Atypical lipomatous tumor (ALT) is a mesenchymal neoplasm derived from adipocytes. Diagnosis of ALT can be challenging because the histopathologic features mimic those of benign lipoma. Here, we report a case of ALT initially diagnosed as lipoma that recurred and was finally diagnosed as ALT by the use of immunohistochemical staining.

A 53-year-old woman presented with a subcutaneous mass on the left side of her trunk. She had had a history of surgery to remove a mass in the same location 6 years previously (Fig. 1A). Before the initial surgery, T2-weighted magnetic resonance imaging (MRI) showed a 7.4 × 4.6 × 3.2-cm mass within the left latissimus dorsi, and the mass showed low intensity on T1-fat suppression (Fig. 1B). The mass was resected, and the surgical specimen showed mature adipocytes without atypia (Fig. 1C), resulting in the diagnosis of lipoma. Six years after the resection, she noticed a 10-cm subcutaneous mass in the same area (Fig. 1D). MRI revealed a T2-high tumor adjacent to the latissimus dorsi, encompassing a low-signal area (Fig. 1E). Histopathologic analysis of the resected specimen revealed variously sized mature adipocytes and septal walls composed of irregularly proliferating collagen fibers with spindle-shaped atypical cells (Figs. 1F, G). Immunohistochemical analysis revealed that the stromal cells were positive for MDM2, CDK4, and p16, while the adipocytes were positive for p16 and negative for MDM2 and CDK4 (Figs. 1H-J). Finally, we diagnosed ALT. To re-evaluate the initial diagnosis, we retrospectively conducted immunohistochemical staining of the initially resected specimen. The results showed positivity of the stromal cells for MDM2 and of both the stromal cells and the adipocytes for p16, which is commonly seen in ALT (Figs. 1K-M); thus, we reclassified the tumor as ALT.

ALT is histologically characterized by fibrous septa containing atypical stromal cells with mature adipocytes, whereas lipoma shows mature and uniform adipocytes without atypia. In our case, the recurrent tumor showed spindle-shaped atypical cells in fibrous stroma, consistent with ALT. By contrast, the initial tumor was composed of mature adipocytes without fibrous stroma, leading to the diagnosis of lipoma. Vargas et al reported cases of ALT initially diagnosed as lipoma because of a lack of cytologic atypia shown by routine hematoxylin-eosin (HE) staining of the specimen. However, these cases were reclassified as ALT because of the presence of MDM2 amplification. Therefore, these cases show that diagnosis of ALT by the use of HE staining alone is difficult.

ALT commonly harbors amplifications of MDM2, CDK4, and/or p16. MDM2 promotes cell growth by acting as an E3 ubiquitin ligase that recognizes the N-terminal transactivation domain of the p53 tumor suppressor protein, resulting in inhibition of p53 transcriptional activity. However, since MDM2 is a factor involved in cell proliferation, MDM2 is expressed not only in tumor cells but also in inflammatory cells, such as histiocytes in ALT. To distinguish lipoma and ALT, it is necessary to evaluate not only MDM2 but also CDK4 and p16 in combination.

CDK4 plays a role in phosphorylation of Rb protein, which is a negative regulator of the cell cycle. Phosphorylation of Rb causes activation of E2F, which leads to cell cycle progression.p16 primarily functions in cell-cycle control as a negative regulator through inhibition of CDK4 function. While p16 is expressed in both lipoma and ALT, p16 positivity is more prevalent in ALT than in lipoma -- 90% as compared with 32%. Presuming that p16 turns to be positive in ALT, overexpression of p16 might be triggered by an increase in levels of CDK4 as a counterpart to cell proliferation. However, the inhibitory function of p16 is bypassed or counteracted by other proteins, such as aberrant SEI-1 expression or expression of viral Tax protein in the host cells on HTLV-1 infection. Therefore, cell transformation and aberrant cell proliferation can occur even in the presence of elevated p16. Given that these molecules are not exclusively expressed in malignant tumors, a combined immunohistochemical analysis of these molecules might help to differentiate ALT from lipoma.

After 6 years of follow-up, the recurrent tumor in this case exhibited positive conversion for CDK4 and MDM2. MDM2 fluorescence in situ hybridization (FISH) should be considered as a diagnostic tool for ALT in equivocal lipomatous tumor cases, particularly for tumors developing in the retroperitoneum, pelvis, abdomen, or extremities and measuring greater than 10.0 cm in individuals aged 50 years or older. FISH analysis could not be performed in our case because of a lack of specialized equipment and facilities. The transformation of a tumor, initially without atypia but shown to be positive for p16 by immunohistochemical staining, into a CDK4-positive and MDM2-positive ALT suggests that immunohistochemical staining may be a viable method for distinguishing ALT from lipomas in resource-limited facilities.