Dedifferentiated Liposarcoma With Myofibroblastic Differentiation Open Access

Dedifferentiated liposarcoma typically presents in middle-aged 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 

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 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.^9–19  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 al¹²  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 al²⁰  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 al²¹  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 al²³  and Jiang et al²⁴  independently reported correlation between atypical features in IMT with negative ALK expression, recurrence, and metastasis. From their findings, Coffin et al²³  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 al²⁵  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 fibrosarcoma²⁶  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, desmoid-type 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 MDM2 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 

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.^27–29  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,^27–29  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.^30–32  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 

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 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 β-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.