Plexiform Fibrohistiocytic Tumor

Ann Diagn Pathol. 2007 Oct;11(5):313-9. Abstract quote

The seminal article of Drs Franz Enzinger and Renyuan Zhang in 1988 defined plexiform fibrohistiocytic tumor (PFHT) as a distinctive entity. They described 65 cases (from 1965 to 1985) in children and young adults, with female and upper extremity predominance.

These tumors were morphologically divided into 3 groups: fibroblastic, histiocytic (often with osteoclast-type giant cells), and mixed. Most tumors exhibited a plexiform and infiltrative arrangement of cells at the dermal/subcutaneous junction. Two fibroblastic PFHT had a metaplastic bone formation. Absence of cellular pleomorphism, low mitotic activity, dense hyalinization, hemorrhage, and chronic inflammation were observed. Vascular invasion was present in 1 recurrent, yet nonmetastatic, case.

Tumors were negative for S100 protein, desmin, cytokeratin, factor VIIIrag, and lysozyme. Most patients were without disease up to 60 years after excision; 32 (37.5%) cases with follow-up recurred and 2 of those patients had regional lymph node metastasis at 9 and 36 months, respectively, yet there were no systemic metastases. In the interim, there have been additional studies on PFHT.

We wanted to update the literature and add 66 new PFHT cases (1986-present) from the Armed Forces Institute of Pathology, since this seminal article, in honor of Dr Franz Enzinger. There were 37 men and 29 women; patient age ranged from 1 to 77 years (median, 20 years; 53% of patients were younger than 20 years). Twenty-eight cases occurred in the upper extremity (mostly forearm), 16 in lower extremity, 11 in trunk, 9 in head and neck, and 2 of unknown site. Although most cases were observed at the dermal/subcutaneous interface, 22 cases were predominantly dermal, and the rest predominantly subcutaneous, with 4 superficially involving skeletal muscle. Except for 12 predominantly dermal cases, most cases had an infiltrative growth pattern. Thirty-four cases were predominantly histiocytic, 16 predominantly fibroblastic, and the remaining 16 mixed. Two fibroblastic cases demonstrated the microfat cells (probably secondary to subcutis infiltration).

All cases exhibited a plexiform growth pattern of small- to medium-sized nodules; 41 cases had giant cells, mainly osteoclast type, often the predominantly histiocytic type. The purely fibroblastic often had surrounding inflammation, 2 cases with marked inflammation. Perineural growth was observed in 5 cases, peri-Pacinian corpuscle growth in 2 cases, adnexal trapping in several, and, increased hyalinized collagen in 17 cases. Eight cases demonstrated focal myxoid change. Only 1 case, a histiocytic, had bone formation. Although increased cytologic atypia and mitotic activity were noted in a few cases, an atypical mitosis was only observed in 1 case. No cases demonstrated vascular or lymphatic invasion or necrosis. The tumors were generally positive for CD68 and SMA, occasionally for MSA, and negative for keratin, desmin, HMB45, S100 protein, and CD34.

Overall, the findings were very similar to the original observations made by Dr Enzinger and his colleague, with the minor exceptions of roughly equal sex distribution (possibly due to timely referral bias), and additional morphologic features of myxoid change, adnexal sparing, increased inflammation, and microfat similar to recently described lipofibromatosis. The relationship between PFHT and cellular neurothekeoma is also explored.

Epidemiology
Pathogenesis
Histopathological Features and Variants
Special Stains/ Immunohistochemistry/ Electron Microscopy
Differential Diagnosis
Prognosis and Treatment
Commonly Used Terms
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HISTOLOGICAL TYPES	CHARACTERIZATION
GENERAL
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. Moosavi C, Jha P, Fanburg-Smith JC. Department of Orthopaedic and Soft Tissue Pathology, Armed Forces Institute of Pathology, Washington, DC 20306-6000, USA.	Ann Diagn Pathol. 2007 Oct;11(5):313-9. Abstract quote The seminal article of Drs Franz Enzinger and Renyuan Zhang in 1988 defined plexiform fibrohistiocytic tumor (PFHT) as a distinctive entity. They described 65 cases (from 1965 to 1985) in children and young adults, with female and upper extremity predominance. These tumors were morphologically divided into 3 groups: fibroblastic, histiocytic (often with osteoclast-type giant cells), and mixed. Most tumors exhibited a plexiform and infiltrative arrangement of cells at the dermal/subcutaneous junction. Two fibroblastic PFHT had a metaplastic bone formation. Absence of cellular pleomorphism, low mitotic activity, dense hyalinization, hemorrhage, and chronic inflammation were observed. Vascular invasion was present in 1 recurrent, yet nonmetastatic, case. Tumors were negative for S100 protein, desmin, cytokeratin, factor VIIIrag, and lysozyme. Most patients were without disease up to 60 years after excision; 32 (37.5%) cases with follow-up recurred and 2 of those patients had regional lymph node metastasis at 9 and 36 months, respectively, yet there were no systemic metastases. In the interim, there have been additional studies on PFHT. We wanted to update the literature and add 66 new PFHT cases (1986-present) from the Armed Forces Institute of Pathology, since this seminal article, in honor of Dr Franz Enzinger. There were 37 men and 29 women; patient age ranged from 1 to 77 years (median, 20 years; 53% of patients were younger than 20 years). Twenty-eight cases occurred in the upper extremity (mostly forearm), 16 in lower extremity, 11 in trunk, 9 in head and neck, and 2 of unknown site. Although most cases were observed at the dermal/subcutaneous interface, 22 cases were predominantly dermal, and the rest predominantly subcutaneous, with 4 superficially involving skeletal muscle. Except for 12 predominantly dermal cases, most cases had an infiltrative growth pattern. Thirty-four cases were predominantly histiocytic, 16 predominantly fibroblastic, and the remaining 16 mixed. Two fibroblastic cases demonstrated the microfat cells (probably secondary to subcutis infiltration). All cases exhibited a plexiform growth pattern of small- to medium-sized nodules; 41 cases had giant cells, mainly osteoclast type, often the predominantly histiocytic type. The purely fibroblastic often had surrounding inflammation, 2 cases with marked inflammation. Perineural growth was observed in 5 cases, peri-Pacinian corpuscle growth in 2 cases, adnexal trapping in several, and, increased hyalinized collagen in 17 cases. Eight cases demonstrated focal myxoid change. Only 1 case, a histiocytic, had bone formation. Although increased cytologic atypia and mitotic activity were noted in a few cases, an atypical mitosis was only observed in 1 case. No cases demonstrated vascular or lymphatic invasion or necrosis. The tumors were generally positive for CD68 and SMA, occasionally for MSA, and negative for keratin, desmin, HMB45, S100 protein, and CD34. Overall, the findings were very similar to the original observations made by Dr Enzinger and his colleague, with the minor exceptions of roughly equal sex distribution (possibly due to timely referral bias), and additional morphologic features of myxoid change, adnexal sparing, increased inflammation, and microfat similar to recently described lipofibromatosis. The relationship between PFHT and cellular neurothekeoma is also explored.
Plexiform fibrohistiocytic tumor presenting in children and young adults. An analysis of 65 cases. Enzinger FM, Zhang RY. Department of Soft Tissue Pathology, Armed Forces Institute of Pathology, Washington, DC 20306.	Am J Surg Pathol 1988 Nov;12(11):818-26 Abstract quote We report 65 cases of a hitherto undescribed neoplasm that occurs chiefly in children and young adults, and has morphologic features reminiscent of both a fibrous histiocytoma and fibromatosis. The median age of the 65 patients was 14.5 years; two-thirds (67.7%) of the patients were younger than 20 years. The lesion was more common in female patients (46 cases) than in male patients (19 cases). It usually presented as a slow-growing, poorly demarcated dermal or subcutaneous mass that rarely exceeded 3 cm in greatest diameter. Its most common location was the upper extremity (63.1%), especially the regions of shoulder and forearm. Under the microscope, the lesions were characterized by a multinodular or plexiform proliferation of histiocyte- and fibroblast-like cells associated with multinuclear giant cells. Differential diagnosis chiefly includes cutaneous fibrous histiocytoma, plexiform neurofibroma, fibromatosis, and benign and malignant giant cell tumor. Twenty of the 32 cases (62.5%) with follow-up information were alive and well after local excision, but the tumor recurred in 12 cases (37.5%). In two patients with recurrence, the disease metastasized to regional lymph nodes 9 and 36 months after the initial excision, respectively. Metastasis to the lung or other organs was not observed. We were unable to demonstrate a close correlation between biologic behavior and any specific clinical or morphologic parameter.
Plexiform fibrohistiocytic tumour with novel phenotypic features. Thomazy V, Nagy A, Gal I, Nemes Z. Department of Pathology, University Medical School of Debrecen, Hungary.	Histopathology 1994 Aug;25(2):165-9 Abstract quote Plexiform fibrohistiocytic tumour is a recently described type of fibrohistiocytic tumour, the differentiation pattern of which is poorly understood. A case representing the predominantly fibrohistiocytic type of the tumour is reported. Immunohistochemical analysis supports the histiocytic origin of this entity. The expression of EBM/11 and tissue transglutaminase both in fibroblast-like and histiocyte-like cells indicate that a single cell line produces the dual morphological features. It is proposed that a non-phagocytic epithelioid pattern of histiocytic differentiation characterizes this tumour.
Plexiform fibrohistiocytic tumor: clinicopathologic analysis of 22 cases. Remstein ED, Arndt CA, Nascimento AG. Department of Laboratory Medicine and Pathology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA.	Am J Surg Pathol 1999 Jun;23(6):662-70 Abstract quote Twenty-two cases of plexiform fibrohistiocytic tumor were reviewed to perform a clinicopathologic correlation with the behavior of the neoplastic entity. The tumor arises more frequently in children, adolescents, and young adults (mean age of presentation, 14.6 years), with strong female predilection (F:M, 6:1). It involves preferentially the upper extremity (64%), especially the fingers, hand, or wrist (45%). Most patients present with a small (average size, 2.5 cm; range, 0.5-8 cm) painless mass that slowly enlarges for months to years. All tumors involve subcutaneous adipose tissue, with extension into the dermis (19%), skeletal muscle (14%), or both (14%). Grossly, the tumors characteristically are poorly circumscribed and of firm consistency. Histologically, they are characterized by a plexiform proliferation of mononuclear histiocyte-like cells, multinucleated osteoclast-like cells, and spindle fibroblast-like cells in variable proportions and have three distinct growth patterns: fibrohistiocytic (36% of tumors), fibroblastic (32%), and mixed (32%), depending on the predominant cell type. Cellular atypia and pleomorphism are usually absent or minimal. Most tumors (78%) display mitotic activity, frequently <3 mitoses/10 high-power fields, and only 14% of the lesions display atypical mitoses. Vascular invasion was seen in only one tumor. Immunohistochemically, all tumors evaluated reacted with antibodies to CD68 that stained mainly the multinucleated giant cells and, to a lesser extent, mononuclear histiocyte-like cells and, occasionally, fibroblast-like cells. Less frequently, staining with antiactin antibodies was observed, restricted mainly to spindle cells. All nine tumors examined had a diploid DNA content. According to latest follow-up data (average period, 3.6 years) from 16 patients, 13 (82%) were alive with no evidence of disease (average, 3.6 years), 1 (6%) was alive with metastatic disease (follow-up, 2.3 years), 1 (6%) was alive with a stable pulmonary nodule of unknown nature (follow-up, 1.75 years), and 1 (6%) had died of disease 3 years after local recurrence and regional lymph node and pulmonary metastases developed. Two patients (12.5%) had local recurrence, 1 (6%) had regional lymph node metastasis, and 3 (19%) had pulmonary metastases. No proven association between clinicopathologic features and outcome was identified. In conclusion, plexiform fibrohistiocytic tumor is a rare mesenchymal neoplasm of young persons characterized by low-grade malignant behavior and is prone to recur locally and occasionally to metastasize regionally and systemically.
VARIANTS
DERMAL/ SUBCUTANEOUS
Dermal and subcutaneous variants of plexiform fibrohistiocytic tumor. Zelger B, Weinlich G, Steiner H, Zelger BG, Egarter-Vigl E. Department of Dermatology, University of Innsbruck, Austria.	Am J Surg Pathol 1997 Feb;21(2):235-41 Abstract quote We report five cases of plexiform fibrohistiocytic tumors, three classic subcutaneous lesions and two dermal ones. \ Both variants had similar profiles and were clinically indistinguishable. The lesions affected the trunk more than the upper extremities and were found in children and young adults (18.4 +/- 12.8 years). They showed a marked female predominance (4:1, including both dermal variants). Clinically, they were skin-colored, hard nodules of 1-2-cm diameter that resulted in such differential diagnoses as fibroma, histiocytoma, pilomatricoma, or cyst. Interestingly, one subcutaneous case with a painful "worms in the sack" presentation was thought to represent a plexiform neurofibroma. Histology revealed well-circumscribed dermal or subcutaneous plexiform lesions with a characteristic biphasic appearance. Most of the tumor bulk consisted of spindle-shaped to stellate myofibroblasts with a variable admixture of collagen or loosening of stroma. In the center of the plexiform strands and nodules, a few osteoclast-like giant cells as well as epithelioid mononuclear cells (< 10%) were found. Myofibroblasts were positive with HHF35 and for smooth muscle actin in three of five cases. Osteoclast-like giant cells were positive with KP1 in all five cases. Both types of cells stained with the macrophage marker Ki-M1p. A broad panel of other markers was negative. This series expands the spectrum of plexiform fibrohistiocytic tumor, but it also broadens the differential diagnosis of (dermal) plexiform lesions, which at present includes spindle cell nevi, schwannomas, neurofibromas, granular cell tumors, nerve sheath myxomas (neurothekeomas), spindle cell lipomas, and tufted angiomas.
MULTINUCLEATED GIANT CELLS-ABSENCE
Plexiform fibrohistiocytic tumor without multinucleated giant cells: a case report. Salamanca J, Rodriguez-Peralto JL, De La Torre JP, Lopez-Rios F.	Am J Dermatopathol 2002 Oct;24(5):399-401 Abstract quote Plexiform fibrohistiocytic tumor (PFT) is a rare but distinctive soft tissue tumor of children and young adults characterized by a mixture of histiocyte-, myofibroblast-, and osteoclast-like giant cells arranged in a plexiform pattern. We report the clinicopathologic and immunohistochemical features of an apparently unique case of PFT without multinucleated giant cells presenting in a 3-year-old child. Light microscopy revealed a subcutaneous tumor composed of a plexiform proliferation of histiocyte- and myofibroblast-like cells. Multinucleated osteoclast-like giant cells, the third classic cellular component of this mesenchymal neoplasm, were not observed. The differential diagnosis is also discussed. Emphasis is placed on the importance of the recognition of PFT, because it may exhibit an aggressive behavior.

SPECIAL STAINS/ IMMUNOPEROXIDASE/ OTHER	CHARACTERIZATION
SPECIAL STAINS
IMMUNOPEROXIDASE
Plexiform fibrohistiocytic tumour: clinicopathological, immunohistochemical and ultrastructural analysis in favour of a myofibroblastic lesion. Hollowood K, Holley MP, Fletcher CD. Department of Histopathology, St Thomas's Hospital (UMDS), London, UK.	Histopathology 1991 Dec;19(6):503-13 Abstract quote Plexiform fibrohistiocytic tumour is a recently described, seemingly benign neoplasm of superficial soft tissue which is poorly recognized and the differentiation pattern of which remains obscure. Fourteen new cases are presented here. These presented predominantly in the upper limb of infants and children, although the age-range was wide. A morphological spectrum depending on the relative proportions of the spindle cellular and nodular histiocyte-like components was evident. Immunohistochemical analysis revealed positivity of tumour cells in both components for smooth muscle actin, suggestive of myofibroblastic differentiation, as was borne out ultrastructurally in two cases. In addition, a minority of the histiocyte-like cells were also CD68 positive but negative for leucocyte common antigen, HLA-DR, Mac387 and lysozyme. In view of the ultrastructural and other immunohistochemical results, this is regarded as further evidence that the CD68 epitope recognized by KP-1 is not confined to cells of monocyte/macrophage or myeloid lineage. Plexiform fibrohistiocytic tumour appears to be a clinicopathologically distinctive myofibroblastic neoplasm which may warrant reclassification in due course.

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
GIANT CELL TUMOR OF SOFT TISSUES
Primary giant cell tumor of soft tissues: a study of 22 cases. Oliveira AM, Dei Tos AP, Fletcher CD, Nascimento AG. Division of Anatomic Pathology, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA.	Am J Surg Pathol 2000 Feb;24(2):248-56 Abstract quote Twenty-two cases of giant cell tumor of soft tissues (GCT-ST) identified in the Mayo Clinic files and the consultation files of two of the authors (A.G.N., C.D.M.F.) were analyzed clinicopathologically. Age at presentation ranged from 5 to 80 years (median, 43 years), and there was no sex predilection (12 male, 10 female). Duration of symptoms ranged from 2 to 12 months (median, 4.5 months), and a painless growing mass was the most common complaint. The lower limbs were the most frequent location (50%), followed by the trunk (31.8%) and the upper limbs (13.6%). The size of the tumors ranged from 1 to 10 cm, and they tended to be superficial (86.4%), forming well-circumscribed (72.7%), multinodular (86.4%) masses. Histologically, all tumors consisted of a mixture of mononuclear cells showing vesicular, round to oval nuclei and osteoclastlike, multinucleated giant cells distributed uniformly throughout the tumors. Foci of stromal hemorrhage were observed in 11 tumors (50%); nine tumors (40.1%) showed metaplastic bone formation and six (27.2%) showed aneurysmal bone cystlike areas. Necrosis was absent in all but one tumor. Mitotic figures were present in all but one tumor, ranging from two to more than 30 mitoses per 10 high-power fields (HPFs; median, 9.5 mitoses per 10 HPFs) and were typical in aspect. Vascular invasion was identified in seven tumors (31.8%), and none of the tumors showed marked cellular atypia or pleomorphism. The tumors were treated surgically, and follow-up information was available for 16 patients (duration of follow-up, 2 to 130 months; median, 51 months). Only one of the 16 patients (6.2%) had local recurrence and lung metastases; this patient died of the tumor. In conclusion, GCT-ST occurs as a primary soft-tissue neoplasm and is identical clinically and morphologically to giant cell tumor of bone. Provided that GCT-ST is treated adequately by complete excision, a benign clinical course is expected because episodes of distant metastasis and tumor-associated death seem to be exceedingly rare.
SPITZ NEVUS
Plexiform spitz nevus: an intradermal spitz nevus with plexiform growth pattern. Spatz A, Peterse S, Fletcher CD, Barnhill RL. Department of Pathology, Institut Gustave-Roussy, Villejuif, France.	Am J Dermatopathol 1999 Dec;21(6):542-6 Abstract quote Two cases of a distinctive variant of Spitz (spindle and epithelioid cell) nevus are described. One lesion developed on the lower leg of a 17-year-old boy and the other lesion on the back of a 52-year-old man. The microscopic appearance was characterized by a plexiform arrangement of bundles and lobules of enlarged spindle to epithelioid melanocytes throughout the superficial and deep dermis. Intraepidermal melanocytic proliferation was unappreciated. Some lobules were circumscribed by a thin rim of compressed fibrous tissue. In both cases a myxoid stroma was present. The cells had abundant eosinophilic cytoplasm with well-defined borders. The nuclei were enlarged, consistently ovoid and vesicular, with small nucleoli. Both cases contained scattered multinucleate giant cells similar to those observed in classical form of Spitz nevi. No melanin pigment was detectable by light microscopy. No mitoses were observed in one case and a rare mitosis was present in the other. Tumor cells were strongly immunoreactive for S-100, but not for HMB-45, desmin, and actin. The differential diagnosis of this distinctive tumor includes desmoplastic/neurotropic melanoma, plexiform spindle cell nevus, cellular blue nevus, plexiform neurofibroma, and cellular neurothekeoma. The designation of "plexiform Spitz nevus" is chosen to emphasize its distinctive plexiform growth pattern.

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSTIC FACTORS	Local recurrence with occasional reports of metastasis
TREATMENT	Complete surgical excision with close clinical follow up