—  SPECIALTY CONFERENCE  —

Bone & Soft Tissue Pathology

Case 1 - Myxoid Liposarcoma with Hypercellular (Transitional) Areas

John R. Goldblum, Cleveland Clinic, Cleveland, OH





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Clinical History
49-year-old female with a 7-cm posterior thigh mass


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Pathological/microscopic findings:
This is a well-circumscribed neoplasm with a distinctly nodular growth pattern. At very low power, one can appreciate less cellular, lighter staining myxoid zones alternating with more cellular darker staining zones. The latter areas comprise the minority of the neoplasm, however. The less cellular myxoid zones are comprised of spindled cells with minimal cytologic atypia deposited in an abundant myxoid stroma. Many of the cells have eccentrically located scalloped nuclei with large cytoplasmic vacuoles resembling lipoblasts. In some areas, a prominent plexiform "chicken wire" vascular pattern can be appreciated. The darker staining areas show a proliferation of cells with an ovoid to round cell morphology and higher-grade nuclear atypia. Myxoid stroma can still be seen between these cells, and in some areas, the arborizing vascular pattern can still be appreciated, although it is less conspicuous. Scattered mitotic figures can be identified and are generally more prominent in the more cellular zones.

Differential diagnosis:
The differential diagnosis includes a variety of myxoid sarcomas, including myxofibrosarcoma, extraskeletal myxoid chondrosarcoma and myxoid liposarcoma. Another consideration might include a well-differentiated liposarcoma with areas of dedifferentiation resembling myxofibrosarcoma.

Final Diagnosis:
Myxoid Liposarcoma with Hypercellular (Transitional) Areas

Discussion:
The pathologist need not panic when one encounters a myxoid soft tissue lesion. In general, these entities can be separated from one another when one pays close attention to certain morphologic features when evaluating such lesions. Immunohistochemical stains (aside from S100 protein) generally play little role in this differential diagnosis, but more recently, molecular analyses using FISH probes to specific genes (e.g. DDIT3, FUS, EWSR1) have become useful in the evaluation of myxoid sarcomas.

There are several benign myxoid soft tissue lesions which one might consider in this case (or in many other myxoid soft tissue lesions). Intramuscular myxoma typically occurs in middle-aged to elderly patients and usually presents as a painless, palpable, fluctuant mass within the deep soft tissue of the thigh, shoulder, buttocks or upper arm, although virtually any site may be involved. [1] In addition, lesions with similar histology can occur in a cutaneous and juxta-articular location. Although usually solitary, multiple intramuscular myxomas have been found to be associated with fibrous dysplasia, and generally occur in the same anatomic region as the bony abnormalities. [2] Rare patients also display melanotic pigmentation of the skin and endocrine abnormalities (Albright syndrome). Myxomas occurring in a cutaneous location may be sporadic or associated with Carney's complex, characterized by an association with endocrine abnormalities, spotting pigmentation, cardiac myxomas and psammomatous melanotic schwannoma (among other lesions), inherited in a autosomal-dominant manner. [3] The juxta-articular myxoma is another variant of myxoma most commonly found in the area of the knee. [4]

Grossly, the intramuscular myxoma appears to be well circumscribed, although a true fibrous capsule is not present. Histologically, these lesions characteristically are of low cellularity, composed of bland spindled or stellate cells with cytoplasmic processes. The cells tend not to touch one another, but rather are separated by abundant myxoid stroma composed of a hyaluronic acid. Although some cells with vacuolated cytoplasm may be present and can resemble lipoblasts, these are actually macrophages that have imbibed products of the myxoid stroma resulting in cytoplasmic vacuolization. In addition, although grossly well circumscribed, there is often some infiltration into the surrounding skeletal muscle with entrapment of atrophic skeletal muscle fibers. Although scattered blood vessels may be present, there is relatively little vascularity, and the vascularity lacks the organization of many myxoid sarcoma (described below). These lesions are essentially cured by local excision and have little tendency to recur, even if incompletely excised.

Aggressive angiomyxoma typically occurs as a large, ill-defined mass within the pelvis, perineum or genital tract in women, [5] although rare cases have also been reported in men. [6] Histologically, aggressive angiomyxoma is composed of spindled or stellate-shaped cells that generally do not touch one another and are separated by an abundant myxoid stroma composed primarily of hyaluronic acid. The cells lack nuclear atypia, and mitotic figures are difficult to identify. Mast cells are frequently prominent. In addition, these lesions are characterized by a prominent vascularity with vessels of different caliber, including thin-walled vessels and thick hyalinized blood vessels. Immunohistochemically, the cells often stain for desmin and estrogen receptor. Although histologically bland, these lesions are characterized by a high rate of local recurrence.

Myxofibrosarcoma (formerly referred to as myxoid MFH) is a low-grade myxoid sarcoma that usually arises in a more superficial location, often on the upper or lower extremities. The tumor has a nodular growth pattern and is comprised of hyperchromatic spindled or stellate-shaped tumor cells deposited in a uniformly myxoid stroma. A characteristic vascular pattern is typically found, with thicker-walled curvilinear blood vessels, often showing perivascular hypercellularity. This lesion has no specific immunophenotype, nor does it show a characteristic cytogenetic aberration.

Also included in the differential diagnosis is low-grade fibromyxoid sarcoma, often referred to as an Evans tumor. This lesion is deceptively bland and is composed of spindled cells of low to moderate cellularity deposited in an alternating fibrous and myxoid stroma. The cells often have a swirling growth pattern and occasional condense in a perivascular location. Cytologically, there is little nuclear atypia, and mitotic figures are extremely difficult to identify. Similar to other myxoid sarcomas, low-grade fibromyxoid sarcoma often has a rich, regular vascular network that is useful in its distinction from a benign lesion. [7, 8, 9] Immunohistochemically, the cells in this neoplasm often stain for epithelial membrane antigen, [10] although more recently, Doyle and colleagues described consistent expression of MUC4. [11] This tumor (and the related hyalinizing spindle cell tumor with giant rosettes) is characterized by a t(7;16) with fusion of the CREB3L2 gene on chromosome 7 with the FUS gene on chromosome 16. [12] Mertens and colleagues reported the presence of CREB3L2-FUS fusions in 22 of 23 (96%) cases of this tumor, [13] although they also noted rare cases of a t(11;16) involving CREB3L1-FUS fusion. We utilize paraffin-embedded tissue for FISH, probing with a FUS breakapart probe to confirm this difficult diagnosis.

Similar to myxoid liposarcoma, extraskeletal myxoid chondrosarcoma also occurs primarily in the deep soft tissues of the extremities. Macroscopically, the neoplasm occurs as a multinodular well-circumscribed mass which frequently shows large areas of hemorrhage. Histologically, this is a lesion of moderate cellularity in which the cells tend to touch one another and are arranged in small cords or strands. The cells show little nuclear atypia, low mitotic activity and have a moderate amount of eosinophilic cytoplasm. The vascularity is not prominent, in contrast to that seen in myxoid liposarcoma and myxofibrosarcoma. Immunohistochemically, these cells rarely stain for S100 protein, and they do not express epithelial markers, unlike soft tissue myoepitheliomas, which typically co-express both of these antigens. In addition, this tumor has been found to harbor a characteristic translocation, t(9;22)(q22;q12) which involves a rearrangement of the EWSR1 gene on 22q12 with the NR4A3 gene on 9q22. [15] Less commonly, a t(9;17) can be detected. Unfortunately, a commercially available probe for NR4A3 is not available and, as such, we currently use FISH to detect aberrations of EWSR1, which is only found in approximately 60-70% of such cases.

The diagnosis in the current case is myxoid liposarcoma, the second most common subtype of liposarcoma. This is a tumor of adult life and typically occurs in the deep soft tissues of the extremities, especially the thigh and popliteal fossa. At low magnification, the most striking feature is the very characteristic delicate plexiform capillary pattern that is found throughout the neoplasm. The spindled cells between the capillaries are primitive mesenchymal cells and vary little from one another without significant nuclear atypia. The cells are evenly distributed and typically do not touch one another. Interspersed between the primitive mesenchymal cells are the diagnostic lipoblasts, which occur in varying numbers.

Round cell liposarcoma is considered to be the poorly differentiated form of myxoid liposarcoma. It is not uncommon to see mixtures of both myxoid and round liposarcoma within the same tumor. Furthermore, the characteristic translocation found in myxoid liposarcoma, t(12;16)(q13;p11), is also found in round cell liposarcoma. [16] At the molecular level, this translocation results in fusion of the DDIT3 (formerly known as the CHOP gene) on 12q13 with the FUS gene on 6p11. Less often, the DDIT3 gene is fused to the N-terminal portion of the EWSR1 gene [t(12;22)(q13;q12)].

A number of studies have found that round cell progression results in a tumor which is much more likely to pursue a more aggressive clinical course. [17, 18, 19, 20, 21, 22] For example, Smith et al studied 29 cases of myxoid/round cell liposarcoma of the extremities and found that those patients whose tumors had >5% round cell component were more likely to develop metastases or died from their disease. [19] Similarly, Antonescu and colleagues found a 5% cut off to be of prognostic significance. [21] This is in contrast to that found by Kilpatrick et al, who found a cut off point of 25% round cell component to be prognostically significant by multivariate analysis. [20]

Part of the problem in the current case is where to establish the cut off for round cell liposarcoma. In many of the aforementioned studies, a precise definition of round cell liposarcoma was not provided. In the study by Smith et al, round cell areas were strictly defined as those areas with a marked increase in cellularity in which the cells were round and separated by little or no myxoid stroma. [18] In these areas, the mitotic index was increased, and the plexiform vascular pattern was difficult to recognize secondary to the overgrowth of primitive round cells. Interestingly, in that study, the authors made a point of defining "transitional zones," defined as areas of increased cellularity compared to typical myxoid liposarcoma, but lacking all of the necessary diagnostic features of round cell liposarcoma mentioned above. Although they had few cases of this type, these hypercellular zones were not found to significantly worsen clinical outcome in the absence of a round cell component. We are currently engaged in a study which is attempting to assess these transitional and round cell zones in a semiquantitative manner in order to more precisely define diagnostic criteria and the impact of such areas on prognosis. In the absence of more definitive data, however, we refer to a case such as the current case as myxoid liposarcoma with hypercellular (transitional) zones, and we typically upgrade such lesions to grade 2/3.

References
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  2. Ireland DC, Soule EH, Ivins JC. Myxoma of somatic soft tissues. A report of 58 patients, 3 with multiple tumors and fibrous dysplasia of bone. Mayo Clin. Proc. 1973;48(6):401-410.

  3. Carney JA, Headington JT, Su WP. Cutaneous myxomas. A major component of the complex of myxomas, spotty pigmentation, and endocrine overactivity. Arch Dermatol. 1986;122(7):790-798.

  4. Meis JM, Enzinger FM. Juxta-articular myxoma: a clinical and pathologic study of 65 cases. Hum. Pathol. 1992;23(6):639-646.

  5. Steeper TA, Rosai J. Aggressive angiomyxoma of the female pelvis and perineum. Report of nine cases of a distinctive type of gynecologic soft-tissue neoplasm. Am. J. Surg. Pathol. 1983;7(5):463-475.

  6. Tsang WY, Chan JK, Lee KC, Fisher C, Fletcher CD. Aggressive angiomyxoma. A report of four cases occurring in men. Am. J. Surg. Pathol. 1992;16(11):1059-1065.

  7. Evans HL. Low-grade fibromyxoid sarcoma. A report of two metastasizing neoplasms having a deceptively benign appearance. Am. J. Clin. Pathol. 1987;88(5):615-619.

  8. Evans HL. Low-grade fibromyxoid sarcoma. A report of 12 cases. Am. J. Surg. Pathol. 1993;17(6):595-600.

  9. Folpe AL, Lane KL, Paull G, Weiss SW. Low-grade fibromyxoid sarcoma and hyalinizing spindle cell tumor with giant rosettes: a clinicopathologic study of 73 cases supporting their identity and assessing the impact of high-grade areas. Am. J. Surg. Pathol. 2000;24(10):1353-1360.

  10. Guillou L, Benhattar J, Gengler C, et al. Translocation-positive low-grade fibromyxoid sarcoma: clinicopathologic and molecular analysis of a series expanding the morphologic spectrum and suggesting potential relationship to sclerosing epithelioid fibrosarcoma: a study from the French Sarcoma Group. Am. J. Surg. Pathol. 2007;31(9):1387-1402.

  11. Doyle LA, Möller E, Dal Cin P, et al. MUC4 is a highly sensitive and specific marker for low-grade fibromyxoid sarcoma. Am. J. Surg. Pathol. 2011;35(5):733-741.

  12. Panagopoulos I, Storlazzi CT, Fletcher CDM, et al. The chimeric FUS/CREB3l2 gene is specific for low-grade fibromyxoid sarcoma. Genes Chromosomes Cancer. 2004;40(3):218-228.

  13. Mertens F, Fletcher CDM, Antonescu CR, et al. Clinicopathologic and molecular genetic characterization of low-grade fibromyxoid sarcoma, and cloning of a novel FUS/CREB3L1 fusion gene. Lab. Invest. 2005;85(3):408-415.

  14. Hinrichs SH, Jaramillo MA, Gumerlock PH, et al. Myxoid chondrosarcoma with a translocation involving chromosomes 9 and 22. Cancer Genet. Cytogenet. 1985;14(3-4):219-226.

  15. Tallini G, Akerman M, Dal Cin P, et al. Combined morphologic and karyotypic study of 28 myxoid liposarcomas. Implications for a revised morphologic typing, (a report from the CHAMP Group). Am. J. Surg. Pathol. 1996;20(9):1047-1055.

  16. Azumi N, Curtis J, Kempson RL, Hendrickson MR. Atypical and malignant neoplasms showing lipomatous differentiation. A study of 111 cases. Am. J. Surg. Pathol. 1987;11(3):161-183.

  17. Enzinger FM, Winslow DJ. Liposarcoma. A study of 103 cases. Virchows Arch Pathol Anat Physiol Klin Med. 1962;335:367-388.

  18. Smith TA, Easley KA, Goldblum JR. Myxoid/round cell liposarcoma of the extremities. A clinicopathologic study of 29 cases with particular attention to extent of round cell liposarcoma. Am. J. Surg. Pathol. 1996;20(2):171-180.

  19. Kilpatrick SE, Doyon J, Choong PF, Sim FH, Nascimento AG. The clinicopathologic spectrum of myxoid and round cell liposarcoma. A study of 95 cases. Cancer. 1996;77(8):1450-1458.

  20. Antonescu CR, Tschernyavsky SJ, Decuseara R, et al. Prognostic impact of P53 status, TLS-CHOP fusion transcript structure, and histological grade in myxoid liposarcoma: a molecular and clinicopathologic study of 82 cases. Clin. Cancer Res. 2001;7(12):3977-3987.

  21. Evans CP, Vaccaro JA, Storrs BG, Christ PJ. Suprarenal occurrence of an adenomatoid tumor. J. Urol. 1988;139(2):348-349.