DFSP typically presents during early or middle adult life as a nodular cutaneous mass. Although early studies reflected its rarity in children, ^, it is increasingly reported in the pediatric age group. In fact, given the indolent growth and long preclinical duration, it is likely that many begin during childhood and become apparent only during young adulthood. Males are affected more frequently than females. Although these tumors occur at almost any site, they are seen most frequently on the trunk and proximal extremities ( Table 11.1 ). Dermatofibrosarcomas involving the hands and feet are rare.

In most cases this tumor is characterized by slow but persistent growth over a long period, often several years. The clinical and gross appearances are determined to a great extent by the stage of the disease. The initial manifestation is usually the development of a firm, plaque-like lesion of the skin, often with surrounding red to blue discoloration. These lesions have been compared with the morphea of scleroderma or morphea-like basal cell carcinoma. Rarely, the lesions appear as a depressed area of atrophy (“atrophic variant”) or as subcutaneous masses without obvious connection to the overlying dermis. Subcutaneous dermatofibrosarcomas involving the breast may clinically closely mimic mammary carcinoma. Less often, multiple small subcutaneous nodules appear initially rather than a plaque. The plaque may grow slowly or remain stationary for a variable period, eventually entering a more rapid growth phase and giving rise to one or more nodules. Thus, only in the fully developed lesion is the typical “protuberant” appearance manifested. Neglected tumors may achieve enormous proportions and have multiple satellite nodules. Despite the large size of many of these tumors, patients appear surprisingly well and lack the signs of cachexia associated with malignancies. Fibrosarcomatous progression is often heralded by a rapid increase in size in a long-standing, often recurrent dermatofibrosarcoma.

Most of these tumors are biopsied during the nodular stage; therefore the specimen consists of a solitary, protuberant, gray–white mass involving subcutis and skin ( Figs. 11.1–11.3 ). In a recent, very large series from China, the median size at the time of surgery was 3 cm. Multiple discrete masses are usually not seen in the original tumor but are more characteristic of recurrent lesions ( Fig. 11.4 ). The skin overlying these tumors is taut or even ulcerated. Skeletal muscle extension is uncommon except in large or recurrent lesions. Rarely, dermatofibrosarcomas are centered in the subcutis, with only subtle dermal involvement. Occasionally, areas of the tumor have a translucent or gelatinous appearance corresponding microscopically to myxoid change. Hemorrhage and cystic change are sometimes seen; necrosis is uncommon.

Typical dermatofibrosarcoma protuberans (DFSP) involving dermis and subcutis in a nodular fashion.

Small dermatofibrosarcoma displaying protuberant growth.

DFSP from the buttock of a young child. It has the red color that some of these lesions exhibit.

Gross appearance of an advanced case of DFSP with multiple tumor nodules.

Despite the apparent gross circumscription of these lesions, the tumor diffusely infiltrates the dermis and subcutis ( Fig. 11.5 ). The tumor may reach the epidermis or leave an uninvolved zone of dermis just underneath the epidermis. In either event, the overlying epidermis does not usually display the hyperplasia that characterizes some cutaneous fibrous histiocytomas ( dermatofibromas ). The peripheral portions of the tumor have a deceptively bland appearance partly caused by the marked attenuation of the cells at their advancing edge. This is especially true in superficial areas, where the spread of slender cells between preexisting collagen is easily mistaken for cutaneous fibrous histiocytoma ( Fig. 11.6A ). In deep regions, the tumor spreads along connective tissue septa and between adnexae ( Fig. 11.7 ), or it intricately interdigitates with lobules of subcutaneous fat, creating a lacelike or honeycomb effect ( Fig. 11.6B ).

Plaque form of DFSP illustrating expansion of the interface between dermis and subcutis and extension into subcutaneous fat.

Superficial ( A ) and deep ( B ) extensions of DFSP. Spread of the tumor between preexisting collagen of the dermis may simulate the appearance of a cutaneous fibrous histiocytoma ( A ). At the deep margin the tumor intricately interdigitates with normal fat ( B ).

DFSP infiltrating between adnexal structures.

The central or main portion of the tumor is composed of a uniform population of slender fibroblasts arranged in a distinct, often monotonous, storiform pattern around an inconspicuous vasculature ( Figs. 11.8 and 11.9 ). There is usually little nuclear pleomorphism and only low to moderate mitotic activity. Secondary elements such as giant cells, xanthoma cells, and inflammatory elements are few in number or absent altogether. In this respect, DFSP displays remarkable uniformity compared with other fibrohistiocytic neoplasms. Although most tumors are characterized by these highly ordered cellular areas, occasional tumors contain myxoid areas ( Fig. 11.10 ). These myxoid areas occur in both primary and recurrent lesions and are characterized by the interstitial accumulation of ground substance material. As the myxoid change of the stroma becomes more pronounced, the storiform pattern becomes less distinct and the vascular pattern more apparent. By virtue of these features, such tumors can resemble myxoid liposarcoma ( Fig. 11.10B ). Confident diagnosis of highly myxoid dermatofibrosarcomas usually requires identification of more typical areas, although molecular genetic study for PDGFB or PDGFD rearrangement or PDGFB RNA in situ hybridization may be helpful in some cases.

Slender spindle cells arranged in a distinct storiform pattern characterize most dermatofibrosarcomas.

DFSP showing greater interstitial collagenization.

( A ) Myxoid change in DFSP. ( B ) When myxoid change is prominent, storiform pattern may be lacking altogether, and the tumor may resemble a myxoid liposarcoma.

Giant cells, similar to those in giant cell fibroblastoma, can be identified in a small percentage of otherwise typical dermatofibrosarcomas. An unusual feature of DFSP is the myoid nodule ( Fig. 11.11 ). Originally construed as evidence of myofibroblastic differentiation, these structures seem to be centered in some cases around blood vessels, ^, and likely represent an unusual nonneoplastic vascular response to the tumor.

( A ) Myoid balls within DFSP. ( B ) Myoid ball centered around a small vessel.

Pigmented DFSP (“Bednar tumor”) consist of conventional DFSP admixed with a widely variable number of melanin-bearing cells. In some, large numbers of melanin-containing cells cause black discoloration of the tumor ( Fig. 11.12 ), whereas in others, melanin is so sparse it can be appreciated only microscopically. These cells are scattered irregularly throughout the tumor ( Fig. 11.13A ). Their tentacle-like processes emanating from a central nucleus-containing zone give them a characteristic bipolar or multipolar shape, depending on the plane of the section ( Fig. 11.13B ). They stain with conventional melanin stains and ultrastructurally contain mature membrane-bound melanosomes. S-100 protein, present in many neural tumors, is absent in Bednar tumors.

Bednar tumor. Gross appearance of the tumor is identical to conventional DFSP, but the substance of the tumor is flecked with melanin pigment.

Pigmented DFSP (Bednar tumor) ( A ) showing dendritic pigmented cells ( B ).

The most clinically significant morphologic change in DFSP is sarcomatous progression, usually resembling adult-type fibrosarcoma ( Figs. 11.14–11.16 ). In a very recent, international, multiinstitutional study of DFSP, fibrosarcomatous progression was noted in 12.6% of 347 tumors, with roughly 50% of these having fibrosarcomatous areas at the time of initial presentation. Generally agreed-upon criteria for the diagnosis of fibrosarcomatous progression in DFSP include an abrupt transition to a hypercellular spindle cell tumor displaying a fascicular (as opposed to storiform) growth pattern, high nuclear grade, and elevated mitotic activity. Mitotic activity within these sarcomatous areas averages 7–15 mitotic figures/10 hpf, ^, as compared with 1–3 mitotic figures/10 hpf in conventional dermatofibrosarcoma. Uncommonly, one may identify elevated mitotic activity in DFSP lacking other features of sarcomatous progression; the significance of this finding is unclear. Expression of CD34 is often, but not always, diminished in these fibrosarcomatous areas ( Fig. 11.20B ). There is no clear consensus with regards to how large the fibrosarcomatous foci should be before the diagnosis of “fibrosarcomatous dermatofibrosarcoma protuberans” is made; we have generally required at least 5% of the tumor to show the morphologic features described above. In exceptional instances, DFSP contains areas resembling undifferentiated pleomorphic sarcoma ( Figs. 11.17 and 11.18 ). ^, Metastatic deposits from fibrosarcomatous DFSP occur most often in the lungs, where they may resemble fibrosarcoma or undifferentiated pleomorphic sarcoma ( Fig. 11.19 ).

( A ) DFSP showing transition to fibrosarcoma ( lower left corner ). ( B ) CD34 immunostain in dermatofibrosarcoma ( upper right ) with fibrosarcomatous areas. Note marked diminution of CD34 immunostain in the fibrosarcomatous portion of the tumor ( lower left ).

Fibrosarcomatous areas within DFSP.

Fibrosarcomatous areas showing increased cellularity and mitotic activity.

DFSP with transformation to undifferentiated pleomorphic sarcoma.

Undifferentiated pleomorphic sarcoma–like areas in DFSP.

Lymph node metastasis from dermatofibrosarcoma protuberans (DFSP).

CD34 immunoreactivity within conventional dermatofibrosarcoma ( A ) compared with greatly reduced immunoreactivity within a fibrosarcomatous area of DFSP ( B ).

DFSP is characterized by the almost consistent presence of CD34 ( Fig. 11.20 ), the human progenitor cell antigen, in a significant proportion of its cells. ^{, ,} Although CD34 expression is widespread in mesenchymal cells and tumors, its presence in DFSP suggests a close linkage to the normal CD34-positive dendritic cells of the dermis, including those that ensheath the adnexae, nerves, and vessels. The nearly consistent expression of this antigen has also proved useful for distinguishing DFSP from benign fibrous histiocytoma, especially when dealing with small biopsies. Although cutaneous fibrous histiocytomas may contain CD34-positive cells, these frequently account for only a minority of the tumor cell population and are often found at the deep border of the tumor. Caution should be used when interpreting CD34 immunostains in spindle cell tumors of the skin, being certain that positively staining cells are neoplastic, not entrapped normal dermal dendritic cells. Apolipoprotein D expression has been reported to be of value in the distinction of DFSP from fibrous histiocytomas, but does not seem to have been embraced by pathologists and dermatopathologists. ALK protein expression may be seen in very rare CD34-positive spindle cell neoplasms resembling DFSP and harboring underlying ALK fusions. As noted above, loss of CD34 expression is often seen in foci of fibrosarcomatous progression, but is not required for this diagnosis.

Both dermatofibrosarcoma and giant cell fibroblastoma are characterized either by a supernumerary ring chromosome, consisting of low-level amplification of sequences from chromosomes 17 and 22 ^, and infrequently 8, or by linear translocation derivatives. The presence of a ring versus a linear translocation may be related to age. ^, Specifically, adult cases typically possess the ring chromosome, whereas pediatric cases have the linear translocation derivative. Either event fuses exon 2 of the platelet-derived growth factor β-chain gene ( PDGFB ) to various exons of the collagen type 1 α ₁ gene ( COL1A1 ), resulting in a fusion transcript that places PDGFB under the control of the COL1A1 promotor. ^, The fusion protein is processed to an end product that is indistinguishable from the normal PDGFB product. Overproduction of PDGFB by dermatofibrosarcoma results in autocrine stimulation and cell proliferation, a sequence of events that can be interrupted by specific tyrosine kinase inhibitors. PDGFB amplification and rearrangement in dermatofibrosarcoma can be detected by fluorescence in situ hybridization (FISH) in formalin-fixed, paraffin-embedded tissue (FFPE) sections. Imatinib mesylate (Gleevec), which is active against PDGFB in addition to other tyrosine kinases (e.g., KIT), has been shown to have significant efficacy in the treatment of patients with locally aggressive and metastatic DFSP, including fibrosarcomatous tumors

Approximately 8% of dermatofibrosarcoma cases have historically been considered to be “fusion-negative,” although this number is declining. In 2018, Dickson et al. reported an interesting series of four morphologically and immunohistochemically typical DFSP from the female breast, all of which harbored novel COL6A3::PDGFD fusions. A similar tumor from the breast, harboring EMILIN2::PDGFD fusion, was reported by Chandler et al., and more recently, Campbell et al. have reported PDGFD -rearranged DFSP occurring in the foot and supraauricular region. An RNA sequencing study of 21 DFSP lacking COL1A1::PDGFB fusion by routine FISH analysis by Dadone-Montaudie et al. identified this fusion in 8/20 (40%); 11 tumors were found to have PDGFD rearrangements with either COL6A3 (nine cases) or EMILIN2 (two cases). An unusual TNC::PDGFD fusion has been reported in exceptionally rare DFSP-like tumors, although it has been suggested that these may be unrelated to conventional DFSP. Finally, a retrospective study of 188 DFSP from Taiwan identified classic PDGFB rearrangement, cryptic COL1A1::PDGFB fusion, and PDGFD rearrangement in 91%, 4%, and 4% of studied cases, respectively.

Relatively little is known about the genetic events underlying fibrosarcomatous progression in DFSP. Park et al. reported a small number of fibrosarcomatous dermatofibrosarcomas showing elevated levels of cyclin D1, Akt/mTOR, STAT3, ERK, and PDL-1 compared with conventional tumors. Alterations in the Akt/mTOR signaling pathway in fibrosarcomatous dermatofibrosarcomas have also been reported by Hiraki-Hotokebuchi et al., with fibrosarcomatous areas showing diminished expression of phosphorylated Akt/mTOR pathway proteins.

DFSP is a locally aggressive neoplasm that recurs in up to one-half of patients. ^{, ,} The high recurrence rate, in part, reflects the extensive infiltration of the tumor into the subcutaneous tissues. It is clear that prompt wide local excision (2–3 cm), the standard of practice for this lesion, can greatly alter the recurrence rate. Recurrence rates for patients treated by wide local excision range from 10% to 20%, compared with 43% when the excision was undefined or conservative. In addition, recurrence rates in patients treated primarily at large referral centers are low (1.75%–33%), ^{, ,} again suggesting that adequate initial surgery is essential for minimizing recurrences. The risk of local recurrence also correlates well with the extent of the wide excision. If the excision margin is 3 cm or more, the recurrence rate is 20%, compared with 41% if the margin is 2 cm or less. If local recurrence develops, it is usually within 3 years of the initial surgery, although about one-third of patients will develop recurrences after 5 years, attesting to the need for long-term follow-up. In patients who develop multiple recurrences, progressively shorter intervals between successive recurrences have been noted.

Mohs micrographic surgery has been met with growing enthusiasm for the treatment of this disease. Advocates of this approach note that DFSP occasionally grows in an asymmetric fashion from its epicenter such that a traditional wide local excision fails to remove all the tumor in a subset of cases. Mohs surgery offers the potential to achieve clear margins with minimum removal of normal tissue, an advantage particularly attractive for sites such as the head and neck. Local recurrence rates following Mohs surgery are less than 10% and in some studies approach 0%. ^{, ,}

Despite its locally aggressive behavior, DFSP only very infrequently metastasizes in the absence of fibrosarcomatous progression. The incidence of metastasis for conventional DFSP is difficult to assess because of the bias introduced when selectively reporting metastasizing tumors, the inability to determine if sarcomatous areas were noted in a subset of reported cases, and the lack of uniform treatment. In a recent systematic review of DFSP with and without fibrosarcomatous progression, the overall rate of distant metastasis in conventional DFSP was estimated to be 1.1%. Metastases seem to occur more often in recurrent tumors, and may occur several years after initial diagnosis. Metastases typically occur in a hematogenous pattern, suggesting that lymphadenectomy should not be routinely carried out in patients with DFSP. Resection of isolated pulmonary metastases has been advocated because of the overall low-grade behavior of the tumor.

There has been considerable disagreement in the literature with regards to the natural history of fibrosarcomatous DFSP, in particular with regards to the risk for local recurrence and distant metastasis, overall outcome, and the impact of complete surgical excision with widely negative margins. ^{, , , , , , ,} In a retrospective, systematic review of 1647 previously reported patients with DFSP, including 225 with fibrosarcomatous progression, Liang et al. found the overall risk of local recurrence, distant metastases, and death from disease in fibrosarcomatous DFSP to be 29.8%, 14.4%, and 14.7%, respectively. In comparison, for conventional DFSP, the rates of local recurrence, distant metastases, and death from disease were 13.7%, 1.1%, and 0.8%. It is not clear whether resection with negative margins has any impact on overall survival.

The natural history of pigmented DFSP (Bednar tumor) seems to be similar to that of more common nonpigmented tumors. Rare cases have been reported to show fibrosarcomatous progression and to metastasize.

The most common problem in the differential diagnosis is distinguishing this tumor from other fibrohistiocytic neoplasms. DFSP has a more uniform appearance, more distinct storiform pattern, and fewer secondary elements (i.e., giant cells, inflammatory cells) than either a benign fibrous histiocytoma or a superficially located undifferentiated pleomorphic sarcoma. The distinction between benign fibrous histiocytoma and dermatofibrosarcoma occasionally proves difficult when only the superficial portion of the dermatofibrosarcoma is present in a biopsy specimen, because these areas appear so well differentiated ( Table 11.2 ). Under these circumstances, knowledge of the size and configuration of the lesion in question suggests the diagnosis, and a biopsy of a deeper portion confirms it. In addition, because CD34 is almost always expressed by dermatofibrosarcoma and is much less often positive in benign fibrous histiocytoma, CD34 is an extremely useful antigen for solving this problem. ^, Undifferentiated pleomorphic sarcoma is not often confused with this tumor because it is characterized by far greater pleomorphism, mitotic activity, and necrosis. Moreover, its typical deep location in muscle and more rapid growth are at variance with the indolent course of this tumor. Rarely, one encounters DFSP with areas of undifferentiated pleomorphic sarcoma (see Figs. 11.17 and 11.18 ). As indicated earlier, when such areas represent more than just a microscopic focus, they should be diagnosed as “sarcoma arising in dermatofibrosarcoma protuberans.”

A second common problem is the confusion of this tumor with benign neural tumors, specifically a diffuse form of neurofibroma . This is most likely to occur when dermatofibrosarcoma is in the plaque stage or when a biopsy is done on only the periphery of the tumor. However, neurofibroma usually contains tactoid structures or other features of neural differentiation, and it lacks the highly cellular areas with mitotic figures that characterize the central portion of a dermatofibrosarcoma. The presence of S-100 protein and SOX10 in virtually all neurofibromas and their absence in dermatofibrosarcoma is an additional point of contrast.

Highly myxoid forms of dermatofibrosarcoma may resemble myxoid liposarcoma by virtue of the prominent vasculature and bland stellate or fusiform cells. However, the superficial location, gross configuration, CD34 immunoreactivity, and complete absence of lipoblasts should raise serious questions concerning the diagnosis of liposarcoma. In such cases, additional sampling of the tumor or review of the original material in a recurrent lesion may reveal the diagnostic cellular areas.

Superficial acral fibromyxoma (cellular digital fibroma), another CD34-positive spindle cell tumor of the dermis, typically occurs in the fingers and toes (unusual locations for dermatofibrosarcomas), contains wiry collagen, and lacks a storiform growth pattern.

Plaque-like CD34-positive dermal fibroma (“medallion-like dermal dendrocyte hamartoma”) is a very rare CD34-positive spindle cell tumor that most often involves the neck and upper extremities. ^, The histologic distinction of this lesion from dermatofibrosarcoma may be extremely challenging, although plaquelike CD34-positive dermal fibroma tends to show a parallel arrangement of tumor cells and sparing of adnexal structures. FISH for PDGFB amplification has been reported to be negative in a small number of studied cases, potentially assisting in the distinction of this lesion from “atrophic” examples of dermatofibrosarcoma.

Superficial CD34-positive fibroblastic tumor , despite occurring in similar superficial soft tissue locations and expressing CD34, is a quite different-appearing tumor, displaying striking nuclear pleomorphism, a mixed inflammatory cell infiltrate, and generally circumscribed borders. In addition to CD34 expression, these distinctive neoplasms often show strong, nuclear WT1 expression and patchy aberrant expression of keratins.

A small number of tumors have recently been reported in the uterine cervix and corpus as COL1A1::PDGFB fusion-associated uterine fibrosarcoma . These tumors have typically occurred in middle-aged or somewhat older women, and show essentially identical morphologic, immunohistochemical, and molecular genetic features as do DFSP. However, some reported cases have shown notably elevated mitotic activity and necrosis, with locally aggressive growth, sometimes leading to death from uncontrolled pelvic tumor extension. Response to imatinib mesylate has been reported in several patients. It is not yet clear whether these very rare gynecologic tumors should be regarded as DFSP (possibly with fibrosarcomatous progression) with some site-specific behavioral differences, or a distinct entity.

Giant cell fibroblastoma develops as a painless nodule or mass in the dermis or subcutis, with a predilection for the back of the thigh, inguinal region, and chest wall. It affects predominantly infants and children, being encountered only infrequently in adults. ^, In our experience, about two-thirds of the children with giant cell fibroblastoma are younger than 5 years when brought to medical attention (median age, 3 years), and about two-thirds of patients are male.

Grossly, the lesions consist of gray to yellow mucoid masses that are poorly circumscribed and measure 1–8 cm. They are composed of loosely arranged, wavy spindle cells with a moderate degree of nuclear pleomorphism that infiltrate the deep dermis and subcutis and encircle adnexal structures in a manner similar to DFSP ( Figs. 11.21–11.28 ). The tumors vary in cellularity from those approximating the cellularity of DFSP ( Figs. 11.23 and 11.27 ) to those that are hypocellular with a myxoid or hyaline stroma ( Figs. 11.24–11.26 ). The characteristic feature of the tumor is the peculiar pseudovascular spaces , which seem to reflect a loss of cellular cohesion. Large and irregular in shape, the pseudovascular spaces are lined by a discontinuous row of multinucleated cells that represent variants of the basic proliferating tumor cell ( Figs. 11.22–11.28 ). Although these cells appear to contain multiple overlapping nuclei on light microscopy, they actually represent multiple sausage-like lobations of a single nucleus ultrastructurally ( Fig. 11.29 ). By immunohistochemistry (IHC), giant cell fibroblastomas show an identical immunophenotype to dermatofibrosarcomas, with expression of CD34 in the absence of other markers.

Classic appearance of giant cell fibroblastoma showing pseudovascular spaces lined by giant cells.

Hyperchromatic giant cells lining pseudovascular spaces in giant cell fibroblastoma.

Cellular areas in giant cell fibroblastoma.

Hypocellular hyalinized zones in giant cell fibroblastoma.

Markedly hyalinized area in giant cell fibroblastoma.

Hypocellular area in giant cell fibroblastoma with giant cells not associated with pseudovascular spaces.

Dermatofibrosarcoma protuberans–like area in giant cell fibroblastoma.

Giant cells in giant cell fibroblastoma.

Electron micrograph of giant cells illustrating hypersegmented nucleus.

Courtesy of Dr. Barry Schmookler.

There have been fewer reports of giant cell fibroblastoma than DFSP in the literature. Recurrences have developed in about one-half of cases, but metastases have not been reported. The treatment of these tumors is ideally a wide local excision. If limited therapy is contemplated, conscientious follow-up is advisable to document and treat recurrences.

Historically, about 40% of giant cell fibroblastomas were misdiagnosed as sarcoma. Because of the myxoid areas and hyperchromatic giant cells, there is a tendency to assume they represent examples of myxoid liposarcoma or myxoid undifferentiated pleomorphic sarcoma occurring in an unusually young individual. Important clues to the diagnosis include the superficial location, lack of an intricate vasculature, and presence of hyperchromatic cells lying preferentially along the pseudovascular spaces.

In approximately 30% of cases, fibrous hamartomas of infancy may contain areas characterized by dense, hyalinized collagen, cracking artifact, and pseudoangiomatous, slit-like spaces lined by flattened and occasionally more prominent, CD34-positive fibroblastic cells, closely simulating giant cell fibroblastoma. In most cases, identification of the typical triphasic architecture of fibrous hamartoma, with fibroblastic fascicles, mature fat, and primitive mesenchyme, will allow this distinction without great difficulty. Occasionally, however, FISH for PDGFB rearrangement/amplification may be necessary to exclude giant cell fibroblastoma.

Plexiform fibrohistiocytic tumor (PFHT), like giant cell fibroblastoma and angiomatoid fibrous histiocytoma (see Chapter 35 ), usually occurs in children and young adults and is rarely encountered after age 30. In 66 cases culled from the AFIP archives, more than 50% of patients were younger than 20, although rare cases occurred in elderly adults as well. In a recent series of 39 cases, reported by Thangaiah et al., 25 tumors occurred in females, with a median patient age of 21 years (range 2–55 years). Interestingly, one patient in this series, with known neurofibromatosis type-1, presented with synchronous tumors of the finger and back. PFHT typically presents as a slowly growing mass of the deep dermis and subcutaneous tissues and most often involves the upper extremities, followed by the lower extremities, trunk, and head/neck. ^,

The lesions are relatively small (1–3 cm), poorly defined masses with a gray–white trabecular appearance. In its most typical form (about 40% of cases), the lesion contains a mixture of two components: a differentiated fibroblastic component and a round cell histiocytic component containing multinucleated giant cells. Low-power microscopy shows numerous tiny cellular nodules occupying the dermis and subcutaneous tissue ( Figs. 11.30 and 11.31 ). These nodules are composed of nests of histiocytic cells that often contain multinucleated, osteoclast-like giant cells and occasionally undergo focal hemorrhage ( Figs. 11.32–11.36 ). The cells in these nodules are well differentiated and, in almost all cases, do not display atypia or significant levels of mitotic activity. Rare cases, however, may contain cells showing a greater degree of cytologic atypia. The nodules, in turn, are circumscribed by short fascicles of fibroblastic cells ( Figs. 11.34 and 11.35 ) that intersect slightly or ramify in the soft tissue, creating a plexiform growth pattern. The fascicles of spindle cells somewhat resemble fibromatosis, except that the cells are usually plumper and the fascicles shorter than those of fibromatosis. In the less typical case, the two components described above may not be equally represented. A “fibroblastic” variant, consisting only of a plexiform proliferation of (myo) fibroblastic spindled cells has been reported, but may instead represent a different entity, “plexiform myofibroblastoma” (see Differential Diagnosis, below).

Plexiform fibrohistiocytic tumor showing ramifying fascicles of tumor in the subcutis.

Plexiform fibrohistiocytic tumor showing relatively paucicellular ramifying fascicles in subcutis.

Irregular fascicles and nodules of plexiform fibrohistiocytic tumor.

Typical “biphasic” appearance of plexiform fibrohistiocytic tumor. Histiocyte-like nodules circumscribed by fibromatosis-like areas.

Nodules of histiocyte-like cells in plexiform fibrohistiocytic tumor.

Plexiform fibrohistiocytic tumor with areas of short, ramifying fascicles of fibroblasts without histiocytes.

High-power view of histiocyte-like cells in tumor nodule of plexiform fibrohistiocytic tumor.

The mononuclear cell component of plexiform fibrohistiocytic tumors has traditionally been assumed to represent histiocytes, largely based on their expression of CD68 ( Fig. 11.37A ), whereas the fibroblastic component lacks this antigen ( Fig. 11.37B ). CD68 is not, however, a lineage-specific marker of histiocytes, and expression of other histiocytic markers, such as CD163, CD11c, HLA-DR, or lysozyme, is absent in subsets of cells within the mononuclear cell nodules. In fact, careful inspection of these mononuclear cell nodules shows them to contain a mixture of cell types, including osteoclast-like giant cells (positive for CD11c and CD4, but not CD163), true histiocytes (positive for CD163, CD11c, and CD4), and an enigmatic cell population lacking expression of all histiocyte-related antigens, but expressing CSF1 mRNA ( Fig. 11.37C ). This observation suggests that the true histiocytes and osteoclast-like giant cells represent recruited rather than neoplastic elements, similar to those present in tenosynovial giant cell tumors. The spindle cells express only smooth muscle actin (SMA), indicative of myofibroblastic differentiation.

Plexiform fibrohistiocytic tumor showing immunoreactivity for CD68 in mononuclear and giant cell–containing nodules ( A ) and absent expression in fibroblastic areas ( B ). Traditionally believed to be of histiocytic origin, close inspection of mononuclear cells shows they are negative for more recently developed histiocyte-specific markers, such as CD163 (shown), CD11c, and CD4. Nonneoplastic histiocytes serve as internal controls ( C ). This suggests the presence of a yet-to-be characterized mesenchymal cell population in these tumors.

Very little is known about the molecular pathogenesis of PFHT. There are only three published cytogenetic studies, showing a variety of nonrecurrent abnormalities, including 46, XY,–6,–8, del (4) (q25q31), del (20) (q11.2), + der (8)t(8;?) (p22;?), + mar, 46, XY,t(4;15)(q21;q15), and 46, X,del(X)(q13)[3]/46,XX[23]. The last of these studies, by Leclerc-Mercier et al., also studied one PFHT with fluorescence in situ hybridization (FISH) and array comparative genomic hybridization analysis (CGH) and did not identify any abnormalities. Thangaiah et al. found one studied case to have a GNAQ mutation, of unknown significance.

The natural history of PFHT is not yet entirely understood. Enzinger and Zhang emphasized the unpredictable malignant potential of PFHT, with 10 of 32 (31%) and two of 32 (6%) patients with follow-up suffering local recurrences and lymph node metastases, respectively. A subsequent study of 14 cases, by Hollowood et al., did not note any metastases, although local recurrences occurred in nearly 50% of patients. Pulmonary metastases in a patient with PFHT were first reported in 1997; interestingly, this tumor was also included in Enzinger and Zhang’s original paper, described again in a series of 22 PFHT reported by Remstein et al., and initially reported as an example of metastasizing soft tissue giant cell tumor. Including this case, Remstein et al. noted pulmonary metastases in three (of 16) patients with follow-up, one of whom (a 4-year-old girl) died of disease. Three other metastasizing PFHT have been reported. A recent large series of PFHT, reported by Thangaiah et al., noted nonaggressive local recurrences in three of 29 patients; no patient developed metastases.

Overall, of roughly 100 reported PFHT with clinical follow-up, definite lymph node and/or distant metastases have developed in no more than six patients (∼6%), with only a single reported death from disease. ^{, ,} It is likely that even this figure overstates the metastatic risk for PFHT, owing to referral and reporting bias. The general indolent natural history of PFHT should be emphasized to clinicians treating children with this disease, many of whom, in our experience, seem to think of PFHT as aggressive. The risk for local recurrence is, of course, considerably higher, likely related to the plexiform, discontiguous growth of the tumor, and complete excision showing histologically negative margins should be attempted whenever feasible.

The differential diagnosis of PFHT includes cellular neurothekeoma, soft tissue giant cell tumor, and a very recently described entity, “plexiform myofibroblastoma”. The morphologic features of cellular neurothekeoma , with multiple nests of histiocytoid cells surrounded by hyalinized fibrous bands, overlap to a degree with those of PHFT, and many cases previously described as representing the so-called “histiocytic” variant of PHFT might be better classified as cellular neurothekeomas. Cellular neurothekeomas are typically smaller and better circumscribed than PFHT, display greater nuclear variability and more abundant cytoplasm, lack the widely dispersed, plexiform growth pattern seen in PFHT, and do not contain cellular fascicles of myofibroblastic cells. Soft tissue giant cell tumors (see below) may grow in a plexiform fashion, with multiple small nodules in the skin and subcutis, but are morphologically similar to giant cell tumor of bone, with innumerable osteoclast-like giant cells and bland mononuclear cells. ^{, ,} Woven bone production and aneurysmal bone cyst-like changes are frequent findings in soft tissue giant cell tumors but are exceedingly rare in PFHT. Plexiform myofibroblastoma , very recently described in a series of 36 cases by Papke et al., occurs most often in children and young adults, involves similar locations as does PHFT, and is microscopically arguably indistinguishable from the so-called “fibroblastic” variant of PHFT, with a plexiform proliferation of fascicles of fibroblastic/myofibroblastic spindle cells growing through the dermis and subcutis. Although the distinction of “fibroblastic” PFHT and plexiform myofibroblastoma is notably subjective (and perhaps impossible), it seems reasonable that tumors lacking the probable neoplastic element of PFHT (“null cells”) likely represent a different entity.