Liposarcoma





Liposarcoma, accounting for 15% to 25% of all sarcomas, is the most common sarcoma of adults. There are several subtypes, which are histologically, biologically, and cytogenetically distinct from one another ( Table 14.1 ). These subtypes range in behavior from nonmetastasizing neoplasms (e.g., atypical lipomatous tumor/well-differentiated liposarcoma [ALT/WDL]) to high-grade sarcomas with full metastatic potential (e.g., pleomorphic liposarcoma). So impressed were Enzinger and Winslow by the diversity of this group of lesions that they wrote in their seminal work on liposarcoma in 1962, “Among mesenchymal tumors, liposarcomas are probably unsurpassed by their wide range in structure and behavior. In fact the variations are striking that it seems more apt to regard them as groups of closely related tumors rather than as a well-defined entity.” These words were truly prophetic. Molecular analysis has validated the distinctness of the subtypes. In no other group of sarcomas does the pathologist receive such a strong mandate to subclassify these lesions. Although histologic subtype remains the most reliable prognostic parameter in daily practice, recent evidence suggests that gene profiles may eventually factor into risk stratification of individual patients.



Table 14.1

Comparison of Liposarcoma Subtypes




























Subtype Age (yr) Location Cytogenetic Abnormality Behavior
Well-differentiated liposarcoma 50-70 Extremity (75%); retroperitoneum Giant marker + ring chromosome Local recurrence high; no metastasis 5%-15% dedifferentiate
Dedifferentiated liposarcoma 50-70 Retroperitoneum (75%) Giant marker + ring + additional abnormalities High local recurrence; metastasis
Myxoid/round cell liposarcoma 25-45 Extremity (75%) t(12;16) Recurrence + metastasis (determined by round cell component)


Although the World Health Organization (WHO) divides liposarcomas into four subtypes—ALT/WDL, myxoid/round cell, dedifferentiated, and pleomorphic —it is useful conceptually to view liposarcomas as three large groups. Well-differentiated liposarcoma (WDL), also termed atypical lipomatous tumor (ALT) when it occurs in superficial soft tissue or in the muscles of the extremity because of its low-grade behavior, and dedifferentiated liposarcoma (DL) comprise one subgroup. Widely disparate in terms of biologic behavior, these are closely related pathogenetically because a subset of ALT/WDL histologically progresses to dedifferentiated sarcomas. With dedifferentiation, the tumor acquires metastatic potential, a phenomenon accompanied by additional cytogenetic abnormalities. The second group is myxoid liposarcoma , which ranges in appearance from pure myxoid tumors at one extreme to primitive round cell (poorly differentiated myxoid) tumors at the other. Pleomorphic liposarcomas are rare, poorly characterized tumors often resembling undifferentiated pleomorphic sarcoma, except for the presence of pleomorphic lipoblasts. Finally, a small number of liposarcomas exhibit unusual features or combine patterns not accounted for in the previous classification. These are best individualized and diagnosed as liposarcomas of unclassifiable or mixed type , respectively, recognizing that the number of such lesions is dwindling because of the ability of molecular testing to assign them to a category.


Certain generalizations should be kept in mind when considering the diagnosis of liposarcoma. First, most liposarcomas occur in deep soft tissue, in contrast to lipomas, which occur in superficial soft tissue. This implies that subcutaneous ALT/WDLs are rare and that the diagnosis should be made only after the more common mimics (e.g., lipoma with fat necrosis, spindle cell lipoma, pleomorphic lipoma, chondroid lipoma, cellular forms of angiolipoma) are excluded from the differential diagnosis. Second, there is little if any evidence that lipomas undergo malignant transformation to liposarcomas, an axiom that derives strong support from the marked difference in location of lipomas and liposarcomas. In reality, most lesions interpreted as malignant transformation of a lipoma are liposarcomas in which inadequate sampling led to an underdiagnosis of malignancy in the original material. Third, liposarcomas rarely occur in children. Liposarcoma-like lesions in pediatric patients usually represent lipoblastomas, a fetal form of lipoma. Fourth, liposarcomas, as a group, rarely develop as a postradiation sarcoma.


Our understanding of liposarcomas has greatly advanced in recent years, largely as a result of cytogenetic studies. The reciprocal translocation between chromosomes 12 and 16, which characterizes most myxoid/round cell liposarcomas, results in the expression of a number of fusion transcripts that appear to play a direct role in oncogenesis. The large group of ALT/WDL, on the other hand, has an entirely different abnormality in the form of giant and ring chromosomes, derived, at least in part, from chromosome 12, resulting in the amplification of a number of genes (e.g., MDM2, CDK4 ) that represent a recurring motif in a number of mesenchymal tumors.


Criteria and Importance of Lipoblasts


Traditionally, great emphasis has been placed on the identification of lipoblasts for diagnosing liposarcoma. Although it is certainly an appropriate task for pathologists to search for these cells in some situations, their importance in other situations has been overemphasized. For example, sclerosing ALT/WDL usually have few lipoblasts. In these cases the overall pattern and cellular components become more important determinants when making the diagnosis. On the other hand, imprecise criteria for the recognition of lipoblasts often lead to an erroneous diagnosis of liposarcoma.


Defined in the context of liposarcoma, the lipoblast is a neoplastic cell that, to some extent, recapitulates the differentiation cascade of normal fat. The earliest cells arise as pericapillary adventitial cells that closely resemble fibroblasts. These spindled cells, endowed with ample endoplasmic reticulum (ER), slowly acquire fat droplets first at the poles of the cell and later throughout the cytoplasm. As fat accumulates in the cytoplasm, the cell loses its ER and assumes a round shape. Gradually, the nucleus becomes indented and pushed to one side of the cell. A similar range of changes can be identified in lipoblasts of some liposarcomas, notably the myxoid/round cell type ( Fig. 14.1 ). In addition, pleomorphic cells with the features of lipoblasts can be identified in ALT/WDLs and pleomorphic liposarcomas ( Fig. 14.2 ), but these cells have no equivalent in the differentiation sequence of normal fat. The pathologist’s task is to decide the point in the differentiation scheme where the cell becomes sufficiently diagnostic to warrant the designation “lipoblast.”




Fig. 14.1


Developing lipoblasts from a myxoid liposarcoma at an early stage of differentiation ( A ) with fine vacuoles, an intermediate stage ( B and C ), and a late stage ( D ) resembling mature white fat.





Fig. 14.2


Pleomorphic lipoblast from a pleomorphic liposarcoma.


Criteria that have proved useful for identifying diagnostic lipoblasts include the following: (1) a hyperchromatic, indented or sharply scalloped nucleus; (2) lipid-rich (neutral fat) droplets in the cytoplasm; and (3) an appropriate histologic background . The importance of the last criterion cannot be overemphasized, because lipoblast-like cells may be seen in a variety of conditions, and failure to consider the overall appearance of a lesion can lead to an erroneous diagnosis of liposarcoma. For example, lipomas with fat necrosis ( Fig. 14.3 ); fat with atrophic changes ( Fig. 14.4 ); hibernomatous change in lipomas ( Fig. 14.5 ); foreign body reaction to silicone ( Fig. 14.6 ); nonspecific accumulation of intracytoplasmic stromal mucin ( Fig. 14.7 ); fixation artifact ( Fig. 14.8 ); and signet-ring melanoma, carcinoma, and lymphoma ( Fig. 14.9 ) all have cells that, to some extent, resemble lipoblasts. In each instance, other features indicate that the diagnosis of liposarcoma is not appropriate. Silicone reactions, for example, exhibit numerous multivacuolated histiocytes that fulfill some of the criteria of lipoblasts, but the histologic background of foreign body giant cells and inflammation should alert the pathologist that the lesion is not a liposarcoma.




Fig. 14.3


Fat necrosis in a lipoma. Scattered macrophages may be confused with atypical stromal cells of liposarcoma.



Fig. 14.4


Atrophic fat occurring with malnutrition. Cells are arranged in lobules ( A ) and are uniformly small with lipofuscin pigment in the cytoplasm ( B ).



Fig. 14.5


Finely vacuolated brown fat cells in lipoma with hibernomatous changes mimicking lipoblasts.



Fig. 14.6


Silicone granuloma with multivacuolated histiocytes resembling lipoblasts.



Fig. 14.7


Cells of myxoid undifferentiated pleomorphic sarcoma distended with hyaluronic acid. These cells are commonly misidentified as lipoblasts.



Fig. 14.8


Large-cell lymphoma ( A ) with poorly fixed areas ( B ) in which the retraction artifact led to erroneous diagnosis of liposarcoma.



Fig. 14.9


Adenocarcinoma arising in Barrett mucosa showing treatment effect with pseudolipoblasts.




Atypical Lipomatous Tumor (Alt)/Well-Differentiated Liposarcoma (Wdl)


Clinical Findings


ALT/WDL liposarcoma, accounting for 30% to 40% of all liposarcomas, is the most common form of liposarcoma encountered in late adult life, reaching a peak incidence during the sixth and seventh decades. Men and women are equally affected, although at certain sites (e.g., groin) there appears to be a predilection for men. In the collective experience of the Armed Forces Institute of Pathology (AFIP) and the Mayo Clinic, 75% of cases developed in the deep muscles of the extremities and 20% in the retroperitoneum, with the remainder divided between the groin, spermatic cord, and miscellaneous sites. Rarely do these tumors develop in the subcutis or miscellaneous parenchymal sites.


Symptoms related to these tumors depend on the anatomic site. Those in the extremities develop as slowly growing masses that are present months or even several years before the patient seeks medical attention, whereas those in the retroperitoneum are associated with the usual symptoms of an intraabdominal mass. Because ALT/WDLs contain a significant component of mature fat, they present on computed tomography (CT) as fat density masses, with mottled or streaky zones of higher density corresponding to the fibrous or sclerotic zones. They also tend to have less well-defined borders than lipomas ( Fig. 14.10 ).




Fig. 14.10


CT scan of atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDL) of the abdominal cavity and retroperitoneum. The mass, with a low attenuation value, replaces abdominal contents.


Gross and Microscopic Features


Grossly, ALT/WDLs are large, multilobular lesions that range in color from deep yellow to ivory ( Fig. 14.11 ). Many could be mistaken for a lipoma, except for their extremely large size and their tendency to have fibrous bands, gelatinous zones, or punctate hemorrhage. The well-developed lobular growth pattern of benign lipomas is often absent as well.




Fig. 14.11


A, ALT/WDL closely resembling normal fat, except for fibrous bands. B, Others have a more gelatinous appearance.


ALT/WDLs have traditionally been divided into three subtypes: (1) lipoma-like, (2) sclerosing, and (3) inflammatory. Because many ALT/WDLs combine features of both lipoma-like and sclerosing subtypes, the distinction between these two types is often arbitrary and of limited practical importance. These lesions are rarely subclassified in daily practice, although the terms serve to draw attention to the range of appearances that these tumors may assume. In the typical lipoma-like ALT/WDL, the tumor consists predominantly of mature fat with a variable number of spindled cells with hyperchromatic nuclei and multivacuolated lipoblasts ( Figs. 14.12 to 14.15 ). In some cases, these atypical spindled cells are numerous, whereas in others the cells are so rare as to require extensive sampling of the tissue. Lipoma-like forms of ALT/WDL will often contain abnormally configured, thick-walled blood vessels containing similar hyperchromatic cells within their walls, a useful clue to this diagnosis in cases with only small numbers of hyperchromatic stromal cells. Sclerosing forms of ALT/WDL, most common in the groin and retroperitoneum, have dense fibrotic zones alternating with mature adipocytes ( Figs. 14.16 to 14.19 ). In some cases the fibrotic zones consist of trabeculae intersecting fat, and in others the fibrous areas consist of broad sheets. The fibrotic areas contain collagen fibrils of varying thickness embedded with scattered spindled and multipolar stromal cells with hyperchromatic nuclei. Similar cells may also be present between the mature adipocytes. Although lipoblasts may be present, they are usually rare. Therefore the diagnosis for this sclerosing pattern of liposarcoma depends more on the identification of stromal cells with a requisite degree of atypia than on the identification of diagnostic lipoblasts. The inflammatory form of ALT/WDL occurs almost exclusively in the paratestis and retroperitoneum and consists of a dense lymphocytic or plasmacytic infiltrate superimposed on a lipoma-like or sclerosing form of ALT/WDL ( Fig. 14.20 ). Because of the intense inflammatory infiltrate, these tumors may be confused with lipogranulomatous inflammation or with hematopoietic neoplasms. Indeed, we have seen cases that were diagnosed repeatedly as “atypical lymphoproliferative processes,” only to be recognized as inflammatory WDL after dedifferentiation.




Fig. 14.12


Lipoma-like ATL/WDL showing only a rare atypical stromal cell amid a mature lipomatous backdrop.



Fig. 14.13


A, Atypical stromal cell in an ALT/WDL illustrating nuclear hyperchromatism. B, Nuclear MDM2 immunostaining in atypical cells in ALT/WDL.



Fig. 14.14


ALT/WDL with a larger number of atypical stromal cells and lipoblasts than in Fig. 14.13 .



Fig. 14.15


Lipoma-like ALT/WDL with numerous lipoblasts.



Fig. 14.16


Patterns within ALT/WDL.

Sclerosing ALT/WDL showing some degree of mature fat ( A ) and no fat ( B ). C, Myxoid pattern in ALT/WDL showing wide separation of fusiform/spindled cells in a stroma having coarse but elaborate vasculature. Areas such as this can be mistaken for myxoid liposarcoma.





Fig. 14.17


Sclerosing ALT/WDL showing sheetlike areas of collagen and fat. Note the multivacuolated lipoblast in this lesion. These cells are typically rare.



Fig. 14.18


Sclerosing ALT/WDL ( A ) with fibrous bands containing atypical cells ( B ).



Fig. 14.19


Lipoblasts in ALT/WDL.



Fig. 14.20


ALT/WDL of the inflammatory type with a dense lymphocytic infiltrate ( A ) and areas of lipoblastic differentiation ( B ).


ALT/WDLs infrequently display areas of relatively mature smooth muscle ( Figs. 14.21 and 14.22 ). These lipoleiomyosarcomas are dual-lineage sarcomas in which both the lipomatous and the smooth muscle component are low grade. Biologically, they have a behavior identical to ALT/WDL, including the ability to dedifferentiate, and are recognized by areas of ALT/WDL blending with fascicles, nodules, or broad expanses of smooth muscle tissue having mild to moderate nuclear atypia and low levels of mitotic activity. In some cases the smooth muscle appears to extend out from the walls of large vessels, which similarly contain atypical smooth muscle cells ( Fig. 14.22 ). The amount of smooth muscle varies considerably from case to case, with some tumors showing only occasional foci and others broad expanses. A less common association is ALT/WDL with low-grade osteosarcoma-like areas. These tumors, occurring primarily in the retroperitoneum, consist of a lipomatous component, which usually predominates and blends with areas resembling parosteal or low-grade intramedullary osteosarcoma. These areas are characterized by relatively mature bone, with or without osteoblastic rimming, embedded in a low-grade fibroblastic backdrop. In a few cases, high-grade osteosarcoma coexists in the low-grade areas. In the few cases studied, MDM2 and CDK4 have been demonstrated immunohistochemically in both the lipomatous and osteosarcomatous components.




Fig. 14.21


ALT/WDL with smooth muscle differentiation (lipoleiomyosarcoma) ( A ) and stained with Masson trichrome stain ( B ).



Fig. 14.22


Lipoleiomyosarcoma showing atypia in a vessel wall.


Occasionally, ALT/WDLs have a predominantly myxoid appearance, a phenomenon that has led to the conjecture that these tumors represent either a variant of myxoid liposarcoma or a mixed type of liposarcoma (see Fig. 14.16C ). In these areas the cells are more spindled and the vessels coarser than in a myxoid liposarcoma. Several studies have shown that these tumors lack DDIT3 rearrangements and therefore are unrelated to myxoid liposarcoma.


Differential Diagnosis


Various neoplastic and nonneoplastic lesions enter the differential diagnosis of ALT/WDL ( Box 14.1 ). For most of these conditions, none of the available histochemical or immunohistochemical stains is useful. Rather, careful sampling of the material and thin, well-stained hematoxylin-eosin sections comprise the mainstay of accurate diagnosis. Lipid stains, although obviously positive in ALT/WDL, also disclose lipid-positive deposits in the vast panorama of reactive lesions in fat and a variety of tumors.




  • Normal fat with Lochkern cells. Normal white fat consists of spherical cells containing one large lipid vacuole that displaces the thin oval nucleus to one side. On routine sections the nucleus of most fat cells is barely perceptible. From time to time, a section grazes an adipocyte nucleus so that it is viewed en face, displaying its characteristic central vacuole, termed Lochkern (German, “hole in the nucleus”) ( Fig. 14.23 ). Lochkern cells are seen more frequently in thick sections and sometimes misinterpreted as evidence of lipoblastic differentiation and therefore a liposarcoma.




    Fig. 14.23


    Intranuclear vacuoles (Lochkern cells) in normal fat.



  • Fat necrosis. In areas of fat necrosis, finely granular or vacuolated macrophages are located in the vicinity of damaged fat characterized by diminished cell size, dropout of adipocytes, and chronic inflammation (see Fig. 14.3 ). Unlike lipoblasts, macrophages are of uniform size and have small, evenly dispersed vacuoles that do not indent the nucleus. The nucleus has a rounded shape with delicate staining. In thick sections the nuclei of macrophages may overlap one another, giving the impression of hyperchromatism , which typifies the atypical stromal cells in ALT/WDL. Lochkern cells are also common in fat necrosis. When making such distinctions, it is important to have suitably thin histologic sections.



  • Atrophy of fat. Starvation, malnutrition, and local trauma result in atrophy of fat. Atrophy is accompanied by a loss of intracellular lipid such that the cell shrinks dramatically and assumes an epithelioid shape (see Fig. 14.4 ). With loss of lipid, the nuclei become more prominent, and the cells superficially resemble lipoblasts. Important observations include cells that appear to be of uniform size and maintain their arrangement in lobules. With extreme atrophy the cells may contain lipofuscin. Such changes are particularly noticeable in subcutaneous tissue and the omentum.



  • Localized massive lymphedema. Massive forms of lymphedema restricted to a portion of the body may be confused clinically and histologically with ALT/WDL. These lesions develop in morbidly obese individuals and appear to be the result of lymphedema secondary to chronic dependency of a fatty panniculus. Not surprisingly, these lesions develop in the proximal extremities and may be aggravated by underlying factors, such as lymphadenectomy. Grossly and microscopically, the lesions exhibit the changes of lymphedema, including thickening of overlying skin, dermal fibrosis, ectasia and proliferation of lymphatics with focal cysts, and expansion of connective tissue septa ( Fig. 14.24 ). A misdiagnosis of liposarcoma is attributable to the expanded connective tissue septa that are believed to be part of a sclerosing liposarcoma. The septa contain mild to moderately atypical fibroblasts and delicate collagen fibrils separated by edema. In addition, there is often striking vascular proliferation at the interface between the expanded connective tissue septa and lobules of fat.




    Fig. 14.24


    Changes of lymphedema that may mimic an ALT/WDL. A, Connective tissue septa are expanded, with B, mildly atypical fibroblasts in the septa.



  • Silicone reaction. Injection of silicone for various therapeutic and cosmetic purposes results in sheets of massively distended multivacuolated histiocytes that are disarming replicas of lipoblasts (see Fig. 14.6 ). Lipoblasts of such quality and number are rarely encountered in true liposarcomas. Silicone reactions are also accompanied by a modest inflammatory and giant cell reaction and a large cyst with eosinophilic borders. Most silicone reactions in clinical practice are encountered around silicone breast implants but occasionally are seen on the face, abdomen, and genital region. Free silicone can also migrate under gravitational effect and therefore is found at sites distant from the original introduction site.



  • Intramuscular lipoma with atrophic muscle. Infrequently, atrophic skeletal muscle fibers are seen in intramuscular lipomas ( Fig. 14.25 ). When these collections retain a clustered arrangement and have identifiable eosinophilic cytoplasm, this phenomenon is easily recognized. Isolated degenerating myofibers with barely perceptible cytoplasm understandably can be misidentified as atypical stromal cells of ALT/WDL. Positive identification can be accomplished with desmin immunostains.




    Fig. 14.25


    Atrophic muscle in an intramuscular lipoma. Degenerating myofibers are occasionally mistaken for atypical cells in liposarcomas.



  • Herniated orbital fat. Prolapse of subconjunctival intraconal fat is a rare cause of an intraorbital mass. Herniated orbital fat, unlike normal orbital fat, contains floret-type giant cells, a feature that often leads to a mistaken diagnosis of liposarcoma ( Fig. 14.26 ). This condition develops in adults in the region of the superotemporal quadrant of the orbit or the lateral canthus below the lacrimal gland. The lesion can be unilateral or bilateral. The nuclei of the multinucleated giant cells present in herniated orbital fat are small, round, and normochromatic, unlike those of ALT/WDL.




    Fig. 14.26


    Herniated orbital fat at low power ( A ) and floret-type giant cells at high power ( B ).



BOX 14.1

Lesions Simulating ALT/WDL





  • Lipoma with fat necrosis



  • Lipoma with Lochkern cells



  • Atrophy of fat



  • Silicone reaction



  • Diffuse lipomatosis



  • Spindle cell lipoma/pleomorphic lipoma



  • Myolipoma



  • Cellular angiolipoma



  • Angiomyolipoma



  • Lipomatous hemangiopericytoma/solitary fibrous tumor




Cytogenetic and Molecular Findings


ALT/WDL are characterized by giant marker and ring chromosomes, sometimes as a sole finding or occasionally in association with other numeric or structural alterations. The giant marker and ring chromosomes contain amplified sequences of 12q13-15, the site of several genes (e.g., MDM2, GLI, SAS, CDK4 , HMGIC ). MDM2 (12q13-14) and HMGA2 (12q15), part of the same amplicon, are consistently amplified as a result of this abnormality. CDK4 , located at 12q13, and TSPAN31 , located at 12q13-q14, belong to a separate amplicon, which is coamplified with MDM2 and HMGIC in about 90% of cases. GLI1 and DDIT3 (12q13.1-q13.2) are infrequently amplified. Amplification of MDM2 and CDK4 results in downstream signaling, the net result of which is to inhibit apoptosis and increase cell proliferation. MDM2 binds to p53, thereby decreasing apoptosis, whereas CDK4 phosphorylates the RB1 gene product, preventing its interaction with E2F transcription factor and allowing the cell cycle to escape the G1-S checkpoint.


The MDM2 -p53 interaction can potentially be exploited for the purposes of targeted therapy. The nutlins are small-molecule antagonists that inhibit the binding of MDM2 to p53, thereby restoring p53 activity and apoptosis. They have been shown to inhibit the growth of MDM2 -amplified liposarcoma cell lines, but not in those without MDM2 amplification. Nutlins are currently in clinical trials.


Immunohistochemical and Molecular Diagnosis of ALT/WDL and DL


Immunostaining for CDK4 and MDM2 is a reasonable first-line tool for separating ALT/WDL from various benign lipomatous lesions. Immunoreactivity can be detected within the majority of ALT/WDLs and DLs; the exact percentage varies depending on the study. MDM2 staining is localized to the nuclei, where it is most easily visualized in the large hyperchromatic cells (see Fig. 14.13B ). The percentage of positive cells also varies from case to case. Immunoreactivity is not generally present within deep lipomas. However, a small percentage of positively staining cells in spindle cell/pleomorphic lipomas express MDM2 and CDK4. In addition, antibodies to CDK4 and MDM2 occasionally stain nuclei of histiocytes within areas of fat necrosis, making it imperative that the character of the immunopositive nuclei be evaluated. Nuclear MDM2 and CDK4 can also be detected by immunohistochemistry (IHC) in a small subset of nonlipomatous sarcomas (e.g., malignant peripheral nerve sheath tumor).


In contrast, MDM2 gene amplification evaluated by fluorescence in situ hybridization (FISH) is a highly sensitive and specific means of diagnosing ALT/WDL, even in needle biopsy material. It is significantly superior to immunostaining, which not only fails to identify all ALT/WDLs, but also is associated with a small but definite false-positive rate. Virtually all ALT/WDLs display amplification of MDM2 in both biopsy and resection specimens. MDM2 is not amplified in lipomas, although spindle cell/pleomorphic lipomas may display polysomy of the 12q locus. Because of its exquisite sensitivity and specificity in the diagnosis of ALT/WDL, FISH has been endorsed for evaluation of ambiguous (vs. obvious) lipomatous lesions. Most often, these are tumors in which the degree of atypia falls short of a threshold level for the diagnosis of malignancy. Admittedly, this threshold is different from pathologist to pathologist, although as a group, pathologists tend to overestimate the degree of atypia present when contemplating a diagnosis of ALT/WDL. The situations in which molecular testing for MDM2 is highly recommended are lipomatous tumors with equivocal cytologic atypia, recurrent lipomas, deep lipomas without atypia that exceed 10 cm, and retroperitoneal or intraabdominal lipomatous tumors lacking cytologic atypia ( Box 14.2 ). These guidelines are especially important in evaluating these lesions in patients older than 50 years, since the risk of liposarcoma increases with age. Using this approach, reasonable evidence now exists to recognize the entity of retroperitoneal lipoma , a diagnosis formerly considered to be hearsay. Nevertheless, although its existence has been established, retroperitoneal lipoma is exceedingly rare. The diagnosis should be made only after WDL has been excluded with FISH.



BOX 14.2

Indications for MDM2 Gene Amplification Analysis in Lipomatous Tumors





  • Lipomatous tumors with equivocal cytologic atypia



  • Recurrent lipomas



  • Deep lipomas without atypia that exceed 10 cm



  • Retroperitoneal or intraabdominal lipomatous tumors lacking cytologic atypia




Clinical Behavior


ALT/WDLs are nonmetastasizing lesions that are traditionally not graded. However, their rate of local recurrence and disease-related mortality are strongly influenced by location. As shown in Table 14.2 , rates of local recurrence for tumors in the extremities (almost 50%) are significantly lower than for tumors in the retroperitoneum (almost 100%). One could argue that ALT/WDL of the retroperitoneum is basically an incurable lesion. About one-third of patients die as a direct result of their disease, but this figure increases with longer follow-up as a result of the indolent growth of these lesions. On the other hand, those rare ALT/WDLs that occur in the subcutaneous tissues are not associated with tumor-related death and are generally cured by limited excision.



Table 14.2

Behavior of 83 ALT/WDL

From Weiss SW and Rao VK. ALT/WDL (atypical lipoma) of deep soft tissue of the extremities, retroperitoneum and miscellaneous sites: a follow-up study of 92 cases with analysis of the incidence of “dedifferentiation.” Am J Surg Pathol . 1992;16:1051–1058.


































Site Recurrence (%) Died of Disease (%) Dedifferentiation (%) Years Follow-up: Range (Median)
Extremity 43 0 6 2-25 (9)
Retroperitoneum 91 33 17 1-35 (10)
Groin 79 14 28 2-25 (8)
total 63 11 13


ALT/WDLs should not be dismissed as little more than benign but locally aggressive lesions, because a small percentage of these tumors over time will progress histologically to a higher-grade lesion (DL). Although this phenomenon occurs most frequently with retroperitoneal liposarcomas, it also occurs with deep extremity lesions; it is rare in subcutaneous tumors. Therefore, it does not appear to be a site-specific phenomenon as formerly believed, but rather a time-dependent phenomenon encountered in locations where there is a high likelihood of clinically persistent disease. With retroperitoneal tumors, for which complete excision is virtually impossible, there is a substantial risk of dedifferentiation (about 10%–15%); it is somewhat lower for extremity lesions (5%). In ALT/WDLs that have been followed longitudinally, dedifferentiation occurs after an average of 7 to 8 years but may be seen as long as 16 to 20 years after the original diagnosis. When dedifferentiation occurs, the lesions can usually be considered fully malignant sarcomas. An exception is the rare tumor in which dedifferentiation is restricted to an extremely small focus (see Differential Diagnosis).


Because of site-dependent differences in the behavior of WDL, atypical lipoma was a term originally introduced in 1979 by Evans et al, who suggested retention of the term ALT/WDL for lesions in the retroperitoneum, but later recommended that the term be abandoned altogether in favor of the term atypical lipomatous tumor . To avoid confusion, WHO has endorsed the combined term ALT/WDL for all lesions previously diagnosed as atypical lipoma, ALT, or ALT/WDL. There is merit in retaining the term WDL for retroperitoneal, paratesticular, mediastinal, or body cavity lesions, to emphasize the life-threatening nature of these tumors in these locations, to ensure adequate therapy and follow-up care, and to acknowledge the risk of dedifferentiation over time. Implied in the foregoing discussion is the understanding that ALT and WDL are synonyms, and the choice of one over the other is based on location, not a constellation of histologic differences. Unfortunately, it has not been possible to predict, in the individual patient, which ALT/WDL will dedifferentiate. Comparison of matched pairs of ALT/WDL with their respective dedifferentiated component discloses minor differences, as discussed in the following section.




Dedifferentiated Liposarcoma


Dedifferentiation, or histologic progression to a higher-grade, less well-differentiated neoplasm, was first described as a late complication in the natural history of well-differentiated chondrosarcoma, but it is now known to occur in other low-grade mesenchymal tumors, including parosteal osteosarcoma, chordoma, and ALT/WDL. Traditionally, DLs were defined as ALT/WDL juxtaposed to areas of high-grade nonlipogenic sarcoma, usually resembling fibrosarcoma or undifferentiated pleomorphic sarcoma (malignant fibrous histiocytoma). Dedifferentiation was believed to occur after a latent period of several years. These views have now been modified. Whereas most DLs display high-grade dedifferentiation, a small number contain exclusively low-grade areas or a combination of low- and high-grade areas. Although some question the concept of low grade dedifferentiation based on these tumors behaving more like ALT/WDL than classic DL, this is not borne out by the experience of most.


Clinical Features


Dedifferentiated liposarcomas account for 18% of liposarcomas. DLs develop in approximately the same age group as ALT/WDL and reach a peak during the early seventh decade. Men and women are affected equally. Unlike ALT/WDL, location in the retroperitoneum is favored over deep soft tissues of the extremities by almost 3:1. Fewer than 20% of DLs occur collectively in the head, neck, trunk, and spermatic cord and rarely in the subcutis. Radiographically, DLs have areas characteristic of ALT/WDL but also have masslike areas of nonfatty tissue. The latter appearance has imaging characteristics similar to other sarcomas, with prolonged T1 and T2 relaxation on magnetic resonance imaging (MRI) and attenuation coefficients higher than those for normal fat on CT scans.


Gross and Microscopic Features


The lesions present as large, multinodular masses ranging in color from yellow to yellow-tan admixed with firm tan-gray areas that correspond to the dedifferentiated foci. Microscopically, the lesions consist of areas of ALT/WDL that display the range of changes described previously and a nonlipogenic (dedifferentiated) component. The interface between the two zones is typically abrupt ( Fig. 14.27 ), although in some cases there is a gradual transition between the two ( Fig. 14.28 ). Rarely, the two patterns commingle, giving the impression of mosaicism ( Fig. 14.29 ).


Mar 10, 2020 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Liposarcoma
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