Case 1 -

Well Differentiated Liposarcoma (Atypical Lipoma) Scott Kilpatrick

Clinical History: The patient is a 31-year-old female with a soft tissue mass involving her left arm. Diagnosis: Well Differentiated Liposarcoma (Atypical Lipoma) Well differentiated liposarcoma (WDL) is synonymous with the designation "atypical lipoma" referring to an adult low grade sarcoma that may locally recur but, in the absence of dedifferentiation, will not metastasize. In the past, the designation of "atypical lipoma" was generally reserved for superficially-located lesions. However, several examples of such lesions have recently been described having undergone dedifferentiation. [1, 2] Furthermore, cytogenetic analysis has revealed ring and giant marker chromosomes in the majority of these atypical lipomatous tumors, regardless of anatomic origin (e.g. subcutaneous vs. intramuscular). [3] For these reasons, it is probably best to diagnose all such lesions as "well differentiated liposarcoma." The classification of WDL includes at least 3 subtypes: lipoma-like, sclerosing, and inflammatory variants. For the purposes of this discussion, we will focus on the more common lipoma-like variant. Histologically, WDL may have areas indistinguishable from ordinary lipoma. Meticulous sampling is sometimes necessary to establish (as well as exclude) the diagnosis, especially among deeply-seated fatty tumors of the extremities or retroperitoneum. At low power, helpful diagnostic clues include heterogeneity of size and shape of individual the adipocytes, an increased amount of non-lipomatous fibrous tissue, and the presence of atypical, stromal cells with enlarged and hyperchromatic nuclei. Multi-nucleated giant stromal cells are randomly distributed throughout the lesion, but their absolute numbers tend to vary from case to case. Classic multi-vacuolated lipoblasts are less commonly observed and not required for the diagnosis. The differential diagnosis for WDL includes conventional lipomas, especially those that have features of fat necrosis or degenerative changes. Careful inspection of the aforementioned features usually avoids a misdiagnosis. Spindle cell lipoma and pleomorphic lipoma, considered to represent the end points of a spectrum of a similar entity, also need to be considered. Spindle cell/pleomorphic lipomas (SLPL) typically occur in older men (>50 years of age) and almost exclusively involve the superficial soft tissues of the shoulder, posterior neck, face and head. [4, 5] Most consider the clinical setting of SLPL to be relatively specific for this entity. Fatty tumors with similar morphology but occurring in younger age groups or different anatomic locations (e.g. lower extremities) are best considered atypical lipomas/WDL, as their biologic behavior and karyotypic abnormalities tend to support this conclusion. [6] SLPL show a mixture of mature-appearing adipose tissue and a distinctive, non-lipogenic component, usually associated with collagen fiber bundles and a variably myxoid stroma. The cell population ranges from a bland and uniform-appearing spindle cell population (spindle cell lipoma) to atypical, multi-lobated to multi-nucleated giant cells with hyperchromatic nuclei (pleomorphic lipoma), or mixtures of the above cell types. Scattered giant cells of pleomorphic lipoma characteristically exhibit peripherally-located nuclei arranged radially around the more central cytoplasm, so-called floret cells. Rarely, SLPL contains abundant vascularity and slit-like cleaves, suggesting angiosarcoma or angiolipoma (pseudoangiomatous variant). Immunohistochemically, the spindled and pleomorphic cells appear diffusely and strongly positive for CD34; S-100 positivity is rarely seen. [7] In the majority of cases, cytogenetic analysis reveals monosomy or partial loss of segments in chromosomes 13 and/or 16. Losses of 16q13 and 13q12 appear to be the most frequent events. [8] A significant proportion of WDL may undergo a process of "dedifferentiation," implying transformation to a higher grade nonliposarcomatous sarcoma. By definition, the diagnosis of dedifferentiated liposarcoma is justified by either the presence of WDL juxtaposed to a nonliposarcomatous sarcoma or the development of a high grade nonliposarcomatous sarcoma in the region of a previously excised WDL. For this reason, I always instruct our residents to sample the adjacent soft tissue immediately surrounding all adult sarcoma cases. Histologically, the high grade component usually manifests as a non-descript spindle cell or pleomorphic sarcoma but rarely may exhibit heterologous differentiation (e.g. leiomyosarcoma, rhabdomyosarcoma, osteosarcoma, etc.). Because the diagnosis of dedifferentiated liposarcoma depends upon the finding of both low and high grade components, it is usually not possible to render a specific diagnosis of dedifferentiated liposarcoma on fine needle aspiration biopsy (FNAB) or core needle biopsy specimens. In my experience, only the high grade component is generally sampled and the diagnosis of pleomorphic sarcoma, not otherwise specified, is rendered. A rather controversial area is the existence of a so-called low grade form of dedifferentiated liposarcoma. Henricks et al. [9] documented 14 cases of pure "low grade" dedifferentiated liposarcoma with the dedifferentiated areas resembling fibromatosis or well differentiated fibrosarcoma. Of the 12 patients with clinical follow-up, 8 developed local recurrences and 3 had metastases. The low grade group had a slightly better survival compared to the high grade form, but it was not statistically significant. Recently, Evans questioned this concept. [10] The original definition of dedifferentiation required that the nonlipogenic component possess at least 5 mitotic figures per 10 high power fields. Such tumors lacking the latter criteria but having areas of increased cellularity were referred to by Evans as "cellular atypical lipomatous tumor." Most of what Henricks et al. [9] had accepted as low grade dedifferentiation did not qualify for "dedifferentiation" by Evans' criteria. In Evans series, the clinical behavior was not significantly different among conventional versus the cellular form of well differentiated liposarcoma. [10] Evans' proposal expands the definition of well differentiated liposarcoma to also include myxoid liposarcoma-like and myxoid MFH-like forms that have mitotic rates below the defined threshold of 5/10 high power fields. Cytogenetic analysis has revealed that such tumors demonstrate ring or giant marker chromosomes rather than the t(12;16) characteristic of myxoid liposarcoma. [3, 8, 11] In virtually all studies, the prognosis of dedifferentiated liposarcoma is most strongly linked to anatomic site, with tumors arising centrally (e.g. retroperitoneum) behaving much more aggressively. Yoshikawa H, Ueda T, Mori S, et al. Dedifferentiated liposarcoma of the subcutis. Am J Surg Pathol 1996;20:1525-1530. McCormick D, Mentzel T, Beham A, et al. Dedifferentiated liposarcoma: clinicopathologic analysis of 32 cases suggesting a better prognostic subgroup among pleomorphic sarcomas. Am J Surg Pathol 1994;18:1213-1223. Rosai J, Akerman M, Dal Cin P, et al. Combined morphologic and karyotypic study of 59 atypical lipomatous tumors: evaluation of their relationship and differential diagnosis with other adipose tumors. A report of the CHAMP study group. Am J Surg Pathol 1996;20:1182-1189. Fletcher CDM, Martin-Bates E. Spindle cell lipoma: a clinicopathological study with some original observations. Histopathology 1987;11:803-817. Shmookler BM, Enzinger FM. Pleomorphic lipoma: a benign tumor simulating liposarcoma. A clinicopathologic analysis of 48 cases. Cancer 1981;47:126-133. Allen PW, Strungs I, MacCormac LB. Atypical subcutaneous fatty tumors: a review of 37 referred cases. Pathology 1998;30:123-135. Suster S, Fisher C. Immunoreactivity for the human hematopoietic progenitor cell antigen (CD34) in lipomatous tumors. Am J Surg Pathol 1997;21:195-200. Fletcher CD, Akerman M, Dal Cin P, et al. Correlation between clinicopathological features and karyotype in lipomatous tumors. A report of 178 cases from the chromosomes and morphology (CHAMP) collaborative study group. Am J Pathol 1996;148:623-630. Henricks W, Chu YC, Goldblum JR, et al. Dedifferentiated liposarcoma: a clinicopathological analysis of 155 cases with a proposal for an expanded definition of dedifferentiation. Am J Surg Pathol 1997;21:271-281. Evans HL. Atypical lipomatous tumor, its variants, and its combined forms: a study of 61 cases, with a minimum follow-up of 10 years. Am J Surg Pathol 2007;21:1-14. Hisaoka M, Morimitsu Y, Hashimoto H, et al. Retroperitoneal liposarcoma with combined well-differentiated and myxoid malignant fibrous histiocytoma-like areas. Am J Surg Pathol 1999;23:1480-1492.