Mesenchymal Tumors of Miscellaneous Type or Uncertain Lineage

Clinical Features

Intramuscular myxomas occur almost exclusively in middle-aged to older adults, more often in women than in men. There is a very strong association between the presence of multiple intramuscular myxomas and fibrous dysplasia, typically of the monostotic type (Mazabraud Syndrome). The large muscles of the buttocks, thigh, shoulder, and upper arm are most commonly involved, although rare cases have been reported in almost any location. These tumors usually present as a nonspecific soft tissue mass, without characteristic clinical or radiographic features. Most are 5–10 cm, although occasional cases can be considerably larger.

Pathologic Features

Gross Findings

Intramuscular myxomas are almost always well-delineated, gelatinous-appearing masses, which may display cystic change ( Fig. 15.1A ).

Ancillary Studies

Differential Diagnosis

Intramuscular myxomas are commonly confused with a wide variety of both benign and malignant myxoid tumors. Myxoid nodular fasciitis is usually much smaller, more often superficially located, and shows at least focal areas of increased cellularity, with short, randomly arranged fascicles of bland myofibroblasts. Myxoid variants of desmoid fibromatosis more often occur within the abdomen, contain a well-developed, thin-walled, nonarborizing vasculature and at least focal areas of typical fibromatosis. Myxoid liposarcoma contains an extremely well-developed, arborizing, capillary-sized vasculature and easily identifiable lipoblasts. Myxofibrosarcoma has a well-developed, thick-walled vasculature and contains hyperchromatic, pleomorphic tumor cells. Extraskeletal myxoid chondrosarcoma is composed of cords and chains of small eosinophilic cells, embedded in a “dense”-appearing myxoid matrix, often with abundant hemorrhage, but with relatively few blood vessels.

Prognosis and Therapy

Intramuscular myxomas are entirely benign lesions that require only simple excision.

Clinical Features

As indicated by their name, these myxomas occur in direct association with the large joints. By far the most common location is adjacent to the knee joint, followed by the shoulder, hip, and ankle. Most patients are older men, frequently with a history of osteoarthritis. The tumors are usually 2–6 cm at the time of diagnosis, although some may be significantly larger.

Pathologic Features

Microscopic Findings

In general, juxta-articular myxomas closely recapitulate the histologic features of intramuscular myxoma. However, a significant subset of these lesions may show features of cellular myxoma, with fascicular growth, areas of well-developed vasculature, and mild pleomorphism ( Fig. 15.2A and B ). As with cellular intramuscular myxomas, the identification of areas of typical myxoma is the key to the correct diagnosis ( Fig. 15.2C ).

Ancillary Studies

Differential Diagnosis

The differential diagnosis of juxta-articular myxoma is essentially the same as that of intramuscular myxoma. Although cellular juxta-articular myxomas in particular may mimic myxofibrosarcoma, among others, the characteristic location around the knee joint and the frequent history of osteoarthritis should point one in the correct direction. In this location adjacent to the knee, a myxoid monophasic fibrous synovial sarcoma may also be a diagnostic consideration. Myxoid change in synovial sarcomas is almost always focal, rather than diffuse, and the identification of areas of more typical synovial sarcoma, characterized by hyperchromatic nuclei, alternating hypo- and hypercellular zones, wiry collagen, and focal keratin immunoreactivity is diagnostic.

Prognosis and Therapy

Juxta-articular myxomas are entirely benign but may recur locally in up to 30% of cases, particularly if incompletely excised.

Differential Diagnosis

Myxofibrosarcoma, myxoid liposarcoma, myxoid chondrosarcoma, myxoid nodular fasciitis, myxoid desmoid-type fibromatosis.

Clinical Features

Cutaneous myxoma, also known as “superficial myxoma” or “superficial angiomyxoma,” is a rare myxoid tumor of the skin and subcutis. Cutaneous myxomas are histologically identical to the cutaneous myxoid tumors seen in patients with Carney complex, although most occur sporadically. Men are affected slightly more often than are women, and the typical patient is a middle-aged adult. The most common locations for sporadic cutaneous myxomas are the trunk, lower extremities, and head and neck; Carney complex-associated myxomas are more often multiple and involve the eyelids and ear.

Pathologic Features

Microscopic Findings

Cutaneous myxomas are considerably more vascular than are other myxomas, as reflected in the alternative term, “superficial angiomyxoma” ( Fig. 15.3A ). This vasculature may be very well-developed and arborizing, reminiscent of myxoid liposarcoma. However, the overall cellularity of the lesion is quite low, and the lesional cells are small, cytologically bland, and spindled to stellate in shape. A prominent neutrophilic infiltrate is often present and is a helpful clue to this diagnosis ( Fig. 15.3B ). Epithelioid structures, probably representing the entrapped adnexal glands, are seen in approximately one-third of cases. A vaguely lobular growth pattern is often present.

Ancillary Studies

In general, cutaneous myxomas lack the expression of markers other than vimentin. The loss of PRKAR1A expression may be seen in cutaneous myxomas, even in the absence of other stigmata of Carney complex ( Fig. 15.3C ).

Differential Diagnosis

Focal cutaneous mucinosis lacks the neutrophils, lobular growth pattern, and elaborate vasculature seen in cutaneous myxoma. Digital mucinous cyst occurs exclusively in the digits and lacks a well-developed vasculature. Deep (aggressive) angiomyxoma is a deeply seated tumor of the genital region, which only focally involves the skin (if at all), lacks neutrophils, and contains ectatic, nonarborizing vessels. Nerve sheath myxoma is more distinctly lobular and is composed of plumper, occasional pleomorphic, S-100 protein-positive cells. Myxoid neurofibromas lack the well-developed vasculature of myxoma and contain wavy, “comma-shaped” cells that express S-100 protein. Myxoid dermatofibrosarcoma protuberans are much more infiltrative, CD34-positive lesions which typically show at least small areas of more typical dermatofibrosarcoma.

Prognosis and Therapy

Cutaneous myxomas are benign but may recur locally, and should be excised completely.

Differential Diagnosis

Cutaneous mucinosis, digital mucinous cyst, aggressive angiomyxoma, nerve sheath myxoma (neurothekeoma), myxoid neurofibroma, myxoid dermatofibrosarcoma protuberans.

Clinical Features

Angiomyofibroblastoma is an uncommon, benign, non-recurring myofibroblastic lesion of the vulva and pelviperineal region. The vast majority of cases are observed in the vulva of middle-aged women, less frequently in the vagina (10–15% of cases), perineum, or inguinal region. Angiomyofibroblastomas present as slow-growing, painless masses, which are usually considered clinically to be Bartholin’s gland cysts.

Pathologic Features

Microscopic Findings

Angiomyofibroblastoma, which develops in the pelviperineal subcutaneous tissue, is composed of small-to-medium-sized well-formed vessels, round to spindled myofibroblasts arranged around the vessels and loose edematous stroma in varying proportions ( Fig. 15.4A ). The tumor cells have eosinophilic cytoplasm and bland nuclei, occasionally with smudged chromatin. Epithelioid to plasmacytoid neoplastic cells may be present as well as bi- or multinucleate cells ( Fig. 15.4B ). Mitotic figures are rare and there is no tumor necrosis. Interstitial mast cells are commonly observed. Approximately 10% of cases also contain mature adipocytes. Fibrosis and perivascular hyalinization are common in long-standing lesions. Some cases show some morphologic overlap with cellular angiofibroma, but it is now understood that the pathogenesis of cellular angiofibroma is related to RB1 loss, whereas angiomyofibroblastomas are not.

Ancillary Studies

Differential Diagnosis

Angiomyofibroblastoma is a small, cellular, superficially located lesion with numerous small vessels, unlike deep (aggressive) angiomyxoma, a large, deeply situated, hypocellular myxoid lesion with gaping vessels. Epithelioid smooth muscle tumors are more solid, eosinophilic tumors which typically exhibit at least small areas of more typical smooth muscle, and are diffusely smooth muscle actin-, caldesmon-, and desmin-positive. Cellular angiofibromas tend to show more uniform spindled growth around the hyalinized blood vessels and exhibit the loss of RB1 expression. Solitary fibrous tumors have more abundant collagen, a pronounced branching, staghorn, vascular pattern, a “patternless” growth pattern, and express STAT6 in a nuclear pattern.

Prognosis and Therapy

Angiomyofibroblastomas are benign non-recurring lesions. Simple excision is curative. Malignant angiomyofibroblastomas have been reported but are exceptional.

Clinical Features

Cellular angiofibromas present as small, slowly-growing masses of the vulva of middle-aged women, less frequently in the vagina (10–15% of cases), perineum, or inguinal region. Cases in males have been reported as “angiomyofibroblastoma-like tumors of the male genital tract”; such lesions typically involve the scrotum, spermatic cord, or inguinal region. This terminology is now discouraged.

Approximately 50% of mammary-type myofibroblastomas occur in the inguinal or groin region, including the vulva/vagina, perineum, and scrotum. Identical cases may be observed in the breast and in a wide variety of somatic soft tissue locations. The great majority involve the skin and subcutis.

Pathologic Features

Microscopic Findings

Cellular angiofibroma is generally well-circumscribed and is composed of proliferating bland spindle cells, arrayed about numerous small-to-medium-sized vessels with hyalinized walls, perivascular fibrinoid deposits and/or intraluminal thrombi ( Fig. 15.5A and B ). In typical examples, the mitotic activity is low and necrosis is absent. Very rare cases of cellular angiofibroma with apparent morphologic progression to sarcoma (or pseudosarcomatous nuclear changes) have been reported; such cases tend to resemble pleomorphic liposarcoma or undifferentiated pleomorphic sarcoma ( Fig. 15.5C ). Some cellular angiofibromas display striking stromal myxoid change ( Fig. 15.5D ). The morphological features of mammary-type myofibroblastoma are quite similar, although in their classical form these lesions tend to have a more distinctly nested architecture, with bands of refractile collagen circumscribing nests of bland spindled cells with ovoid to pointed nuclei ( Fig. 15.5G ). A variable component of mature fat is present in both tumors.

Ancillary Studies

Differential Diagnosis

Angiomyofibroblastomas are more myxoid, have small gaping blood vessels, are composed of epithelioid cells, and have retained expression of RB1. Deep angiomyxomas are deeply situated, large, extensively myxoid lesions lacking the compact spindle cell growth seen in both cellular angiofibroma and myofibroblastoma. The distinction of both from spindle cell lipoma is difficult and possibly arbitrary. The presence of areas of typical cellular angiofibroma distinguishes very rare cellular angiofibromas with morphologic progression to sarcoma from primary soft tissue sarcomas of the inguinopelvic region. Solitary fibrous tumors lack desmin expression, have retained RB1 expression, and express STAT6 in a nuclear pattern.

Prognosis and Therapy

Cellular angiofibromas and mammary-type myofibroblastomas are benign and do not typically recur. Recurrences and/or metastases have not as yet been reported in sarcomatous cellular angiofibromas.

Immunohistochemical Features

Cellular angiofibromas are usually smooth muscle actin- and desmin-negative, with variable expression of CD34. Mammary-type myofibroblastomas typically have strong CD34 and desmin co-expression. Both express ER and PR and display the loss of RB1 expression.

Differential Diagnosis

Angiomyofibroblastoma, angiomyxoma, spindle cell lipoma, solitary fibrous tumor.

Clinical Features

Most deep angiomyxomas occur in the genital, perineal, and pelvic region of reproductive-aged women, although rare cases also occur in the pelvis, spermatic cord, or scrotum of men (female/male ratio 6:1). These tumors typically present as slowly-growing, deeply situated masses which may infiltrate the adjacent structures, including the soft tissues surrounding the rectum and vagina. Owing to their infiltrative growth and myxoid nature, deep angiomyxomas may be difficult to excise completely, and have been reported to recur in up to 30% of cases. More recent series have, however, emphasized that correctly diagnosed and appropriately treated angiomyxomas have a much lower rate of local recurrence (<10%) and that almost all patients are cured with a single re-excision. Metastases are not observed.

Pathologic Features

Microscopic Findings

Deep angiomyxomas are composed of very bland, spindled to stellate cells widely dispersed in a myxoid matrix ( Fig. 15.6A ). A characteristic feature is the presence of numerous blood vessels, ranging from capillaries up to large, gaping vessels with hyalinized walls ( Fig. 15.6B ). In general, these vessels tend to be nonarborizing. Small aggregates of conventional appearing smooth muscle cells often are observed in close proximity to the blood vessels ( Fig. 15.6C ). Cellularity is typically low, mitotic figures are very rare, and necrosis is absent. Mast cells and lymphoid aggregates may be present.

Ancillary Studies

Differential Diagnosis

Extensively myxoid leiomyomas may closely mimic deep angiomyxoma, but are typically better circumscribed, contain larger areas of more typical smooth muscle, and have larger, thick-walled blood vessels. Angiomyofibroblastomas are superficially located and smaller, and consist of epithelioid cells arranged in a perivascular distribution. Myxoid change is very unusual in angiomyofibroblastoma. Fibroepithelial polyps of the genital region blend into the overlying epidermis or mucosa, without a Grenz zone, and are usually much more cellular and cytologically variably than are angiomyxomas. Myxofibrosarcomas are almost always subcutaneous tumors of the extremities, which display much greater cytological atypia and have a well-developed, arborizing, thick-walled vasculature. Myxofibrosarcoma-like histology in a deeply situated lesion should suggest dedifferentiated liposarcoma. Myxomas, including cutaneous myxoma, are very unusual in the genital region and have distinctive histological features, as described earlier in this chapter.

Prognosis and Therapy

Despite its original name, deep angiomyxoma is not an especially aggressive lesion. It does, however, have significant potential for local recurrence, owing to its infiltrative growth pattern and the difficulty of completely resecting extensively myxoid tumors. As noted above, incompletely excised deep angiomyxomas have risk of recurrence of approximately 30%; this risk decreases with more complete initial resection. Deep angiomyxoma has no potential for distant metastasis or malignant transformation.

Immunohistochemical Features

Positive for desmin, smooth muscle actins, and HMGA2; often negative for CD34, S-100 protein, and cytokeratins.

Differential Diagnosis

Angiomyofibroblastoma, myxoid leiomyoma, other myxomas, myxofibrosarcoma, fibroepithelial polyp.

Clinical Features

These tumors typically present as painless masses of the extremities, frequently involving or adjacent to the large joints, and may be either subcutaneous or intramuscular. Most occur in middle-aged adults, with a slight female predominance.

Pathologic Features

Microscopic Findings

Microscopically, these tumors show a variably myxoid to collagenized stroma, with a moderately cellular proliferation of bland, fibroblastic spindled cells ( Fig. 15.7A ). They are most notable for their elaborate vasculature, with some areas containing innumerable small, arborizing vessels, reminiscent of myxoid liposarcoma, and others having larger, branched vessels, similar to those seen in solitary fibrous tumor ( Fig. 15.7B ). Perivascular collagen deposition and marked hyalinization or fibrinoid necrosis of the medium-sized vessel walls is often present. Foamy macrophages, hemosiderin deposition, and chronic inflammation are also often present.

Angiofibroma of Soft Tissue—Fact Sheet

Definition

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  Benign mesenchymal tumor of the subcutis and muscle showing mixed features of solitary fibrous tumor and myxoid liposarcoma

Incidence and Location

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  Rare

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  Most common around knees but may occur in any somatic soft tissue location

Morbidity and Mortality

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  None

Gender, Race, and Age Distribution

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  Most common in middle-aged women

Clinical Features

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  Painless soft tissue mass, often around the knee

Prognosis and Treatment

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  Benign, rarely recurs locally

Angiofibroma of Soft Tissue— Pathologic Features

Gross Findings

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  Variably myxoid, non-descript soft tissue mass

Microscopic Findings

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  Myxoid to collagenized stroma

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  Moderately cellular; bland, fibroblastic spindled cells

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  Highly vascular, with innumerable small, arborizing vessels (myxoid liposarcoma-like) and thicker, branching vessels (solitary fibrous tumor-like)

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  Perivascular collagen deposition, hyalinization, and/or fibrinoid necrosis of vessel walls

Immunohistochemical Features

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  Limited CD34 expression

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  STAT6-negative

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  May contain desmin-positive dendritic cells

Ancillary Studies

Genetics

Most cases of AFST are characterized by the AHRR- NCOA2 fusion gene. Less commonly, GTF2I-NCOA2 or GAB1-ABL1 fusions are found instead.

Differential Diagnosis

Historically, AFST were likely confused with solitary fibrous tumors. However, AFST lacks the “patternless” proliferation of bland fibroblastic spindled cells and the abundant hyalinized collagen that characterizes solitary fibrous tumors, contains areas with diffuse proliferation of small-caliber vessels, and lacks STAT6 expression. The elaborate vasculature present in AFST may also suggest myxoid liposarcoma, but lipoblasts and mature fat are absent.

Prognosis and Therapy

AFST are benign tumors with limited capacity for local recurrence.

Genetics

AHRR-NCOA2 fusion; less commonly GTF2I-NCOA2 or GAB1-ABL1 fusions.

Differential Diagnosis

Solitary fibrous tumor, myxoid liposarcoma.

Clinical Features

Tumors arise over a wide age range, are more common in women, and arise in the dermis or subcutaneous tissue of the distal extremities. They have some potential for local recurrence but have not been reported to metastasize.

Pathologic Features

Microscopic Findings

EWSR1-SMAD3-rearranged fibroblastic tumors typically involve the dermis and subcutis ( Fig. 15.8A and B ), and display an infiltrative growth pattern, with the entrapment of adnexal structures or subcutaneous fat. Histologically the tumors are comprised of interlocking, cellular fascicles of fibroblasts admixed with distinctive, hypocellular hyalinized zones, which may be calcified ( Fig. 15.8C ). Cellular and hypocellular areas may be intermingled or display a zonal pattern, with hyalinized areas at the center. Lesional cells display bland nuclear features, with elongated, sometimes wavy nuclei, without atypia or mitotic activity ( Fig. 15.8D ).

Immunohistochemistry

EWSR1-SMAD3 -rearranged fibroblastic tumors are strongly positive for ERG in a nuclear pattern ( Fig. 15.8E ), and negative for CD34, EMA, and smooth muscle actin.