Liposarcomas are the most common subtype of soft tissue sarcomas, accounting for at least 20% of all sarcomas in adults. Soft tissue sarcomas are rare neoplasms with over 150 different histological subtypes or forms. Liposarcomas arise from the precursor lipoblasts of the adipocytes (i.e. fat cells) in adipose (i.e. fat) tissues. Adipose tissues are distributed throughout the body, including such sites as the deep and more superficial layers of subcutaneous tissues as well as in less surgically accessible sites like the retroperitoneum (i.e. space behind the abdominal cavity) and visceral fat inside the abdominal cavity.
All liposarcomas consist of at least some cells that bear a resemblance to fat cells when examined for their histopathologic appearances under a microscope. However, the liposarcomas do have several forms based on differences in their clinical presentations (e.g. ages, gender preferences, sites of tumors, signs, and symptoms), severities (i.e. potential to invade local tissues, recur after surgical removal, and metastasize to distal tissues), genetic abnormalities, prognoses, and preferred treatment regimens. The World Health Organization in 2020 reclassified liposarcomas into five more or less distinct forms: 1) atypical lipomatous tumor/well-differentiated liposarcoma (WD-LPS); 2) dedifferentiated liposarcoma (DD-LPS); 3) myxoid liposarcoma; 4) pleomorphic liposarcoma; and 5) myxoid pleomorphic liposarcoma. (Pleomorphic indicates the presence of cells that have abnormal and often large variations in their size and shape and/or the size and shape of their nuclei.)
While liposarcoma forms are classified as being aggressive and malignant or, in the case of the atypical lipomatous tumor/well-differentiated liposarcoma, as relatively non-aggressive and benign, all five liposarcoma forms can infiltrate locally to injure nearby tissues and organs, occur in surgically inaccessible sites adjacent to vital organs (e.g. the retroperitoneum), recur after surgical removal, and progress to life-threatening diseases. Studies to date find that all five liposarcoma forms, while usually treatable at least initially by surgical resection, are often only marginally responsive to currently used chemotherapy and radiotherapy regimens. The liposarcomas require a wide range of further studies to determine their responsiveness to various radiotherapy, chemotherapy, and more novel treatment regimens as used individually and in various combinations that would include, where possible, surgical removal.
Etymology "fatty tumor" (plural lipomata), 1830, medical Latin, from Greek lipos "fat" (n.), from PIE root *leip- "to stick, adhere", also used to form words for "fat", + -oma.
1650s, "fleshy excrescence", (plural liposarcomata), Medical Latin, from Latinized form of Greek sarkoma "fleshy substance" (Galen), from sarkoun "to produce flesh, grow fleshy", from sarx (genitive sarkos) "flesh", + -oma.
Forms of liposarcomas
Liposarcomas are generally large tumors (>10 cm) but can be of almost any size. They occur mainly in adults with only 0.7% of cases occurring in those <16 years old. In adults, liposarcomas occur predominantly in and after middle-age. The very rare cases occurring in children and adolescents are diagnosed predominantly as being the myxoid liposarcoma form.
The five liposarcoma forms must be distinguished not only from each other but also from certain other soft tissue tumors. These other tumors along with some of their distinguishing histopathologic features are: 1) dysplastic lipomas (i.e. benign tumors that have sites of tissue necrosis and neoplastic, variably sized fat cells containing variable sized/shaped nuclei; these neoplastic cells, unlike most neoplastic cell in the liposarcomas, do not overexpress the MDM2 gene); 2) atypical spindle cell lipomas (i.e. benign tumors with mildly atypical spindle-shaped cells in a fibrous-to-myxoid stroma intermixed with vacuolated lipoblasts and variable-sized adipocytes with atypical nuclei; 3) pleomorphic lipomas (i.e. benign tumors characterized by giant cells with overlapping nuclei); and 4) solitary fibrous tumors (i.e. tumors, up to 22% of which exhibit malignant behavior, consisting of spindle- or ovoid-shape cells within a collagenous background stroma intermixed with blood vessels with a characteristic staghorn shape).
Atypical lipomatous tumor/well-differentiated liposarcoma Together, atypical lipomatous tumors (ALTs) and well-differentiated liposarcomas (WDLs) account for 4045% of all liposarcomas. They rarely if ever metastasize and therefore are regarded as benign or premalignant tumors. However, they are locally invasive and may transform to a more aggressive and potentially metastasizing liposarcoma, i.e. a dedifferentiated liposarcoma. Furthermore, a surgically removed atypical lipomatous tumor/well-differentiated liposarcoma may recur as a dedifferentiated liposarcoma.
Presentation
ALTs and WDLs are considered virtually identical tumors except that by definition ALTs designate tumors that develop in the arms or legs while WDLs designate tumors that develop in less surgically accessible sites such as the deep, centrally located soft tissues of the retroperitoneum, paratesticular region (i.e. area within the scrotum including the testes, spermatic cord, testicular tunic, epididymis, and appendix of testis), oral cavity, and eye socket. This terminology has prognostic implications: less than 7% of ALT tumors convert to dedifferentiated liposarcomas within a median time of 7 years while 17% of WDL tumors convert to this more malignant liposarcoma within a median time of 8 years. ALT and WDL (hereafter termed ALT/WDL) tumors typically present in middle-aged and older individuals as slowly enlarging masses that tend to be larger and at a more advanced stage when located in deep tissues. These tumors usually are not painful and if located superficially, readily apparent; they can also cause extensive edema (i.e. swelling due to the local accumulation of fluid) in involved areas such as the thigh (see adjacent figure) due to their invasion into the blood and/or lymphatic vessels draining the tumor's site. Deep-seated ALT/WDL tumors may be asymptomatic but, depending on their location, produce serious signs and/or symptoms of disfunction in any one of the various organs which they infiltrate. These organs include those close to or in the retroperitoneum (e.g. intestines, kidney, and the kidney's ureters); the paratesticular region; the mediastinum (e.g. trachea and lung's major bronchi); and the head (e.g. the retrobulbar space behind the globe of the eye).
Pathology
Histopathologically, ALT/WDL tumors are divided into adipocytic/lipoma-like, sclerosing, and inflammatory variants with adipocyte/lipoma-like being the most common. Adipocytic/lipoma-like ALT/WDL tumors consist of lobules of mature fat cells variably intersected with irregular fibrous septa (see the adjacent H&E stained photomicrograph). Sclerosing ALT/WDL tumors, the second most common variant, develop primarily in the retroperitoneal and paratesticular areas; it consists of scattered, atypical stromal cells within a collagenous (i.e. collagen-containing) stromal tissue background. Rare vacuole-containing lipoblasts populate this tissue. Inflammatory ALT/WDL tumors are the rarest variant. they occur most frequently in the retroperitoneum and consists of chronic inflammatory cells, e.g. lymphocytes and plasma cells plus occasional lymph node-like follicles interspersed throughout a tissue background containing fat cells.
Genetics The neoplastic cells in ALT/WDL tumors contain one or more extra ring-shaped small supernumerary marker chromosome (sSMC) or an abnormal giant marker chromosome (i.e. a formerly normal chromosome that is made abnormal by having a duplication of parts of its own or one or more other chromosome's genetic material). These abnormal chromosomes contain extra copies of chromosome 12's long arm (also termed the q arm) at bands 13 through 15. This stretch of chromosome 12 includes the MDM2 proto-oncogene (a potentially tumor-causing gene when overexpressed) located at band 15 and CDK4 (a gene that when overexpressed promotes the development of various tumors) located at band 14.1. The amplification (i.e. increased copies of a gene without a proportional increase in other genes) of these two genes is a highly sensitive and specific indicator that a liposarcoma is either an ALT/WDL or a dedifferentiated liposarcoma rather than any other liposarcoma or lipoma form. In addition to the MDM2 and CDK4 genes, this band 13–15 chromosome area also contains the TSPAN31 and HMGA2 genes which, when overexpressed, are associated with various tumors and/or cancers. One or more of these overexpressed genes, it has been suggested, promote and/or contribute to the development and/or progression of ALT/WDL tumors.
Diagnosis The diagnosis of ALT/WDL tumors is made based on the features of their clinical presentations, histopathology, and genetic findings. In particular, detection in the ALT/WDL tumor cells of an overexpressed MDM2 or CDK4 gene or the presence of either the specific ALT/WDL-associated sSMC or giant marker chromosome (as defined by next generation DNA sequencing, comparative genomic hybridization, and/or highly specialized cytogenetic G banding analyses) strongly supports the diagnosis of ALT/WDL or dedifferentiated liposarcoma. The clinical presentation and histopathology differences between the latter two liposarcoma forms usually help distinguish between them.
Treatment and prognosis ALT/WDL tumors are treated by radical surgical resection to remove all tumor neoplastic tissues. However, these tumors recur locally in 30–50% of cases. Recurrences occur most often in tumors located in less accessible sites such those in the retroperitoneum, mediastinum, and spermatic cord. These less surgically assessible tumors tend to recur repeatedly and ultimately may cause death due to their injurious effects on vital organs. While ALT/WDL tumors have very little potential to metastasize, about 10% will convert to an overtly malignant and potentially metastasizing liposarcoma form, dedifferentiated liposarcoma. The median time for this malignant transformation is about 7–9 years. In addition, a surgically removed ALT/WDL may recur after a variable interval as a dedifferentiated liposarcoma. A large randomized controlled trial comparing radiotherapy followed by surgery to surgery alone in ALT/WDL tumors found little difference between the two regimens. Smaller studies employing selective inhibitors of the protein products of the CDK4 or MDM2 genes implicated in ALT/WDL have shown at best only modest effects. Further studies using these or completely novel treatment regimens are under investigation. A review study in 2012 reported the 5 and 10 year survival rates of individuals with ALT/WDL to be 100% and 87%, respectively.
Novel therapies The novel therapies of ALT/WDL are the same as those listed in the Novel therapies section of Dedifferentiated liposarcoma.
Dedifferentiated liposarcoma Dedifferentiated liposarcomas are malignant tumors which in ~10% of cases develop in an existing atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDL) tumor or at the site were an ALT/WPL tumor was surgically removed. Individuals with a de novo diagnosis of this tumor may have had an ALT/WDL that progressed to a dedifferentiated liposarcoma but went undetected because it developed asymptomatically in a highly sequestered site such as the retroperitoneum or abdominal cavity. Many of the dedifferentiated liposarcoma tumors' clinical and genetic features are similar to those found in ALT/WDL tumors.
Presentation