Angiomatoid Fibrous Histiocytoma
Click on each slide thumbnail image for an enlarged view
A female age 11 presents with a 5 cm mass on her right medial knee. The lesion was present for at
least 7 months and originally had the appearance of a "bruise". The parents report that the patient has
experienced significantly reduced appetite and weight loss over the last several months. Fifteen months
after the initial complete excision of the knee mass, a second mass (2.5 cm) appeared in the right lower
quadrant (pelvis) adjacent to the iliopsoas muscle with radiologic features suggestive of extensive
hemorrhage. Multiple CT-guided biopsies revealed only hemorrhagic material. Ultimately a 4.6 cm mass
was excised that was primarily hemorrhagic but showed focal areas of spindle cells identical to previous
excision. This pelvic mass was regarded as a regional metastasis. The patient currently has no evidence
of disease 9 months after this second resection.
Case 1 - Slide 1
The tumor is cystic and hemorrhagic and surrounded by a lymphoplasmacytic infiltrate and fibrosis, 20x.
The lymphoid infiltrate focally forms germinal centers, 100x.
The eosinophilic spindle cell component shows bland cytomorphology and is arranged in fascicular to slightly storiform pattern, 200x.
Hemorrhage is noted within the bland, eosinophilic spindle cell component, 100x.
Cystic areas filled with eosinophilic proteinaceous fluid are noted, 100x.
The lymphoplasmacytic infiltrate is intimately associated with the spindle cells, 100x.
Hemosiderin deposition is focally prominent, 100x.
The sections show a tumor that is cystic, hemorrhagic, rimmed by a lymphohistiocytoc infiltrate and
surrounded by a fibrous pseudocapsule. No subcapsular sinus is noted at the inner edge of the
pseudocapsule and thus this lesion does not appear to represent a lymph node despite the prominent
peripheral lymphoid tissue with germinal center formation. The eosinophilic spindle cell component shows
bland cytomorphology and is arrayed in fascicular to slightly storiform pattern. The lymphoplasmacytic
infiltrate is intimately associated with the spindle cells. Hemorrhage and hemosiderin deposition is
noted within the spindle cell and more lymphoid portions of the tumor. Focally, cystic areas filled with
eosinophilic proteinaceous fluid are noted and these lack an endothelial lining as do the hemorrhagic
Immunohistochemical studies revealed patchy reactivity for epithelial membrane antigen (EMA) and CD68,
and weak patchy reactivity for CD99. The neoplastic cells were negative for SMA, desmin, cytokeratins,
S100, CD21, CD23, CD35, HHV8, CD31, CD34, Factor VIII and Factor XIIIa.
Fluorescence in situ hybridization (FISH) with break-apart probes
revealed rearrangement of both the EWSR1 (22q12) and CREB1 (2q33) loci strongly implicating the presence of a reciprocal translocation.
On the basis of the histologic images presented, the differential diagnosis would include:
- Nodular fasciitis
- Follicular dendritic cell sarcoma/tumor
- Aneurysmal/angiomatoid benign fibrous histiocytoma
- Spindle cell hemangioma
- Kaposi sarcoma
- Angiomatoid fibrous histiocytoma
Angiomatoid Fibrous Histiocytoma
(WHO, 2002) (previously "angiomatoid malignant fibrous histiocytoma")
A discussion of the differential diagnosis listed above follows:
The spindle cells in the present case are relatively uniform and lack the tissue culture-like features
of nodular fasciitis. The lack of smooth muscle actin (SMA) expression also mitigates against this
Follicular dendritic cell sarcoma/tumor (FDCS):
The spindle cells lack the storiform or whirling pattern of FDSC. While lymphocytes are present, they
are generally not present as sprinkled, single cells within the spindle cell component. Characteristic
immunoreactivity for CD21, CD23 and CD35 is not seen. The lack of S100 staining effectively excludes
interdigitating dendritic cell sarcoma/tumor.
Aneurysmal (benign) fibrous histiocytoma (BFH):
Aneurysmal BFH is essentially a relatively cellular BFH with prominent areas of cystic hemorrhage that
are not lined by endothelium.
This present case is deeper and the spindle cells are
more uniform than usually seen in BFH. Furthermore, this case lacks the characteristic entrapping of
collagen at the edges seen in BFH. Deep forms of BFH are encountered from time to time  and
these tumors can be more sharply circumscribed and composed of more uniform cells than their much more
common superficial counterparts.  Some cases may even adopt a conspicuous storiform
pattern. However, the expression of EMA and CD99 argues against BFH and while not entirely specific,
this present case lacked significant expression of Factor XIIIa.
Spindle cell hemangioma (SCH):
No convincing vasoformation (particularly of the cavernous type) is noted and the cystic hemorrhagic
areas lack an endothelial lining. The cells are less spindled than usually encountered in SCH, the
degree of associated lymphocytic infiltrate would be unusual, and there is no evidence of endothelial
differentiation by immunohistochemistry (CD34, CD31 and Factor VIII are negative). Finally, SCH often
displays areas of more epithelioid cells with prominent vacuolization. 
Kaposi sarcoma (KS):
An 11 year-old female child would be an unusual setting for KS and if considered, this case would be
suggestive of the nodular stage. Furthermore, this case lacks vasoformative areas and the
characteristic, but sometimes elusive, small hyaline globules. Lymphocytes are often present in KS, but
the degree seen in this case would be unusual. Finally, there is no evidence of endothelial
differentiation by immunohistochemistry (CD34, CD31 and Factor VIII are negative) as is HHV8, which is
seen in most cases of KS.  Similar reasoning excludes kaposiform hemangioendothelioma,
 though the HHV8 results are not relevant in this regard.
Angiomatoid fibrous histiocytoma:
Angiomatoid fibrous histiocytoma (AFH) is an uncommon soft tissue neoplasm first described by Enzinger
in 1979.  It was initially considered a low-grade malignancy but is currently considered as
"intermediate, rarely metastasizing" under the 2002 WHO classification. Metastases are rare and usually
regional, occurring in about 1% of cases. Local recurrence can be seen in approximately 10% of cases.
Death from metastases is exceedingly rare.
Thus, the present case is exceptional in
this regard even though the metastasis is clearly regional in nature. Given the overall quite favorable
prognosis, the 2002 WHO classification recommends the changing the original nomenclature "angiomatoid
malignant fibrous histiocytoma"  to "angiomatoid fibrous histiocytoma".
"new" nomenclature should not be taken to imply that the line of differentiation in this tumor is now
understood. Indeed, the characteristic immunophenotype of EMA, desmin and CD99 is an unusual combination
(each seen in up to 50 % of cases), though all three are not seen simultaneously in every case. EMA and
desmin also tend to be patchy and non-uniform in their distribution. CD68 and CD99 are present in many
cases, but lack specificity.
It is also important to recognize that this neoplasm is
not a member of the undifferentiated pleomorphic sarcoma / malignant fibrous histiocytoma family of
nor should its name be confused with the unrelated aneurysmal (benign) fibrous
Often systemic symptoms or findings such as fever, malaise, anorexia and paraproteinemia are
associated with this tumor as in the present case.
Cases have been described at all
ages, but the majority of cases occur in younger patients, usually below the age of 30. AFH has a
propensity to occur in the extremities more often than the trunk and is often seen in areas rich in
lymphoid tissue such as the popliteal or decubital fossa and the neck. While AFH are often associated
with a significant lymphocytic infiltrate, with germinal center formation, the lesions do not appear to
arise in lymph nodes on close histological examination. The ability of these lesions to simulate
involvement of a lymph node may lead to misinterpretation as nodal metastasis particularly in recurrent
cases. It has been suggested that the spindle cells of this lesion may show the differentiation toward
the lineage of fibroblastic reticulum cells  which are a component of the non-lymphoid,
non-vascular stroma of lymph nodes based on histologic and immunophenotypic features. This could explain
the peculiar association with lymphoid tissue, though the lineage of differentiation of this tumor is
certainly not understood. From a diagnostic perspective, it is important to remember that lymphoid
tissue and hemorrhage can be minimal to absent leaving only the characteristic spindle cells.
Using cytogenetics, several cases were initially described with translocations between the EWSR1 (22q12) and ATF1 (12q13).
Further analysis revealed that the EWSR1-ATF1 fusion transcripts demonstrated were identical to those
encountered in clear cell sarcoma (CCS), but these were present in only a small subset of investigated
cases. FUS (16p11) was seen to substitute for EWSR1 in an additional case.  Antonescu and colleagues demonstrated
that primary clear cell sarcoma of the gastrointestinal tract (GI-CCS) was often associated with fusion
genes formed by EWSR1 and CREB1 (2q33),
a close homolog of ATF1 that is also activated by cyclic AMP
(cAMP). Antonescu and colleagues subsequently demonstrated that EWSR1-CREB1
was the most common fusion event in AFH,  and was again identical to that seen in GI-CCS.
Others have confirmed this finding 
and evidence indicates that the EWSR1-CREB1 fusion is present in the majority of AFH cases with EWSR1-ATF1 and FUS-ATF1 seen in a smaller portion of
cases. This can be exploited diagnostically using either FISH or reverse transcription PCR to confirm a
suspected diagnosis of AFH.
The EWSR1-ATF1 fusion protein appears to bind cAMP responsive elements (CREs) in the promoter region
of genes and acts as an aberrant transcription factor no longer regulated by cAMP. 
Interestingly, the consequences of the EWSR1-ATF1 fusion transcript are different depending on the
tumor. For instance, in CCS, the EWSR1-ATF1 fusion transcript induces expression the melanocytic master
regulatory gene, microopthalmia transcription factor (MITF), that ultimately promotes the production of
melanosomes among its other functions.
In contrast, MITF expression is not seen
in AFH associated with EWSR1-ATF1.
The EWSR1-CREB1 does not appear to be associated
with melanocytic differentiation in either GI-CCS or AFH.
Perhaps when and where
(precise cell type, state of differentiation and environment) the fusion gene is expressed leads to two
different tumors, AFH and CCS, with very different histologic properties and natural histories. The
recent work of Capecchi and colleagues to produce mouse models of alveolar rhabdomyosarcoma (RMS)
and synovial sarcoma
and by others
in a Drosophila model of
alveolar RMS  supports this idea that the fusion
products produce tumors only when expressed in certain cell types at specific stages of development.
Bullet points :
It is not possible to given helpful bullet points in the absence of the diagnosis as these would be
non-specific and general and helpful to this particular case.
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