Patel, Rajiv M. MD*; Billings, Steven D. MD†
Certain soft tissue tumors, benign and malignant, tend to prompt expletive remarks from pathologists engaged in their diagnosis. In the authors’ experiences, these lesions have deceptive morphologic features which often cause diagnostic difficulties and obscure the true nature of the neoplastic process. This review discusses entities which present such diagnostically challenging findings and reviews their clinical, histologic, immunophenotypic and, where appropriate, molecular features, and prognosis and differential diagnosis.
ANGIOMATOID FIBROUS HISTIOCYTOMA
Angiomatoid fibrous histiocytoma (AFH) was first described by Enzinger1 in 1979 as angiomatoid malignant fibrous histiocytoma. The tumor was subsequently renamed AFH to reflect the rarity of metastasis and its overall good prognosis. AFH is a distinctive fibrohistiocytic tumor of intermediate malignancy. It typically presents in children and young adults as cutaneous/subcutaneous nodules, usually on the extremities. That being said, it may present at any age and in a variety of anatomic sites, including such diverse locations as the lungs, mediastinum, vulva, retroperitoneum, hard palate, bone, and orbit.2–7 Occasionally, there may be systemic symptoms such as weight loss and night sweats. The tumor has a high rate of local recurrence (∼20% to 40%) but metastasis is rare (<5%).8,9
Grossly AFH are firm circumscribed tumors that usually measure a few centimeters in diameter. Microscopically AFH has a circumscribed silhouette delineated by a fibrous pseudocapsule containing lymphoid aggregates (Fig. 1A). The latter features impart a overall resemblance to a lymph node at low power. Most typically, the tumor is composed of histiocytic cells with a sheet-like to swirling growth pattern with dilated pseudovascular spaces lined by compressed tumor cells and hemosiderin deposits within the tumor (Fig. 1B).1,2,8–9 Interestingly, in perhaps the largest series of AFH, the dilated pseudovascular spaces from which the tumor derives its namesake were present in about 50% of cases.9 In tumors with these characteristic histologic features, the diagnosis is often relatively straightforward. Unfortunately, AFH has a much wider range of histologic appearances than is widely recognized. Myxoid change, a reticulated cord-like pattern, clear cell morphology, pleomorphism, and even rhabdomyoblast-like cells have been reported.1,2,8–9 We have also recently encountered a case with numerous eosinophils causing diagnostic confusion with an epithelioid hemangioma (angiolymphoid hyperplasia with eosinophilia).
Perhaps the histologic feature that is most expletive inducing is the presence of marked pleomorphism. Marked cytologic atypia causes confusion with pleomorphic undifferentiated sarcoma (malignant fibrous histiocytoma; Figs. 1C–D).10 Obviously, mistaking a tumor of intermediate malignancy, AFH, for a pleomorphic undifferentiated sarcoma has serious implications for the patient. Key to the recognition of AFH in such situations is the presence of features encountered in more conventional cases. In our experience, the presence of a fibrous pseudocapsule and lymphoid aggregates are the most helpful clues to the diagnosis when morphologic variants are encountered.
In terms of ancillary studies, immunohistochemistry can be helpful but is largely supportive rather than definitively diagnostic. Roughly 50% of cases are positive for desmin, EMA, CD68, and/or CD99.9 The immunophenotype also has diagnostic pitfalls. As AFH is frequently encountered in children and young adults, desmin immunoreactivity could prompt consideration of the diagnosis of rhabdomyosarcoma. This is especially true in tumors with pleomorphism, and we have encountered cases of AFH misdiagnosed as rhabdomyosarcoma for this reason. Fortunately, AFH is consistently negative for skeletal muscle specific markers myogenin and MYO-D1. EMA immunoreactivity could also erroneously support a misdiagnosis of metastatic carcinoma involving a lymph node, though this is less of a practical concern as immunostains for cytokeratins are more commonly used in this situation.
Molecular studies have emerged as the best ancillary tool in the diagnosis of AFH with unusual histologic features. Cytogenetically AFH has 1 of 3 different recurring translocations: t(12;16)(q13;p11) resulting in a FUS/ATF1 fusion gene, t(12;22)(q13;q12) resulting in a EWSR1/ATF1 fusion, and t(2;22)(q33;q12) resulting in a EWSR1/CREB1 fusion.11,12 The last seems to be the most common translocation variant, which is present in approximately 70% of cases.13 Given the sometimes confusing morphologic pattern and inconsistent immunophenotype, fluorescence in situ hybridization (FISH) to detect evidence of a translocation has become invaluable in the diagnosis of this tumor. FISH using break-apart probes for either EWSR1 or FUS is positive in 80% or more of cases (Fig. 2A). In difficult cases, we routinely perform FISH for EWSR1 and reserve FUS FISH for EWSR1 negative cases. It should be pointed out that in a small proportion of AFH, FISH studies will be negative. This could be the result of technical issues, a cryptic translocation not detectable by FISH or the tumor may harbor an as yet unidentified translocation.14 As with immunohistochemical stains, interpretation of FISH results needs to be accomplished in the correct histologic context, as Ewing sarcoma, clear cell sarcoma, and a subset of myoepithelial tumors also harbor translocations involving EWSR1.
The differential diagnosis of AFH is varied. As previously discussed, misinterpretation of AFH as representing metastatic tumor involving a lymph node is a diagnostic pitfall. Recognition that the tumor lacks the true subcapsular sinus of a lymph node is helpful in this distinction. Pleomorphic cases may be mistaken for a pleomorphic undifferentiated sarcoma and desmin immunoreactivity may result in AFH erroneously diagnosed as rhabdomyosarcoma. The pseudovascular spaces can cause confusion with a vascular tumor, but AFH lacks immunoreactivity for vascular markers such as CD31 and CD34.
Finally, another entity that enters the differential diagnosis is largely because of nomenclature. Dermatofibromas may have intratumoral hemorrhage. When originally described, both terms aneurysmal and angiomatoid were used.15 This has caused confusion, with the terms angiomatoid and aneurysmal being interchangeably applied to dermatofibroma (benign fibrous histiocytoma) with intratumoral hemorrhage and AFH. Microscopically, there is relatively little overlap. AFH lacks peripheral collagen trapping and dermatofibromas do not have a fibrous pseudocapsule with lymphoid aggregates. We strongly recommend that the term angiomatoid in this context to be reserved for the diagnosis of AFH to avoid confusion on the part of the clinician reading the pathology report. When one encounters a dermatofibroma/benign fibrous histiocytoma with prominent intratumoral hemorrhage, we recommend the diagnosis of “dermatofibroma with aneurysmal change” to avoid this potential confusion.
MYXOID DERMATOFIBROSARCOMA PROTUBERANS
Dermatofibrosarcoma protuberans (DFSP) is one of the more commonly encountered cutaneous soft tissue malignancies. Clinically, DFSP usually presents on the trunk of young to middle aged adults, most commonly on the trunk or proximal extremities, but a wide age range may be affected and almost any location can be involved.
Histologically, DFSP is composed of uniform hyperchromatic spindled cells deposed in a storiform growth pattern and typically infiltrates into the subcutaneous fat in a characteristic “honeycomb” fashion. There are a number of variants of DFSP that have been described including giant cell fibroblastoma, pigmented DFSP, DFSP with myoid nodules, fibrosarcomatous DFSP, and myxoid variants.16 In our experience the myxoid variant is a source of diagnostic difficulty and error. In myxoid DFSP, there is an abundant myxoid stroma that results in the loss of the characteristic storiform growth pattern and accentuation of the underlying vasculature, which is not readily apparent in conventional DFSP (Fig. 3A).17–19 The vasculature may be hyalinized vessels or delicate and branching, reminiscent of the vasculature of myxoid liposarcoma. The tumor cells frequently take on a more stellate rather than purely spindled morphology (Fig. 3B). Interestingly and somewhat counter intuitively, the advancing edge of myxoid DFSP may have a more nodular, pushing border rather than the typical diffusely infiltrative growth pattern of conventional DFSP. Careful examination will reveal at least focal areas with infiltrative growth in myxoid DFSP. Sampling is critical in myxoid DFSP; areas of conventional DFSP are present in >60% of cases.18,19 Other DFSP variants may also be present in a minority of cases. Myxoid DFSP retains immunoreactivity for CD34 but it may be patchy and less intense than conventional DFSP.
Myxoid DFSP may get confused with myxoid liposarcoma, especially in cases with a more delicate plexiform capillary vasculature. However, the vasculature of myxoid DFSP is less uniform than myxoid liposarcoma. The cells of myxoid liposarcoma are spindled and not typically stellate like in myxoid DFSP. In myxoid liposarcoma, there are usually true lipoblasts. Myxoid liposarcoma does not typically express CD34. One should also keep in mind that myxoid liposarcoma presents as a deep soft tissue tumor, not as a superficial tumor involving the dermis and subcutis. In cases where the diagnosis is still in question cytogenetic testing can be done as myxoid liposarcoma harbors a t(12;16) rather than the t(17;22) of DFSP.20
Superficial angiomyxoma may be especially difficult to distinguish from myxoid DFSP based on limited biopsy material, as the morphology of the individual tumor cells can be strikingly similar and superficial angiomyxoma may also be CD34 positive. However, superficial angiomyxoma is usually restricted to the dermis. The growth pattern is the most important distinguishing factor. Superficial angiomyxoma has a lobular rather than infiltrative growth pattern and is less uniformly cellular.21 The presence of entrapped epithelial structures and stromal neutrophils may be helpful. DFSPs do not have entrapped adnexal structures, but it should be pointed out that perivascular neutrophils may be present in up to 10% to 30% of myxoid DFSPs.18
Epithelioid sarcoma (ES) was first described as a distinct clinicopathologic entity by Enzinger in 197022 and further characterized by Chase and Enzinger in 1985.23 Before Enzinger’s seminal paper this distinctive malignant neoplasm of disputed histiogenesis had been included in the spectrum of synovial sarcoma and clear cell sarcoma as a “tendosynovial sarcoma.” ES is infamous for its frequent misdiagnosis, most notoriously for being mistaken as a benign lesion, with potentially disastrous results for the patient.
ES usually presents in young adults, most commonly on the distal extremities, but ES can occur in almost any location, and it has been described in a variety of unusual locations including the face, vulva, and penis.22,23 It occurs in a wide age range with a median age of 26 years and a male predominance of 2:1.23 ES is rare in children and older adults, but does very rarely occur in these age groups.24 Lesions may arise in the dermis, subcutis, and/or deeper tissues and often involve tendons and aponeuroses.22,23 ES involving the dermis often clinically presents as single or multiple, ulcerated, firm nodules. The clinical presentation is often as a nondescript subcutaneous mass, but ulceration is relatively common and should always be a warning sign for potential ES in a cutaneous soft tissue lesion. In some cases the ulcerated cutaneous lesions of ES can have a sporotrichoid appearance. ES has a high rate of local recurrence, between 50% and 85% of patients and a metastatic rate of 30% to 50%, often with late metastases. Favored metastatic sites are the lung and regional lymph nodes.23
Grossly ES presents as one or more tan-white nodules with infiltrative margins.23 Microscopically, ES usually demonstrates nodules of epithelioid cells with densely eosinophilic cytoplasm that resemble histiocytes (Fig. 4A). The nodules can have a pseudogranulomatous pattern, especially in nodules that have central necrosis. The tumor nuclei are enlarged but generally bland without prominent nucleoli. Cases can have an interstitial pattern that can superficially resemble granuloma annulare (Fig. 4B). Occasional cases can have a predominantly or exclusively spindled morphology and are often embedded in a hyalinized stroma (Fig. 4C).25 This morphology can be extraordinarily deceptive. In some cases the clinical history of an ulcerated lesion can lead to the diagnosis of ES even when the diagnosis is not suspected histologically. Areas of hemorrhage, pseudovascular differentiation, hyalinized collagen, and bone may also be present.22–25 A “proximal-type” variant with greater pleomorphism, rhabdoid cytomorphology and geographic necrosis has been described.26,27 Mitotic figures are usually present but the mitotic rate is usually relatively low. The hyalinized collagen in spindled ES (fibroma-like ES) can contribute to misinterpretation as a cellular fibrous histiocytoma or inflammatory processes such as granuloma annulare or necrobiosis lipoidica.25
By immunohistochemistry, ES is positive for cytokeratins and will be positive for antibodies AE1/3, CAM5.2, and CK7. They are negative for CK20, and most are negative for CK5/6. ES is positive for EMA, vimentin, and approximately 50% are positive for CD34. ES is negative for CD31.28 It should be noted that ES may be positive for factor XIIIa, a potential diagnostic pitfall in cytologically bland cases. More recently negativity for INI-1 has been demonstrated as a useful finding in the diagnosis of ES. INI-1 is the product of the hSNF5/INI1/SMARCB1/BAF47 gene, which encodes for a tumor suppressor involved in ATP-dependent chromatin remodeling, cell cycle control, and regulation of the cytoskeleton. Loss of INI-1 expression is the hallmark of pediatric rhabdoid tumors and atypical teratoid rhabdoid tumors of the central nervous system. Loss of INI-1 is seen in >90% of ES of all types.29 Non-neoplastic tissue is essentially always positive for this nuclear marker, as are most tumors in the differential diagnosis (Fig. 4D).
The differential diagnosis of ES is varied. In more epithelioid tumors, the differential diagnosis includes granulomatous disease such as infection, granuloma annulare, and sarcoidosis. The presence of at least focal nuclear atypia and immunoreactivity for cytokeratin is helpful in allowing distinction. Metastatic carcinoma or sarcomatoid carcinoma can also be considerations in selected cases because of immunoreactivity for cytokeratins and/or EMA. Absence of expression of CK5/6 and INI-1 can help identify ES in such cases.
Exclusively or largely spindled ES (the so-called fibroma-like ES) like the illustrated case (Fig. 4C) are often deceptively bland appearing and are the most expletive inducing variant of ES. The stromal collagen is hyalinized, causing diagnostic confusion with benign fibrous histiocytomas, interstitial granuloma annulare, fibroma of tendon sheath, or nonspecific reactive fibroblastic proliferations.25 The absence of secondary elements such as foamy macrophages and siderophages and peripheral collagen trapping can help distinguish ES from benign fibrous histiocytoma. Interstitial granuloma annulare typically has dermal mucin deposition associated with degenerative collagen bundles. Fibroma of tendon sheath is negative for cytokeratins and is histologically very bland. In ES there is usually at least focal hyperchromasia and atypia, which helps differentiate ES from all of these entities. Of course, immunoreactivity for cytokeratins is helpful and essential in difficult cases. For this reason, we are in the practice of routinely immunostaining any unusual “fibroblastic” appearing lesion on the distal extremities with cytokeratins, particularly in younger patients. We also recommend considering immunostains if the clinical setting is suspicious. For example, in the illustrated case of the spindled ES (Fig. 4C), the patient had a history of an ulcerated painful lesion. It was the clinical presentation that lead us to order immunohistochemical stains, as ES was not our initial consideration based solely on the histologic appearance. By the same token, one should not hesitate to consider ES with more typical histology when presenting in unusual locations.
Two vascular tumors figure largely in the differential diagnosis of ES: epithelioid hemangioendothelioma (EHE) and ES-like hemangioendothelioma (ES-H; also known as pseudomyogenic hemangioendothelioma). EHE typically presents in adults but with a relatively nondescript clinical appearance, usually a skin-colored nodule that lacks the violaceous appearance of vascular tumors. A vascular lesion is suspected in only a minority of cases. Microscopically, EHE is composed of cords to nests of epithelioid endothelial cells. Cells with intracytoplasmic vacuoles (blister cells) are typical, but may be inconspicuous. Classically, approximately 50% of EHE have a vasculocentric growth pattern with tumor cells filling the affected vessel and extending out in a centrifugal fashion.30,31 This vasculocentric pattern, however, is less frequently encountered in cutaneous tumors.32 The most characteristic feature is the cord-like arrangement of the epithelioid endothelial cells that are embedded within a myxohyaline stroma. In some cases the cord-like morphology is difficult to appreciate causing potential confusion with ES. EHE is usually immunoreactive for both CD34 and CD31, and approximately 25% are immunoreactive for cytokeratin.33 The combination of cytokeratin and CD34 immunoreactivity can cause confusion with ES. Immunoreactivity for CD31 and retained INI-1 expression is helpful in distinguishing EHE in difficult cases. Recently a novel WWTR1-CAMTA1 gene fusion has been found to be a consistent abnormality in EHE of different sites.34,35 ES-H is a rare vascular tumor of apparent intermediate malignancy that bears striking resemblance to ES. Clinically ES-H can present as an ulcerated tumor or may present multifocally.36,37The tumor is composed of sheets and fascicles of plump epithelioid to spindled cells with relatively abundant eosinophilic cytoplasm. Unlike ES, it does not grow in nodular aggregates. Mitotic rate is typically low and areas of central necrosis are not seen. The tumor has a unique immunophenotype. It is positive for cytokeratin AE1/3, Fli-1, CD31, and has retained INI-1 but is negative for CD34.36,37 In a recent series the same tumor was described under a different name (pseudomyogenic hemangioendothelioma). In this most recent series, roughly 50% of the cases were positive for CD31 and there was a male predominance.36 In our opinion the term ES-H is preferred as the most likely misdiagnosis is classifying this tumor as an ES. The distinction is not trivial, as ES-H is a much less aggressive tumor that has not to date demonstrated the potential for distant metastasis.
CUTANEOUS EPITHELIOID ANGIOMATOUS NODULE
This is a relatively new entity first described in 2004.38 Clinically it usually presents in middle-aged adults, but may occur over a broad age range with rare cases arising in childhood and elderly patients. The majority of cases are small (<1.0 cm) solitary lesions but occasional multiple or eruptive forms have been described. They are usually erythematous to violaceous. The location is varied, most have been described on the trunk but a significant subset has also been described on the extremities and the head and neck area.38,39
Grossly cutaneous epithelioid angiomatous nodule (CEAN) is a solitary dermal nodule and microscopically is circumscribed, but unencapsulated (Fig. 5A). Recognizable vascular channel formation is usually focal in nature. They are largely solid and composed of epithelial endothelial cells with abundant eosinophilic cytoplasm (Fig. 5B). Intracytoplasmic vacuoles are usually apparent. The nuclei do not show significant pleomorphism but they typically are somewhat enlarged with a conspicuous nucleolus. These are mitotically active tumors with a mitotic rate up to 5 mitotic figures per 10 high-power fields, but atypical forms are not seen. There is a variable inflammatory infiltrate usually composed of lymphocytes and histiocytes associated with CEAN. Occasional cases may show a significant eosinophil component. CEAN is typically positive for at least 1 vascular marker and negative for cytokeratin. This is a benign tumor and is unrelated to underlying immunosuppression. The treatment is variable. Cases have responded to simple excision and topical steroids. There have been no reported cases of local recurrence or metastasis.38,39
The differential diagnosis of CEAN includes epithelioid hemangioma (EH) (angiolymphoid hyperplasia with eosinophilia), and it has been suggested that CEAN may be related to EH.39 EH usually presents in the head and neck area of young adults as solitary or locally multiple lesions. Microscopically, EH has more well-formed capillaries lined by epithelioid endothelial cells and is associated with lymphoid aggregates and numerous eosinophils. There is frequently a larger damaged vessel toward the central portion of EH suggesting that this may be a reactive process.40
Because of the epithelioid nature of the endothelial cells, EHE can also be considered in the differential diagnosis. EHE is discussed in detail above.
Epithelioid angiosarcoma (EA) could also be considered in the differential diagnosis of CEAN. EA typically occurs in adults and may occur as a cutaneous lesion41 but it is more common as a deep soft tissue mass of the extremities.42 Microscopically, the growth pattern is variable from solid sheets to obvious vasoformative channels. The tumor cells have an epithelioid morphology but more prominent nuclear atypia, frequent mitotic figures and atypical mitotic figures. EA is also frequently immunoreactive for cytokeratin, a potential diagnostic pitfall.42 Cytokeratin immunoreactivity has not been described in CEAN despite its epithelioid morphology.
Cutaneous angiosarcoma can be generally separated into several clinically defined groups. These include sporadic (not associated with lymphedema or radiation), lymphedema-associated and radiation-induced angiosarcoma.43–46 The sporadic form most commonly arises on sun-damaged skin of the head and neck of elderly patients. Lymphedema-associated and radiation-induced angiosarcoma, arise in a background of chronic lymphedema or radiation treatment, respectively. Angiosarcoma may very rarely present in children and are generally associated with preexisting congenital lymphovascular abnormalities.47 Most cases of angiosarcoma of all types present as rapidly expanding erythematous to violaceous patches or nodules, but occasional cases can clinically mimic other entities including nonvascular tumors. The prognosis of angiosarcoma is poor.45,48,49
Grossly tumors are composed of ill-defined hemorrhagic foci within the dermis and subcutis. By histology most cases of angiosarcoma show complex vessels lined by atypical endothelial cells with an interanastomosing pattern and intratumoral hemorrhage. In some angiosarcomas vascular differentiation may be an extremely subtle finding on hematoxylin and eosin–stained sections and require vascular immunohistochemical markers for recognition. Angiosarcoma can be predominantly composed of fascicles of spindled cells with little evidence of vascular differentiation (Fig. 6A). The presence of atypical vessels at the periphery and, when present, intratumoral hemorrhage are clues to the diagnosis (Fig. 6B). The lack of prominent vascular differentiation seen in the illustrated case can result in a differential diagnosis of sarcomatoid squamous cell carcinoma, spindle cell melanoma, atypical fibroxanthoma, or leiomyosarcoma. Recognition of the atypical vessels at the periphery and immunostains for vascular markers helps distinguish this histologic variant of angiosarcoma from melanoma or spindled squamous cell carcinoma. Immunohistochemistry for vascular markers such as CD31 and CD34 are the most helpful in demonstrating vascular differentiation and distinguishing angiosarcoma from its morphologic mimics. CD31-positive intratumoral macrophages may yield false-positive results and represents a diagnostic pitfall.50 Newer nuclear immunohistochemical markers of vascular differentiation such as Fli-1 and ERG are very useful and gaining popularity.51,52 We now routinely perform CD31 and ERG immunohistochemical stains for the diagnosis of suspected vascular tumors when the lineage is uncertain. The degree of cytologic atypia in CAS is greater than what is seen in Kaposi sarcoma and CAS is negative for HHV8 by immunohistochemistry.53
Another difficult differential diagnosis in the setting of vascular tumors is encountered in postradiation vascular lesions. The differential diagnosis of radiation-induced atypical vascular lesions (AVL) and radiation-induced angiosarcoma tumors is very difficult on routine histologic sections. Highlighting this difficulty is the series out of Stanford where approximately 50% of cases initially diagnosed as AVL were reclassified as angiosarcoma on examination of the resection specimens.54 This is further complicated by the fact that some angiosarcomas arise from a precursor AVL.44,46
Clinically, AVLs tend to be smaller, less violaceous lesions compared with angiosarcomas but there is clinical overlap. Both occur in the radiation field and present with a typically short average latency from 3 to 5 years, respectively. Both can present as early as 1 year after radiation therapy.
Microscopically AVL has been subdivided in lymphatic types, owing to their resemblance to lymphangiomas (Fig. 7A) and vascular types (Fig. 7B) when more diffusely composed of relatively well-formed, less ectatic blood vessels.46 Both can have enlarged hyperchromatic endothelial cells with mild atypia, but they usually lack pleomorphism and multilayering of endothelial cells. Postradiation angiosarcomas have a wide range of histologic appearances ranging from well-differentiated to poorly differentiated tumors. Discriminating well-differentiated angiosarcoma from AVL is particularly vexing on routine sections in the typical small punch biopsy encountered in routine practice. Conventional immunohistochemical stains are typically of little help.
It has recently been discovered that postradiation and lymphedema-associated angiosarcoma demonstrate MYC amplification, which can be detected by PCR, FISH, or immunohistochemistry (Fig. 2B). Initial reports demonstrated MYC amplification in 55% of postradiation angiosarcoma.55 Subsequent reports have demonstrated amplification in up to 100% of cases.56,57 By contrast AVLs are consistently negative for MYC amplification. Immunohistochemistry for MYC seems to be almost equivalent to molecular methods.57 AVLs can show focal positivity in rare cases, however.56 From a personal experience standpoint, the immunoreactivity needs to be strong before it is interpreted as positive. We have encountered weak, blush nuclear immunoreactivity in the absence of amplification demonstrated by FISH. Such staining should be interpreted as negative or equivocal and followed with molecular techniques to confirm the presence of MYC amplification.
LOW-GRADE FIBROMYXOID SARCOMA
Low-grade fibromyxoid sarcoma (LGFMS) is an uncommon sarcoma. It was originally described in 1987 by Harry Evans who reported 2 cases of a deceptively bland sarcoma with paradoxically aggressive behavior.58,59 Also described in the late 1990s was the hyalinizing spindle cell tumor with giant collagen rosettes.60 It was noted that this tumor had similar clinical and histologic features to LGFMS and it was suggested that it was possibly a variant of LGFMS.60,61 This relationship was confirmed with the identification of a novel t(7;16) usually involving fusion of the FUS/CREB3L2 genes, which was shared by both tumors, supporting that the concept that they represented ends of a spectrum of the same tumor.62–65
LGFMS usually occurs in young to middle-aged adults. It typically presents as a deep soft tissue mass most commonly in the lower extremity, but may arise in almost any location. A subsequent study demonstrated that up to 20% of LGFMS present as a superficial neoplasm of the dermis or subcutis (Fig. 8A).66 In this series, a disproportionate number of the superficial tumors were seen in children. Over all, pediatric cases account for 10% to 20% of cases of LGFMS, but in superficial cases, children represent almost 40% of the cases.
Microscopically LGFMS is notorious for its deceptively bland histologic features. It is composed of mildly atypical hyperchromatic spindled cells arranged in a swirling growth pattern (Fig. 8B). The tumor modulates from fibrous to myxoid zones, often with abrupt transitions (Fig. 8C).58–61,65–67 In the more fibrous areas the tumor may take on a fascicular growth pattern similar to fibromatosis (Fig. 8D). In more purely myxoid zones arcing vessels may be prominent (Fig. 8E). In a subset of cases there are circumscribed nodules of dense collagen rosettes, often surrounded by a rim of more rounded tumor cells occurring in a background of otherwise typical LGFMS (Fig. 8F). The tumor cells have relatively uniform, mildly atypical hyperchromatic spindled nuclei. Rarely higher grade foci may be present. The mitotic rate is typically low.
Up until recently, immunohistochemical stains for superficial LGFMS have been of relatively little use and a source of diagnostic pitfalls. LGFMS is immunoreactive for vimentin and may occasionally show focal immunoreactivity for EMA, CD34, and actin. LGFMS is typically negative for S100 protein, desmin, and cytokeratin. Recently, immunohistochemical stains for MUC4 have shown promise in the diagnosis of LGFMS.68 FISH utilizing breakaway probes for FUS are a useful adjunct to the diagnosis of LGFMS, and are positive in >70% of cases (Fig. 2C).69,70 PCR techniques may also be used to demonstrate the characteristic translocation.
The reason this tumor is so vexing is that most of the entities in the differential diagnosis are benign. Misdiagnosis of benignity in a case of LGFMS will contribute to the potential for an adverse outcome, including metastasis and death.58,59,61 Perineurioma is a benign nerve sheath tumor that can bear a striking resemblance to LGFMS, with a similar swirling growth pattern and variably fibrous and myxoid stroma. Perineurioma expresses EMA, but so can a subset of LGFMSs. LGFMSs usually have more cytologic atypia, but there has been one series of cytogenetically confirmed LGFMSs that were almost indistinguishable from perineurioma.71 Fortunately, this is rare.
Other benign tumors that can be confused with LGFMS include nodular fasciitis, benign fibrous histiocytoma, and fibromatosis. Nodular fasciitis has a looser, tissue culture-like growth pattern with areas of cystic breakdown. Benign fibrous histiocytomas exhibit collagen trapping without alternating from fibrous to myxoid areas. Although focal areas of LGFMS may have long fascicles similar to fibromatosis, fibromatosis does not have areas with a swirling growth pattern or myxoid foci.
In summary, we have presented a selection of entities that at various times in our careers have caused us to use rather coarse language and sometimes question our chosen profession. It seems that soft tissue pathology, especially in its intersection with dermatopathology, is a frequent source of such introspection among pathologists. It is our hope that the reader will be somewhat less likely to shout “Oh, S%*@!” the next time these entities are encountered.
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