Modern Pathology (2014) 27, S39–S46 & 2014 USCAP, Inc. All rights reserved 0893-3952/14 $32.00 S39 An approach to pleomorphic sarcomas: can we subclassify, and does it matter? John R Goldblum Department of Anatomic Pathology, Cleveland Clinic, Cleveland, OH, USA The term malignant fibrous histiocytoma (MFH) has been supplanted by undifferentiated pleomorphic sarcoma (UPS). Even now, however, a number of pleomorphic neoplasms are classified as UPSs when in fact at least a subgroup of these can be more precisely classified as a pleomorphic sarcoma with a specific line of differentiation. Still others are pseudosarcomas, most commonly sarcomatoid carcinomas. This review will discuss historical aspects of MFH/UPS as well as provide an approach to the pleomorphic malignant neoplasm with a discussion of useful ancillary techniques in the evaluation of such cases. Modern Pathology (2014) 27, S39–S46; doi:10.1038/modpathol.2013.174 Keywords: malignant fibrous histiocytoma; pleomorphic sarcoma; sarcomatoid carcinoma; undifferentiated pleomorphic sarcoma The concept of malignant fibrous histiocytoma pleomorphic sarcomas, when subjected to rigorous (MFH) has undergone significant change over the evaluation, remain unclassified. These discre- past five decades. The term was first introduced in pancies, nonetheless, underscore the fact that the 1963 to refer to a group of soft tissue tumors criteria by which a pleomorphic tumor is provision- characterized by a storiform or cartwheel-like growth ally labeled as an undifferentiated pleomorphic pattern, which were believed to be derived from sarcoma (UPS/MFH) as well as the criteria by histiocytes on the basis of early tissue culture studies which some are reclassified differ from institution demonstrating ameboid movement and phagocytosis to institution. of explanted tumor cells.1,2 However, ultrastructural Whatever the true incidence of this lesion, there is studies both endorsed and refuted the histiocytic agreement that the term MFH should be used origin of these tumors. With the advent of immuno- synonymously with UPS which, by a combination histochemistry and the accessibility of numerous of sampling and immunohistochemistry, shows no monoclonal antibodies directed against various definable line of differentiation and by electron structural proteins of specific cell types, the pheno- microscopy manifests fibroblastic/myofibroblastic type of this tumor was shown to be more closely features.8 At this point, we use the term UPS in aligned with a fibroblast than a histiocyte.3–6 our diagnostic reports, but also state that this is Furthermore, many, but not all, lesions labeled as synonymous with so-called MFH in parentheses so ‘malignant fibrous histiocytoma’ could, upon close as to avert any misunderstanding with clinicians scrutiny, be subclassified as lineage-specific sarco- who continue to be familiar with that term. mas, an observation that led some to question the Whenever I encounter a soft tissue neoplasm with existence of MFH as a distinct entity.7 The extent to a ‘MFH-like’ pattern, I consider several broad which such lesions can be subclassified as sarcomas possibilities before concluding that the lesion is in of alternative type is, in large part, dependent on fact an UPS. First, I consider whether the lesion in definitional criteria and the number of ancillary question is some type of pleomorphic sarcoma with studies a pathologist is willing to bring to bear on the a specific line of differentiation that can be identi- evaluation of a pleomorphic sarcoma. There is still fied through light microscopy and/or immuno- no general agreement as to what percentage of histochemistry. The rationale behind attempting to more precisely classify a pleomorphic sarcoma is discussed below. Second, I consider the possibility Correspondence: Dr JR Goldblum, MD, Department of Anatomic that the lesion could be a component of a dediffer- Pathology, Cleveland Clinic, 9500 Euclid Avenue L25, Cleveland, entiated sarcoma, particularly when dealing with a OH 44195, USA. E-mail: [email protected] sarcoma in the retroperitoneum. Thorough sampling Received 14 June 2013; revised 28 June 2013; accepted 29 June is often required in order to recognize the low-grade 2013 sarcoma from which the dedifferentiated ‘MFH-like’ www.modernpathology.org Pleomorphic sarcomas S40 JR Goldblum areas arose. Importantly, I also want to exclude the is recognized by the presence of large cells with possibility that the lesion is a non-mesenchymal eosinophilic cytoplasm and cross striations neoplasm. The most common consideration is that (Figure 4), which can be confirmed by the immuno- of a sarcomatoid carcinoma, particularly when the histochemical demonstration of skeletal muscle lesion arises on a mucosal surface, skin, or within a differentiation (desmin, MyoD1, myogenin). A defi- parenchymal organ. Other considerations might nitive diagnosis of pleomorphic malignant periph- include (depending upon site and other clinical eral nerve sheath tumor can be difficult unless the factors) sarcomatoid mesothelioma, melanoma, and pleomorphic sarcoma clearly arises from a benign even anaplastic lymphoma. Finally, if all of these nerve sheath tumor or arises from a peripheral can be excluded, then one can arrive at the nerve in a patient with type 1 neurofibromatosis conclusion that the lesion is a UPS (Figure 1). (Figure 5). The only criterion for recognizing extraskeletal osteosarcoma is the production of osteoid or bone by cytologically malignant cells Pleomorphic sarcoma with a specific line (Figure 6). As mentioned, several studies have suggested that of differentiation pleomorphic sarcomas with myogenic differentiated A variety of pleomorphic sarcomas may have areas are clinically more aggressive than those without 9–11 that resemble UPS. In some cases, determining the myogenic differentiation. Fletcher et al reviewed specific line of differentiation may rely on random 100 cases diagnosed as ‘MFH’ and concluded (based sampling of a small area within a large tumor. upon morphology and immunohistochemistry) that Although a specific type of pleomorphic sarcoma 70 of these tumors were non-myogenic pleomorphic may be suggested by histologic features, immuno- sarcomas, whereas 30 showed evidence of myogenic histochemical stains are often required to confirm the diagnosis. Although it could be argued that subtyp- ing pleomorphic sarcomas is nothing more than an academic exercise, there is some evidence to suggest that pleomorphic sarcomas with myogenic differen- tiation are more clinically aggressive than those without myogenic differentiation9–11 (see below). The only criterion for rendering a diagnosis of pleomorphic liposarcoma is the recognition of multivacuolated pleomorphic lipoblasts (Figure 2). The major difficulty in such cases is separating pleomorphic sarcomas that infiltrate fat and isolate individual cells from those with true lipoblasts. Pleomorphic leiomyosarcoma is composed of cells with distinct cytoplasmic eosinophilia (Figure 3). At least focally, most cases have areas with a fascicular arrangement and cells with blunt-ended nuclei with a perinuclear vacuole and deeply eosino- Figure 2 Pleomorphic liposarcoma characterized by the presence philic cytoplasm. Pleomorphic rhabdomyosarcoma of pleomorphic lipoblasts. Figure 1 This high-grade pleomorphic malignant neoplasm was Figure 3 Pleomorphic leiomyosarcoma characterized by pleo- ultimately classified as an undifferentiated pleomorphic sarcoma, morphic spindled cells with eosinophilic cytoplasm. This tumor a diagnosis of exclusion. stains strongly for smooth muscle actin. Modern Pathology (2014) 27, S39–S46 Pleomorphic sarcomas JR Goldblum S41 differentiation.10 Of these 30 cases, 20 were were more aggressive than those with fewer markers. classified as leiomyosarcoma, 9 as myogenic Massi et al evaluated 65 pleomorphic sarcomas of sarcoma, not otherwise specified, and 1 as rhabdo- the extremities and compared 31 sarcomas with myosarcoma. The pleomorphic sarcomas with myogenic differentiation (22 leiomyosarcomas, 4 myogenic differentiation were significantly more rhabdomyosarcomas, and 5 myofibrosarcomas) likely to be deep-seated when compared with those with 34 non-myogenic pleomorphic sarcomas.11 without myogenic differentiation (83% versus 63%; The tumors were classified into diagnostic P ¼ 0.04), and they were also more likely to be grade categories based upon morphology, immunohisto- 4 tumors (97 versus 67%; P ¼ 0.02). Similarly, in chemistry, and, in some cases, ultrastructural 2003, Deyrup et al compared 42 cases of analysis. Tumor site and myogenic differentiation pleomorphic sarcoma with myogenic differentia- were both found to be independent predictors of tion to 50 pleomorphic sarcomas without myogenic disease relapse for localized tumors by multivariate differentiation.9 The only significant difference analysis, but only myogenic differentiation was between these two groups was that the tumors found to be an independent predictor of overall with myogenic differentiation were significantly survival by multivariate analysis. more likely to be grade 3 sarcomas (88% versus In summary, there are at least three studies that 74%; P ¼ 0.038). There was a significant difference strongly suggest the adverse prognostic effect of in overall survival, as those sarcomas with myogenic myogenic differentiation in a pleomorphic sarcoma. differentiation had shorter overall survival. Overall However, there are a number of practical issues that survival was also directly