the tumor is hypocellular with prominent myxoid stroma; it appears fairly well circumscribed at its superficial aspect.
Multilobular appearance of cutaneous myxoma.
Cutaneous myxoma. Fibrous septa subdivide the tumor into poorly defined lobules.
Cutaneous myxoma. Prominent arborizing vasculature is present, mimicking that found in myxoid liposarcoma.
Cutaneous myxoma. Higher-power view of arborizing vessels, moderately variable, and spindled to stellate tumor cells ( A ). Stromal neutrophils are present, a helpful finding ( B ).
Cutaneous myxoma in patient with Carney complex. Note the adnexal structures surrounded by myxoid matrix.
Cutaneous myxoma in patient with Carney complex. Numerous epithelial strands are found in the substance of the neoplasm.
Cutaneous myxoma in patient with Carney complex. High-magnification view of elongated epithelial strands that appear to be compressed by surrounding neoplasm.
By IHC the tumor cells consistently express CD34 and are generally negative for other tested markers. , Occasional cells stain for smooth muscle actin, muscle-specific actin, or desmin, suggesting focal myofibroblastic differentiation. Loss of PRKAR1A expression is seen in 55%–80% of cutaneous myxomas, and is not seen in other myxoid tumors in this differential diagnosis (e.g., myxofibrosarcoma, myxoid dermatofibrosarcoma, superficial acral fibromyxoma, digital mucous cyst) ( Fig. 32.22 ). , , , Loss of PRKAR1A is a feature of both sporadic and syndromic angiomyxomas.
Loss of PRKAR1A expression in the tumor cells of cutaneous myxoma.
Outcome
Cutaneous myxoma has a propensity for local recurrence if incompletely excised. Allen et al. reported that 8 of 20 tumors (40%) recurred, including 5 of 8 (63%) with epithelial components. Calonje et al. reported a recurrence rate of 30%, including one case that recurred three times; recurrences developed a median of 12 months after initial excision. In contrast, however, a more recent, larger series by Sharma et al. noted local recurrences in only 1 of 28 patients with follow-up. Similarly, local recurrence was noted in only a single (of 19) patient with follow-up in the Baranov et al. series of mammary angiomyxomas. Cutaneous myxomas have not been reported to metastasize.
Differential Diagnosis
The differential diagnosis of cutaneous myxoma is extensive and includes many benign and low-grade malignant myxoid lesions, including deep angiomyxoma, focal cutaneous mucinosis, digital mucous cyst, dermal nerve sheath myxoma, myxoid neurofibroma, superficial acral fibromyxoma, myxoid liposarcoma, and myxofibrosarcoma.
Some cutaneous myxomas arise in the genital region and thus may be confused with deep angiomyxoma . The latter lesion, however, tends to be much larger, involves deeper structures, usually in the female pelvic region, and has a vascular pattern that differs from that of cutaneous myxoma. Focal cutaneous mucinosis lacks the lobular architecture, stromal neutrophils, and epithelial structures found in cutaneous myxoma. Digital mucous cyst is easily distinguished given its almost exclusive location on the fingers. Similarly, superficial acral fibromyxoma arises almost exclusively on the fingers and toes of middle-aged adults, and is composed of compact fascicles of uniform spindled cells in association with wiry collagen. Nerve sheath myxoma has a more pronounced lobular growth pattern and is characterized by plumper cells that are positive for S-100 protein and SOX10. Myxoid neurofibroma is composed of cells with wavy or buckled nuclei that are also S-100 protein/SOX10 positive.
Myoepithelioma and cutaneous mixed tumor have spindled cells with a more plasmacytoid appearance and generally stain for some combination of S100 protein, epithelial markers, and muscle markers, all of which are reliably negative in cutaneous myxomas. Myxoid liposarcoma is usually more deeply located and larger than cutaneous myxoma and is characterized by a chicken-wire plexiform vasculature with scattered lipoblasts. Myxofibrosarcoma has a greater degree of nuclear atypia and hyperchromasia, as well as curvilinear vessels often lined by hyperchromatic tumor cells.
Carney Complex
The triad of cutaneous and cardiac myxomas, spotty pigmentation, and endocrine overactivity was first described by Carney et al. in 1985. The disorder is familial and is transmitted as an autosomal dominant trait and principally affects young adults. Most individuals with the complex harbor a mutation of the PRKAR1A gene (located at 17q22-24), which encodes for the regulatory R1 alpha subunit of protein kinase A.
The cutaneous myxomas arising in this complex have a predilection for the eyelids and range from small sessile papules to large pedunculated, finger-like masses. They are multiple in most cases and are characterized by an appearance during early adulthood (mean age: 18 years). The lesions are found in the dermis or subcutaneous tissue, are usually sharply circumscribed, and are characterized by cytologically bland, spindled, and stellate-shaped cells deposited in an abundant myxoid stroma with a prominent capillary vasculature, identical to the sporadic cutaneous myxomas previously discussed. They are often associated with a basaloid proliferation of the surface epithelium, which may cause misclassification of some of these lesions as basal cell carcinoma or trichofolliculoma. In 1994, Ferreiro and Carney reported the association of myxomas of the external ear with Carney complex. Of the 152 patients with this complex known to these authors at that time, 22 (14%) had myxomas of the external ear, and 22 of 26 patients (85%) with external ear myxomas were found to have Carney complex. Multifocal myxoid fibroadenomas and myxomatosis of the breast are also occasional components of this complex. There is recent data to suggest that some tumors historically classified as myxoid fibroadenoma may in fact represent intramammary superficial angiomyxomas, showing PRKAR1A loss.
The most serious components of the syndrome are malignant melanotic nerve sheath tumor ( melanotic schwannoma ) and cardiac myxoma . Cardiac myxomas, regardless of their association with this syndrome, may be associated with peripheral tumor emboli, and up to 24% of all patients with cardiac myxomas die of its complications ( Figs. 32.23 and 32.24 ).
Gross photograph of a cardiac myxoma arising in the left atrium. The cut section reveals mucoid tissue with variegation, often arising from a stalk or short pedicle.
Courtesy of Dr. Joseph Maleszewski, Mayo Clinic, Rochester, MN.
Histologically, cardiac myxomas are characterized by bland spindle cells (“myxoma cells”) that occur singly and in clusters/cords within a myxoid background ( A ). These cells frequently form rings around the small intratumor blood vessels, so-called “perivascular rings” ( B ).
Courtesy of Dr. Joseph Maleszewski, Mayo Clinic, Rochester, MN.
The spotty skin pigmentation includes lentigines that predominantly affect the face, particularly the vermilion border of the lips, and epithelioid melanocytoma, first described as epithelioid blue nevus. Endocrine overactivity may be caused by the presence of primary pigmented nodular adrenocortical disease resulting in the Cushing syndrome, pituitary adenoma resulting in acromegaly, or sexual precocity associated with testicular lesions, particularly large cell calcifying Sertoli cell tumor. , Thyroid gland abnormalities ranging from follicular hyperplasia to cystic carcinoma have been associated with Carney complex. , Patients with Carney complex may also have an increased risk of pancreatic ductal and acinar neoplasms.
Ganglion Cyst
Ganglion cysts are by far the most common and best known of the more superficially located myxoid lesions. They occur as unilocular or multilocular cystic or myxoid masses, almost always on the dorsal surface of the wrist in young persons, especially women, generally 25–45 years old. Less often, they are found on the volar surface of the wrist or fingers and the dorsum of the foot and toes. In fact, ganglion cysts are the most common lesion of the hand and wrist, accounting for 50%–70% of all masses in this location. In about half the cases, the condition is associated with tenderness or mild pain and causes interference of function. A history of trauma is provided in about 50% of patients.
Ganglion cysts usually measure 1–3 cm in diameter. They are frequently attached to the joint capsule and tendon sheaths and probably are the result of excessive mucin production by fibroblasts rather than disintegration of preformed fibrous structures. There is no communication between the ganglion cyst and the joint space. Some lesions are easily confused with myxomas, especially during the initial myxoid stage of development. Most, however, are readily recognized by their characteristic location and the presence of multiple thick-walled cystic spaces of variable size in association with myxoid areas. Focal myxoid change is noted in the earliest stage. Subsequently, microscopic cysts develop and coalesce into larger ones until finally the lesion assumes its typical form of a dominant cyst ( Figs. 32.25–32.27 ). Most of these lesions can be treated nonoperatively, but a select group is surgically excised with a low rate of recurrence.
Low-magnification view of ganglion cyst with multiple irregular thick-walled cystic spaces and focal myxoid change in surrounding matrix.
High-magnification view of focal myxoid change with bland spindle-shaped cells in ganglion cyst.
Ganglion. Dominant cyst with prominent myxoid change in the surrounding soft tissue.
Hemosiderotic Fibrolipomatous Tumor and Pleomorphic Hyalinizing Angiectatic Tumor
Pleomorphic hyalinizing angiectatic tumor (PHAT), initially described in 1996 in a series of 14 cases by Smith et al., is a rare yet distinctive tumor with locally aggressive behavior. Since its initial description, fewer than 130 additional cases of PHAT have been reported, and this neoplasm likely continues to be mistaken for other entities, in particular undifferentiated pleomorphic sarcoma and schwannoma. Hemosiderotic fibrolipomatous tumor (HFLT) shows considerable clinical, morphologic, and molecular genetic overlap with PHAT, and almost certainly represents a different manifestation of the same entity. As such, these two tumors are considered together. Although we have proposed the alternative term “early PHAT” for HFLT, we use instead the HFLT nomenclature, for reasons of continuity with the literature. Accurate recognition of these neoplasms is of clinical importance given their propensity for local recurrence and occasional progression to myxoid sarcoma.
Hemosiderotic Fibrolipomatous Tumor
Hemosiderotic fibrolipomatous tumor was originally described as “hemosiderotic fibrohistiocytic lipomatous lesion” and was initially regarded as reactive in nature. However, the almost 50% rate of local recurrence seen in this initial series and in subsequent studies indicates that these represent instead neoplasms, a point of view reflected in the current World Health Organization (WHO) classification, which designates them as “hemosiderotic fibrolipomatous tumor.”
Clinical Features.
HFLT most often occurs in the foot and ankle region of middle-aged adults (median age: 51). , The size of reported tumors has been highly variable, but most are relatively small (4–5 cm). Many are mistaken clinically for an adipocytic tumor ( Fig. 32.28 ). MRI studies typically show an infiltrative, adipose tissue-rich mass, a variable component of fibrous tissue, and hemosiderin deposition; the presence of hemosiderin may be helpful in distinguishing HFLT from other superficially located fat-containing tumors.
Hemosiderotic fibrolipomatous tumor, presenting as a fatty-appearing, multinodular mass.
Microscopic and Immunohistochemical Findings.
Microscopically, HFLT consists of a distinctive admixture of mature fat, myxoid stroma, moderately cellular fascicles of generally bland monomorphic spindled cells with intracytoplasmic hemosiderin, iron-laden macrophages, and mixed chronic inflammatory cells , , ( Figs. 32.29 and 32.30 ). Other characteristic features of this lesion include small aggregates of damaged-appearing capillary-sized vessels, perivascular hyalinization, and scattered tumor cells with enlarged, pleomorphic nuclei and intranuclear pseudoinclusions. Close inspection of these lesions may disclose areas resembling “miniature” pleomorphic hyalinizing angiectatic tumors, with small, ectatic, fibrin-filled vessels ( Fig. 32.30C ).
Hemosiderotic fibrolipomatous tumor illustrating wispy proliferation of spindled cells in fat associated with some characteristic vessels.
Hemosiderotic fibrolipomatous tumor showing hemosiderin-laden spindled cells ( A ) with focal atypia infiltrating fat ( B ). “PHAT-like” vascular changes are commonly seen in HFLTs, emphasizing their close relationship to pleomorphic hyalinizing angiectatic tumor ( C ).
By immunohistochemistry, the spindled cells of HFLT are strongly positive for CD34 and negative for S-100 protein, muscle actins, and desmin. , ,
Pleomorphic Hyalinizing Angiectatic Tumor of Soft Parts
Clinical Findings.
First described by Smith et al., PHAT is a distinctive hemorrhagic tumor of the subcutis characterized by ectatic fibrin-filled vessels. The tumor presents as a long-standing mass in patients ranging in age from 10 to 79 years (median: 51). There is a slight female predilection. In most cases, the clinical impression is that of a hematoma, a benign neoplasm, or even Kaposi sarcoma. PHAT arises most often in the subcutaneous tissue of the lower extremity, particularly the ankle/foot, although other sites include the perineum, buttock, vulva and arm. , Rarely the tumors originate in skeletal muscle. Most average between 5 and 10 cm.
Gross and Microscopic Findings.
Grossly, most PHATs have a lobulated appearance with a cut surface that varies in color from white-tan to maroon ( Fig. 32.31 ). Rare examples have a prominent cystic component, and others show conspicuous myxoid change. Although having demarcated borders grossly, most actually show diffusely infiltrative margins with trapping of normal tissues at the tumor periphery.
Pleomorphic hyalinizing angiectatic tumor. Gross specimen with hemorrhagic appearance.
Microscopically, the most striking feature at low magnification is the presence of clusters of thin-walled ectatic blood vessels scattered throughout the lesion. The vessels range in size from small to macroscopic, and they tend to be distributed in small clusters ( Figs. 32.32–32.35 ). Typically, the ectatic vessels are lined by endothelium with a thick subjacent rim of amorphous eosinophilic material that is often surrounded by lamellated collagen. Some vessels contain organizing intraluminal thrombi with papillary endothelial hyperplasia. Hyaline material emanates from the vessels and extends into the stroma of the neoplasm, trapping neoplastic cells. The constituent cells are plump, spindled, and rounded with pleomorphic nuclei arranged in sheets or occasionally in fascicles reminiscent of fibrosarcoma ( Fig. 32.34 ). In general, the cells have hyperchromatic, pleomorphic nuclei and lack discernible cytoplasmic differentiation. Intranuclear cytoplasmic inclusions can be prominent ( Fig. 32.35 ). Despite the striking degree of nuclear pleomorphism, mitotic figures are scarce (usually <1/50 hpf). Occasional tumor cells, particularly those adjacent to ectatic vessels, contain intracytoplasmic hemosiderin. The tumors have a variable inflammatory infiltrate, most prominently mast cells, although lymphocytes, plasma cells, and eosinophils are conspicuous in some lesions. Foci of psammomatous calcification are occasionally present.
Pleomorphic hyalinizing angiectatic tumor with clusters of thin-walled ectatic fibrin-rimmed vessels punctuating stroma that varies from cellular ( A ) to more hyalinized ( B ).
Pleomorphic hyalinizing angiectatic tumor with fibrin lined vessels ( A ) containing organizing thrombus ( B ).
Pleomorphic hyalinizing angiectatic tumor showing pleomorphic cells with variable atypia ( A ) and hemosiderin ( B ).
Cells with atypia, hemosiderin, and intranuclear cytoplasmic inclusions in pleomorphic hyalinizing angiectatic tumor.
Areas morphologically indistinguishable from HFLT are present at the periphery in almost 50% of classic cases of PHAT. Folpe and Weiss labeled such areas “early pleomorphic hyalinizing angiectatic tumor” and considered them to represent the precursor lesion to classic PHAT, Additionally, as previously noted, small foci reminiscent of classic PHAT are often found in otherwise-typical HFLT, including small, damaged blood vessels surrounded by fibrin exudates and occasional pleomorphic cells with intranuclear pseudoinclusions (“micro-PHATs”). , Tumors showing mixed features of HFLT and PHAT have been reported by other investigators as well. Although Smith et al. did not comment on HFLT-like areas in PHAT in their seminal description of this entity, such areas are illustrated in Fig. 8 from this paper.
Immunohistochemical Findings.
By IHC the lesional cells of PHAT express CD34, but are negative for actins, desmin, keratin, epithelial membrane antigen (EMA), von Willebrand factor, and CD31. Groisman et al. reported immunoreactivity for vascular endothelial growth factor (VEGF), a secreted protein implicated in tumor-associated angiogenesis, in both tumoral and endothelial cells.
Genetic Findings in HFLT and PHAT.
In 2008, Wettach et al. first elucidated the genetics of HFLT, reporting a case with a reciprocal t(1; 10) as well as a derivative chromosome involving chromosomes 1 and 3. Hallor et al. and Antonescu et al. subsequently confirmed the ubiquitous nature of this genetic event in HFLT and identified rearrangement of TGFBR3 and/or OGA ( MGEA5 ) in 13 of 14 studied HFLTs. Others reported similar findings. ,
Until recently, little was known about the genetics of PHAT. The only conventional cytogenetic study, of a tumor showing mixed features of HFLT and PHAT, found two unbalanced translocations involving chromosomes 1 and 3 and chromosomes 1 and 10, with a karyotype of 45,XX,der(1)t(1; 3) (p31; q12),-3,der(10)t(1; 10) (p31; q25)[11]/46,XX[4]. These findings are similar (but not identical) to those previously reported in HFLT. , , Subsequently, TGFBR3 and/or OGA rearrangements have been identified in more than 60% of studied PHATs (all containing HFLT-like elements). , We have seen in consultation other cases of PHAT showing rearrangements of both genes. In one reported PHAT, targeted RNA-sequencing identified fusion of TGFBR3 with FBXW4 , rather than OGA .
Agaimy et al. have recently reported a very interesting example of HFLT with progression to a highly aggressive SMARCA4-deficient sarcoma with rhabdoid morphology; rearrangements of TGFBR3 and OGA were present both in areas of conventional HFLT and in the rhabdoid sarcoma. Rearrangements of BRAF , present in a subset of myxoinflammatory fibroblastic sarcomas, are not seen in pure HFLT, hybrid HFLT-PHAT, or HFLT showing progression to myxoid sarcoma.
It should be noted that other studies have not identified TGFBR3 or OGA rearrangements in PHAT. , These differing results may represent statistical variation or the use of different diagnostic criteria for PHAT, in particular the inclusion of cases lacking an HFLT-like component. Some may also have represented “PHAT-like” pleomorphic sarcomas, which are known to lack TGFBR3 and OGA rearrangements.
Outcome in HFLT and PHAT.
Local recurrences develop in approximately 30%–50% of both HFLT and PHAT. , , In one unusual example of PHAT, recurrences over a 25-year period ultimately necessitated amputation.
In addition to having locally recurring potential, HFLT and PHAT appear in some instances to progress to myxoid sarcoma ( Figs. 32.36 and 32.37 ) Elco et al. first reported this in their study of an unusual t(1; 10)-positive ankle mass showing typical morphologic features of HFLT and areas of infiltrative, variably pleomorphic, mitotically active myxoid sarcoma. Although regarded as a tumor with hybrid features of HFLT and myxoinflammatory fibroblastic sarcoma, this lesion lacked many of the cardinal morphologic features of the sarcoma (see below). Subsequently, Antonescu et al. reported three unusual tumors showing TGFBR3 and OGA rearrangements as “hybrid hemosiderotic fibrolipomatous tumor–myxoinflammatory fibroblastic sarcoma,” including two with both HFLT and myxoid sarcoma in the primary tumors and one HFLT that recurred as myxoid sarcoma. Others have reported similar cases, also usually showing TGFBR3 and/or OGA rearrangements. , , , Myxoid sarcomas most often arise in recurrent HFLT and may behave aggressively. , , Identical myxoid sarcomas may arise from tumors showing mixed morphologic features of HFLT and PHAT. ,
Hemosiderotic fibrolipomatous tumor ( A ) with progression to myxoid sarcoma, so-called “hybrid hemosiderotic fibrolipomatous tumor–myxoinflammatory fibroblastic sarcoma” ( B ). This tumor was positive for TGFBR3 and OGA rearrangement on FISH.
Undifferentiated pleomorphic sarcoma (left) arising in hemosiderotic fibrolipomatous tumor (right) ( A ). Higher-power view of partially necrotic, variably myxoid pleomorphic sarcoma ( B ).
In general, both HFLT and PHAT are chiefly managed in a surgical fashion, with oncologic excision showing histologically negative margins. However, the infiltrative growth pattern of these tumors may make such excision challenging. Sarcomas arising in HFLT and PHAT should be managed as myxoid sarcomas of equivalent grade.
Differential Diagnosis of HFLT and PHAT
The differential diagnosis of HFLT includes reactive processes, such as fat necrosis with myofibroblastic proliferation and hemosiderin deposition, as well as other infiltrative, CD34-positive spindle cell tumors, in particular dermatofibrosarcoma protuberans . In general, recognition of the distinctive morphologic features of HFLT, especially the presence of intracytoplasmic hemosiderin pigment and the distinctive vascular changes, should allow these distinctions without great difficulty. HFLT do not express S100 protein or TRK, as would be expected in a superficially located, NTRK -rearranged neoplasm such as “lipofibromatosis-like neural neoplasm”.
The differential diagnosis of PHAT includes schwannoma, malignant melanotic nerve sheath tumor (melanotic schwannoma), undifferentiated pleomorphic sarcoma, and superficial CD34-positive fibroblastic tumor. Although the vascular architecture and pleomorphic cells of PHAT may suggest a schwannoma with ancient change, PHAT is not encapsulated, usually grows in an infiltrative manner, lacks distinct Antoni A and B zones, and does not express S-100 protein. PHAT with abundant hemosiderin pigment and occasional schwannomas may simulate malignant melanotic nerve sheath tumor , but lacks expression of S-100 protein and melanocytic markers (e.g., HMB-45, melan A). The pronounced nuclear pleomorphism in the absence of specific features of differentiation of PHAT often suggests the diagnosis of undifferentiated pleomorphic sarcoma . Despite the striking cellularity of many PHATs, this tumor lacks significant mitotic activity, displays intranuclear cytoplasmic inclusions, and expresses CD34, a constellation of findings not characteristic of undifferentiated pleomorphic sarcomas. Conversely, ectatic, fibrin-filled blood vessels may be seen in some undifferentiated pleomorphic sarcomas, and one should be very hesitant to diagnose PHAT in lesions occurring in atypical locations, showing appreciable mitotic activity and lacking other typical features of PHAT, including HFLT-like areas. Cases of high-grade myxofibrosarcoma closely mimicking PHAT have been reported. , Although s uperficial CD34-positive fibroblastic tumor may contain ectatic, fibrin-filled vessels, it tends to occur in more proximal locations than PHAT, does not show peripheral areas of HFLT, and shows patchy expression of keratins, nuclear WT1 positivity, and CADM3 expression. ,
Myxoinflammatory Fibroblastic Sarcoma
In 1998, Montgomery et al. reported 49 cases of a previously undescribed tumor of the distal extremities with unusual histologic features, often prompting a misdiagnosis of an inflammatory or infectious process. Because of the presence of scattered bizarre cells with vesicular nuclei and macronucleoli and a prominent inflammatory background, the lesion was described as an “ inflammatory myxohyaline tumor of distal extremities with virocyte or Reed-Sternberg – like cells. ” Local recurrences occurred in almost one-fourth of the patients, although none developed metastatic disease. Meis-Kindblom and Kindblom reported a series describing the identical tumor, including one patient with biopsy-proven metastasis, and used “ acral myxoinflammatory fibroblastic sarcoma ” to emphasize the occasionally aggressive clinical course. Similar cases were also reported as “ inflammatory myxoid tumor of the soft parts with bizarre giant cells.” Because it is now clear that these lesions may involve nonacral locations, the WHO recommends the use of the term myxoinflammatory fibroblastic sarcoma (MIFS).
Clinical Findings.
Although the age range is broad, most patients with MIFS are in the fourth and fifth decades of life. Patients ranged in age from 17 to 83 years (mean: 42) in the AFIP series of 104 cases. Males and females are affected equally, and most patients present with a slowly growing, painless, poorly defined mass of the distal extremities, particularly in the dorsal soft tissues. The upper extremities are affected more often than the lower extremities, with the most common site being the soft tissues of the fingers and hand ( Fig. 32.38 ), although some lesions arise in the lower arm and wrist. On the lower extremities, these tumors may arise in the toes, feet, ankles, and lower legs. Few cases have been reported arising in extraacral sites, although these locations are typically involved by the so-called “nodular necrotizing” variant. Some patients report mild pain and decreased mobility of the affected site, occasionally with a history of antecedent trauma, which brings the tumor to clinical attention. Given its location, the lesion is often thought to represent a ganglion cyst or some form of tenosynovitis. MRI findings are not diagnostic but typically reveal a poorly circumscribed mass involving the underlying tendon sheath. ,
