Case 5 -

Plexiform Fibrohistiocytic Tumor Cyril Fisher Royal Marsden Hospital London, UK

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Immunohistochemistry The spindle cells showed focal positivity for SMA and calponin. CD68 was positive in some of the rounded cells and in the osteoclast-like giant cells. CD34, S100 protein, desmin, h-caldesmon, cytokeratins and EMA were negative. Case 5 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 5 - Figure 1 The lesion is located in deep dermis and subcutis. It has a nodular or plexiform pattern. Case 5 - Figure 2 Plexiform pattern with confluent and discrete tumor nodules extending into subcutaneous fat. Case 5 - Figure 3 Tumor is present within dermis and incorporates adnexa. Case 5 - Figure 4 At the deep aspect foci of tumor involve skeletal muscle. Case 5 - Figure 5 Tumor nodules in fat show peripheral fibrosis. Case 5 - Figure 6 The nodules comprise rounded mononuclear cells, bland spindle cells and an admixture of osteoclast-like giant cells, with focal fibrosis. Case 5 - Figure 7 Cells in tumor nodules show no pleomorphism or mitotic activity. There is a lymphocytic infiltrate. Case 5 - Figure 8 Some nodules manifest marked sclerosis or hyalinization with residual cellular component. Diagnosis Plexiform Fibrohistiocytic Tumor Discussion Plexiform fibrohistiocytic tumor (PFHT) was first described in 1988 with 65 cases in the original report by Enzinger and Zhang. [1] Subsequent series of 14 [2] and 22 [3]cases, as well as numerous smaller series and single case reports, and most recently a further series of 66 cases from AFIP (without follow up information), [4] have been added to the literature, and confirm the original description. There are now 200 published cases. One case arose in an irradiation field seven years after treatment for malignant haemangiopericytoma. [5] PFHT is a slowly growing tumor which occurs mainly in adolescents and young adults, originally with a female predominance but with more equal sex distribution in later series. Most examples arise at the dermal-subcutaneous junction, and can extend superficially or deeply, but sometimes are wholly in dermis. Two principal histological patterns are described. In the original series, 43% displayed a fibrohistiocytic picture with nodules of rounded or spindled cells with scattered osteoclast-like multinucleate giant cells, chronic inflammation, microhemorrhages and hemosiderin, and rare bone formation. 17% were predominantly fibroblastic with plexiform bundles of spindle cells, and 40% had a mixed pattern. Occasional pleomorphic cells were seen, and mitotic figures were described up to 7/10 hpf. Subsequent reports have confirmed these findings with fibrohistiocytic (43%) or mixed (34%) patterns predominating, and noted rare myxoid change, [6] bone formation, [4] and an atypical variant. [7] With immunohistochemistry, as well as vimentin, CD68 is found in rounded cells and in the multinucleate giant cells, which are probably histiocytic and non-neoplastic. The spindle cells have a myofibroblastic immunophenotype with focal reactivity for smooth muscle actin, and occasionally for calponin, but none for desmin or h-caldesmon. S100 protein is nearly always negative. FXIIIa and CD34 are negative in lesional cells. Ultrastructurally, the few reports variously indicate fibroblasts, myofibroblasts, and undifferentiated mesenchymal cells. [2, 8] The findings are similar to those in other benign or malignant fibrohistiocytic tumors. Clonal genetic abnormalities have been reported in two cases, but no consistent changes have been found. One had a complex karyotype with numerous deletions [9] and the other demonstrated a simpler karyotype of 46,XY,t(4;15)(q21;q15). [10] All cases examined have been diploid. [3] Behavior In the 2002 WHO classification, PFHT is placed as a so-called fibrohistiocytic tumor of intermediate (rarely metastasizing) biologic potential. Over one third (37%) of the original series of plexiform fibrohistiocytic tumor recurred, usually within two years, and two cases (3%) metastasized to regional lymph nodes. The overall recurrence rate is 33%, but only 2/16 (12.5%) recurred in one series of 22 patients. [3] However, one case metastasizing to lymph node and two additional cases metastasizing to lung (one of whom died of disease) were also reported in the same series. One further example with apparent lymph node metastasis has been reported. [11] The true figures might be higher because most reports have been submitted after relatively brief follow-up periods. There seems to be no correlation between histological features and behavior. A case with cytologic atypia has not recurred after 10 years. [7] Differential Diagnosis Plexiform fibrohistiocytic tumor with nodular pattern closely resembles cellular neurothekeoma. The differential diagnosis includes other neoplasms with a plexiform pattern; other types of fibrohistiocytic tumor, and perhaps epithelioid sarcoma; and in the fibroblastic variant, fasciitis and fibromatosis. Cases with a prominent giant cell component need distinction from other giant cell tumors. 1. Cellular neurothekeoma (CNT) CNT was originally thought to be a cellular variant of nerve sheath myxoma [12] and the term neurothekeoma has included both entities. However, the lesion recognized since 1969 [13] as (dermal) nerve sheath myxoma is a circumscribed lesion with multiple myxoid nodules containing S100 protein-positive Schwann cells, with peripheral EMA-positive perineurial cells. [14] This is clearly a different entity from cellular neurothekeoma, a non-neural tumor, even though the latter can show myxoid change. [15] CNT and PFHT have several overlapping features. [12, 16, 17, 18] CNT, which is more common than PFHT, also occurs in young adults in head and neck sites and upper extremity. The tumor is usually located in the dermis with occasional extension into subcutis. It is composed of ovoid or sometimes spindled cells with eosinophilic cytoplasm in rounded nodules enclosed and separated by collagen bundles, and sometimes in sheets. Multinucleated lesional cells can be seen in up to 40% of cases, and moderate to marked nuclear atypia in up to 25% of cases, as well as mitotic activity including abnormal forms. Myxoid change, with cellular spindling, predominates in about 20% of cases, and about 30% of cases are mixed cellular and myxoid lesions. A small number are distinctly plexiform, and osteoclast-like giant cells are seen in up to 30% of lesions. Thus, the age and anatomic distribution of CNT are similar to those of PFHT, both can be plexiform and both can have osteoclast-like giant cells (though they are less commonly seen in CNT). Histologic differences between the two entities include in CNT the absence of fibromatosis-like areas and of nodular hyalinization, and less hemosiderin, and in PFHT the much less frequent occurrence of myxoid change and atypia. Also, CNT has a lower recurrence rate and is not reported to have metastasized. There are no significant immunohistochemical differences. Immunoreactivity for melanoma markers NKI-C3 [19] and microphthalmia-associated transcription factor (MiTF) [20] is present in most CNT, but these are also detectable in other fibrohistiocytic neoplasms, including PFHT; [4] whereas S100 protein, and the melanocytic markers melan-A and HMB45, are negative in both tumors. In some cases, distinction between CNT and PFHT can be impossible and it has been proposed that the two entities are closely related if not identical. [15, 21] 2. Plexiform variants of several soft tissue tumors have been described. Among nerve sheath tumors, these include neurofibroma,schwannoma, malignant peripheral nerve sheath tumor of infancy and childhood, granular cell tumor and perineurial cell tumor. The first four have characteristic morphology and S100 protein immunostaining, and perineurial cell tumors display EMA and the typical ultrastructure, with long processes, pinocytosis and external lamina. Plexiform types of xanthomatous tumor [22], spindle cell nevus, and Spitz nevus [23] should not cause difficulties. Plexiform ossifying fibromyxoid tumor (ofmt with satellite nodules [24]) can be recognized by the encapsulation of each nodule, the glomus-like cells and immunoreactivity for S100 protein and GFAP. [25] 3. Giant cell tumor of soft parts (of low malignant potential) [26, 27, 28] forms multinodular or circumscribed lesions in superficial or deep soft tissue, commonly in upper limb. Histologically, it is similar to giant cell tumor of bone, with bland mononuclear and short spindle cells and uniformly distributed osteoclast-like multinucleated giant cells. Sometimes there is metaplastic bone or osteoid, usually peripherally, and aneurysmal spaces. Vascular space invasion is common, but none has metastasized, although a proportion recurs. 4. Nodular fasciitis has a very short history, sometimes of only a few days, a loose myxoid stroma with myofibroblasts, and no pleomorphism or atypical mitoses. Small multinucleated cells can be seen in longer-standing lesions and are usually focal around areas of hemorrhage. 5. Fibromatosis is infiltrative but displays evenly spaced cells in a collagenous stroma, with mast cells and a characteristic vasculature. Again, atypia is not a feature. Nuclear immunoreactivity for beta-catenin is helpful for diagnosis especially in deeper lesions. 6. Cellular cutaneous fibrous histiocytomas occasionally develop peripheral plexiform features particularly when extending into subcutis. However, they tend to be more superficial; they have spindle fascicular or storiform morphology, with little collagen, and normal mitoses, but no atypical forms or significant pleomorphism. 7. Deep benign fibrous histiocytoma is better circumscribed, with epiphenomena, haemangiopericytomatous pattern, and no significant atypia. Benign fibrous histiocytomas may be immunoreactive for SMA, but not usually for CD34. Dermatofibrosarcoma protuberans has infiltrative margins, but with honeycombing or in parallel layers rather than in a plexiform fashion. Also, it is characterized by a more marked and uniform storiform pattern, with few epiphenomena, and cytologic pleomorphism is not a feature. DFSP is usually strongly CD34 positive, especially at the periphery, and FXIIIa negative; some cases display muscle actins. Giant cell fibroblastoma has different type giant cells in a spindle cell and myxoid background, with pseudovascular spaces and CD34 reactivity, with or without a component of DFSP. 8. Malignant fibrous histiocytoma (undifferentiated pleomorphic sarcoma), giant cell type, is located in subcutis or deep soft tissue and displays more polymorphism, widespread pleomorphism and necrosis. 9. Hemosiderotic fibrohistiocytic lipomatous lesion occurs in the subcutaneous tissue of the foot/ankle region of older females. [29] It is an infiltrative, differentiated fatty lesion with scattered foci of slightly pleomorphic CD34 positive spindle cells, scattered inflammatory cells and abundant iron pigment. Similar features have been found in early examples of pleomorphic hyalinizing angiectatic tumor. [30] 10. The fibroma-like variant of epithelioid sarcoma may need consideration, but such cases display cytokeratin and EMA positivity. [31, 32] References Enzinger FM, Zhang RY. Plexiform fibrohistiocytic tumor presenting in children and young adults. An analysis of 65 cases. Am J Surg Pathol 1988;12;818-826. Hollowood K, Holley MP, Fletcher CD. Plexiform fibrohistiocytic tumour: clinicopathological, immunohistochemical and ultrastructural analysis in favour of a myofibroblastic lesion. Histopathology 1991;19;503-513. Remstein ED, Arndt CA, Nascimento AG. Plexiform fibrohistiocytic tumor: clinicopathologic analysis of 22 cases. Am J Surg Pathol 1999;23;662-670. Moosavi C, Jha P, Fanburg-Smith JC. An update on plexiform fibrohistiocytic tumor and addition of 66 new cases from the Armed Forces Institute of Pathology, in honor of Franz M. Enzinger, MD. Ann Diagn Pathol 2007;11;313-319. August C, Holzhausen HJ, Zornig C et al. [Plexiform fibrohistiocytic tumor. 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