Orthopedics

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Radiologic Case Study 

Radiologic Case Study

Flavia A. Sakamoto, MD; Carl S. Winalski, MD; Karen Fritchie, MD; Steven A. Lietman, MD; Murali Sundaram, MD

Abstract

Drs Sakamoto, Winalski, and Sundaram are from the Imaging Institute, Drs Winalski and Lietman are from the Department of Biomedical Engineering, Lerner Research Institute, Dr Fritchie is from the Pathology and Laboratory Medicine Institute, and Dr Lietman is from the Orthopaedic and Rheumatologic Institute, Cleveland Clinic, Cleveland, Ohio.

Drs Sakamoto, Winalski, Fritchie, Lietman, and Sundaram have no relevant financial relationships to disclose.

Correspondence should be addressed to: Carl S. Winalski, MD, Imaging Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195 (wi-nalsc@ccf.org).

At a follow-up appointment for a shoulder arthroscopy, a 41-year-old man reported feeling pain in his right thigh for approximately 3 months. He described the sensation as a constant throbbing and burning pain, 3 out of 10 on a pain scale, with itching.

Your diagnosis?

For answer see page 627

Dedifferentiated Liposarcoma

Answer to Radiologic Case Study

Case facts appear on page 561

A 41-year-old man presented with itching and a burning pain in his right thigh. He reported that the pain increased after activity but was relieved with non-steroidal anti-inflammatory drugs. On physical examination, the patient’s right leg was noticeably larger than the left, but the patient reported that this was not new, as he was a slalom water skier and his right leg was his “power leg.” The patient had not noticed any unusual enlargement of the thigh. Radiographs were performed to assess for potential lesions. A large lipomatous mass involving the vastus muscles was found; this mass contained a structure with soft tissue density (Figure 1). These findings were suggestive of a sarcoma, although a lipoma with an internal hematoma was another possible diagnosis. Magnetic resonance imaging (MRI) confirmed the presence of a massive intramuscular lipoma with a large focal non-fatty component, suggesting a diagnosis of dedifferentiated liposarcoma (Figure 2).

Enhance your diagnostic skills with this “test yourself” monthly column, which features a radiograph and challenges you to make a diagnosis.

Drs Sakamoto, Winalski, and Sundaram are from the Imaging Institute, Drs Winalski and Lietman are from the Department of Biomedical Engineering, Lerner Research Institute, Dr Fritchie is from the Pathology and Laboratory Medicine Institute, and Dr Lietman is from the Orthopaedic and Rheumatologic Institute, Cleveland Clinic, Cleveland, Ohio.

Drs Sakamoto, Winalski, Fritchie, Lietman, and Sundaram have no relevant financial relationships to disclose.

Correspondence should be addressed to: Carl S. Winalski, MD, Imaging Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195 (wi-nalsc@ccf.org).

The Case:

At a follow-up appointment for a shoulder arthroscopy, a 41-year-old man reported feeling pain in his right thigh for approximately 3 months. He described the sensation as a constant throbbing and burning pain, 3 out of 10 on a pain scale, with itching.

Your diagnosis?

For answer see page 627

Diagnosis:

Dedifferentiated Liposarcoma

Answer to Radiologic Case Study

Case facts appear on page 561

A 41-year-old man presented with itching and a burning pain in his right thigh. He reported that the pain increased after activity but was relieved with non-steroidal anti-inflammatory drugs. On physical examination, the patient’s right leg was noticeably larger than the left, but the patient reported that this was not new, as he was a slalom water skier and his right leg was his “power leg.” The patient had not noticed any unusual enlargement of the thigh. Radiographs were performed to assess for potential lesions. A large lipomatous mass involving the vastus muscles was found; this mass contained a structure with soft tissue density (Figure 1). These findings were suggestive of a sarcoma, although a lipoma with an internal hematoma was another possible diagnosis. Magnetic resonance imaging (MRI) confirmed the presence of a massive intramuscular lipoma with a large focal non-fatty component, suggesting a diagnosis of dedifferentiated liposarcoma (Figure 2).

Frontal (A) and lateral (B) radiographs of the right thigh show a large fat density mass (arrowheads) involving the vastus muscles. This mass contains an ovoid non-fatty soft tissue density (arrow), which corresponds to the dedifferentiated component of the tumor.

Figure 1: Frontal (A) and lateral (B) radiographs of the right thigh show a large fat density mass (arrowheads) involving the vastus muscles. This mass contains an ovoid non-fatty soft tissue density (arrow), which corresponds to the dedifferentiated component of the tumor.

Abrupt transition between lipomatous and dedifferentiated areas is typical for dedifferentiated liposarcoma. Axial proton density-weighted, non-fat-suppressed fast spin echo (A), coronal short T1 inversion recovery (B), and axial T2-weighted fat-suppressed fast spin echo (C) MRIs show the coexistence of fatty (arrowheads) and non-fatty solid components (arrow) within the intramuscular tumor. The dedifferentiated, non-fatty nodule of tissue has an inhomogeneous intermediate to high signal that is important to recognize. Post-contrast axial (D) and coronal (E) T1-weighted fat-suppressed MRIs show enhancement of the dedifferentiated region (arrow) except for a region of necrosis (arrowhead).

Figure 2: Abrupt transition between lipomatous and dedifferentiated areas is typical for dedifferentiated liposarcoma. Axial proton density-weighted, non-fat-suppressed fast spin echo (A), coronal short T1 inversion recovery (B), and axial T2-weighted fat-suppressed fast spin echo (C) MRIs show the coexistence of fatty (arrowheads) and non-fatty solid components (arrow) within the intramuscular tumor. The dedifferentiated, non-fatty nodule of tissue has an inhomogeneous intermediate to high signal that is important to recognize. Post-contrast axial (D) and coronal (E) T1-weighted fat-suppressed MRIs show enhancement of the dedifferentiated region (arrow) except for a region of necrosis (arrowhead).

The patient underwent a radical resection of the mass without a biopsy due to our certainty of the diagnosis based on the MRI appearance. The resected specimen was composed of a large fatty mass that contained a non-fatty element portion (Figure 3), correlating well with the MRI. Microscopic images showed the biphasic morphology of the neoplasm, which included a well-differentiated lipomatous proliferation composed of adipocytes admixed with fibrous bands containing atypical hyperchromatic stromal cells with an abrupt transition to a nonlipogenic component consisting of pleomorphic spindled and epithelioid cells with eosinophilic cytoplasm, hyperchromatic nuclei, and frequent mitotic figures (Figure 4). This combination of a well-differentiated lipomatous tumor immediately adjacent to a nonlipogenic sarcoma was definitive for dedifferentiated liposarcoma. The patient has done well postoperatively, walks without a limp, and has returned to his job as a firefighter.

Gross image demonstrates a biphasic neoplasm composed of large, multinodular yellow mass with a large solid, nonlipomatous component. The dedifferentiated component (arrow) may have a variable histological grade. Most often they resemble a malignant fibrous histiocytoma or fibrosarcoma.

Figure 3: Gross image demonstrates a biphasic neoplasm composed of large, multinodular yellow mass with a large solid, nonlipomatous component. The dedifferentiated component (arrow) may have a variable histological grade. Most often they resemble a malignant fibrous histiocytoma or fibrosarcoma.

On histology, well-differentiated and dedifferentiated components normally have an abrupt transition (A). The well-differentiated component is composed of mature adipose tissue with fibrous septa containing atypical hyperchromatic stromal cells (B). The nonlipogenic component consists of pleomorphic spindled and epithelioid cells with eosinophilic cytoplasm, hyperchromatic nuclei, and frequent mitotic figures (C).

Figure 4: On histology, well-differentiated and dedifferentiated components normally have an abrupt transition (A). The well-differentiated component is composed of mature adipose tissue with fibrous septa containing atypical hyperchromatic stromal cells (B). The nonlipogenic component consists of pleomorphic spindled and epithelioid cells with eosinophilic cytoplasm, hyperchromatic nuclei, and frequent mitotic figures (C).

Classification and Incidence

Dedifferentiated liposarcoma is a biphasic malignant adipocytic neoplasm that contains an atypical lipomatous tumor/well-differentiated liposarcoma component juxtaposed with a nonlipogenic sarcoma of variable histological grade.1 Dedifferentiation of a tumor indicates histological progression of the neoplasm to a higher grade. This was first reported in well-differentiated chondrosarcomas2 and was later described in soft tissue liposarcomas.3 The phenomenon has since been found with other neoplasms, including chordoma, parosteal osteosarcoma, giant cell tumor of bone, and low-grade central osteosarcoma.4,5 Dedifferentiation occurs in 6% to 28% of atypical lipomatous tumors/well-differentiated liposarcomas, more frequently in those of the retroperitoneum and groin than the extremities, and is thought to be a time-dependent phenomenon.6 Dedifferentiated liposarcoma most often occur de novo (90%), but may arise in a pre-existing well-differentiated liposarcoma (10%).7

According to the World Health Organization (WHO) classification, dedifferentiated liposarcoma is 1 of the 4 main histological types of liposarcomas, along with well-differentiated, myxoid/round cell, and pleomorphic liposarcoma.1 Liposarcomas account for at least 20% of all sarcomas in adulthood, and dedifferentiated liposarcomas account for up to 10% of liposarcomas.8 Dedifferentiated liposarcoma is most common in late adulthood, with a peak incidence in the sixth and seventh decades. The occurrence of dedifferentiated liposarcoma in childhood is extremely rare.1,9 No sex predilection has been observed.1,5

Distribution

Dedifferentiated liposarcoma occurs most commonly in the retroperitoneum; deep-seated lesions in the extremities are the next most common location. Fewer than 20% of dedifferentiated liposarcoma cases occur in other locations. Reported cases have arisen in the spermatic cord, head, neck, and trunk; notably, the subcutaneous tissue is rarely the site of origin (1%).1,5,7,10,11 It has been suggested that the higher incidence of tumors in the retroperitoneum may be due to difficulty in obtaining negative surgical margins at this site when an atypical lipomatous tumor/well-differentiated liposarcoma is resected, or delayed diagnosis of the retroperitoneal lipomatous tumors resulting in larger tumor size at presentation compared to extremity lesions.6

Clinical Presentation

Dedifferentiated liposarcoma usually presents as a large, painless mass, which may be found only by chance, particularly in the retroperitoneum. In the limbs, a history of a long-standing mass exhibiting a recent size increase often indicates dedifferentiation.1

Histopathology

On macroscopic evaluation, dedifferentiated liposarcoma usually consists of large, multinodular yellow masses that contain areas of discrete, solid, nonlipomatous material (Figure 3). These dedifferentiated areas may show signs of necrosis. The transition between the lipomatous and dedifferentiated areas is typically abrupt but may occasionally be more gradual3; rarely, well-differentiated and high-grade areas may appear to be intermingled. Many cases demonstrate >1 of these interface patterns.7

Morphologic examination of these tumors reveals a biphasic neoplasm composed of a well-differentiated lipomatous proliferation and any type of nonlipogenic sarcoma (Figure 4). The well-differentiated component is composed of mature adipose tissue with fibrous septa containing atypical spindled cells with large, hyperchromatic nuclei.

Most areas of the dedifferentiated component resemble a malignant fibrous histiocytoma or fibrosarcoma, but occasionally the tumor may show evidence of differentiation to leiomyosarcoma, rhabdomyosarcoma, or even osteosarcoma.12 Angiosarcomatous elements, neural-like or meningothelial-like whorling patterns of dedifferentiation, and a reactive lymphocytic infiltration have also been described.1,13

Recent literature has suggested that homologous lipoblastic differentiation may occur in the dedifferentiated component.14 Occasionally low-grade dedifferentiation may also occur, and these areas may resemble fibromatosis with little cytologic atypia and a low mitotic rate.7 The extent of dedifferentiation in dedifferentiated liposarcoma is variable, but it is typically visible morphologically and confirmed microscopically.

Local recurrences of dedifferentiated liposarcomas may be entirely well differentiated,1 whereas metastases from dedifferentiated liposarcomas may resemble the dedifferentiated component of the primary tumor without the well-differentiated component.3

Cytogenetic studies have found that atypical lipomatous tumor/well-differentiated and dedifferentiated liposarcomas contain supernumerary ring chromosomes and/or giant marker chromosomes composed of amplified genomic sequences that are derived from chromosome 12q13–q15.15 Immunopositivity for murine double minute 2 (MDM2), cyclin-dependent kinase 4 (CDK4), and high-mobility group 1C (HMG1C) has also been identified in cases of atypical lipomatous tumor/well-differentiated and dedifferentiated liposarcomas.16,17 Immunohistochemistry studies also aid in the recognition of divergent differentiation and exclude other tumor types.

Molecular studies also are a helpful ancillary tool in the diagnosis of these tumors. While amplification of the MDM2 gene region may be seen in other pleomorphic sarcomas, detecting MDM2 amplification in the well-differentiated component can be helpful in cases with minimal atypia in these areas.

Imaging

In dedifferentiated liposarcoma, radiographic, computed tomography (CT), and MRI techniques show the coexistence of fatty and non-fatty solid components, usually with an abrupt transition between these segments.1,18 Radiographs or CT images can delineate mineralization, cortical bone erosion, or bone destruction more clearly than MRIs. On CT, the dedifferentiated non-fatty tissue has an attenuation coefficient similar to that of muscle; on MRIs, this tissue has a nonspecific appearance with intermediate signal on T1-weighted and bright signal on T2-weighted sequences (Figure 2).18,19

Post-contrast MRIs typically show diffuse contrast enhancement in the area of dedifferentiation. This may be useful in distinguishing dedifferentiated liposarcoma from an area of fat necrosis in a low-grade lipomatous tumor since the latter will only show rim enhancement.19 In dedifferentiated liposarcoma, scintigraphy shows areas of markedly increased uptake on all phases of the bone scan in the histologically high-grade component and minimal uptake in the well-differentiated areas.18 Although chest radiography can also be used as an initial screening study for pulmonary metastases, chest CT is the more sensitive, preferred modality.

Atypical lipomatous tumor/well-differentiated liposarcoma affects a similar patient population as dedifferentiated liposarcoma and occurs most frequently in deep soft tissue of the limbs, especially the thigh. It may present as large lipomatous masses containing septations but should not have any large, solid nonlipomatous regions (Figure 5).1 It is essential to look for any solid nodular focus (>2 cm) within an atypical lipomatous tumor/well-differentiated liposarcoma on imaging examinations and, if found, to then perform a biopsy to determine the true grade of the lesion and exclude dedifferentiated liposarcoma.19 Clinicians also need to be able to recognize other causes of focal nonlipomatous regions within a well-differentiated liposarcoma, including collagenized areas, metaplastic mineralization, and fat necrosis.19

Atypical lipomatous tumor/well-differentiated liposarcoma of the thigh appears as a large fatty mass with septations but no nodules of nonlipomatous tissue. The large lipomatous tumor within the biceps femoris muscle fascia appears similar to subcutaneous fat on coronal T1-weighted fast spin echo MRI (A) and coronal CT reconstruction (B).

Figure 5: Atypical lipomatous tumor/well-differentiated liposarcoma of the thigh appears as a large fatty mass with septations but no nodules of nonlipomatous tissue. The large lipomatous tumor within the biceps femoris muscle fascia appears similar to subcutaneous fat on coronal T1-weighted fast spin echo MRI (A) and coronal CT reconstruction (B).

Differential Diagnosis

The main differential diagnosis for dedifferentiated liposarcoma is sarcoma infiltrating non-neoplastic adipose tissue. Dedifferentiated liposarcoma should demonstrate areas characteristic of atypical lipomatous tumor/well-differentiated liposarcoma some distance from the dedifferentiated areas,5 and dedifferentiated liposarcomas rarely arise in the subcutaneous fat. On histology, atypical fibroblasts and myofibroblasts may be identified in adipose tissue adjacent to renal cell carcinoma and may mimic the atypical hyperchromatic stromal cells of well-differentiated liposarcoma.20 Fluorescence in situ hybridization studies for MDM2 gene amplification will be negative in atypical fibroblasts/myofibroblasts but positive in cells of well-differentiated liposarcoma.

The absolute amount of dedifferentiation needed before applying the label of dedifferentiated liposarcoma has not been strictly defined, but it is generally accepted that macroscopically visible (>1.0 cm) areas should be identifiable.5 In most cases of dedifferentiated liposarcoma, however, significant amounts of dedifferentiation are found and this is not an issue. Evans21 described 3 cases of dedifferentiated liposarcoma with <1 cm of dedifferentiation and found that these tumors either did not recur or recurred as atypical lipomatous tumor.

Treatment

In general, clinicians should treat dedifferentiated liposarcoma by following the guidelines established for soft tissue sarcoma treatment. Complete surgical resection with adequate margins is recommended. Radiation and chemotherapy have not been found to confer any real survival benefit in patients with these sarcomas.17,22 Recent research has focused on drugs that specifically target genetic- and epigenetic-associated deregulations associated with this condition; drugs such as these could eliminate liposarcoma cells while sparing healthy tissue.17

Prognosis

The most important prognostic factor in dedifferentiated liposarcoma is the location of the tumor; retroperitoneal lesions are associated with the worst prognosis. The extent of dedifferentiation does not seem to be a prognostic indicator, as tumors with either low-grade or high-grade dedifferentiation have the ability to metastasize and cause death.7 Overall, however, dedifferentiated liposarcoma exhibits a less aggressive clinical course than other types of high-grade pleomorphic sarcomas.23 Dedifferentiated liposarcoma recurs locally in at least 40% of cases,1,7 and all retroperitoneal tumors recurred in a study with follow-up of 10 to 20 years.1 Distant metastases to the lungs, liver, and bone occur in 15% to 20% of cases,7,19 with an overall 5-year mortality rate of 28% to 30%1,7 and higher mortality at 10 to 20 years.1

Conclusion

Dedifferentiated liposarcoma is a rare entity. It is important to recognize any solid nodular focus within an atypical lipomatous tumor/well-differentiated liposarcoma on imaging examinations since dedifferentiated liposarcomas require more aggressive treatment. Magnetic resonance imaging is the best modality for diagnosis and surgical planning. Occasionally, as in our case, radiographs can identify the dedifferentiated area and suggest the diagnosis.

References

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  11. Coulibaly B, Bouvier C, Payan MJ, Thomas P. Recurrent dedifferentiated liposarcoma of mediastinum involving lung and pleura [published online ahead of print July 9, 2009]. Interact Cardiovasc Thorac Surg. 2009; 9(4):741–742. doi:10.1510/icvts.2009.209494 [CrossRef]
  12. Yu L, Jung S, Hojnowski L, Damron T. Best cases from the AFIP: Dedifferentiated liposarcoma of soft tissue with high-grade osteosarcomatous dedifferentiation. Radiographics. 2005; 25(4):1082–1086. doi:10.1148/rg.254045204 [CrossRef]
  13. Kuhnen C, Mentzel T, Sciot R, Lehnhardt M, Homann HH, Debiec-Rychter M. Dedifferentiated liposarcoma with extensive lymphoid component. Pathol Res Pract. 2005; 201(4):347–353. doi:10.1016/j.prp.2005.01.009 [CrossRef]
  14. Mariño-Enríquez A, Fletcher CD, Dal Cin P, Hornick JL. Dedifferentiated liposarcoma with “homologous” lipoblastic (pleomorphic liposarcoma-like) differentiation: clinicopathologic and molecular analysis of a series suggesting revised diagnostic criteria. Am J Surg Pathol. 2010; 34(8):1122–1131. doi:10.1097/PAS.0b013e3181e5dc49 [CrossRef]
  15. Pedeutour F, Forus A, Coindre JM, et al. Structure of the supernumerary ring and giant rod chromosomes in adipose tissue tumors. Genes Chromosomes Cancer. 1999; 24(1):30–41. doi:10.1002/(SICI)1098-2264(199901)24:1<30::AID-GCC5>3.0.CO;2-P [CrossRef]
  16. Binh MB, Sastre-Garau X, Guillou L, et al. MDM2 and CDK4 immunostainings are useful adjuncts in diagnosing well-differentiated and dedifferentiated liposarcoma subtypes: a comparative analysis of 559 soft tissue neoplasms with genetic data. Am J Surg Pathol. 2005; 29(10):1340–1347. doi:10.1097/01.pas.0000170343.09562.39 [CrossRef]
  17. Hoffman A, Lazar AJ, Pollock RE, Lev D. New frontiers in the treatment of liposarcoma, a therapeutically resistant malignant cohort [published online ahead of print December 18, 2010]. Drug Resist Updat. 2011; 14(1):52–66. doi:10.1016/j.drup.2010.11.001 [CrossRef]
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  20. Tanas MR, Sthapanachai C, Nonaka D, et al. Pseudosarcomatous fibroblastic/myofibroblastic proliferation in perinephric adipose tissue adjacent to renal cell carcinoma: a lesion mimicking well-differentiated liposarcoma [published online ahead of print June 12, 2009]. Mod Pathol. 2009; 22(9):1196–1200. doi:10.1038/modpathol.2009.84 [CrossRef]
  21. Evans HL. Atypical lipomatous tumor, its variants, and its combined forms: a study of 61 cases, with a minimum follow-up of 10 years. Am J Surg Pathol. 2007; 31(1):1–14. doi:10.1097/01.pas.0000213406.95440.7a [CrossRef]
  22. Illuminati G, Ceccanei G, Pacilè MA, et al. Surgical outcomes for liposarcoma of the lower limbs with synchronous pulmonary metastases. J Surg Oncol. 2010; 102(7):827–831. doi:10.1002/jso.21706 [CrossRef]
  23. McCormick D, Mentzel T, Beham A, Fletcher CD. Dedifferentiated liposarcoma. Clinicopathologic analysis of 32 cases suggesting a better prognostic subgroup among pleomorphic sarcomas. Am J Surg Pathol. 1994; 18(12):1213–1223. doi:10.1097/00000478-199412000-00004 [CrossRef]
Frontal (A) and lateral (B) radiographs of the right thigh.

Figure: Frontal (A) and lateral (B) radiographs of the right thigh.

Enhance your diagnostic skills with this “test yourself” monthly column, which features a radiograph and challenges you to make a diagnosis.

Authors

Drs Sakamoto, Winalski, and Sundaram are from the Imaging Institute, Drs Winalski and Lietman are from the Department of Biomedical Engineering, Lerner Research Institute, Dr Fritchie is from the Pathology and Laboratory Medicine Institute, and Dr Lietman is from the Orthopaedic and Rheumatologic Institute, Cleveland Clinic, Cleveland, Ohio.

Drs Sakamoto, Winalski, Fritchie, Lietman, and Sundaram have no relevant financial relationships to disclose.

Correspondence should be addressed to: Carl S. Winalski, MD, Imaging Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195 (wi-nalsc@ccf.org).

10.3928/01477447-20110627-34

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