Abstract
Atypical lipomatous tumor (ALT) is an intermediate (locally aggressive) mesenchymal neoplasm with the potential to dedifferentiate to higher grades over time. It is cytogenetically characterized by the presence of one or more supernumerary ring and giant marker chromosomes. These abnormal chromosomes invariably contain amplified sequences derived from the 12q14-15 region. We describe a unique cytogenetic finding of ALT arising in the right lower back of a 42-year-old man. Magnetic resonance imaging demonstrated a predominantly fatty mass with irregularly thickened, linear, swirled, and nodular septa. Contrast-enhanced fat-suppressed T1-weighted images showed significant enhancement of the non-adipose areas. A sub-extensive resection was performed. Histologically, the tumor consisted predominantly of mature fat cells with atypical stromal cells and multivacuolated lipoblasts. Immunohistochemically, the tumor cells were positive for p16 (diffuse and strong signal) and cyclin-dependent kinase-4 (focal and weak signal) but negative for murine double-minute 2. Cytogenetic analysis displayed a t(3;8)(q28;q13) translocation as the sole anomaly or concomitant with a few other numerical and structural alterations. There has been no evidence of local recurrence two months after surgery. To the best of our knowledge, this is the first case of ALT with structural aberrations involving chromosomes 3 and 8, associated with an absence of 12q rearrangements.
Atypical lipomatous tumor (ALT) is a locally aggressive mesenchymal neoplasm composed either entirely or in part of a mature adipocytic proliferation exhibiting at least focal nuclear atypia in adipocytes or stromal cells. It occurs most frequently in the deep soft tissue of the limbs but may also arise in the subcutaneous tissue (1). ALT usually presents as a painless, slowly-growing mass that can attain a very large size. Three main histological subtypes of ALT are recognized: adipocytic (lipoma-like), sclerosing, and inflammatory (1). Immunostaining for p16, cyclin-dependent kinase-4 (CDK4), and murine double-minute-2 (MDM2) has recently been shown to be a highly sensitive and specific means of distinguishing ALTs from other adipocytic tumors (2). The cytogenetic hallmark of ALT is the presence of one or more supernumerary ring and giant marker chromosomes (3). These supernumerary chromosomes consistently contain amplified material from chromosome 12 (4). A few cases of ALT with other types of chromosomal aberrations have been reported (5, 6). In this article, we describe a unique cytogenetic finding of subcutaneous ALT occurring in the lower back of a middle-aged man.
Case Report
A 42-year-old man presented with a painless mass in the right lower back. The patient's past medical history was unremarkable. Physical examination revealed an 11-cm, soft, mobile, non-tender mass. Neurovascular examinations were unremarkable. Laboratory values were within normal ranges. Magnetic resonance imaging (MRI) showed a well-circumscribed, subcutaneous mass, measuring 11×7×3 cm. The mass exhibited predominant signal intensity of fat with multiple thick septa and several nonadipose areas of intermediate signal intensity on T1- and T2-weighted images (Figure 1A and B). Contrast-enhanced fat-suppressed T1-weighted images (Figure 1C) demonstrated significant enhancement of the nonadiposal areas. Based on these features, ALT was considered.
A sub-extensive resection was performed. Microscopically, the tumor was composed chiefly of mature fat cells with a variable number of atypical stromal cells and multivacuolated lipoblasts (Figure 2A and B). Immunohistochemically, the tumor cells were diffusely and strongly positive for p16 (Figure 2C) and focally and weakly for CDK4 (Figure 2D) but negative for MDM2. The histological findings were compatible with ALT.
Axial magnetic resonance images of atypical lipomatous tumor involving the right lower back. T1- (A) and T2- (B) weighted images exhibiting a largely lipomatous subcutaneous mass with prominent thick septa and several nonadipose areas. Contrast-enhanced fat-suppressed T1-weighted image (C) shows significant enhancement of the non-adiposal areas.
Cytogenetic analysis showed a reciprocal translocation involving the long arms of chromosomes 3 and 8 (Figure 3). The karyotype was as follows: 46,XY,t(3;8)(q28;q13)[1]/44,idem,-10,-13,add(16)(q11.2)[17]/46,XY[2].
The postoperative course was uneventful, and the patient is doing well without local recurrence two months after surgery.
Discussion
Cytogenetic analysis of adipocytic tumors has shown that the various histologic subtypes are characterized by distinctive clonal chromosomal aberrations (3). Ordinary lipomas typically display translocations involving the 12q13-15 region. The most frequent translocation is t(3;12)(q27-28;q13-15) (7). Lipoblastomas are characterized by 8q11-13 rearrangements (8). ALTs are characterized by the presence of one or more supernumerary ring and giant marker chromosomes (3-5). Fluorescence in situ hybridization and comparative genomic hybridization studies have shown that these supernumerary chromosomes always contain amplified sequences of the 12q14-15 region, including the CDK4 and MDM2 genes (4). A variety of other chromosomal regions, including 12q21-22 and 1q21-25 for the most frequently involved, have also been shown to be co-amplified in these supernumerary chromosomes (5).
In the present case, we did not identify any supernumerary ring or giant marker chromosomes containing 12q amplification or any other chromosome 12 rearrangements. Instead, we observed a t(3;8)(q28;q13) translocation as the sole anomaly or concomitant with a few other numerical and structural alterations. This reciprocal translocation is not usual in ALTs. Cytogenetic changes of 3q27-28 are found in a subset of ordinary lipomas. The lipoma preferred partner (LPP) gene, located at 3q28, plays a crucial role in the pathogenesis of ordinary lipomas (7). On the other hand, structural rearrangements of 8q11-13 are seen in almost all lipoblastomas (8). The pleomorphic adenoma gene 1 (PLAG1) gene, located at 8q12, is the target of the 8q rearrangements (7). Only one case of ALT with 8q11 rearrangement resulting in PLAG1 rearrangement has been described (9). Brandal et al. reported that the sensitivity of 8q11-13 rearrangements for diagnosing lipoblastomas when found in an adipocytic tumor was 77% and the corresponding specificity was 98% (9). Although the finding of 8q13 rearrangements had led to a revision of the diagnosis, the ALT diagnosis was histologically quite certain.
Deletions and structural rearrangements of chromosome 13 are frequently detected in adipocytic tumors, including ALT (10). In the present case, we observed monosomy 13. Dahlén et al. suggested that deletions of a limited segment within 13q14 may play an important role in the development of a subset of adipocytic tumors (10). Recent single nucleotide polymorphism array analyses have revealed that only the chromosome 13 open reading frame 1 (C13orf1) gene is significantly down-regulated in ordinary lipomas and spindle cell lipomas with 13q14 deletions (11).
p16/CDKN2A, located at 9p21, is a tumor-suppressor gene and encodes for a nuclear protein that can block cell-cycle progression by effectively inhibiting the kinase activity of CDK4/6. Although its precise role remains unknown, overexpression has been shown in ALT relative to normal fat (12). A recent study has shown that immunostaining for p16 is effective in distinguishing ALTs from ordinary lipomas, which do not overexpress this protein (13). More recently, Thway et al. reported that p16 was the most sensitive and specific marker for detecting ALT (2). In the present case, diffuse and strong nuclear staining for p16 was observed, strongly supporting a diagnosis of ALT. On the other hand, overexpression of MDM2 and CDK4 has also been indentified in ALTs (2, 14). The present case failed to show MDM2 immunopositivity and revealed very weak expression of CDK4. Generally, gene amplification is the main mechanism of overexpression of MDM2 and CDK4 in soft tissue tumors. We speculate that these findings may be correlated with the absence of any supernumerary ring and giant marker chromosomes containing 12q amplification.
Histological and immunohistochemical findings of atypical lipomatous tumor. A: The tumor consists predominantly of mature fat cells showing marked variation in cell size (H&E staining, original magnification ×40). B: Atypical, hyperchromatic stromal cells are also found (H&E staining, original magnification ×100). Immunohistochemically, the tumor cells are diffusely and strongly positive for p16 (C) and focally and weakly positive for CDK4 (D) (C and D, original magnification ×100).
A representative G-banded karyotype of atypical lipomatous tumor displaying a t(3;8)(q28;q13) translocation (arrows).
In summary, we believe that we have described the first case of ALT with structural rearrangements involving chromosomes 3 and 8. The present case did not show any of the chromosomal features usually described in ALTs, such as supernumerary ring or giant marker chromosomes. Further studies are required to elucidate the role of this rare translocation in the pathogenesis of ALT.
Acknowledgements
This study was supported in part by the Foundation for the Promotion of Medical Science and JSPS KAKENHI Grant Number 25462355.
- Received February 25, 2014.
- Revision received April 29, 2014.
- Accepted April 30, 2014.
- Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
