In previous editions of this textbook, several entities of uncertain type were placed into either benign or malignant categories. Although these entities still remain an enigma with regard to line of cellular differentiation, larger clinicopathologic studies of each of these entities have revealed a better understanding of their clinical behavior. Whereas some of these entities were initially placed into the “benign” category (e.g., ossifying fibromyxoid tumor, pleomorphic hyalinizing angiectatic tumor of soft parts), these lesions clearly have a significant risk for local recurrence and can even metastasize on occasion. Similarly, other entities of uncertain type were originally categorized among the “malignant” tumors (angiomatoid fibrous histiocytoma, formerly “angiomatoid malignant fibrous histiocytoma”) but, given the lower risk for metastasis, especially with adequate therapy, behave less aggressively than the other lesions in this category. As such, we believe there is ample justification to categorize these tumors with those of intermediate malignancy, although of uncertain lineage.
Ossifying Fibromyxoid Tumor of Soft Tissue
Ossifying fibromyxoid tumor (OFMT) of soft tissue, first described in a series of 59 cases from the Armed Forces Institute of Pathology (AFIP) in 1989, is a rare tumor of uncertain differentiation that usually arises in the extremities. Almost 200 cases have been reported in the literature, in three large series, as well as numerous case reports or small series. Although the original description of this tumor by Enzinger et al. emphasized the bland morphologic appearance and typically benign clinical behavior, even this series indicated that exceptional examples act in a clinically aggressive fashion. Several subsequent reports described tumors with typical features that unexpectedly metastasized, or tumors with atypical or overtly malignant histologic features, some of which behaved aggressively. Although some have suggested that malignant OFMTs represent instead other tumor types, recent studies have clearly confirmed the existence of atypical and malignant forms of this tumor. As such, it seems reasonable to consider OFMT a neoplasm of uncertain differentiation, spanning a morphologic and clinical spectrum from benign-appearing lesions that almost always behave benignly to histologically malignant lesions with a high risk for aggressive behavior.
Clinical Findings
OFMT almost exclusively affects adults (mean age almost 50 years), with only rare examples documented in children. Men are affected more often than women. Most patients present with a small, painless, well-defined, often lobulated subcutaneous mass that involves the extremities in approximately 70% of cases. Less frequently involved sites include the trunk, head and neck, mediastinum, and retroperitoneum. Radiographic studies usually reveal a well-circumscribed mass with an incomplete ring of peripheral calcification and scattered calcifications in the substance of the neoplasm ( Fig. 32.1 ). Erosion of underlying bone and periosteal reaction are rarely seen.
Pathologic Findings
Grossly, OFMT is usually well circumscribed, spherical, lobulated or multinodular, and typically covered by a thick fibrous pseudocapsule ( Fig. 32.2 ). Most measure 3 to 5 cm, but occasional lesions are 15 cm or larger. On cut section, the tumor is tan-white and often has a gritty texture, as one would expect in a tumor that frequently has calcifications.
Microscopically, the majority are located in the subcutaneous tissue, but some are attached to tendons or fascia or involve the underlying skeletal muscle. A typical OFMT is composed of uniform round, ovoid, or spindle-shaped cells arranged in nests and cords and deposited in a variably myxoid and collagenous stroma ( Figs. 32.3 to 32.7 ). In approximately 70% of cases, an incomplete shell of lamellar bone is found at the periphery of the nodules, either within or immediately beneath a dense fibrous pseudocapsule and sometimes extending into the substance of the tumor ( Fig. 32.8 ). Bone is found in approximately 75% of histologically typical tumors, compared with approximately 50% of those showing atypical histologic features.
The cells, which vary minimally in size and shape, are characterized by pale-staining vesicular nuclei with minute nucleoli and small amounts of eosinophilic cytoplasm ( Fig. 32.9 ). The cells may be deposited in a variety of patterns, including cords, nests, or sheets, or may be randomly distributed in a fibromyxoid matrix. Small pseudorosette-like structures are typically present. Some lesions are predominantly myxoid with an abundant stroma of Alcian blue–positive, hyaluronidase-sensitive acid mucopolysaccharides, occasionally forming microcysts. Other tumors are predominantly collagenous. Small foci of calcification and rarely metaplastic cartilage may also be seen in the tumor nodules. Most have a rich vasculature, with many vessels exhibiting perivascular hyalinization and others subintimal fibrin deposition or thrombosis.
It is now well recognized that a subset of OFMTs have atypical or overtly malignant features, usually consisting of some combination of high nuclear grade, high cellularity, or increased mitotic activity (>2 mitotic figures [MF] per 50 high-power fields [hpf]). It should be emphasized that such cases maintain the overall cytoarchitectural features of typical OFMT and may be conceptualized as representing a phenomenon akin to myxoid and round cell liposarcoma rather than “dedifferentiation,” in which a stark histologic departure from the original tumor occurs. Some malignant OFMTs show areas resembling sclerosing epithelioid fibrosarcoma, with densely hyalinized collagen and epithelioid cells. Osteoid and/or woven bone may be present within the center of malignant-appearing tumors, and their presence is not indicative of osteosarcoma in a tumor otherwise showing morphologic features of OFMT. In general, confident diagnosis of malignant OFMT requires identification of areas of typical OFMT, either adjacent to malignant zones or present in an earlier manifestation of a recurrent lesion ( Figs. 32.10 to 32.12 ). Exceptionally, the tumor is composed exclusively of malignant-appearing areas. The clinical significance of these areas is discussed later.
Immunohistochemical Findings
On immunohistochemistry (IHC), the cells are positive for vimentin and express S-100 protein in about 70% of cases ( Fig. 32.13 ). However, immunoreactivity for S-100 tends to be less intense and uniform than in schwannoma. Entirely typical OFMTs can show only patchy S-100 protein expression. Atypical or malignant areas express S-100 protein less often than typical areas. SOX10 expression has not been formally studied in OFMTs; in our experience it is typically negative. Scattered cells are positive for desmin and/or neurofilament protein in up to 40% and 80% of tumors, respectively ( Fig. 32.13 ). The cells may also occasionally express CD56, CD57, neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP), smooth muscle actin (SMA), or cytokeratins. Loss of expression of the SMARCB1/INI1 tumor suppressor gene product in a distinctive “mosaic” pattern has been reported by Graham et al. in approximately 70% of tested cases, reflecting hemizygous loss of the SMARCB1 locus and other regions of 22q, as determined by FISH.
Genetic Findings
Early studies of OFMT showed a variety of chromosomal abnormalities, without a consistent aberration. In 2012, Gebre-Medhin et al. found three OFMTs to have complex karyotypes, including different structural rearrangements of chromosome band 6p21. Mapping of this breakpoint by fluorescence in situ hybridization (FISH) demonstrated rearrangements of the PHF1 gene, a transcriptional repressor previously shown to be consistently rearranged in endometrial stromal sarcomas. This finding was further confirmed by interphase FISH, showing PHF1 rearrangements in OFMT of all types ( Fig. 32.14 ). Confirmatory reverse-transcriptase polymerase chain reaction (RT-PCR) analysis of one case demonstrated an EP400/PHF1 fusion transcript. PHF1 is known to interact with polycomb group proteins, regulators of homeotic ( Hox ) genes, including PRC2 , and dysregulation of PRC2 target genes may underlie the pathogenesis of OFMT. The presence of frequent PHF1 rearrangements in typical, atypical, and malignant OFMT was subsequently confirmed by Graham et al. More recently, next-generation sequencing studies by Antonescu et al. and Kao et al. have identified a number of novel fusions in OFMTs, including ZC3H7B-BCOR , MEAF6-PHF1 , EPC-PHF1 , CREBBP-BCORL1, and KDM2A-WWTR1 . Overall, PHF1 rearrangements are most common, occurring in approximately 45% of OFMT of all types.
FISH analyses of OFMT have also consistently noted hemizygous loss of chromosome 22 or 22q, including but not limited to the SMARCB1 locus ( Fig. 32.15 ). It is currently unclear what role this plays in the pathogenesis of OFMT.
Differential Diagnosis
The differential diagnosis includes benign and malignant epithelioid nerve sheath tumors (epithelioid neurofibroma, epithelioid schwannoma, epithelioid malignant peripheral nerve sheath tumor), chondroid syringoma (cutaneous mixed tumor), myxoid chondrosarcoma, and epithelioid smooth muscle tumors.
OFMT has some features suggestive of nerve sheath differentiation, including bland, round to ovoid, S-100 protein–positive cells. However, OFMT does not arise from peripheral nerves, lacks SOX10 expression, and does not show typical morphologic features of epithelioid neurofibroma or epithelioid schwannoma (see Chapter 26 ). The cells of OFMT lack the “melanoma-like” cytologic atypia characteristic of epithelioid malignant peripheral nerve sheath tumors.
The general absence of epithelial markers in OFMT helps exclude chondroid syringoma as a diagnostic consideration. The lobulated architecture and arrangement of the neoplastic cells into cordlike structures somewhat resemble extraskeletal myxoid chondrosarcoma , but the stroma of OFMT varies between myxoid and collagenous, and the neoplastic cells have less eosinophilic cytoplasm than those of myxoid chondrosarcoma. Epithelioid smooth muscle tumors usually express myoid antigens and lack S-100 protein. Although malignant OFMT may contain areas resembling sclerosing epithelioid fibrosarcoma and show limited MUC4 expression, they contain diagnostic PHF1 rearrangements and lack EWSR1 or FUS rearrangements, the molecular hallmarks of sclerosing epithelioid fibrosarcomas and related low-grade fibromyxoid sarcomas (see Chapter 9 ).
Discussion
The behavior of OFMT is highly variable. The vast majority of these tumors are histologically benign and have the characteristic features described in the original AFIP series (“typical OFMT”). Not unexpectedly, most of these pursue a benign clinical course. However, even histologically typical tumors may rarely locally recur and metastasize. For example, Yoshida et al. described a case that lacked malignant features but locally recurred, metastasized, and ultimately killed the patient. In the original report of typical OFMTs, 11 of 41 patients (27%) for whom follow-up information was available experienced one or more recurrences. In addition, one patient with three recurrences developed a similar tumor in the contralateral thigh that was presumed to be a metastasis. One additional patient developed a recurrence that showed histologic progression with increased bone production, originally interpreted as representing “well-differentiated osteosarcoma.” Based on a compilation of the largest studies, the recurrence and metastatic rates of typical OFMT are 17% and less than 5%, respectively, thereby supporting the view that it is a lesion of intermediate or borderline malignancy with a low risk of distant metastasis.
Some OFMTs have atypical histologic features, including high nuclear grade, increased cellularity, and increased mitotic activity. Such tumors show identical genetic events as do more typical tumors, establishing that typical, atypical, and malignant OFMTs represent a morphologic continuum within a single entity. Folpe and Weiss proposed a classification system for OFMT based on a combination of nuclear features, cellularity, and mitotic activity. This system has been validated in subsequent studies and correlates well with the clinical behavior of these tumors ( Tables 32.1 and 32.2 ).
| Diagnostic Criteria | |
|---|---|
| Typical OFMT | Low nuclear grade and low cellularity with mitotic activity <2 MF/50 hpf |
| Atypical OFMT | Tumors deviating from typical OFMT but not meeting criteria for malignant OFMT |
| Malignant OFMT | High nuclear grade or high cellularity and mitotic activity >2 MF/50 hpf |
| No. Cases with Follow-up | Local Recurrences (%) | Metastases (%) | |
|---|---|---|---|
| Typical OFMT | 25 | 3 (12) | 1 (4) |
| Atypical OFMT | 16 | 2 (13) | 1 (6) |
| Malignant OFMT | 10 | 6 (60) | 6 (60) |
Line of Differentiation
The line of differentiation of OFMT has been the subject of considerable debate over the years, with investigators favoring cartilaginous, osteogenous, or myoepithelial differentiation. Until recently, however, the most widely accepted theory was that OFMT represented an unusual “peripheral nerve sheath tumor,” on the basis of its encapsulation, expression of nerve sheath–related markers (e.g., S-100 protein, CD57, GFAP), and some ultrastructural features.
Gene expression profiling and proteomic study of OFMT suggests limited neural differentiation, with upregulation of neuron-related genes, such as EAAT4 and HuC , and downregulation of Schwann cell–associated genes, such as peripheral myelin protein 22 ( PMP22 ) and myelin expression factor 2 ( MYEF2 ). Additionally, cluster and principal component analyses show that OFMT is clearly segregated from true nerve sheath tumors, such as schwannoma and nerve sheath myxoma ( Fig. 32.16 ). Proteomic data show expression of proteins related to neuronal, schwannian, and cartilaginous differentiation. These findings, and more importantly recent molecular genetic studies showing a variety of different gene fusions in these tumors, strongly suggest that OFMT show a “scrambled phenotype” without an obvious normal counterpart, as seen in other translocation-associated soft tissue tumors.
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 propose 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 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 relative small (4-5 cm). Many are mistaken clinically for an adipocytic tumor.
Pathologic 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. 32.17 and 32.18 ). 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. 32.18C ).
Immunohistochemical and Genetic Features
On IHC the spindled cells of HFLT are strongly positive for CD34 and negative for S-100 protein, muscle actins, and desmin. Wettach et al. first elucidated the genetics of HFLT in 2008, 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 MGEA5 in 13 of 14 studied HFLTs ( Fig. 32.19 ). Others reported similar findings.
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, and arm. Rarely the tumors originate in skeletal muscle. Most average between 5 and 10 cm. Recurrences develop in approximately 30% to 50% of cases. In one unusual case, recurrences over a 25-year period ultimately necessitated amputation. In a limited number of cases, progression to a myxoid sarcoma results in subsequent recurrences. Wide local excision is recommended as the best therapeutic approach whenever possible.
Pathologic Findings
Grossly, most PHATs have a lobulated appearance with a cut surface that varies in color from white-tan to maroon ( Fig. 32.20 ). 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.
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. 32.21 to 32.24 ). 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. 32.23A ). In general, the cells have hyperchromatic, pleomorphic nuclei and lack discernible cytoplasmic differentiation. Intranuclear cytoplasmic inclusions can be prominent ( Fig. 32.24 ). 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.
On IHC the lesional cells of PHAT express CD34 and vimentin, 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.
Relationship to Hemosiderotic Fibrolipomatous Tumor
Folpe and Weiss first suggested the hypothesis that PHAT was related to HFLT because of the presence of areas morphologically indistinguishable from HFLT at the periphery in almost 50% of classic cases of PHAT. These HFLT-like areas were labeled “early pleomorphic hyalinizing angiectatic tumor” and were thought to represent the precursor lesion to classic PHAT. In addition, as previously noted, cases only with features of HFLT sometimes displayed subtle features reminiscent of classic PHAT. These included small, damaged blood vessels surrounded by fibrin exudates and occasional pleomorphic cells with intranuclear pseudoinclusions. Others have reported cases showing mixed features of HFLT and PHAT as well. Although Smith et al. did not comment on HFLT-like areas in PHAT, such areas are illustrated in Figures 1 and 3 of their seminal description.
Genetic 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 MGEA5 genetic 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.
However, other studies have not identified TGFBR3 or MGEA5 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 a HFLT-like component. Some may also have represented “PHAT-like” pleomorphic sarcomas, which are known to lack TGFBR3 and MGEA5 rearrangements.
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.
The differential diagnosis of PHAT includes schwannoma, malignant melanotic schwannian tumor (melanotic schwannoma), undifferentiated pleomorphic sarcoma, and the recently described superficial CD34-positive fibroblastic tumor (see later). 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 schwannian tumors , 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 diagnosis 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. Superficial CD34-positive fibroblastic tumor tends to occur in more proximal locations than PHAT; lacks ectatic vessels, intracytoplasmic hemosiderin, and coexisting HFLT; and shows patchy expression of keratins (see later section).
HFLT and PHAT Showing Progression to Myxoid Sarcoma
In addition to having locally recurring potential and a close relationship to PHAT, HFLT appears in some cases to progress to myxoid sarcoma (see Fig 32.19 ). 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 Chapter 9 ). Subsequently, Antonescu et al. reported three unusual tumors showing TGFBR3 and MGEA5 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 MGEA5 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.
Myoepithelioma/Mixed Tumor of Soft Tissue (Parachordoma)
The previous edition of this textbook viewed parachordoma and myoepithelioma of soft tissue as related, if not necessarily entirely identical, entities. Over the past several years, it has become increasingly clear that the clinicopathologic similarities between these two entities greatly outweigh any minor morphologic differences, and that both tumors show rearrangements of the EWSR1 gene in many cases. WHO currently regards myoepithelioma and parachordoma as synonyms, with myoepithelioma the preferred term.
Parachordoma was first described by Laskowski in 1951 as “chordoma periphericum,” but it was more fully described in a series of 10 cases by Dabska in 1977. Although the authors believed at the time they were describing chordomas arising in a paramidline or peripheral location, over time it became apparent their lesions were histologically distinct from true chordomas. Since that time, fewer than 60 cases have been described in the literature, mostly in the form of case reports or small series. This small number of reported cases reflects both the rarity of this tumor and the increasing tendency of pathologists to label such lesions as “myoepithelioma.”
The term myoepithelioma/mixed tumor of soft tissue was first introduced by Kilpatrick et al. in 1997 in a series of 19 cases. Subsequently, more than 200 soft tissue myoepithelial tumors have been published in four large series and many case reports. A morphologically distinctive variant of myoepithelioma occurring in the skin, termed cutaneous syncytial myoepithelioma, has also been recently reported.
Clinical Findings
Myoepitheliomas arise in patients of all ages, but there is a peak incidence in the second through fourth decades of life. However, a significant number of myoepitheliomas arise in pediatric patients, often showing malignant histologic features and an aggressive clinical course ( myoepithelial carcinoma ). There is no significant gender predilection, and most patients present with a slowly enlarging, painless mass in the deep soft tissue of the extremities, usually in the muscles of the thigh, groin, calf, upper arm, or forearm. The head and neck are also relatively common locations for these tumors. The tumor may be situated primarily in the subcutis or deep to the fascia; less often the lesion may be centered in or may secondarily involve the dermis. Cutaneous syncytial myoepithelioma typically presents as a small, polypoid or papular lesion of the skin in middle aged adults, most often on the upper extremity.
Pathologic Findings
Grossly, myoepitheliomas form a nodular mass ranging in size from 1 to 12 cm in greatest dimension, but most are 3 to 7 cm ( Fig. 32.25 ). In the series from Brigham and Women’s Hospital, tumor size ranged from slightly less than 1 cm to 20 cm (mean: 4.7 cm), although histologically benign tumors were significantly smaller than histologically malignant tumors (3.8 cm and 5.9 cm, respectively). Most are grossly well circumscribed and have a yellow-white to tan cut surface that is glistening, myxoid, or gelatinous. Necrosis is rarely a prominent feature.
The histologic appearance of mixed tumor/myoepitheliomas spans a morphologic spectrum similar to that observed in their counterparts in the salivary gland ( Figs. 32.26 and 32.27 ). Myoepitheliomas show a predominantly reticular growth pattern with cords of epithelioid, ovoid, or spindled cells deposited in a variably collagenous or chondromyxoid stroma. Although grossly well circumscribed, there are frequently small nests of cells separated from the main tumor and trailing off into the surrounding soft tissue structures, sometimes evoking a desmoplastic stromal response ( Fig. 32.28 ). In some cases the cells are arranged in nests or large sheets, but mixed architectural patterns are common. Tumors classically described as “parachordoma” consist of small nests of pale-staining cells, somewhat resembling the cells of the notochord. Most of the cells are round, eosinophilic cells arranged in cords, chains, or pseudoacini reminiscent of myxoid chondrosarcoma ( Figs. 32.29 to 32.38 ). The cells can show a transition to spindle-shaped cells or small, round glomoid cells ( Fig. 32.37A and B ). All lesions have a population of cells with vacuolated cytoplasm resembling physaliferous cells found in chordomas. “Parachordoma-like” areas may be seen in a minority of otherwise typical myoepitheliomas, emphasizing the unity of these tumors. The stroma varies in character from case to case and in different areas of the same tumor. Metaplastic cartilage, bone, or both can be seen in a small percentage of cases.
Most myoepitheliomas show only a mild degree of nuclear atypia, and mitotic figures are inconspicuous, usually with less than 1 MF/20 hpf. However, some have cytologically malignant features and are composed of larger cells with vesicular or coarse chromatin and prominent nucleoli ( Fig 32.37C ). In the series by Hornick and Fletcher, 61 of 101 tumors were classified as histologically benign, whereas 40 tumors were thought to be histologically malignant based on the cytologic features (malignant myoepithelioma, malignant mixed tumor, or myoepithelial carcinoma). Some histologically malignant tumors show small foci of classic benign-appearing areas; others have foci of heterologous chondrosarcomatous or osteosarcomatous differentiation. A greater percentage of pediatric myoepithelial tumors appear to show atypical features.
The morphologic features of cutaneous syncytial myoepithelioma differ from those of other myoepithelial tumors. These lesions usually grow in a circumscribed manner and consist of a solid, sheetlike proliferation of pale, eosinophilic, spindled to histiocytoid cells with an unusual syncytial appearance ( Figs. 32.39 to 32.41 ). Mitotic activity is typically low, and other worrisome features, such as necrosis and vascular space involvement, are absent. Adipocytic metaplasia may be present.
Immunohistochemical Findings
The cells of conventional soft tissue myoepithelioma generally coexpress epithelial markers (keratins and/or EMA) and S-100 protein (see Fig. 32.38 ). Myoepitheliomas are more often positive with antibodies directed against broad-spectrum (e.g., AE1/AE3) and low-molecular-weight keratins (e.g., Cam 5.2), and less often for high-molecular-weight keratins (e.g., 34βE12, CK14), EMA, CK7, and CK20. Keratin expression in myoepithelial tumors, however, may be very limited. There are no strict guidelines as to how much keratin or S-100 protein must be present before a given lesion can be labeled “myoepithelioma,” and this diagnosis requires a synthesis of available morphologic, immunohistochemical, and molecular genetic findings (see next) and exclusion of potential morphologic mimics, in particular extraskeletal myxoid chondrosarcoma (see Chapter 33 ). Expression of other myoepithelial markers, including muscle actins, GFAP, calponin, and p63, is seen in 15% to 50% of cases. The immunophenotype of cutaneous syncytial myoepithelioma differs from that of conventional soft tissue myoepithelioma, with keratin expression in only a small minority of cases (4 of 33). In contrast, EMA is uniformly positive in these tumors, and most are strongly S-100 protein positive. Smaller percentages of cutaneous syncytial myoepitheliomas express GFAP, SMA, and p16.
Cytogenetic and Molecular Genetic Findings
Soft tissue myoepitheliomas are characterized most often by the presence of EWSR1 gene rearrangements, with a variety of different fusion partners, including PBX1, ZNF44, POU5F1, PBX3, and KLF17 . Rare cases have a fusion involving FUS rather than EWSR1 . A possible association has been suggested between fusion type and morphology in soft tissue myoepithelial tumors: EWSR1-POU5F1 tumors often occur in younger patients and have a clear cell appearance, and EWSR1-PBX1 tumors have a bland sclerotic appearance or clear cell morphology. Flucke et al. subsequently showed that EWSR1 rearrangements occur in significant subsets of myoepithelial tumors of the skin as well, including one case with a proven EWSR1-ATF1 fusion. Most recently, the Memorial Sloan Kettering group has reported EWSR1- and FUS-KLF17 fusion in soft tissue myoepitheliomas. Cutaneous syncytial myoepitheliomas show EWSR1 rearrangements in more than 82% of cases with unknown partners.
Interestingly, soft tissue myoepithelial tumors with ductal differentiation and salivary gland myoepithelial tumors are generally EWSR1 negative. In contrast, true mixed tumors of the skin and soft tissue have been shown to harbor PLAG1 rearrangements, similar to their salivary gland counterparts.
Differential Diagnosis
Given the morphologic heterogeneity of this group of tumors, the differential diagnosis is quite broad and largely depends on the predominant cell type and stromal component. If ducts are present, the diagnosis of mixed tumor is straightforward. Common considerations include extraskeletal myxoid chondrosarcoma, OFMT, and chordoma.
Distinction from extraskeletal myxoid chondrosarcoma may be particularly challenging. This tumor typically shows a multinodular pattern with cords of eosinophilic spindled to ovoid cells deposited in a myxoid matrix. There is such a significant degree of morphologic overlap with myoepithelioma that IHC or molecular diagnostic testing is often required. However, the presence of dense sclerosis, hemorrhage, hemosiderin, and hematoidin pigment surrounding nodules of tumor, characteristic of extraskeletal myxoid chondrosarcoma but not myoepithelioma, may be quite helpful in this distinction. Myoepitheliomas typically coexpress keratin (or EMA) and S-100 protein, whereas extraskeletal myxoid chondrosarcoma expresses S-100 protein in very few cases and does not typically express keratins. It is important to keep in mind that both extraskeletal myxoid chondrosarcoma and myoepithelioma often show rearrangements involving the EWSR1 locus. FISH for the NR4A3 gene, rearranged in extraskeletal myxoid chondrosarcoma but to date not in myoepithelioma, assists in resolving this differential diagnosis.
Ossifying fibromyxoid tumor also enters the differential diagnosis (see earlier section). This tumor is a lobulated neoplasm composed of cords or nests of uniform, pale-staining, ovoid cells deposited in a variably myxoid or hyalinized stroma with a rim of metaplastic bone at the periphery in 70% of cases. Most OFMTs express S-100 protein, and about 50% desmin. Focal keratin positivity is very uncommon. EWSR1 rearrangements have not been shown in ossifying fibromyxoid tumor.
Chordoma , particularly extraaxial chordoma, is also a consideration, especially for tumors with a focal or predominant “parachordoma-like” pattern. Myoepithelial tumors and chordomas show significant immunohistochemical overlap with respect to keratin and S-100 protein expression, although chordomas are more likely to express high-molecular-weight cytokeratins. IHC for the specific notochordal marker brachyury, expressed by virtually all chordomas but not myoepithelial tumors, may be helpful ( Fig. 32.42 ).
Myoepithelial carcinoma (malignant myoepithelioma) may be confused with metastatic carcinoma, metastatic melanoma, and even epithelioid sarcoma, especially the proximal type. History of a primary carcinoma or a melanoma elsewhere is of paramount importance. In the absence of such a history, IHC can be extremely helpful in distinguishing among these lesions. Immunoreactivity for muscle markers (e.g., calponin, desmin), S-100 protein, and GFAP support a diagnosis of myoepithelial carcinoma over metastatic carcinoma. Melanomas typically coexpress S-100 protein and melanocytic antigens such as HMB-45 or melan A and rarely express keratins, GFAP, or muscle markers. Epithelioid sarcoma frequently expresses keratin and EMA, but not S-100 protein, GFAP, or myogenic markers. Loss of expression of SMARCB1 is seen in approximately 90% of epithelioid sarcomas but may also be seen in malignant myoepitheliomas. Epithelioid sarcomas do not show EWSR1 rearrangements.
Cutaneous syncytial myoepitheliomas should be distinguished from epithelioid fibrous histiocytomas. Although both tumors may show EMA expression, anaplastic lymphoma kinase (ALK) expression is seen only in epithelioid fibrous histiocytomas. Epithelioid fibrous histiocytomas also frequently show an epidermal collarette and lack the distinctive syncytial growth pattern.
Discussion
Although most mixed tumor/myoepitheliomas of soft tissue are histologically and clinically benign, some cases locally recur, and others are histologically malignant, clinically malignant, or both. In the series of 12 cutaneous and soft tissue myoepitheliomas by Michal and Miettinen, one patient developed metastatic disease and died as a direct result of the tumor. Similarly, of the 10 patients with clinical follow-up information in the series by Kilpatrick et al., two patients developed local recurrence, and two additional patients developed lung and lymph node metastases and died of their tumor. In the much larger subsequent series reported by Hornick and Fletcher, of the 33 histologically benign cases with follow-up, six locally recurred (18%), but none metastasized (mean follow-up: 36 months). Of the 31 histologically malignant cases with follow-up, 13 (42%) recurred and 10 (32%) metastasized (mean follow-up: 50 months). Four patients died of metastatic tumor, with metastatic sites including lung, mediastinum, spine, orbit, bone, brain, and other unusual soft tissue sites ( Table 32.3 ). There was no apparent correlation between margin status and risk of local recurrence, but local recurrence and metastasis were significantly more likely in patients with histologically malignant tumors. These authors suggested that the presence of at least moderate cytologic atypia (prominent nucleoli, vesicular or coarse chromatin, nuclear pleomorphism) warrants classification as a malignant myoepithelioma/myoepithelial carcinoma. Most cases previously reported as “parachordoma” have behaved in an indolent fashion, chiefly with locally recurring potential. Two cases of “parachordoma” have been reported with metastatic disease.
| Histologic Category | No. Cases | Local Recurrence (%) | Metastases (%) |
|---|---|---|---|
| Benign myoepithelial tumors | 33 | 6 (18) | 0 |
| Malignant myoepithelial tumors | 31 | 13 (42) | 10 (32) |
Solitary Fibrous Tumor (Hemangiopericytoma)
The term hemangiopericytoma was first coined in the 1940s by Stout and Murray for tumors thought to originate from the pericytes, a modified dendritic-like smooth muscle cell encircling blood vessels. Unfortunately, the original descriptions were vague and clearly included other lesions, such as myofibroma. Enzinger and Smith finally provided a more useful architectural and cytologic description of hemangiopericytoma in 1976. Their classic description emphasized the “staghorn,” partially hyalinized vessels surrounded by small, rounded, and fusiform cells that displayed no obvious light microscopic features of differentiation. Just as importantly, the authors highlighted the importance of distinguishing hemangiopericytomas from other lesions that could have a pericytic vascular pattern, notably high-grade synovial sarcomas. They also defined features associated with malignancy. The importance of this paper seemed forgotten over the years as the term “hemangiopericytoma” grew increasingly unpopular because pericytic differentiation could be confirmed in only a minority of cases ultrastructurally, and actin, a marker of pericytes, was infrequently present in these lesions. Moreover, as a diagnosis of exclusion, diagnostic reproducibility among pathologists was often poor.
The waning popularity of the diagnosis of hemangiopericytoma also coincided with the increasing popularity of the diagnosis of “solitary fibrous tumor,” a pleural-based lesion first described by Klemperer and Rabin. The observation that similar lesions occurred outside the pleura and had overlapping features with classic hemangiopericytoma, including CD34 immunoreactivity, paved the way for our understanding that hemangiopericytomas and solitary fibrous tumors represented different manifestations of the same entity. This concept is strongly supported by the finding of identical NAB2-STAT6 fusions and nuclear STAT6 expression in tumors classified as hemangiopericytoma and solitary fibrous tumor in all anatomic locations, including the meninges. Solitary fibrous tumor is now the term endorsed by WHO for all these lesions, with those previously classified as “hemangiopericytoma” representing the “cellular phase” of solitary fibrous tumor.
Clinical Findings
Solitary fibrous tumor (SFT) is primarily a tumor of adult life that affects the sexes equally. It is located almost exclusively in deep soft tissue, particularly the thigh, pelvic fossa, retroperitoneum, and serosal surfaces. Tumors in these locations often chiefly show cellular features, as previously labeled “hemangiopericytoma.” Although formerly believed to be restricted to the pleura, tumors showing features of classic SFT are increasingly recognized in extrapulmonary sites. Specific symptoms are related to the location of the tumor. Those in somatic soft tissue present as painless enlarging masses, whereas those within the abdominal cavity produce symptoms referable to impingement on specific organs. Serosal lesions are preferentially located on the pleura, where they are usually discovered as incidental findings during workup for another abnormality. Most are rounded, sharply outlined, homogeneous densities or masses on a pedicle that shifts with positional changes ( Fig. 32.43 ). Less often, they grow endophytically into the lung, or as a plaquelike mass over the fissures.
Hypoglycemia has been reported in about 5% of patients with SFT, most often those located in the pelvis and retroperitoneum, and may lead to symptoms of sweating, headache, disorientation, convulsions, and even coma. It is mediated through production of insulin-like growth factors (IGFs) by the tumor. IGFs and their receptor (IGF-R) messenger RNA (mRNA) can be identified in tumor cells even in the absence of clinical hypoglycemia. Hypoglycemic symptoms abate with tumor removal. In addition, the IGFs stimulate proliferation of tumor cells through an autocrine loop that can be abolished when the receptors are inactivated.
Meningeal solitary fibrous tumors (previously classified as “solitary fibrous tumor” when histologically benign and “hemangiopericytoma” when histologically malignant) are morphologically, immunohistochemically, and genetically indistinguishable from SFTs at other sites and are no longer considered variants of meningioma. Unlike conventional meningiomas, meningeal SFTs lack EMA, do not display mutations in the NF2 locus on chromosome 22, , and show NAB2-STAT6 fusions with nuclear expression of STAT6 protein. They occur at a younger age than meningiomas, grow more often along the sinuses, bleed profusely at surgery, tend to recur, and may metastasize to extracranial sites. Guthrie et al., in a review of 44 meningeal SFTs, reported 5- and 15-year survival rates of 67% and 23%, respectively. In another large series, Mena et al. noted a recurrence rate of 60.6% and a metastatic rate of 23.4%. Current risk stratification systems developed for soft tissue SFT (see later) do not appear to be applicable to meningeal SFT, and there is a need for a meninges-specific classification.
Pathologic Findings
SFTs grow in deep soft tissue as a circumscribed mass or as exophytic lesions from the serosal surfaces ( Fig. 32.44 ). Most measure 5 to 10 cm in diameter and have a gray-white to red-brown color on cut section. Hemorrhage and cystic degeneration may be seen.
SFTs are highly variable in appearance depending on the relative proportion of cells and fibrous stroma. The cellular end of this spectrum corresponds to “classic hemangiopericytoma” ( Figs 32.45 to 32.53 ) and the hyalinized end to “classic solitary fibrous tumor.” However, it should be emphasized that many cases have hybrid features ( Figs. 32.54 to 32.58 ). The cellular phase of SFT consists of tightly packed, round to fusiform cells with indistinct cytoplasmic borders arranged around an elaborate vasculature. The vessels form a continuous, ramifying vascular network that exhibits striking variation in caliber. As a rule, the dilated, branching vessels divide and communicate with small or minute vessels that may be partly compressed and obscured by the surrounding cellular proliferation. Typically, the dividing sinusoidal vessels have a “staghorn” or “antlerlike” configuration ( Fig. 32.55A ). The vessels, particularly large ones, are usually invested with a thick coat of collagen that extends into the interstitium. Myxoid change is common ( Fig. 32.49 ) and, when extreme, may produce an appearance similar to a myxoid liposarcoma. However, the presence of coarse-walled vessels and interstitial hyalinization and the absence of lipoblasts are important features that distinguish these hemangiopericytomas from myxoid liposarcomas. Similar changes have been observed in classic SFT.
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