Lipoma

G.P. Nielsen N. Mandahl (WHO Blue Book)

Definition

Lipoma is a benign tumour composed of mature white adipocytes and is the most common soft tissue mesenchymal neoplasm in adults.

Epidemiology

Conventional lipoma occurs over a wide age range but is most common between the ages of 40 and 60 years and is more frequent in obese individuals. Lipomas are rare in children. Approximately 5% of patients have multiple lipomas. Sites of involvement Conventional lipoma can arise within subcutaneous tissue (superficial lipoma) or within deep soft tissues (deep lipoma) or even on the surfaces of bone (parosteal lipoma). Deep seated lipomas that arise within or between skeletal muscle fibres are called intramuscular or intermuscular lipomas, respectively. Intramuscular lipoma arises during mid to late adulthood and involves skeletal muscle in a variety of locations including the trunk, head and neck region, upper and lower extremities. Intermuscular lipoma arises between muscles most frequently in the anterior abdominal wall, and involves a similar age group as the intramuscular lipoma. So-called lipoma arborescens (villous lipomatous proliferation of synovial membrane) is characterized by fatty infiltration of the subsynovial connective tissue and may represent a reactive process.

Histopathology

Conventional lipoma is composed of lobules of mature adipocytes. The cells are identical to the surrounding adipose tissue except for slight variation in the size and shape of the cells in lipomas. Lipomas can occasionally have areas of bone formation (osteolipoma), cartilage (chondrolipoma), abundant fibrous tissue (fibrolipoma), or extensive myxoid change (myxolipoma). Intramuscular lipoma may be either well demarcated from the surrounding skeletal muscle or, more often, shows an infiltrative growth pattern with mature adipocytes infiltrating and encasing skeletal muscle fibres that often show evidence of atrophy. In lipoma arbor-escens the subsynovial connective tissue is infiltrated by mature adipocytes; scattered inflammatory cells are also usually present.

Immunophenotype

Mature adipocytes stain for vimentin, S100 protein and leptin.

Ultrastructure

Lipoma is composed of cells that have a large, single lipid droplet compressing a peripherally situated nucleus.Pinocytotic vesicles are present and external lamina is seen surrounding the cells.

Clinical features

Lipomas usually present as a painless soft tissue mass, except for larger ones that can be painful when they compress peripheral nerves. Superficial lipomas are generally smaller (<5cm) than the deep seated ones (>5cm). Patients with lipoma arborescens are usually adult men that complain of gradual swelling of the affected joint. Imaging studies show a homogeneous soft tissue mass that is isodense to the subcutaneous tissue and demonstrates fat saturation. Attenuated fibrous strands can be seen but they are not as prominent as seen in the atypical lipomas. Intramuscular lipomas are more variably circumscribed, and lipoma arborescens shows diffuse fatty infiltration of the synovium.

Aetiology

Unknown. Lipomas are more common in obese individuals.

Macroscopy

Grossly, lipomas are well circumscribed and have a yellow, greasy cut surface. Different types are basically similar in appearance, however bone formation can be seen in osteolipoma and grey glistening nodules may be seen in chondrolipoma. Intramuscular and intermuscular lipoma do not show any specific gross features except that a portion of skeletal muscle is often attached to the periphery of the tumour. In lipoma arborescens the entire synovium assumes a nodular and papillary appearance and has a bright yellow cut surface.

Genetics

Cytogenetics Lipomas have been analysed extensively by chromosome banding. In larger cytogenetically investigated series, chromosome aberrations have been found in 55-75% of the cases. Among the abnormal tumours, about 75% show seemingly balanced karyotypes and in more than 50% there is a single abnormality in at least one clone. On average, signs of clonal evolution is found in every sixth tumour. Numerical chromosome changes are rare and randomly distributed, and chromosome numbers deviating from 46 are exceedingly rare. The pattern of cytogenetic aberrations is quite heterogeneous, but three cytogenetically defined subgroups have been distinguished: 1) the major subgroup consisting of tumours with aberrations involving 12q13-15, 2) tumours with aberrations involving 6p21- 23, and 3) tumours with loss of material from 13q. Patients with and without aberrations of 12q13-15 show no differences with respect to age distribution and gender. The frequency of abnormal karyotypes seems to be higher among older patients. Otherwise, no clear, consistent correlations between clinical and cytogenetic data have been identified. Tumours with 12q13-15 aberrations About two-thirds of tumours with abnormal karyotypes show aberrations of 12q13-15, which has been found to recombine with a large number of bands in all chromosomes except 16 and Y. The preferred rearrangement, seen in more than 20% of tumours with 12q13-15 aberrations, is t(3;12)(q27-28;q13-15). Other recurrent recombination partner regions, present in 3-7% of these tumours, are 1p36, 1p32-34, 2p22-24, 2q35-37, 5q33, 11q13, 12p11-12, 12q24, 13q12-14, 17q23-25, and 21q21-22. The majority of these aberrations originate through translocations or insertions. One in six of these tumours show more or less complex intrachromosomal rearrangements - including primarily inversions, but also deletions and duplications - leading to recombination between 12q13-15 and other segments of chromosome 12, primarily 12p11-12 and 12q24. Tumours without 12q13-15 aberrations Among these tumours, constituting onethird of lipomas with acquired chromosome aberrations, all chromosomes except 20 have been involved, but the only distinct clustering of breakpoints seen is to 6p21-23, 13q11-22, and, less often, 12q22-24, together constituting about half of this group of tumours. Involvement of 6p21-23, mostly in the form of seemingly balanced translocations, has been found in more than 20% of these tumours. The only recurrent translocation partner has been 3q27-28 in two cases. Aberrations affecting the long arm of chromosome 13 are dominated by deletions, which have been found in slightly less than 20% of the cases. Most aberrations are interstitial deletions with breakpoints in 13q12-14 and 13q22, respectively. There is an overlap between 6p21-23 rearrangements and 13q deletions, with some tumours showing both aberrations, but more often these aberrations occur as sole anomalies. Simultaneous involvement of 6p21-23 and 12q13-15 is uncommon, in contrast to the coexistence of 12q13-15 aberrations and 13q losses. In tumours with combinations of 6p, 12q, and 13q aberrations, 13q is mostly involved in balanced translocations when recombining with 6p21-23 or 12q13-15, whereas deletions in 13q are predominating when aberrations of 6p21-23 or 12q13-15 are present but recombine with other chromosome segments. Among tumours without rearrangements of 12q13-15 or 6p21-23 or loss of 13q sequences, one-fifth of the breakpoints coincide with those recurrently recombining with 12q13-15.

Molecular genetics

The HMGIC (a.k.a. HMGA2) gene, encoding a family member of the high mobility group of proteins, located in 12q15 is affected in at least some lipomas with rearrangements of 12q13-15 {90,1890}. In tumours with t(3;12)(q27- 28;q13-15), the consequence at the molecular level is the formation of a fusion gene involving HMGIC and LPP in 3q27-28, a member of the LIM protein gene family {1696}. In addition, this fusion gene has been observed in a few cases with complex karyotypic changes including 12q13-15 but not 3q27-28 and in cases with normal karyotypes, indicating that cytogenetic analysis underestimates the frequency of tumours with recombination between these two chromosome segments. In all cases, the chimeric HMGIC/LPP transcript is expressed, whereas the reciprocal LPP/HMGIC transcript is expressed only occasionally. Alternative fusion transcripts, encoding the three DNA binding AT-hook domains of HMGIC and two or three LIM domains of LPP have been reported, thus excluding the 3´ acidic, protein-binding domain and the N-terminal leucine-zipper motif, respectively. The preferred breakpoints are in the large intron 3 of HMGIC and LPP intron 8. The chimeric transcript is not unique for lipomas of the soft tissues but has also been detected in parosteal lipoma and pulmonary chondroid hamartoma. Rearrangement of HMGIC has been detected also in tumours with changes involving 12q13-15 and other chromosome segments. In a single case of lipoma with t(12;13)(q13-15;q12), an HMGIC/LHFP fusion transcript has been reported. Also in this case, the breakpoint was in HMGIC intron 3. In lipomas with recombination between 12q13-15 and 12p11, due to inversion, fusion of putative but yet unidentified gene sequences in 12p11 with HMGIC was found {1081}, and ectopic sequences mapping to chromosome 15 have been implicated. Possibly, the related HMGIY (HMGA1B) gene is the target, directly or indirectly, in lipomas with 6p21-23 aberrations; split FISH signals, using probes covering HMGIY, have been reported in cases with translocations involving 6p. Transcriptional activation of HMGIC or HMGIY is indicated by immunohistochemical studies, and correlates well with cytogenetic findings of breakpoints in the regions where these two gene loci are located.

Prognostic factors

The subclassification of conventional lipoma does not have any prognostic significance except for the infiltrating intramuscular lipoma that has a higher local recurrence rate, therefore total removal of the involved muscle or a compartmental resection has been suggested for these infiltrating tumours in order to minimize local recurrence.

Selected Abstracts on Synovial Lipoma