Case 3 -

Inflammatory Myxohyaline Tumor of the Distal Extremities John R. Goldblum The Cleveland Clinic Cleveland Clinic Lerner College of Medicine Cleveland, Ohio

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History 43-year-old female with a slowly growing 2 cm mass on the ring finger Case 3 - Figure 1 - Low-magnification view of this patient's finger mass. The lesion appears to be well circumscribed and show an intermixed pattern of inflammatory cells associated with small myxoid foci. Case 3 - Figure 2 - Low-magnification view of intermixed inflammatory and myxoid zones. Case 3 - Figure 3 - Most of the inflammatory cells are lymphocytes or plasma cells. This myxoid zone shows vacuolated cells that can resemble lipoblasts. Case 3 - Figure 4 - Some of these cells in the cellular zones are binucleated and resemble Reed-Sternberg cells. Case 3 - Figure 5 - Other cells in the cellular zones are mononucleated and resemble CMV-infected cells. Description At low magnification, this lesion has a multinodular, heterogeneous appearance. Although some areas are relatively hypocellular and focally hyalinized, most of this lesion is much more cellular and associated with a dense inflammatory infiltrate. Large areas show areas show myxoid degeneration. The constituent cells are heterogeneous in appearance. Some are spindled, but others are epithelioid, and many have a bizarre appearance. Some cells have large eosinophilic nucleoli and are reminiscent of virocytes. Others have large nuclei with smudgy chromatin, and still others resemble Reed-Sternberg cells. Most of the inflammatory cells are mature lymphocytes and plasma cells. Immunohistochemical Data Scattered cells stained for CD68, CD34 and smooth muscle actin. Immunostains for S-100 protein, HMB45, desmin, cytokeratins, leukocyte common antigen, CD15 and CD30 were negative. Most of the lymphocytes stained for CD3 with only scattered lymphocytes staining for CD20. Diagnosis Inflammatory Myxohyaline Tumor of the Distal Extremities Discussion In 1997, Montgomery et al were the first to report a series of cases of an unusual tumor found on the distal extremities that often prompted a misdiagnosis of an inflammatory or infectious process. [1] The authors coined the term inflammatory myxohyaline tumor of distal extremities with virocyte or Reed-Sternberg-like cells. Subsequently, Meis-Kindblom and Kindblom reported a large series of identical tumors and used the term "acral myxoinflammatory fibroblastic sarcoma" because one of the patients was found to have metastatic disease. [2] It is clear that these two terms refer to identical lesions even though minor differences were noted in these two studies. Most patients with this tumor are in the fourth and fifth decades of life. [1, 2, 3] Males and females are equally affected, and the vast majority present with a slowly growing, painless, ill-defined mass of the distal extremities. The upper extremities are affected more commonly than the lower extremities with the majority of lesions being found in the soft tissues of the fingers and hand. On the lower extremities, these tumors may arise in the toes, feet, ankles and lower leg. Very rare lesions arise in an axial location, including the trunk. [4] The tumor is typically multinodular and poorly circumscribed and is usually removed piecemeal by the surgeon. Gelatinous and fibrous zones are grossly appreciable. Most of the tumors range between 3 and 4 cm at the time of excision. Histologically, the tumor is multinodular and poorly circumscribed and frequently involves surrounding soft tissue structures such as tendon sheaths and synovium. Most are centered in the subcutaneous tissue, but some involve the dermis and others infiltrate the underlying skeletal muscle. At low magnification, a heterogeneous appearance is apparent with an admixture of dense inflammatory cells mixed with myxoid and hyaline zones. In most cases, leukocytes and plasma cells predominate, although neutrophils and eosinophils may be conspicuous in some examples. Germinal centers may also be seen. The amount of myxoid and hyalinized stroma varies from case to case and in different regions of the same tumor. Some tumors are composed predominantly of hypocellular myxoid zones, whereas others are composed predominantly of hyalinized or inflammatory zones. The constituent cells are bizarre and range in shape from plump spindled cells to histiocytoid or epithelioid cells. The spindled cells have a moderate degree of nuclear atypia, whereas the larger epithelioid cells often have large vesicular nuclei with macronucleoli and prominent eosinophilic cytoplasm closely resembling virocytes or Reed-Sternberg cells. Despite this marked nuclear atypia, mitotic figures are quite rare (usually less than 2/50 HPF). Ganglion-like cells resembling those seen in proliferative fasciitis may be widely scattered or form small nodular collections. Some of the bizarre cells may have multivacuolated cytoplasm, thus resembling lipoblasts. Occasional bizarre cells may also engulf inflammatory cells. Immunohistochemically, the mononuclear and large bizarre cells show variable staining for CD68, CD34 and smooth muscle actin. Most of the lymphocytes stain for T cell markers with a much smaller population of B cells. Immunostains for S-100 protein, HMB45, desmin, epithelial membrane antigen, leukocyte common antigen CD15 and CD30 are typically negative in the large bizarre cells. Rare cells may show focal immunoreactivity for cytokeratins. Differential Diagnosis The differential diagnosis depends in part on the cellularity of the lesion and the relative amount of myxoid and hyaline stroma. An infectious or inflammatory process is often a strong consideration given the prominent inflammatory background and virocyte-like cells. However, special stains for microbial organisms are consistently negative, as are immunohistochemical stains for CMV. Montgomery et al analyzed ten cases by PCR for Epstein Barr virus. [1] Although four patients were found to harbor EBV, the level of amplification was compatible with latent, rather than active, viral infection. Giant cell tumor of tendon sheath is often a diagnostic consideration given the location of the tumor, the prominent inflammatory component and the presence of Touton-like giant cells and hemosiderin. The recognition of large bizarre cells is critical for distinguishing these lesions since these types of cells are not found in giant cell tumor of tendon sheath. This tumor also has features that overlap with those found in inflammatory myofibroblastic tumor/inflammatory fibrosarcoma, although the cells of inflammatory myxohyaline tumor are more bizarre and lack the well-developed immunohistochemical and ultrastructural features of myofibroblasts. Moreover, the acral location of inflammatory myxohyaline tumor is not characteristic of inflammatory myofibroblastic tumor/inflammatory fibrosarcoma, which are most commonly found in the abdomen or thorax. A variety of myxoid lesions also enter the differential diagnosis for those cases with prominent myxoid stroma. In particular, distinction from myxoid malignant fibrous histiocytoma is the most difficult aspect of the differential diagnosis, although both tumors have enough distinguishing characteristics to support the contention that they are distinct entities. The presence of focal areas of high-grade, pleomorphic-storiform MFH help in the recognition of myxoid MFH. Additional differences include the alternating myxoid and hyalinized zones, a more striking inflammatory infiltrate, the presence of virocyte-like cells and the acral location typical of inflammatory myxohyaline tumor. The presence of Reed-Sternberg-like cells also raises the possibility of Hodgkin's disease, but immunohistochemically the large atypical cells lack expression of CD15 and CD30, antigens that one would expect to be found in the Reed-Sternberg cells of Hodgkin's disease. Natural History In the series of 51 cases reported by Montgomery et al, [1] six of 27 patients with follow-up information (22%) developed at least one local recurrence, but none developed metastatic disease. In the study of 44 cases by Meis-Kindblom and Kindblom, [2] 67% of patients developed a local recurrence, including 13 patients who had two or more local recurrences. In addition, one patient developed a histologically documented inguinal lymph node metastasis 1.5 years after initial excision. A second patient developed suspected pulmonary metastases five years after initial presentation, although metastatic disease was not documented histologically. Wide local excision without adjuvant therapy is probably the therapy of choice. Molecular Genetics Very few examples of this entity have been evaluated at the molecular/cytogenetic level. Soon after the initial description of this tumor, Lambert and colleagues described a case with a reciprocal translocation t(1;10)(p22;q24) in addition to the loss of chromosomes 3 and 13. [5] More recently, Mansoor et al described a second case showing supernumerary ring chromosomes composed of chromosome 3 segments and a derivative chromosome 13. [6] Not only do these reports support the neoplastic nature of this lesion, but they also raise the possibility that there is a characteristic cytogenetic aberration found in this tumor, although additional cases need to be evaluated. References Montgomery EA, Devaney KO, Giordano TJ, Weiss SW. Inflammatory myxohyaline tumor of distal extremities with virocyte or Reed-Sternberg-like cells: a distinctive lesion with features simulating inflammatory conditions, Hodgkin's disease and various sarcomas. Mod Pathol 1998;11:384-91. Meis-Kindblom JM, Kindblom L-G. Acral myxoinflammatory fibroblastic sarcoma: a low-grade tumor of the hands and feet. Am J Surg Pathol 1998;22:911-24. Michal M. Inflammatory myxoid tumor of the soft parts with bizarre giant cells. Pathol Res Pract 1998;194:529-33. Jurcic V, Zidar A, Montiel MD, et al. Myxoinflammatory fibroblastic sarcoma: a tumor not restricted to acral sites. Ann Diagn Pathol 2002;6:272-80. Lambert I, Debiec-Rychter M, Guelinckx P, et al. Acral myxoinflammatory fibroblastic sarcoma with unique clonal chromosomal changes. Virchows Arch 2001;438:509-12. Mansoor A, Fidda N, Himoe E, et al. Myxoinflammatory fibroblastic sarcoma with complex supernumerary ring chromosomes composed of chromosome 3 segments. Cancer Genet Cytogenet 2004;152:61-65.