Bone & Soft Tissue Pathology
Case 5 -
Plexiform Fibrohistiocytic Tumor
Royal Marsden Hospital
Click on each slide thumbnail image for an enlarged view
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
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.
Plexiform Fibrohistiocytic Tumor
Plexiform fibrohistiocytic tumor (PFHT) was first described in 1988 with 65 cases in the original
report by Enzinger and Zhang. 
Subsequent series of 14 
and 22 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),  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.  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, 
bone formation, 
and an atypical variant. 
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.
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  and the other
demonstrated a simpler karyotype of 46,XY,t(4;15)(q21;q15).  All cases examined have been
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.  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.  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. 
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  and the term neurothekeoma has included both entities. However, the
lesion recognized since 1969  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.  This is clearly a different entity from cellular neurothekeoma, a
non-neural tumor, even though the latter can show myxoid change. 
CNT and PFHT have several overlapping features.
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 
and microphthalmia-associated transcription factor (MiTF)  is present in most CNT, but these
are also detectable in other fibrohistiocytic neoplasms, including PFHT;  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.
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 , spindle cell nevus,
and Spitz nevus  should not cause difficulties.
Plexiform ossifying fibromyxoid tumor (ofmt with satellite nodules
) can be recognized by the encapsulation of each nodule, the
glomus-like cells and immunoreactivity for S100 protein and GFAP. 
cell tumor of soft parts (of low malignant potential)
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.
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.
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.  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. 
10. The fibroma-like variant of epithelioid sarcoma may need consideration, but such cases display cytokeratin and
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