Case 2 -

Sarcoma, Favor Undifferentiated Pleomorphic Sarcoma (UPS) [MFH] of the Hippopotamus Alexander Lazar, UT-MD Anderson Cancer Center, Houston, TX

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Clinical History Initial: Female aged 53 with renal failure. Expanded (from Autopsy report; google translate from Portuguese): This patient immigrated to Brazil in 1964. Over the last 4 weeks she developed progressive weight loss and appetite loss. On July 26 she had an episode of colic, was quite agitated in the water, splashing through the nostrils, and nystagmus. This framework was responsive to the application of anti-inflammatory therapy for 3 days, with improvement in clinical status. As part of investigating the continued appetite loss, anesthesia was given to attempt a more accurate diagnosis. The anesthetic procedure was fairly unremarkable, there was an oral cavity examination, transrectal ultrasonography, blood collection and radiography of the limbs. We found serious dental problems, arthritis and severe urea and creatinine with very high values. Chronic renal failure was expected. During the week, this evolved to a picture of anorexia and severe apathy with no response to treatment and poor quality of life. Euthanasia was performed on 05/08/11 followed by autopsy. Case 2 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: Histologic Features: The sections show a malignant spindle cell neoplasm. The degree of atypia is generally moderate and pleomorphism was but a focal feature. Mitoses numbered greater than 20 per HPF. Areas of necrosis were noted. Under FNCLCC criteria, this tumor would be morphologically best regarded as high grade. Ancillary Studies: Immunohistochemical studies revealed patchy reactivity for smooth muscle actin (SMA) and diffuse reactivity for vimentin while pan-cytokeratins, desmin, S100 protein, and CD34 were negative. Differential Diagnosis: On the basis of the histologic images presented, the differential diagnosis would include: Sarcomatoid carcinoma Melanoma Mesenchymal/Sarcoma Nodular fasciitis Undifferentiated pleomorphic sarcoma (UPS) / malignant fibrous histiocytoma (MFH) Malignant peripheral nerve sheath tumor (MPNST) Unclassified sarcoma Final Diagnosis: Sarcoma, Favor Undifferentiated Pleomorphic Sarcoma (UPS) [MFH] of the Hippopotamus. This case represents an autopsy of a hippopotamus which this author participated in at the Sao Paulo, Brazil Zoo in 2011. Case Discussion: A discussion of the differential diagnosis listed above follows: Sarcomatoid carcinoma: No connection with the skin (deeper compartment), no expression of cytokeratins. Melanoma: Again, no association with the overlying skin. The nuclear features are not typical (no cherry-red, prominent nucleoli) and lack of S100 protein reactivity would be unusual. Nodular fasciitis: The degree of atypia focally goes beyond that characteristic of nodular fasciitis and Malignant peripheral nerve sheath tumor (MPNST): This case was not definitely associated with a nerve root on dissection and lacked patchy S100 protein reactivity. The morphologic features are within the spectrum of MPNST, but there is nothing definitely to push it into this category. Unclassified (spindle cell) sarcoma The tumor appears to be mesenchymal and is behaving in a highly malignant fashion. This is not an unreasonable diagnosis, but as pathologists we usually want to be more definitive if we can. Undifferentiated pleomorphic sarcoma (UPS) / malignant fibrous histiocytoma (MFH) This is a reasonable diagnosis here. This is basically a diagnosis of exclusion and while the present case is somewhat less pleomorphic than usually encountered, it does fit within this spectrum arguably better than any other from the differential diagnosis list above. Review of the Literature/Treatment Options: Hippopotamus amphibius Interestingly, the hippopoatumis is considered the closest living evolutionary relative of the Cetacea group, marine mammals including whales, dolphins and porpoises (Masato, 1999). It resides in sub-Saharan Africa and is the third largest land mammal after the elephant and rhinoceros. They fall into the artiodactyla group of even-toed ungulates. While considered cute by many, these animals have a reputation for very aggressive behavior toward humans. Currently in Pubmed, there are no reports of sarcoma occurring in the hippopotamus. Undifferentiated pleomorphic sarcoma (UPS) / malignant fibrous histiocytoma (MFH): A very brief and thus necessarily biased review of a complex historical subject Since there is much discussion regarding the appropriateness of the name malignant fibrous histiocytoma and nature of the tumors falling under this name, a brief history of the development of this group is presented (for more extensive review see Fritchie et al, 2011). In the beginning (1961), Kauffman and Stout described one of the earliest classifications of histiocytic tumors. Interestingly, this was in a pediatric population. Over time, there developed a belief that these lesions were composed of facultative fibroblasts where features could range from more histiocytic to more fibrocytic (basically histiocytes becoming more fibroblastic). These studies were supported by tissue culture and electron microscopy studies where it was believed that a histiocytic-fibroblastic continuum could be demonstrated. Over the years, conceptualization in the field has ranged from the tumor mixed cellularity arising from an undifferentiated stem cell to a determination that the lineage was basically undefinable. Myofibroblastic differentiation was also recognized and suggested (Churg & Kahn, 1977). Weiss and Enzinger (1978) initially laid out three primary histologic formats: storiform, pleomorphic and fascicular. The usefulness of the diagnostic category was later reaffirmed (Weiss, 1982) and the four morphologic forms canonized as: storiform-pleomorphic, myxoid, giant cell and inflammatory. MFH began to be defined as a diagnosis of exclusion and the ability to exclude becomes better with electron microscopy, immunohistochemistry, and now molecular and genomic characterization as we will see below. In a reversal of conceptualization, a process was ultimately proposed differentiation from a primitive precursor to fibroblast and these fibroblasts having some ability to cause histiocyte-like features. Basically, this was a turn of the table to have facultative phagocytes (Hoffman and Dickerson, 1983). Fibroblastic differentiation has proponents as well with MFH basically representing pleomorphic fibrosarcoma (Erlandson and Antonescu, 2004). Pleomorphic myxofibrosarcoma has also been suggested as a potential line of differentiation (Montgomery, 2001). With time, MFH was suggested to represent a final common pathway (late) in sarcoma progression (Brooks, 1986). The more widespread advent of immunohistochemistry around this time helped to define and exclude other entities from MFH. Given the admittedly untidy nature of the conceptualization of MFH, some have proposed that the term be discarded with the admission that MFH represents a mixed grab bag of perhaps numerous entities with the great majority of those cases able to be reclassified into other categories with extensive sampling, careful observation and use of ancillary techniques (Fletcher, 1992 & 2001). This approach was greatly aided by the advent of specific markers that support distinguishing tumors where light microscopy alone is les definitive. The accepted morphologic range of categories into which one can use to redistribute MFH also plays a role here. These studies bore home the important point that MFH should truly be a diagnosis of exclusion. More recently, genetic evidence has suggested that MFH could be considered to cluster close to leiomyosarcoma thus some cases could represent leiomyosarcomas that have progressed to the point where they are no recognizable as such and would thus be categorized as MFH (Derre, 2001; Segal, 2003; Lee, 2003; Gibault, 2011). Consistent with this Rubin and colleagues (2011) noted that a mouse model of embryonal rhabdomyosarcoma could be pushed to MFH by adding additional genetic aberrations. Others have created mouse models suggesting that MFH-like lesion may arise more directly from mesenchymal stem cells (Choi, 2010). The 2002 Bone and Soft Tissue WHO states: "The term pleomorphic malignant fibrous histiocytoma is reserved for a small group of undifferentiated pleomorphic sarcomas…[where] current technology does not show a definable line of differentiation" (emphasis added). For many of us working at high volume sarcoma treatment centers, such UPS/MFH cases can comprise 15 to 20 % of our clinical volume (following vigorous attempts to exclude from this category) and are major sources of mortality, though likely this elevated percentage represents some degree of institutional referral bias. Based on the history above, it is clear that learned about this complex group of malignancies over the last half century and our understanding of them has been greatly influenced by the tools at hand for their study. Regardless of what one calls this group, UPS, MFH or something else entirely, we should remember than a name is only a reference to the thing that is signified and if rigorously defined even arbitrary or imprecise names can perform this role. Future study will continue to refine our understanding of this group with genomic characterization being a currently exciting and fruitful arena. Acknowledgements: Drs. Isabela Werneck da Cunha, Brian Rubin, Cyril Fisher, Jean-Michel Coindre and Karen Fritchie are thanked for helpful discussions. References: Brooks JJ. The significance of double phenotypic patterns and markers in human sarcoma. A new model of mesenchymal differentiation. Am J Pathol 1986; 125: 113-123. Choi J, Curtis SJ, Roy DM, Flesken-Nikitin A, Nikitin AY. Local mesenchymal stem/progenitor cells are preferential target for initiation of adult soft tissue sarcomas associated with p53 and Rb deficiency. Am J Pathol 2010; 177: 2645-2658. Churg AM, Kahn LB. Myofibroblasts and related cells in malignant fibrous and fibrohistiocytic tumors. Hum Pathol 1977; 8: 205-218. Derre J, Lagace R, Nicolas A et al. Leiomyosarcomas and most malignant fibrous histiocytomas share very similar comparative genomic hybridization imbalances: an analysis of a series of 27 leiomyosarcomas. Lab Invest 2001; 81: 211-215. Erlandson RA, Antonescu CR. The rise and fall of malignant fibrous histiocytoma. Ultrastruct Pathol 2004; 28: 283-289. Fletcher CDM. Pleomorphic malignant fibrous histiocytoma: fact or fiction? A clinical reappraisal based on 159 tumors diagnosed as pleomorphic sarcoma. Am J Surg Pathol 1992; 16: 213-228. Fletcher CDM, Gustafson P, Rydholm A, Willen H, Akerman M. Clinicopathologic re-evaluation of 100 malignant fibrous histiocytomas: prognostic relevance of subclassification. J Clin Oncol 2001; 19: 3045-3050. Fletcher CDM, Unii KK, Mertens F. Pathology and Genetics of Tumours of Soft Tissue and Bone (IARC Classification of Tumours), 2002. 37 Segal NH, Pavlidis P, Antonescu CR et al. Classification and subtype prediction of adult soft tissue sarcoma by functional genomics. Am J Pathol 2003; 163: 691-700. Fritchie K, Fisher C, Coindre J-M, Lazar AJ, Rubin BP. A brief history and contemporary re-assessment of malignant fibrous histiocytoma: "fact or fancy". Diagn Histopathol 2011; 18:340-347. Gibault L, Perot G, Chibon F. New insights in sarcoma oncogenesis: a comprehensive analysis of a large series of 160 soft tissue sarcomas with complex genomics. J Pathol 2011; 223: 64-71. Hoffman MA, Dickersin GR. Malignant fibrous histiocytoma: an ultrastructural study of eleven cases. Hum Pathol 1983; 14: 913-922. Kauffman SL, Stout AP. Histiocytic tumors (fibrous xanthoma and histiocytoma) in children. Cancer 1961; 14: 469-482. Lee YF, John M, Edwards S et al. Molecular classification of synovial sarcomas, leiomyosarcomas and malignant fibrous histiocytoma by gene expression profiling. Br J Cancer 2003; 88: 510-515. Montgomery E, Fisher C. Myofibroblastic differentiation in malignant fibrous histiocytoma (pleomorphic myofibrosarcoma): a clinicopathologic study. Histopathology 2001; 38: 499-509. Nikado M, Alejandro AP, Okada N. Phylogenetic relationships among cetartiodactyls based on insertions of short and long interpersed elements: Hippopotamuses are the closest extant relatives of whales PNAS USA 1999; 96:10261-10266. Rubin BP, Nishijo K, Chen HI, et al. Evidence for unanticipated relationship between undifferentiated pleomorphic sarcoma and embryonal rhabdomyosarcoma. Cancer Cell 2011; 19: 177-191. Weiss SW, Enzinger FM. Malignant fibrous histiocytoma. An analysis of 200 cases. Cancer 1978; 41: 2240-2266. Weiss SW. Malignant fibrous histiocytoma. A reaffirmation. Am J Surg Pathol 1982; 6: 773-784.