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Subclassification of pleomorphic sarcomas: How and why should we care?
Accepted Manuscript Subclassification of pleomorphic sarcomas: How and why should we care?
Jason L. Hornick PII: DOI: Reference:
S1092-9134(18)30321-6 doi:10.1016/j.anndiagpath.2018.10.006 YADPA 51303
To appear in: Received date: Accepted date:
10 October 2018 10 October 2018
Please cite this article as: Jason L. Hornick , Subclassification of pleomorphic sarcomas: How and why should we care?. Yadpa (2018), doi:10.1016/j.anndiagpath.2018.10.006
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Subclassification of Pleomorphic Sarcomas: How and Why Should We Care?
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Jason L. Hornick, M.D., Ph.D.
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Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston,
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MA, United States.
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Corresponding author: Jason L. Hornick, M.D., Ph.D. Department of Pathology Brigham and Women’s Hospital 75 Francis Street Boston, MA 02115 Telephone: 617-525-7257 Fax: 617-566-3897 Email: [email protected]
Running title: Subclassification of pleomorphic sarcomas
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Subclassification of Pleomorphic Sarcomas: How and Why Should We Care?
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Running title: Subclassification of pleomorphic sarcomas
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ACCEPTED MANUSCRIPT ABSTRACT Pleomorphic sarcomas are a heterogeneous group of mesenchymal neoplasms with widely varied clinical behavior but overlapping histologic appearances. The following guidelines are helpful when approaching the diagnosis of a pleomorphic sarcoma. (1) Be aware of the relative
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incidence of the various sarcoma types: several pleomorphic sarcomas are relatively common
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(e.g., dedifferentiated liposarcoma and undifferentiated pleomorphic sarcoma), whereas others are exceptionally rare. (2) Pay attention to anatomic location: some pleomorphic sarcomas have a
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predilection for somatic soft tissues, especially the thigh (e.g., undifferentiated pleomorphic sarcoma, pleomorphic liposarcoma, pleomorphic rhabdomyosarcoma), whereas other
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pleomorphic sarcomas most often arise in the retroperitoneum (e.g., dedifferentiated
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liposarcoma). (3) Carefully sample the resection specimen, paying particular attention to areas with differences in gross appearances (e.g., fleshy, fibrous, mucoid, or gritty). (4) Search for
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histologic clues (i.e., myxoid stroma, lipoblasts, and osteoid matrix, in order to diagnose
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myxofibrosarcoma, pleomorphic liposarcoma, and extraskeletal osteosarcoma, respectively); these critical diagnostic features may be limited in extent. (5) Apply immunohistochemistry
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judiciously, after generating a differential diagnosis; always exclude metastatic sarcomatoid
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carcinoma and melanoma before diagnosing a pleomorphic sarcoma. This review will present an approach to the diagnosis of pleomorphic sarcomas, emphasizing differential diagnosis and the application of ancillary studies (immunohistochemistry and FISH), when relevant. Key words: Pleomorphic sarcoma, myxofibrosarcoma, dedifferentiated liposarcoma, immunohistochemistry, MDM2
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ACCEPTED MANUSCRIPT 1.1. Introduction Pleomorphic sarcomas are a heterogeneous group of mesenchymal neoplasms with widely varied clinical behavior (Table 1).1,2 For example, at one end of the spectrum, dedifferentiated liposarcoma, when arising at central body cavity sites (most often
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retroperitoneum), has significant potential for local recurrence (even following multi-visceral
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resection), although the metastatic risk is only 15-20%. Patients with high-grade myxofibrosarcoma have a 25-30% risk of metastasis, lower than many other pleomorphic
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sarcomas; however, myxofibrosarcoma is among the most infiltrative sarcoma types, with an exceptionally high local recurrence rate without wide surgical margins. At the other end of the
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spectrum, pleomorphic myogenic sarcomas have very high metastatic potential,3,4 up to 90% for
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pleomorphic rhabdomyosarcoma. These marked differences in patterns of recurrence and risks of metastasis are strong arguments for subclassification of pleomorphic sarcomas; the most
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important reason for tumor classification is to provide useful information for patient care and
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prognostication. It is critical to exclude metastatic (sarcomatoid) carcinoma and metastatic melanoma before diagnosing a pleomorphic sarcoma. Following a general discussion of an
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approach to the diagnosis of pleomorphic sarcomas, each tumor type will be discussed in turn,
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emphasizing key histologic features and ways in which to distinguish among the various tumor
2.1 Approach to pleomorphic sarcomas The following guidelines are helpful when approaching a pleomorphic sarcoma. (1) Be aware of the relative incidence of the various sarcoma types: several pleomorphic sarcomas are relatively common (e.g., dedifferentiated liposarcoma and undifferentiated pleomorphic 4
ACCEPTED MANUSCRIPT sarcoma), whereas others are exceptionally rare. (2) Pay attention to anatomic location: some pleomorphic sarcomas have a predilection for somatic soft tissues, especially the thigh (Table 2), whereas other pleomorphic sarcomas most often arise in the retroperitoneum (Table 3). (3) Carefully sample the resection specimen, paying particular attention to areas with differences in
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gross appearances (e.g., fleshy, fibrous, mucoid, or gritty). (4) Search for histologic clues (i.e.,
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myxoid stroma, lipoblasts, and osteoid matrix; Table 4); these critical diagnostic features may be
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limited in extent. (5) Apply immunohistochemistry (IHC) judiciously, after generating a differential diagnosis; this is true of all soft tissue tumor pathology (and all oncologic
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pathology!). It is important not to let IHC ordering get out of control; it is rare for a case to
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require more than 6-8 markers (even in cases of undifferentiated sarcomas). The IHC markers that are helpful for subclassification of pleomorphic sarcomas are listed in Table 5. Most
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pleomorphic sarcomas show complex (diagnostically unhelpful) cytogenetics; IHC using
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differentiation (lineage) markers is helpful to support the diagnosis of some of these tumor types (i.e., the myogenic sarcomas). The only exception is dedifferentiated liposarcoma, which shows
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relatively simple cytogenetics and harbors ring and giant marker chromosomes containing
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12q13-15 amplification, including MDM2 and CDK4: IHC or FISH assessing protein
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overexpression or gene amplification is therefore diagnostically useful. 3.1 Myxofibrosarcoma Myxofibrosarcoma usually affects middle-aged to elderly adults; in fact, myxofibrosarcoma is the most common sarcoma of the elderly.5-7 The extremities and trunk are the most common anatomic sites. Myxofibrosarcoma does not arise in the retroperitoneum, abdominal cavity or pelvis; if the histologic appearances resemble myxofibrosarcoma at such 5
ACCEPTED MANUSCRIPT sites, the tumor is nearly always dedifferentiated liposarcoma.8 Myxofibrosarcoma usually arises in superficial soft tissues (subcutis and dermis), which is unusual among the pleomorphic sarcomas: 70% are superficial and 30% are deep. As mentioned previously, myxofibrosarcoma has a high risk of local recurrence, owing to its characteristically diffuse infiltration along fascial
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planes.9-12 In contemporary sarcoma management, myxofibrosarcoma is one of the few sarcoma
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types that still sometimes results in amputations, following multiple local recurrences.11 The
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metastatic risk for low-grade myxofibrosarcoma is <5%, whereas the risk for high-grade tumors is 25-30%.6,7,9,10 The epithelioid variant of myxofibrosarcoma pursues a more aggressive clinical
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course, with at least 50% of patients developing metastases.13,14 Of note, tumor grade often
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increases with local recurrence.15
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Myxofibrosarcoma usually shows a lobulated appearance (Figure 1). Low-grade myxofibrosarcomas are hypocellular tumors dominated by myxoid stroma; curvilinear, thin-
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walled blood vessels and scattered large, sometimes pleomorphic cells with hyperchromatic
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nuclei, often clustered around the blood vessels, are typical findings (see Figure 1).7,9 High-grade tumors may be dominated by sheets of non-descript pleomorphic cells (resembling all the other
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pleomorphic sarcomas); a search for myxoid areas showing typical histologic appearances is
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critical to make an accurate diagnosis (see Figure 1). The epithelioid variant of myxofibrosarcoma is dominated by large, epithelioid cells; such tumors may mimic metastatic carcinoma or melanoma.13 IHC does not play a significant role in diagnosis of this sarcoma type. As mentioned above, histologically similar tumors in the retroperitoneum and other central body cavity sites are usually dedifferentiated liposarcomas.8 The differential diagnosis can also include pleomorphic liposarcoma, a subset of which shows significant histologic overlap with myxofibrosarcoma.16,17 Sharp circumscription and the lack of a lobulated growth pattern argue 6
ACCEPTED MANUSCRIPT against myxofibrosarcoma; identification of lipoblasts confirms pleomorphic liposarcoma (see section 4.1). 4.1 Pleomorphic liposarcoma
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Pleomorphic liposarcoma is a rare tumor type, representing only 5% of sarcomas
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designated “liposarcoma”. This tumor type typically affects middle-aged to elderly adults with a
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marked predilection for the extremities; the retroperitoneum is rarely involved.16-19 Similar to many other pleomorphic sarcomas, pleomorphic liposarcoma usually arises in deep (subfascial)
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soft tissues (90%). Only 10% of such tumors arise in the subcutis; very rarely, pleomorphic
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liposarcoma may arise in the dermis. The metastatic risk for pleomorphic liposarcoma is 50%, intermediate among the pleomorphic sarcomas.16-19
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Pleomorphic liposarcomas show a wide range in histologic appearances (Table 6), unified
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by the presence of lipoblasts.16,17 Of note, identifying lipoblasts is not required for the diagnosis of other liposarcomas (well-differentiated, dedifferentiated, and myxoid liposarcomas) but is
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necessary to diagnose pleomorphic liposarcoma.20 Most pleomorphic liposarcomas resemble an
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undifferentiated pleomorphic sarcoma, with wide variation in cell size, including spindle cells and pleomorphic cells with very large, often bizarre nuclei, and scattered pleomorphic lipoblasts,
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defined as cells with hyperchromatic nuclei indented (scalloped) by lipid-containing vacuoles (Figure 2). Without identifying the lipoblasts, proper diagnosis is impossible. As mentioned previously, some pleomorphic liposarcomas have areas resembling myxofibrosarcoma (and some are nearly identical to myxofibrosarcoma), other than the presence of lipoblasts (see Figure 2).17 Finally, some pleomorphic liposarcomas have epithelioid features, closely mimicking adrenal cortical or renal cell carcinoma (see Figure 2); when an adrenal cortical carcinoma-like tumor is 7
ACCEPTED MANUSCRIPT encountered on the extremities (and there is no radiologic evidence of a primary tumor in the retroperitoneum), the epithelioid variant of pleomorphic liposarcoma should be considered.21 5.1 Extraskeletal osteosarcoma
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Primary extraskeletal osteosarcoma is a rare tumor type mostly of older adults, with a
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male predominance.22-26 Proximal extremities (especially thigh), trunk, shoulder, and pelvic
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girdle are the most common anatomic sites. Nearly all extraskeletal osteosarcomas are deepseated. If a pleomorphic sarcoma with focal ossification is encountered in the retroperitoneum or
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abdominal cavity, dedifferentiated liposarcoma should be excluded (see section 8.1). Although
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data are limited, reported local recurrence and distant metastatic rates are 40% and 60%, respectively.22-26 The optimal systemic therapeutic approach for extraskeletal osteosarcoma is not
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clear; some medical oncologists with expertise in sarcoma management favor treating
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extraskeletal osteosarcoma in a similar fashion as other pleomorphic sarcomas of adults, whereas
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others favor conventional osteosarcoma chemotherapy.27 The diagnosis of extraskeletal osteosarcoma relies upon the identification of osteoid
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matrix associated with cytologically malignant cells (similar to conventional osteosarcoma);25 the tumor cells may be pleomorphic, epithelioid, or spindled (Figure 3). The presence of
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osteoclast-like giant cells is a helpful clue to the diagnosis of osteosarcoma. The typical lacy pattern of osteoid surrounding tumor cells, with variable calcification, should be sought. It is notoriously challenging to distinguish bona fide osteoid from hyalinized collagen (the latter is commonly identified in a wide range of soft tissue tumor types). IHC for the osteoblast nuclear transcription factor SATB2 can be helpful to make this distinction: when tumor cells adjacent to potential osteoid matrix show strong nuclear staining, one can be more certain of the diagnosis 8
ACCEPTED MANUSCRIPT (see Figure 3).28 Of note, other tumor types that show heterologous osseous differentiation (and benign tumors with metaplastic ossification) will also express SATB2 in the cells associated with osteoid; SATB2 is therefore not specific for osteosarcoma among mesenchymal neoplasms.28
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6.1 Pleomorphic rhabdomyosarcoma
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Pleomorphic rhabdomyosarcoma is a rare sarcoma type that usually arises in the deep
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soft tissues of the extremities of older adults.29,30 As previously mentioned, pleomorphic rhabdomyosarcoma has the worst prognosis with the highest metastatic potential of all the
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pleomorphic sarcomas (see Table 1).29,30 It is not clear whether patients with pleomorphic
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rhabdomyosarcoma should be treated in a similar fashion as children and young adults with the more common embryonal and alveolar rhabdomyosarcomas, although chemotherapeutic
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approaches similar to those administered for other adult sarcomas is likely more appropriate.31
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Pleomorphic rhabdomyosarcoma shows the most intense cytoplasmic eosinophilia of the
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pleomorphic sarcomas; the quality of the cytoplasm is a helpful diagnostic feature, which is often notable from low-power examination. The tumor cells range from pleomorphic to epithelioid or
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spindled, usually with marked nuclear atypia, coarse chromatin, occasional large, bizarre cells, and often abundant brightly eosinophilic cytoplasm (Figure 4).29,30 Desmin is diffusely positive,
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whereas myogenin and MyoD1 typically show limited staining in only scattered cells.30 When the tumor shows a fascicular, spindle-cell appearance, leiomyosarcoma may be a serious diagnostic consideration; leiomyosarcomas are usually positive for SMA and often for caldesmon; myogenin and MyoD1 distinguish rhabdomyosarcomas from leiomyosarcoma. 7.1 Pleomorphic leiomyosarcoma
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ACCEPTED MANUSCRIPT Pleomorphic leiomyosarcoma refers to leiomyosarcomas with significant pleomorphic cells, such that they resemble other pleomorphic sarcomas.32,33 The extent of pleomorphism required for this designation is not well defined; however, since leiomyosarcomas with marked pleomorphism have similar clinical behavior as other high-grade leiomyosarcomas, this
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distinction is not critical. Pleomorphic leiomyosarcomas affect older adults; this variant has a
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predilection for deep soft tissues of the extremities and retroperitoneum.32,33 Pleomorphic
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leiomyosarcoma has at least a 70% risk of metastasis; lungs, bone, and liver are the most
metastasize to the skin (especially the scalp).34
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common metastatic sites.32,33 Of note, leiomyosarcoma is the most common sarcoma to
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Pleomorphic leiomyosarcoma cells are often an admixture of large, bizarre cells and
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more conventional elongated spindle cells, with brightly eosinophilic cytoplasm, usually less intensely eosinophilic than pleomorphic rhabdomyosarcoma (see Figure 4).32 By IHC,
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expression of SMA, desmin, and caldesmon is helpful to support the diagnosis; caldesmon is the
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most specific but least sensitive of these markers. There is no well-defined minimal extent of SMA and desmin required to diagnose leiomyosarcoma; in order to render a diagnosis of
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pleomorphic leiomyosarcoma, areas of conventional histology with a fascicular architecture and
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broad, blunt-ended nuclei should be sought (see Figure 4), although some cases are nearly completely pleomorphic with only few cells showing typical cytomorphology. Pleomorphic rhabdomyosarcomas are usually negative for SMA (although focal expression may be observed); staining for the skeletal muscle nuclear transcription factors myogenin and MyoD1 is specific for rhabdomyosarcoma. Undifferentiated pleomorphic sarcomas may show focal staining for SMA; this finding is insufficient evidence for a diagnosis of leiomyosarcoma.
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ACCEPTED MANUSCRIPT 8.1 Dedifferentiated liposarcoma Dedifferentiated liposarcoma nearly exclusively affects adults, usually middle-aged to elderly, and has a marked predilection for central body cavity sites, especially the retroperitoneum, pelvis, and abdomen.35,36 Dedifferentiated liposarcoma rarely arises in the
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extremities and trunk wall.37 As discussed previously, dedifferentiated liposarcoma has an
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exceptionally high local recurrence rate, although the metastatic potential is low among the pleomorphic sarcomas (only 15-20%). Multivisceral resections (removing adjacent organs along
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with the tumor) improves recurrence-free survival; nonetheless, most patient eventually succumb to uncontrolled local recurrence, sometimes decades following initial surgery for the primary
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tumor.38-41 Recent studies suggest that histologic grading (using the FNCLCC system) predicts
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metastatic risk: high-grade dedifferentiated liposarcomas have higher metastatic potential than
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intermediate-grade tumors.38-40
Dedifferentiated liposarcoma is defined as a (usually abrupt) transition from well-
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differentiated liposarcoma to a non-lipogenic sarcoma,20 although in some cases the transition is
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more gradual. Since we now understand the molecular genetic basis for this tumor type, it is possible to make the diagnosis without identifying a well-differentiated component (see below).
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Dedifferentiated liposarcoma shows highly variable morphology; tumors may include pleomorphic, spindle cell, and epithelioid components, and myxoid stroma may be observed (Figure 5).35,36,42 In fact, marked intratumoral heterogeneity in a sarcoma should raise suspicion for dedifferentiated liposarcoma. Around 10% of dedifferentiated liposarcomas show heterologous differentiation (most often rhabdomyoblastic or chondro-osseous);43 tumors with rhabdomyoblastic differentiation appear to pursue a more aggressive clinical course.39 Rarely, 11
ACCEPTED MANUSCRIPT dedifferentiated liposarcoma may show “homologous” lipoblastic differentiation in the otherwise undifferentiated component, closely mimicking pleomorphic liposarcoma;44,45 when such a tumor is encountered in the retroperitoneum, dedifferentiated liposarcoma should be excluded (by IHC or FISH; see below) before diagnosing pleomorphic liposarcoma. Dedifferentiated
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liposarcomas with myxoid stroma may closely resemble myxofibrosarcoma;8 however,
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myxofibrosarcoma does not arise in the retroperitoneum or abdominal cavity – anatomic location
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alone is a helpful distinguishing feature.
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Dedifferentiated liposarcoma characteristically shows amplification of the chromosome 12q13-15 region, in the form of ring and giant marker chromosomes.46,47 These amplification
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events nearly always involve MDM2; CDK4 is also often amplified.46 FISH for MDM2 can
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therefore be used to confirm the diagnosis; this is especially helpful in a limited core needle biopsy or fine needle aspiration specimen. Amplification leads to overexpression of the MDM2
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(and often CDK4) proteins; IHC can also be used to support the diagnosis (see Figure 5),48
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although available antibodies are difficult to optimize, and many laboratories prefer to go directly to FISH.49 IHC for these markers is less specific than FISH,48,50 although the
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combination of MDM2 and CDK4 staining is relatively specific for dedifferentiated liposarcoma
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among the pleomorphic sarcomas (Table 7).48 To summarize: consider dedifferentiated liposarcoma (1) at central body cavity sites (retroperitoneum, abdominal cavity, pelvis), and (2) when there is marked intratumoral heterogeneity (spindle cell, pleomorphic, epithelioid, and myxoid components). In a resection specimen, search for an adjacent well-differentiated liposarcoma component; if such a component is identified, no ancillary studies are needed. 12
ACCEPTED MANUSCRIPT 9.1 Undifferentiated pleomorphic sarcoma Undifferentiated pleomorphic sarcoma is a diagnosis of exclusion.51,52 In a resection specimen, extensively sampling should be undertaken, in order to search for lipoblasts, osteoid matrix, and a well-differentiated liposarcoma component. IHC should be performed to exclude
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metastatic sarcomatoid carcinoma (keratins) and melanoma (S100 protein and/or SOX10),
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pleomorphic myogenic sarcomas (SMA and desmin), and, at central body cavity sites, dedifferentiated liposarcoma (IHC for MDM2 and CDK4 or FISH for MDM2). Undifferentiated
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pleomorphic sarcomas are not histologically distinctive and may show a fascicular, storiform, or sheet-like appearance and are often composed of an admixture of spindle cells and pleomorphic,
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occasionally multinucleated cells, with palely eosinophilic or somewhat basophilic cytoplasm
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(Figure 6).51 Expression of CD34 and focal SMA may be observed; these findings are non-
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specific.
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10.1 Summary
Subclassification of pleomorphic sarcomas is clinically important, given their marked
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differences in metastatic potential and local recurrence rates. Thorough sampling of resection specimens is critical, in order to search for focal, sometimes subtle histologic clues (myxoid
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areas, lipoblasts, and osteoid matrix). IHC plays a central role in confirming the diagnosis of pleomorphic myogenic sarcomas, which have the worst prognosis among the pleomorphic sarcomas. IHC or FISH is helpful to support the diagnosis of dedifferentiated liposarcoma, especially in limited biopsy samples; dedifferentiated liposarcoma should always be a diagnostic consideration for large tumors of the retroperitoneum and abdominal cavity.
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recurrence and improves risk stratification in primary retroperitoneal sarcoma. Ann Surg.
epithelioid/epithelial features. Am J Surg Pathol. 2017;41:1523-1531. Evans HL, Khurana KK, Kemp BL, et al. Heterologous elements in the dedifferentiated
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component of dedifferentiated liposarcoma. Am J Surg Pathol. 1994;18:1150–1157. 44.
Mariño-Enríquez A, Fletcher CD, Dal Cin P, et al. 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;34:1122–1131. 18
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Boland JM, Weiss SW, Oliveira AM, et al. Liposarcomas with mixed well-differentiated
and pleomorphic features: a clinicopathologic study of 12 cases. Am J Surg Pathol. 2010;34:837843. 46.
Dei Tos AP, Doglioni C, Piccinin S, et al. Coordinated expression and amplification of
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the MDM2, CDK4, and HMGI-C genes in atypical lipomatous tumours. J Pathol 2000;190:531-
Sirvent N, Coindre JM, Maire G, et al. Detection of MDM2-CDK4 amplification by
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47.
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fluorescence in situ hybridization in 200 paraffin-embedded tumor samples: utility in diagnosing
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adipocytic lesions and comparison with immunohistochemistry and real-time PCR. Am J Surg
48.
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Pathol 2007;31:1476-1489.
Binh MB, Sastre-Garau X, Guillou L, et al. MDM2 and CDK4 immunostainings are
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useful adjuncts in diagnosing well-differentiated and dedifferentiated liposarcoma subtypes: a
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comparative analysis of 559 soft tissue neoplasms with genetic data. Am J Surg Pathol 2005;29:1340-1347.
Thway K, Wang J, Swansbury J, et al. Fluorescence in situ hybridization for MDM2
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49.
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amplification as a routine ancillary diagnostic tool for suspected well-differentiated and dedifferentiated liposarcomas: experience at a tertiary center. Sarcoma. 2015;2015:812089. Makise N, Sekimizu M, Kubo T, et al. Clarifying the distinction between malignant
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peripheral nerve sheath tumor and dedifferentiated liposarcoma: a critical reappraisal of the diagnostic utility of MDM2 and H3K27me3 status. Am J Surg Pathol. 2018;42:656-664. 51.
Dei Tos AP. Classification of pleomorphic sarcomas: where are we now?
Histopathology. 2006;48:51-62.
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Widemann BC, Italiano A. Biology and management of undifferentiated pleomorphic
sarcoma, myxofibrosarcoma, and malignant peripheral nerve sheath tumors: state of the art and
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perspectives. J Clin Oncol. 2018;36:160-167.
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ACCEPTED MANUSCRIPT FIGURE LEGENDS
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Figure 1. Myxofibrosarcoma. (A) Myxofibrosarcoma typically shows a lobulated appearance from low magnification. This example contains abundant myxoid stroma. (B) Curvilinear blood vessels and scattered cells with enlarged, hyperchromatic nuclei are characteristic features in the myxoid areas. (C) An example of myxofibrosarcoma with increased cellularity. Note the curvilinear blood vessels. (D) High-grade myxofibrosarcomas may contain extensive areas indistinguishable from undifferentiated pleomorphic sarcoma. A careful search for a myxoid component (right side) is mandatory for proper diagnosis.
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Figure 2. Pleomorphic liposarcoma. (A) In some tumors, lipoblasts can be few and far between. In this field, a single diagnostic lipoblast with a hyperchromatic nucleus indented by lipid vacuoles is seen in the middle of an otherwise non-distinctive pleomorphic sarcoma. (B) Other examples show extensive lipoblastic differentiation. Not the large, bizarre cell in the center of a sea of lipoblasts. (C) Some pleomorphic liposarcomas closely mimic myxofibrosarcoma. Identification of lipoblasts (left lower corner) allows for the correct diagnosis. (D) The epithelioid variant of pleomorphic liposarcoma may closely resemble adrenal cortical carcinoma. Note the lipoblasts on the right side of the field.
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Figure 3. Extraskeletal osteosarcoma. (A) The tumor consists of sheets of epithelioid and spindle cells with marked nuclear atypia. Osteoid matrix may be difficult to distinguish from hyalinized collagen. (B) Strong nuclear staining for SATB2 by immunohistochemistry supports the diagnosis of osteosarcoma, although this marker is not entirely specific and is also expressed in benign bone-forming tumors.
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Figure 4. Pleomorphic myogenic sarcomas. (A) Pleomorphic rhabdomyosarcoma consisting of an admixture of epithelioid and spindle cells with abundant, intensely eosinophilic cytoplasm, including scattered pleomorphic cells with large nucleoli. (B) Pleomorphic leiomyosarcoma containing bizarre, pleomorphic cells. Note the eosinophilic cytoplasm and area of more conventional morphology (bottom).
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Figure 5. Dedifferentiated liposarcoma. (A) This tumor type may be indistinguishable from undifferentiated pleomorphic sarcoma. (B) Some examples show spindle-cell morphology and a more uniform appearance. (C) Myxoid stroma may be seen (left side); such tumors can mimic myxofibrosarcoma, but the latter tumor type does not arise at central body cavity sites such as the retroperitoneum. Not the fascicular, spindle-cell component that resembles leiomyosarcoma (right side). (D) Immunohistochemistry for MDM2 can be used to support the diagnosis. Many laboratories prefer fluorescence in situ hybridization (FISH), in part because the available antibodies are difficult to optimize; moreover, MDM2 gene amplification is more specific for dedifferentiated liposarcoma than MDM2 protein overexpression. Figure 6. Undifferentiated pleomorphic sarcoma. (A) A pleomorphic sarcoma composed of spindle cells and large, bizarre and multinucleated cells with palely basophilic cytoplasm, arranged in a somewhat storiform growth pattern. Note the numerous mitotic figures. (B) Undifferentiated pleomorphic sarcoma with eosinophilic cytoplasm may mimic pleomorphic leiomyosarcoma or pleomorphic rhabdomyosarcoma. Immunohistochemistry for myogenic 21
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markers can distinguish among these tumor types. Undifferentiated pleomorphic sarcoma is a diagnosis of exclusion.
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Table 1. Metastatic potential of pleomorphic sarcomas Metastatic rate
Dedifferentiated liposarcoma
15-20%
Myxofibrosarcoma (high grade)
25-30%
Undifferentiated pleomorphic sarcoma
50%
Pleomorphic liposarcoma
50%
Extraskeletal osteosarcoma
60%
Pleomorphic leiomyosarcoma
70%
Pleomorphic rhabdomyosarcoma
90%
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Tumor type
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Table 2. Pleomorphic sarcomas of somatic soft tissue (especially thigh) Rare
Myxofibrosarcoma
Pleomorphic liposarcoma
Undifferentiated pleomorphic sarcoma
Pleomorphic rhabdomyosarcoma
Pleomorphic leiomyosarcoma
Extraskeletal osteosarcoma
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Relatively common
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Table 3. Pleomorphic sarcomas of the retroperitoneum Rare
Dedifferentiated liposarcoma
Undifferentiated pleomorphic sarcoma
Pleomorphic leiomyosarcoma
Pleomorphic liposarcoma
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Relatively common
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Table 4. Histologic features of pleomorphic sarcomas Histologic finding
Tumor types
Myxoid stroma Myxofibrosarcoma
Subset of cases
Dedifferentiated liposarcoma
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Defining feature
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Pleomorphic liposarcoma
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Undifferentiated pleomorphic sarcoma Lipoblasts
Pleomorphic liposarcoma
Subset of cases
Dedifferentiated liposarcoma
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Defining feature
Osteoid
Extraskeletal osteosarcoma
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Dedifferentiated liposarcoma
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Table 5. Immunohistochemical markers helpful to subclassify pleomorphic sarcomas Marker
Pleomorphic leiomyosarcoma
SMA, desmin, caldesmon
Pleomorphic rhabdomyosarcoma
desmin, myogenin, MyoD1
Dedifferentiated liposarcoma
MDM2, CDK4
Extraskeletal osteosarcoma
SATB2
Metastatic carcinoma
Keratins
Metastatic melanoma
S100 protein, SOX10
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Tumor type
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Table 6. Histologic variability in pleomorphic liposarcoma Frequency
Pleomorphic sarcoma with scattered or sheets of lipoblasts
65%
Focal areas resembling myxofibrosarcoma
45%
Almost entirely myxofibrosarcoma-like
15%
Epithelioid areas
25%
Pure epithelioid variant
10%
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Histologic pattern
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MDM2
CDK4
Dedifferentiated liposarcoma
98%
92%
Malignant peripheral nerve sheath tumor
65%
10%
Myxofibrosarcoma
40%
15%
Leiomyosarcoma
5%
1%
Gastrointestinal stromal tumor
0%
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Tumor type
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Table 7. Immunohistochemistry for MDM2 and CDK4 in pleomorphic and spindle cell sarcomas
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0%
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Highlights Pleomorphic sarcomas are a heterogeneous group of tumors with widely varied metastatic potential
A careful search for histologic clues (myxoid stroma, lipoblasts, osteoid matrix) is mandatory
Metastatic sarcomatoid carcinoma and melanoma should always be excluded
Immunohistochemistry or FISH for MDM2 aids in the diagnosis of dedifferentiated liposarcoma
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Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Jason L. Hornick PII: DOI: Reference:
S1092-9134(18)30321-6 doi:10.1016/j.anndiagpath.2018.10.006 YADPA 51303
To appear in: Received date: Accepted date:
10 October 2018 10 October 2018
Please cite this article as: Jason L. Hornick , Subclassification of pleomorphic sarcomas: How and why should we care?. Yadpa (2018), doi:10.1016/j.anndiagpath.2018.10.006
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Subclassification of Pleomorphic Sarcomas: How and Why Should We Care?
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Jason L. Hornick, M.D., Ph.D.
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Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston,
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MA, United States.
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Corresponding author: Jason L. Hornick, M.D., Ph.D. Department of Pathology Brigham and Women’s Hospital 75 Francis Street Boston, MA 02115 Telephone: 617-525-7257 Fax: 617-566-3897 Email: [email protected]
Running title: Subclassification of pleomorphic sarcomas
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Subclassification of Pleomorphic Sarcomas: How and Why Should We Care?
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Running title: Subclassification of pleomorphic sarcomas
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ACCEPTED MANUSCRIPT ABSTRACT Pleomorphic sarcomas are a heterogeneous group of mesenchymal neoplasms with widely varied clinical behavior but overlapping histologic appearances. The following guidelines are helpful when approaching the diagnosis of a pleomorphic sarcoma. (1) Be aware of the relative
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incidence of the various sarcoma types: several pleomorphic sarcomas are relatively common
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(e.g., dedifferentiated liposarcoma and undifferentiated pleomorphic sarcoma), whereas others are exceptionally rare. (2) Pay attention to anatomic location: some pleomorphic sarcomas have a
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predilection for somatic soft tissues, especially the thigh (e.g., undifferentiated pleomorphic sarcoma, pleomorphic liposarcoma, pleomorphic rhabdomyosarcoma), whereas other
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pleomorphic sarcomas most often arise in the retroperitoneum (e.g., dedifferentiated
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liposarcoma). (3) Carefully sample the resection specimen, paying particular attention to areas with differences in gross appearances (e.g., fleshy, fibrous, mucoid, or gritty). (4) Search for
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histologic clues (i.e., myxoid stroma, lipoblasts, and osteoid matrix, in order to diagnose
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myxofibrosarcoma, pleomorphic liposarcoma, and extraskeletal osteosarcoma, respectively); these critical diagnostic features may be limited in extent. (5) Apply immunohistochemistry
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judiciously, after generating a differential diagnosis; always exclude metastatic sarcomatoid
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carcinoma and melanoma before diagnosing a pleomorphic sarcoma. This review will present an approach to the diagnosis of pleomorphic sarcomas, emphasizing differential diagnosis and the application of ancillary studies (immunohistochemistry and FISH), when relevant. Key words: Pleomorphic sarcoma, myxofibrosarcoma, dedifferentiated liposarcoma, immunohistochemistry, MDM2
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ACCEPTED MANUSCRIPT 1.1. Introduction Pleomorphic sarcomas are a heterogeneous group of mesenchymal neoplasms with widely varied clinical behavior (Table 1).1,2 For example, at one end of the spectrum, dedifferentiated liposarcoma, when arising at central body cavity sites (most often
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retroperitoneum), has significant potential for local recurrence (even following multi-visceral
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resection), although the metastatic risk is only 15-20%. Patients with high-grade myxofibrosarcoma have a 25-30% risk of metastasis, lower than many other pleomorphic
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sarcomas; however, myxofibrosarcoma is among the most infiltrative sarcoma types, with an exceptionally high local recurrence rate without wide surgical margins. At the other end of the
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spectrum, pleomorphic myogenic sarcomas have very high metastatic potential,3,4 up to 90% for
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pleomorphic rhabdomyosarcoma. These marked differences in patterns of recurrence and risks of metastasis are strong arguments for subclassification of pleomorphic sarcomas; the most
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important reason for tumor classification is to provide useful information for patient care and
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prognostication. It is critical to exclude metastatic (sarcomatoid) carcinoma and metastatic melanoma before diagnosing a pleomorphic sarcoma. Following a general discussion of an
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approach to the diagnosis of pleomorphic sarcomas, each tumor type will be discussed in turn,
types.
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emphasizing key histologic features and ways in which to distinguish among the various tumor
2.1 Approach to pleomorphic sarcomas The following guidelines are helpful when approaching a pleomorphic sarcoma. (1) Be aware of the relative incidence of the various sarcoma types: several pleomorphic sarcomas are relatively common (e.g., dedifferentiated liposarcoma and undifferentiated pleomorphic 4
ACCEPTED MANUSCRIPT sarcoma), whereas others are exceptionally rare. (2) Pay attention to anatomic location: some pleomorphic sarcomas have a predilection for somatic soft tissues, especially the thigh (Table 2), whereas other pleomorphic sarcomas most often arise in the retroperitoneum (Table 3). (3) Carefully sample the resection specimen, paying particular attention to areas with differences in
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gross appearances (e.g., fleshy, fibrous, mucoid, or gritty). (4) Search for histologic clues (i.e.,
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myxoid stroma, lipoblasts, and osteoid matrix; Table 4); these critical diagnostic features may be
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limited in extent. (5) Apply immunohistochemistry (IHC) judiciously, after generating a differential diagnosis; this is true of all soft tissue tumor pathology (and all oncologic
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pathology!). It is important not to let IHC ordering get out of control; it is rare for a case to
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require more than 6-8 markers (even in cases of undifferentiated sarcomas). The IHC markers that are helpful for subclassification of pleomorphic sarcomas are listed in Table 5. Most
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pleomorphic sarcomas show complex (diagnostically unhelpful) cytogenetics; IHC using
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differentiation (lineage) markers is helpful to support the diagnosis of some of these tumor types (i.e., the myogenic sarcomas). The only exception is dedifferentiated liposarcoma, which shows
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relatively simple cytogenetics and harbors ring and giant marker chromosomes containing
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12q13-15 amplification, including MDM2 and CDK4: IHC or FISH assessing protein
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overexpression or gene amplification is therefore diagnostically useful. 3.1 Myxofibrosarcoma Myxofibrosarcoma usually affects middle-aged to elderly adults; in fact, myxofibrosarcoma is the most common sarcoma of the elderly.5-7 The extremities and trunk are the most common anatomic sites. Myxofibrosarcoma does not arise in the retroperitoneum, abdominal cavity or pelvis; if the histologic appearances resemble myxofibrosarcoma at such 5
ACCEPTED MANUSCRIPT sites, the tumor is nearly always dedifferentiated liposarcoma.8 Myxofibrosarcoma usually arises in superficial soft tissues (subcutis and dermis), which is unusual among the pleomorphic sarcomas: 70% are superficial and 30% are deep. As mentioned previously, myxofibrosarcoma has a high risk of local recurrence, owing to its characteristically diffuse infiltration along fascial
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planes.9-12 In contemporary sarcoma management, myxofibrosarcoma is one of the few sarcoma
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types that still sometimes results in amputations, following multiple local recurrences.11 The
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metastatic risk for low-grade myxofibrosarcoma is <5%, whereas the risk for high-grade tumors is 25-30%.6,7,9,10 The epithelioid variant of myxofibrosarcoma pursues a more aggressive clinical
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course, with at least 50% of patients developing metastases.13,14 Of note, tumor grade often
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increases with local recurrence.15
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Myxofibrosarcoma usually shows a lobulated appearance (Figure 1). Low-grade myxofibrosarcomas are hypocellular tumors dominated by myxoid stroma; curvilinear, thin-
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walled blood vessels and scattered large, sometimes pleomorphic cells with hyperchromatic
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nuclei, often clustered around the blood vessels, are typical findings (see Figure 1).7,9 High-grade tumors may be dominated by sheets of non-descript pleomorphic cells (resembling all the other
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pleomorphic sarcomas); a search for myxoid areas showing typical histologic appearances is
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critical to make an accurate diagnosis (see Figure 1). The epithelioid variant of myxofibrosarcoma is dominated by large, epithelioid cells; such tumors may mimic metastatic carcinoma or melanoma.13 IHC does not play a significant role in diagnosis of this sarcoma type. As mentioned above, histologically similar tumors in the retroperitoneum and other central body cavity sites are usually dedifferentiated liposarcomas.8 The differential diagnosis can also include pleomorphic liposarcoma, a subset of which shows significant histologic overlap with myxofibrosarcoma.16,17 Sharp circumscription and the lack of a lobulated growth pattern argue 6
ACCEPTED MANUSCRIPT against myxofibrosarcoma; identification of lipoblasts confirms pleomorphic liposarcoma (see section 4.1). 4.1 Pleomorphic liposarcoma
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Pleomorphic liposarcoma is a rare tumor type, representing only 5% of sarcomas
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designated “liposarcoma”. This tumor type typically affects middle-aged to elderly adults with a
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marked predilection for the extremities; the retroperitoneum is rarely involved.16-19 Similar to many other pleomorphic sarcomas, pleomorphic liposarcoma usually arises in deep (subfascial)
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soft tissues (90%). Only 10% of such tumors arise in the subcutis; very rarely, pleomorphic
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liposarcoma may arise in the dermis. The metastatic risk for pleomorphic liposarcoma is 50%, intermediate among the pleomorphic sarcomas.16-19
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Pleomorphic liposarcomas show a wide range in histologic appearances (Table 6), unified
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by the presence of lipoblasts.16,17 Of note, identifying lipoblasts is not required for the diagnosis of other liposarcomas (well-differentiated, dedifferentiated, and myxoid liposarcomas) but is
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necessary to diagnose pleomorphic liposarcoma.20 Most pleomorphic liposarcomas resemble an
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undifferentiated pleomorphic sarcoma, with wide variation in cell size, including spindle cells and pleomorphic cells with very large, often bizarre nuclei, and scattered pleomorphic lipoblasts,
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defined as cells with hyperchromatic nuclei indented (scalloped) by lipid-containing vacuoles (Figure 2). Without identifying the lipoblasts, proper diagnosis is impossible. As mentioned previously, some pleomorphic liposarcomas have areas resembling myxofibrosarcoma (and some are nearly identical to myxofibrosarcoma), other than the presence of lipoblasts (see Figure 2).17 Finally, some pleomorphic liposarcomas have epithelioid features, closely mimicking adrenal cortical or renal cell carcinoma (see Figure 2); when an adrenal cortical carcinoma-like tumor is 7
ACCEPTED MANUSCRIPT encountered on the extremities (and there is no radiologic evidence of a primary tumor in the retroperitoneum), the epithelioid variant of pleomorphic liposarcoma should be considered.21 5.1 Extraskeletal osteosarcoma
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Primary extraskeletal osteosarcoma is a rare tumor type mostly of older adults, with a
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male predominance.22-26 Proximal extremities (especially thigh), trunk, shoulder, and pelvic
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girdle are the most common anatomic sites. Nearly all extraskeletal osteosarcomas are deepseated. If a pleomorphic sarcoma with focal ossification is encountered in the retroperitoneum or
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abdominal cavity, dedifferentiated liposarcoma should be excluded (see section 8.1). Although
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data are limited, reported local recurrence and distant metastatic rates are 40% and 60%, respectively.22-26 The optimal systemic therapeutic approach for extraskeletal osteosarcoma is not
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clear; some medical oncologists with expertise in sarcoma management favor treating
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extraskeletal osteosarcoma in a similar fashion as other pleomorphic sarcomas of adults, whereas
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others favor conventional osteosarcoma chemotherapy.27 The diagnosis of extraskeletal osteosarcoma relies upon the identification of osteoid
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matrix associated with cytologically malignant cells (similar to conventional osteosarcoma);25 the tumor cells may be pleomorphic, epithelioid, or spindled (Figure 3). The presence of
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osteoclast-like giant cells is a helpful clue to the diagnosis of osteosarcoma. The typical lacy pattern of osteoid surrounding tumor cells, with variable calcification, should be sought. It is notoriously challenging to distinguish bona fide osteoid from hyalinized collagen (the latter is commonly identified in a wide range of soft tissue tumor types). IHC for the osteoblast nuclear transcription factor SATB2 can be helpful to make this distinction: when tumor cells adjacent to potential osteoid matrix show strong nuclear staining, one can be more certain of the diagnosis 8
ACCEPTED MANUSCRIPT (see Figure 3).28 Of note, other tumor types that show heterologous osseous differentiation (and benign tumors with metaplastic ossification) will also express SATB2 in the cells associated with osteoid; SATB2 is therefore not specific for osteosarcoma among mesenchymal neoplasms.28
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6.1 Pleomorphic rhabdomyosarcoma
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Pleomorphic rhabdomyosarcoma is a rare sarcoma type that usually arises in the deep
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soft tissues of the extremities of older adults.29,30 As previously mentioned, pleomorphic rhabdomyosarcoma has the worst prognosis with the highest metastatic potential of all the
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pleomorphic sarcomas (see Table 1).29,30 It is not clear whether patients with pleomorphic
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rhabdomyosarcoma should be treated in a similar fashion as children and young adults with the more common embryonal and alveolar rhabdomyosarcomas, although chemotherapeutic
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approaches similar to those administered for other adult sarcomas is likely more appropriate.31
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Pleomorphic rhabdomyosarcoma shows the most intense cytoplasmic eosinophilia of the
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pleomorphic sarcomas; the quality of the cytoplasm is a helpful diagnostic feature, which is often notable from low-power examination. The tumor cells range from pleomorphic to epithelioid or
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spindled, usually with marked nuclear atypia, coarse chromatin, occasional large, bizarre cells, and often abundant brightly eosinophilic cytoplasm (Figure 4).29,30 Desmin is diffusely positive,
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whereas myogenin and MyoD1 typically show limited staining in only scattered cells.30 When the tumor shows a fascicular, spindle-cell appearance, leiomyosarcoma may be a serious diagnostic consideration; leiomyosarcomas are usually positive for SMA and often for caldesmon; myogenin and MyoD1 distinguish rhabdomyosarcomas from leiomyosarcoma. 7.1 Pleomorphic leiomyosarcoma
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ACCEPTED MANUSCRIPT Pleomorphic leiomyosarcoma refers to leiomyosarcomas with significant pleomorphic cells, such that they resemble other pleomorphic sarcomas.32,33 The extent of pleomorphism required for this designation is not well defined; however, since leiomyosarcomas with marked pleomorphism have similar clinical behavior as other high-grade leiomyosarcomas, this
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distinction is not critical. Pleomorphic leiomyosarcomas affect older adults; this variant has a
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predilection for deep soft tissues of the extremities and retroperitoneum.32,33 Pleomorphic
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leiomyosarcoma has at least a 70% risk of metastasis; lungs, bone, and liver are the most
metastasize to the skin (especially the scalp).34
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common metastatic sites.32,33 Of note, leiomyosarcoma is the most common sarcoma to
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Pleomorphic leiomyosarcoma cells are often an admixture of large, bizarre cells and
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more conventional elongated spindle cells, with brightly eosinophilic cytoplasm, usually less intensely eosinophilic than pleomorphic rhabdomyosarcoma (see Figure 4).32 By IHC,
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expression of SMA, desmin, and caldesmon is helpful to support the diagnosis; caldesmon is the
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most specific but least sensitive of these markers. There is no well-defined minimal extent of SMA and desmin required to diagnose leiomyosarcoma; in order to render a diagnosis of
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pleomorphic leiomyosarcoma, areas of conventional histology with a fascicular architecture and
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broad, blunt-ended nuclei should be sought (see Figure 4), although some cases are nearly completely pleomorphic with only few cells showing typical cytomorphology. Pleomorphic rhabdomyosarcomas are usually negative for SMA (although focal expression may be observed); staining for the skeletal muscle nuclear transcription factors myogenin and MyoD1 is specific for rhabdomyosarcoma. Undifferentiated pleomorphic sarcomas may show focal staining for SMA; this finding is insufficient evidence for a diagnosis of leiomyosarcoma.
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ACCEPTED MANUSCRIPT 8.1 Dedifferentiated liposarcoma Dedifferentiated liposarcoma nearly exclusively affects adults, usually middle-aged to elderly, and has a marked predilection for central body cavity sites, especially the retroperitoneum, pelvis, and abdomen.35,36 Dedifferentiated liposarcoma rarely arises in the
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extremities and trunk wall.37 As discussed previously, dedifferentiated liposarcoma has an
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exceptionally high local recurrence rate, although the metastatic potential is low among the pleomorphic sarcomas (only 15-20%). Multivisceral resections (removing adjacent organs along
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with the tumor) improves recurrence-free survival; nonetheless, most patient eventually succumb to uncontrolled local recurrence, sometimes decades following initial surgery for the primary
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tumor.38-41 Recent studies suggest that histologic grading (using the FNCLCC system) predicts
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metastatic risk: high-grade dedifferentiated liposarcomas have higher metastatic potential than
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intermediate-grade tumors.38-40
Dedifferentiated liposarcoma is defined as a (usually abrupt) transition from well-
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differentiated liposarcoma to a non-lipogenic sarcoma,20 although in some cases the transition is
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more gradual. Since we now understand the molecular genetic basis for this tumor type, it is possible to make the diagnosis without identifying a well-differentiated component (see below).
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Dedifferentiated liposarcoma shows highly variable morphology; tumors may include pleomorphic, spindle cell, and epithelioid components, and myxoid stroma may be observed (Figure 5).35,36,42 In fact, marked intratumoral heterogeneity in a sarcoma should raise suspicion for dedifferentiated liposarcoma. Around 10% of dedifferentiated liposarcomas show heterologous differentiation (most often rhabdomyoblastic or chondro-osseous);43 tumors with rhabdomyoblastic differentiation appear to pursue a more aggressive clinical course.39 Rarely, 11
ACCEPTED MANUSCRIPT dedifferentiated liposarcoma may show “homologous” lipoblastic differentiation in the otherwise undifferentiated component, closely mimicking pleomorphic liposarcoma;44,45 when such a tumor is encountered in the retroperitoneum, dedifferentiated liposarcoma should be excluded (by IHC or FISH; see below) before diagnosing pleomorphic liposarcoma. Dedifferentiated
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liposarcomas with myxoid stroma may closely resemble myxofibrosarcoma;8 however,
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myxofibrosarcoma does not arise in the retroperitoneum or abdominal cavity – anatomic location
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alone is a helpful distinguishing feature.
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Dedifferentiated liposarcoma characteristically shows amplification of the chromosome 12q13-15 region, in the form of ring and giant marker chromosomes.46,47 These amplification
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events nearly always involve MDM2; CDK4 is also often amplified.46 FISH for MDM2 can
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therefore be used to confirm the diagnosis; this is especially helpful in a limited core needle biopsy or fine needle aspiration specimen. Amplification leads to overexpression of the MDM2
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(and often CDK4) proteins; IHC can also be used to support the diagnosis (see Figure 5),48
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although available antibodies are difficult to optimize, and many laboratories prefer to go directly to FISH.49 IHC for these markers is less specific than FISH,48,50 although the
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combination of MDM2 and CDK4 staining is relatively specific for dedifferentiated liposarcoma
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among the pleomorphic sarcomas (Table 7).48 To summarize: consider dedifferentiated liposarcoma (1) at central body cavity sites (retroperitoneum, abdominal cavity, pelvis), and (2) when there is marked intratumoral heterogeneity (spindle cell, pleomorphic, epithelioid, and myxoid components). In a resection specimen, search for an adjacent well-differentiated liposarcoma component; if such a component is identified, no ancillary studies are needed. 12
ACCEPTED MANUSCRIPT 9.1 Undifferentiated pleomorphic sarcoma Undifferentiated pleomorphic sarcoma is a diagnosis of exclusion.51,52 In a resection specimen, extensively sampling should be undertaken, in order to search for lipoblasts, osteoid matrix, and a well-differentiated liposarcoma component. IHC should be performed to exclude
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metastatic sarcomatoid carcinoma (keratins) and melanoma (S100 protein and/or SOX10),
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pleomorphic myogenic sarcomas (SMA and desmin), and, at central body cavity sites, dedifferentiated liposarcoma (IHC for MDM2 and CDK4 or FISH for MDM2). Undifferentiated
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pleomorphic sarcomas are not histologically distinctive and may show a fascicular, storiform, or sheet-like appearance and are often composed of an admixture of spindle cells and pleomorphic,
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occasionally multinucleated cells, with palely eosinophilic or somewhat basophilic cytoplasm
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(Figure 6).51 Expression of CD34 and focal SMA may be observed; these findings are non-
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10.1 Summary
Subclassification of pleomorphic sarcomas is clinically important, given their marked
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differences in metastatic potential and local recurrence rates. Thorough sampling of resection specimens is critical, in order to search for focal, sometimes subtle histologic clues (myxoid
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areas, lipoblasts, and osteoid matrix). IHC plays a central role in confirming the diagnosis of pleomorphic myogenic sarcomas, which have the worst prognosis among the pleomorphic sarcomas. IHC or FISH is helpful to support the diagnosis of dedifferentiated liposarcoma, especially in limited biopsy samples; dedifferentiated liposarcoma should always be a diagnostic consideration for large tumors of the retroperitoneum and abdominal cavity.
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Figure 1. Myxofibrosarcoma. (A) Myxofibrosarcoma typically shows a lobulated appearance from low magnification. This example contains abundant myxoid stroma. (B) Curvilinear blood vessels and scattered cells with enlarged, hyperchromatic nuclei are characteristic features in the myxoid areas. (C) An example of myxofibrosarcoma with increased cellularity. Note the curvilinear blood vessels. (D) High-grade myxofibrosarcomas may contain extensive areas indistinguishable from undifferentiated pleomorphic sarcoma. A careful search for a myxoid component (right side) is mandatory for proper diagnosis.
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Figure 2. Pleomorphic liposarcoma. (A) In some tumors, lipoblasts can be few and far between. In this field, a single diagnostic lipoblast with a hyperchromatic nucleus indented by lipid vacuoles is seen in the middle of an otherwise non-distinctive pleomorphic sarcoma. (B) Other examples show extensive lipoblastic differentiation. Not the large, bizarre cell in the center of a sea of lipoblasts. (C) Some pleomorphic liposarcomas closely mimic myxofibrosarcoma. Identification of lipoblasts (left lower corner) allows for the correct diagnosis. (D) The epithelioid variant of pleomorphic liposarcoma may closely resemble adrenal cortical carcinoma. Note the lipoblasts on the right side of the field.
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Figure 3. Extraskeletal osteosarcoma. (A) The tumor consists of sheets of epithelioid and spindle cells with marked nuclear atypia. Osteoid matrix may be difficult to distinguish from hyalinized collagen. (B) Strong nuclear staining for SATB2 by immunohistochemistry supports the diagnosis of osteosarcoma, although this marker is not entirely specific and is also expressed in benign bone-forming tumors.
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Figure 4. Pleomorphic myogenic sarcomas. (A) Pleomorphic rhabdomyosarcoma consisting of an admixture of epithelioid and spindle cells with abundant, intensely eosinophilic cytoplasm, including scattered pleomorphic cells with large nucleoli. (B) Pleomorphic leiomyosarcoma containing bizarre, pleomorphic cells. Note the eosinophilic cytoplasm and area of more conventional morphology (bottom).
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Figure 5. Dedifferentiated liposarcoma. (A) This tumor type may be indistinguishable from undifferentiated pleomorphic sarcoma. (B) Some examples show spindle-cell morphology and a more uniform appearance. (C) Myxoid stroma may be seen (left side); such tumors can mimic myxofibrosarcoma, but the latter tumor type does not arise at central body cavity sites such as the retroperitoneum. Not the fascicular, spindle-cell component that resembles leiomyosarcoma (right side). (D) Immunohistochemistry for MDM2 can be used to support the diagnosis. Many laboratories prefer fluorescence in situ hybridization (FISH), in part because the available antibodies are difficult to optimize; moreover, MDM2 gene amplification is more specific for dedifferentiated liposarcoma than MDM2 protein overexpression. Figure 6. Undifferentiated pleomorphic sarcoma. (A) A pleomorphic sarcoma composed of spindle cells and large, bizarre and multinucleated cells with palely basophilic cytoplasm, arranged in a somewhat storiform growth pattern. Note the numerous mitotic figures. (B) Undifferentiated pleomorphic sarcoma with eosinophilic cytoplasm may mimic pleomorphic leiomyosarcoma or pleomorphic rhabdomyosarcoma. Immunohistochemistry for myogenic 21
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markers can distinguish among these tumor types. Undifferentiated pleomorphic sarcoma is a diagnosis of exclusion.
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Table 1. Metastatic potential of pleomorphic sarcomas Metastatic rate
Dedifferentiated liposarcoma
15-20%
Myxofibrosarcoma (high grade)
25-30%
Undifferentiated pleomorphic sarcoma
50%
Pleomorphic liposarcoma
50%
Extraskeletal osteosarcoma
60%
Pleomorphic leiomyosarcoma
70%
Pleomorphic rhabdomyosarcoma
90%
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Tumor type
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Table 2. Pleomorphic sarcomas of somatic soft tissue (especially thigh) Rare
Myxofibrosarcoma
Pleomorphic liposarcoma
Undifferentiated pleomorphic sarcoma
Pleomorphic rhabdomyosarcoma
Pleomorphic leiomyosarcoma
Extraskeletal osteosarcoma
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Relatively common
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Table 3. Pleomorphic sarcomas of the retroperitoneum Rare
Dedifferentiated liposarcoma
Undifferentiated pleomorphic sarcoma
Pleomorphic leiomyosarcoma
Pleomorphic liposarcoma
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Relatively common
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Table 4. Histologic features of pleomorphic sarcomas Histologic finding
Tumor types
Myxoid stroma Myxofibrosarcoma
Subset of cases
Dedifferentiated liposarcoma
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Defining feature
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Pleomorphic liposarcoma
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Undifferentiated pleomorphic sarcoma Lipoblasts
Pleomorphic liposarcoma
Subset of cases
Dedifferentiated liposarcoma
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Defining feature
Osteoid
Extraskeletal osteosarcoma
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Dedifferentiated liposarcoma
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Table 5. Immunohistochemical markers helpful to subclassify pleomorphic sarcomas Marker
Pleomorphic leiomyosarcoma
SMA, desmin, caldesmon
Pleomorphic rhabdomyosarcoma
desmin, myogenin, MyoD1
Dedifferentiated liposarcoma
MDM2, CDK4
Extraskeletal osteosarcoma
SATB2
Metastatic carcinoma
Keratins
Metastatic melanoma
S100 protein, SOX10
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Tumor type
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Table 6. Histologic variability in pleomorphic liposarcoma Frequency
Pleomorphic sarcoma with scattered or sheets of lipoblasts
65%
Focal areas resembling myxofibrosarcoma
45%
Almost entirely myxofibrosarcoma-like
15%
Epithelioid areas
25%
Pure epithelioid variant
10%
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Histologic pattern
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MDM2
CDK4
Dedifferentiated liposarcoma
98%
92%
Malignant peripheral nerve sheath tumor
65%
10%
Myxofibrosarcoma
40%
15%
Leiomyosarcoma
5%
1%
Gastrointestinal stromal tumor
0%
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Table 7. Immunohistochemistry for MDM2 and CDK4 in pleomorphic and spindle cell sarcomas
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0%
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Highlights Pleomorphic sarcomas are a heterogeneous group of tumors with widely varied metastatic potential
A careful search for histologic clues (myxoid stroma, lipoblasts, osteoid matrix) is mandatory
Metastatic sarcomatoid carcinoma and melanoma should always be excluded
Immunohistochemistry or FISH for MDM2 aids in the diagnosis of dedifferentiated liposarcoma
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Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6