Liposarcomas are classified into myxoid, pleomorphic,

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1 Dedifferentiated Liposarcoma With Myofibroblastic Differentiation Grace Y. Wang, MD; David R. Lucas, MD Context. Liposarcoma is divided into myxoid, pleomorphic, well-differentiated, and dedifferentiated subtypes. Dedifferentiated liposarcoma displays the greatest histomorphologic diversity, including a subset with myofibroblastic differentiation that shares similarities with a spectrum of reactive, benign, and malignant soft tissue lesions. Misdiagnosis may lead to deleterious consequences, as dedifferentiated liposarcoma differs significantly in its prognosis and treatment from its mimics. Objective. To review the clinicopathologic, immunohistochemical, and molecular features of the myofibroblastic variant of dedifferentiated liposarcoma as well as the key distinguishing features from its mimics. Data Sources. Review of pertinent literature on major features and current understanding of dedifferentiated liposarcoma with myofibroblastic differentiation. Conclusions. The myofibroblastic variant of dedifferentiated liposarcoma is an uncommon and underrecognized sarcoma with several important differential diagnoses, and likely represents the major subset of aggressive retroperitoneal tumors that may have been misdiagnosed as desmoid-type fibromatosis, inflammatory myofibroblastic tumor, or another type of sarcoma in the past. (Arch Pathol Lab Med. 2018;142: ; doi: /arpa RA) Liposarcomas are classified into myxoid, pleomorphic, well-differentiated, and dedifferentiated subtypes. 1 Myxoid liposarcoma is a fully malignant neoplasm characterized by recurrent chromosomal translocations t(12;16) (q13;p11) or less often t(12;22)(q13;q12) that result in FUS- DDIT3 or EWSR1-DDIT3 fusion products, respectively. Behavior is largely determined by the amount of round cell sarcoma present. Pleomorphic liposarcoma is the least common liposarcoma. It has a complex karyotype and portends the worst prognosis among the 4 subtypes. 2 Welldifferentiated liposarcoma (WDL), also known as atypical lipomatous tumor, is the most common subtype. Although having no potential for metastasis, it has a high rate of local recurrence, especially for retroperitoneal tumors where surgical options are limited owing to anatomic constraints. Dedifferentiated liposarcoma (DL) most commonly arises de novo, but may also arise within a recurrent WDL. 2 The relationship between WDL and DL is supported by shared genetic abnormalities of supernumerary ring and giant marker chromosomes that harbor amplified oncogenes, notably MDM2, HMGA2, and CDK4 on chromosome 12q(13-15). 3 Dedifferentiated liposarcoma typically has additional genetic abnormalities as compared to WDL. 3 Accepted for publication May 10, From the Department of Pathology, University of Michigan, Ann Arbor. The authors have no relevant financial interest in the products or companies described in this article. Presented in part at the New Frontiers in Pathology meeting; October 19 21, 2017; Ann Arbor, Michigan. Corresponding author: David R. Lucas, MD, Department of Pathology, University of Michigan, 2G332 UH, 1500 West Medical Center Drive, Ann Arbor, MI ( drlucas@umich.edu). Dedifferentiated liposarcoma is the most heterogeneous of all sarcomas with a wide variety of histologic patterns including tumors with distinctive patterns, tumors with heterologous and homologous differentiation, and lowgrade tumors. Dedifferentiated liposarcoma with myofibroblastic differentiation is largely underrecognized and can be mistaken for other entities such as desmoid-type fibromatosis, inflammatory myofibroblastic tumor (IMT), 4 and an exuberant reactive proliferation. Distinguishing DL with myofibroblastic differentiation from its histologic look-alikes is important, as DL is not only associated with a worse prognosis in many cases, but also may be a potential candidate for targeted molecular therapeutics. 5 7 Herein, we review the clinicopathologic, immunohistochemical, and molecular findings of DL with myofibroblastic differentiation and discuss the diagnostic pitfalls. CLINICAL FEATURES Dedifferentiated liposarcoma typically presents in middleaged and older adults as a large, deep-seated mass. 3,8 The most common site is retroperitoneum, which accounts for approximately half the cases, followed by inguinoscrotal region and thigh. 3 While some DLs are detected incidentally, others are symptomatic owing to obstruction of surrounding structures. 3 Approximately 90% of DLs present de novo, while the remainder arise within a recurrent WDL. 3,4,8 HISTOLOGIC FEATURES Dedifferentiated liposarcoma exhibits a wide spectrum of histologic features. By definition, DL has both a WDL and a higher-grade, usually nonlipogenic component. The interface between them can appear sharply demarcated or comingled. The higher-grade element in most tumors is a Arch Pathol Lab Med Vol 142, October 2018 Myofibroblastic Dedifferentiated Liposarcoma Wang & Lucas 1159

2 grade 2 or 3 spindle cell or pleomorphic sarcoma without a specific line of differentiation. Other patterns include tumors with meningothelial-like whorls, metaplastic bone formation, and myxoid stroma; tumors resembling solitary fibrous tumor and inflammatory malignant fibrous histiocytoma; and tumors with prominent epithelioid features. Tumors with various forms of heterologous differentiation such as leiomyosarcomatous, rhabdomyosarcomatous, and osteosarcomatous differentiation, as well as tumors with homologous (pleomorphic liposarcomatous) differentiation are well recognized Tumors with low-grade histology have also been documented. 12 In 2010, we added to its morphologic diversity through a series of 6 cases with inflammatory myofibroblastic tumor-like features. 4 The myofibroblastic variant of DL demonstrates classic myofibroblastic histology similarly seen in other myofibroblastic soft tissue tumors (Figure 1, A through D). The neoplastic myofibroblasts are spindle to stellate in shape, and sometimes are ganglion-like with rounded contours and eccentric nuclei. The cytoplasm is finely granular and amphophilic with well-delineated cytoplasmic borders, and the neoplastic cells are separated by collagen bundles. The nuclei are elongated with vesicular chromatin and 1 to 2 or more conspicuous central nucleoli. High-grade tumors are typically hypercellular and consist of atypical spindle cells and pleomorphic cells arranged haphazardly or in fascicles and have high mitotic rates and necrosis. 1,3,12,20 In a study of 115 DLs, Henricks et al 12 described low-grade tumors resembling desmoid-type fibromatosis as well as a tumor with myofibroblastic cells admixed with amianthoid fibers reminiscent of a myofibroblastoma. Subsequently, in a review of 32 DLs, Hasegawa et al 20 reported 3 tumors with myofibroblastic features, including one that resembled inflammatory fibrosarcoma. Their findings were further supported by smooth muscle actin and desmin expression in 44% of their DL cases and ultrastructural evidence of myofibroblastic differentiation in 2 tumors. Myofibroblastic DL with low-grade histology should be distinguished from desmoid-type fibromatosis, low-grade myofibroblastic sarcoma, and a reactive myofibroblastic proliferation. Dedifferentiated liposarcoma that resembles desmoid-type fibromatosis tends to be hypocellular and consist of bland spindle cells streaming through collagenous stroma. Unlike desmoid-type fibromatosis, however, myofibroblastic DL shows at least focal nuclear enlargement or atypical mitotic figures. Low-grade DL with higher cellularity may share striking similarities with low-grade myofibroblastic sarcoma, a tumor composed of fusiform spindle cells, often with minimal cytologic atypia, arranged in a storiform pattern or in fascicles. The stroma of myofibroblastic sarcoma is often collagenous with varying degrees of hyalinization. Myofibroblastic DL can also mimic a reactive, mass-forming myofibroblastic proliferation. Reactive processes such as the desmoplastic stroma of an unsampled carcinoma, carcinoid tumor or lymphoma, active scar tissue, wall of an organizing hematoma or abscess, ischemic/proliferative fasciitis, and exuberant fibrous adhesions may impart a fasciitis-like morphology with its fascicles of myofibroblasts and loose edematous stroma. Rapid growth, hypercellularity, reactive cytologic atypia, and high mitotic activity are common findings in reactive processes. For example, Yantiss et al 21 reported a series of reactive myofibroblastic proliferations mimicking primary neoplasms in the gastrointestinal tract. These lesions, termed reactive nodular fibrous pseudotumors by the authors, were associated with antecedent injury to the abdomen and consisted of a proliferation of histologically, immunohistochemically, and ultrastructurally benign myofibroblasts. All tumors in their series followed a benign clinical course with no progression or recurrence following resection. In 2010, we reported 6 cases of DL with inflammatory myofibroblastic tumor-like features (Figure 2, A through D). These tumors had variable areas resembling the 3 classic patterns described in IMT: myxoid, cellular, and hypocellular fibrous areas as well as areas closely resembling fibromatosis and nodular fasciitis. 4 Although well-characterized variants of atypical IMT are recognized, some with distinctive genetic alterations such as epithelioid IMT, 22 such tumors have overlapping features with DL with inflammatory myofibroblastoma-like features. Atypia in IMT is characterized by hypercellularity, fascicular architecture, nuclear pleomorphism, large ganglion-like cells, giant cells, atypical mitoses, and necrosis. Interestingly, Coffin et al 23 and Jiang et al 24 independently reported correlation between atypical features in IMT with negative ALK expression, recurrence, and metastasis. From their findings, Coffin et al 23 suggested that an ALK-negative spindle cell neoplasm occurring in an unusual site in an older adult should prompt alternative diagnostic considerations, including DL. More recently, Reagh et al 25 described a case of retroperitoneal DL that at initial presentation mimicked IMT with atypical features. From the evidence in current literature and from our own experience, we believe that most cases of atypical IMT and previously denoted inflammatory fibrosarcoma 26 represent unrecognized DL with inflammatory myofibroblastic tumor-like features. Finally, DL with inflammatory myofibroblastoma-like features can be mistaken for a fibrosclerosing lesion such as retroperitoneal fibrosis/igg4 disease in a limited biopsy sample. Differentiating DL from its myofibroblastic look-alikes can be very challenging. In some cases, especially in small biopsy specimens, DL can be morphologically indistinguishable from its mimics. Diagnosis should begin with a thorough review of the clinical history. Clinical information such as tumor size and location, patient age, and imaging characteristics, especially identification of a lipomatous component on imaging, may provide clues to the diagnosis. For example, DL with myofibroblastic differentiation, like conventional DL, has a predilection for the retroperitoneum and inguinal region of older patients. 4 By contrast, desmoidtype fibromatosis and IMT are uncommon in the retroperitoneum, while low-grade myofibroblastic sarcoma tends to occur in the extremities and more commonly affects children and young adults. The keys to diagnosing myofibroblastic DL in the absence of finding a well-differentiated liposarcomatous component are identifying enlarged cells with pleomorphic nuclei (which may be scattered), atypical mitotic figures, and MDM2 amplification or overexpression. Myofibroblastic DL can also be mistaken for a leiomyosarcoma owing to its frequent expression of smooth muscle actin and desmin (Figure 3, A and B), a distinction made by careful assessment of the cytologic features of the neoplastic cells and MDM2 amplification/overexpression. Histologically, a cellular and (usually) nonlipogenic sarcoma associated with a well-differentiated liposarcomatous component is diagnostic of DL, and this relationship denotes histologic progression in a WDL. In tumors where a well-differentiated component is not identified, however, DL can still be diagnosed by the detection of MDM Arch Pathol Lab Med Vol 142, October 2018 Myofibroblastic Dedifferentiated Liposarcoma Wang & Lucas

3 Figure 1. Grossly, the dedifferentiated component in this dedifferentiated liposarcoma with myofibroblastic features forms a firm, white mass (arrow) distinct from the larger, fatty, yellow well-differentiated component (A). Identification of a well-differentiated component (B) in association with a cellular and (usually) nonlipogenic sarcoma is diagnostic of dedifferentiated liposarcoma (DL), an indicator of histologic progression from a well-differentiated liposarcoma. The dedifferentiated component consists of myofibroblastic spindle cells with abundant finely granular, amphophilic, bipolar, and stellate cytoplasm; vesicular nuclei containing prominent nucleoli; and abundant extracellular collagenous stroma (C). MDM2 amplification by fluorescence in situ hybridization (FISH) confirms the histologic diagnosis in the absence of an identifiable well-differentiated component (D); FISH for MDM2 (red) and CEP12 (green) (hematoxylin-eosin, original magnification 3400 [B and C]; original magnification [D]). amplification via fluorescence in situ hybridization (FISH) or real-time polymerase chain reaction, 2,3,20 which is also true for myofibroblastic DL. Alternatively, MDM2 immunohistochemical stain can demonstrate overexpression at the protein level and is diagnostically useful in some cases. 2 4,8 TREATMENT AND PROGNOSIS The 5-year survival rate associated with DL is 20% to 40%. 27,28 The metastatic potential and overall survival associated with DL with myofibroblastic differentiation appears to be similar to that of conventional DL. 11,12 Until recently, low-grade DLs, most of which show myofibroblastic differentiation, have not been associated with better prognosis. 4,10,12 However, a recent study suggests a more aggressive clinical course for high-grade versus low-grade tumors. 13 The poor clinical outcome of DL can be attributed to its propensity to infiltrate locally, recur, and metastasize Complete surgical resection is the primary and a potentially curative treatment. However, this is often difficult to achieve owing to anatomic complexity, high tumor burden, and infiltration of surrounding structures and organs, all of which have been observed in myofibroblastic DL. 4 In general, preoperative and postoperative radiation therapy reduce the risk of local recurrence in DL, but does not appear to have significant benefit in overall survival The role of adjunctive chemotherapy remains controversial. 29,30,33,34 The recurrent oncogenic role of MDM2 and CDK4 in both WDL and DL prompted significant effort to develop targeted therapies. Several MDM2 antagonists and CDK4 inhibitors are now in the early stages of clinical trial. The efficacy of targeted therapy is still under investigation. 2 CONCLUSIONS Although underrecognized, prominent myofibroblastic differentiation is a relatively common occurrence within the broad histologic spectrum of DL. It consists of spindle, stellate, and ganglion-like cells with abundant amphophilic Arch Pathol Lab Med Vol 142, October 2018 Myofibroblastic Dedifferentiated Liposarcoma Wang & Lucas 1161

4 Figure 2. Dedifferentiated liposarcoma with inflammatory myofibroblastic tumor-like features has variable hypercellularity (A), hypocellularity resembling desmoid-type fibromatosis (B), and fasciitis-like features (C). The prominent inflammatory background consists of lymphocytes, plasma cells, and eosinophils (D) (hematoxylin-eosin, original magnifications 3200 [A] and 3400 [B through D]). Figure 3. Confirmation of myofibroblastic differentiation can be made by immunohistochemical reactivity for desmin (A) or smooth muscle actin (B) stains, which should not be misinterpreted as evidence of smooth muscle differentiation (immunoperoxidase, original magnification 3400) Arch Pathol Lab Med Vol 142, October 2018 Myofibroblastic Dedifferentiated Liposarcoma Wang & Lucas

5 cytoplasm, vesicular nuclei, and abundant, often inflamed fibrous stroma. Like conventional DL, myofibroblastic DL has a propensity to occur in the retroperitoneum and a high rate of local recurrence. Distinguishing it from its myofibroblastic mimickers such as desmoid-type fibromatosis, IMT (and atypical IMT), and reactive myofibroblastic lesions can be challenging. Immunohistochemistry for b-catenin and ALK, and FISH for MDM2 amplification can be very useful in such situations. Myofibroblastic DL can also be mistaken for a smooth muscle neoplasm owing to its frequent expression of smooth muscle actin and desmin. Pathologists should be aware of this variant of DL to avoid misdiagnosis. References 1. Evans HL. Liposarcoma: a study of 55 cases with a reassessment of its classification. Am J Surg Pathol. 1979;3(6): Lee ATJ, Thway K, Huang PH, Jones RL. Clinical and molecular spectrum of liposarcoma. J Clin Oncol. 2018;36(2): Thway K, Jones RL, Noujaim J, Zaidi S, Miah AB, Fisher C. 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