Case 4 -
Angiosarcoma in Renal Transplant Recipient Arising in Arteriovenous Fistula Previously Used for Dialysis
Royal Marsden Hospital
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A 50 year old male with congenital deafness and abnormalities of upper limb digits
was diagnosed in 1997 (aged 38) with focal segmental glomerulonephritis. Immuno- suppressive treatment
was commenced but in 2001 he became short of breath and was found to have cannon-ball pulmonary lesions.
Biopsy showed Epstein-Barr virus-related lymphoproliferative disorder in lung, necessitating reduction of
immunosuppression. The lung lesions resolved but his renal function deteriorated and he required
hemodialysis for which a right upper limb native brachial arteriovenous (AV) fistula was performed in
2005. The following year he underwent an ABO incompatible live donor renal transplant. Intra-
operatively the kidney, donated by his wife, was found to have a 1cm renal cell cancer. The transplant
team resected the tumor and proceeded with the operation. The transplanted kidney functioned well and in
2007 the brachial AV fistula was ligated. One year later he presented with an eight week history of
worsening pain, swelling and discoloration over the AV fistula site which failed to resolve on
antibiotics for a suspected infection. A thrombosed aneurysmal portion of the fistula was excised.
Subsequently, a lump grew rapidly at this site and an excision was performed.
Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
There was extensive
thrombosis in the large vessels of the subcutaneous AV shunt, extending proximally and distally along the
limb. Adjacent tissue was hemorrhagic and contained separate deposits of tumor, which also formed raised
purple skin nodules. Microscopically there was organized thrombus and adjacent recent hemorrhage
containing a tumor composed of atypical, mostly polygonal cells, some lining vascular channels and in
other places forming a more solid proliferation of epithelioid cells with prominent nucleoli and atypical
mitoses. Tumor was present within lumen and infiltrated wall of vessel, adjacent to suture material.
Adjacent angiectatic vessels were infiltrated by tumor. The tumor cells were immunoreactive for CD34,
CD31, FVIIIRAg, FLI1 and INI1, and focally for cytokeratins and EMA, and negative for CD30, CD45, desmin,
HHV8, EBER, and S100 protein.
Case 4 - Figure 1
Low magnification shows vessel lumen and wall with tumor.
Case 4 - Figure 2
The vessel wall is fibrosed around suture material. Irregular foci of infiltrating tumor are seen.
Case 4 - Figure 3
Foci of discohesive tumor cells adjacent to suture material.
Case 4 - Figure 4
Tumor cells are intimately related to suture material. Note the epithelioid morphology of the lesional cells.
Case 4 - Figure 5
Tumor is present both in the vessel wall and in the lumen of dilated vessel.
Case 4 - Figure 6
A focus of hemorrhagic tumor is seen in soft tissue adjacent to vessel.
Case 4 - Figure 7
The tumor infiltrates adjacent soft tissue with sheets of polygonal cells lining irregular vascular spaces.
Case 4 - Figure 8
More solid area of invasive tumor showing minimal space formation.
Case 4 - Figure 9
The tumor in this area is composed of epithelioid cells with vesicular nuclei, focally prominent nucleoli and mitotic activity.
Case 4 - Figure 10
This vein is filled with epithelioid tumor cells. Tumor cells also infiltrate adjacent tissue.
The differential diagnosis includes other (non-endothelial) neoplasms with epithelioid morphology, and
also other endothelial neoplasms with endothelial differentiation.
- Carcinomas express epithelial antigens and INI1, but lack CD34 and CD31
in almost all cases. An associated dysplastic or in-situ carcinomatous component can sometimes be seen.
- Melanoma is S100 protein positive and expresses melanocytic antigens
HMB45 and melan A in a proportion of cases. Although aberrant cytokeratin is sometimes found, markers of
endothelial differentiation are usually absent.
- Anaplastic large cell lymphoma often is positive for CD30, ALK and T-cell
markers and can show clonal rearrangement of T-cell receptor and most commonly t(2;5)(p23;q35).
- Pleomorphic rhabdomyosarcoma can be composed of polygonal cells with
prominent nucleoli, but they express desmin in cytoplasm and myogenin focally in nuclei, and lack
- Epithelioid sarcoma
 arises in skin, subcutis, or in tendon
sheaths. It forms centrally necrotic granuloma-like nodules composed of cells with mildly pleomorphic
nuclei and eosinophilic cytoplasm. The proximal aggressive variant is axial, extends deeply and is
composed of cells with vesicular nuclei, prominent nucleoli, frequent mitoses and focal rhabdoid change.
Immunohistochemistry is positive for CK, EMA, and CD34 (in about 50% of cases) but negative for CD31.
Diagnostically, nuclei lack INI1 immunoreactivity in the majority of cases.  Malignant
rhabdoid tumor is CD34 negative also lacks INI positivity in nuclei.
- Epithelioid malignant peripheral nerve sheath tumor has similar
cytomorphology but shows diffuse positivity for S100 protein and lacks endothelial markers and CK. 50%
are negative for INI1.  A spindle cell component is often also found peripherally.
- Epithelioid hemangioendothelioma can rise in skin, soft tissues, bone
and viscera. A proportion arise form a medium-sized or small vessel. It comprises cords and nests of
cells in a myxohyaline stroma with occasional ossification and giant cells. The cells often have
intracytoplasmic lumina, and express CD34, CD31 and FLI-1. Occasional examples are cytokeratin-positive,
but the morphology is usually, sufficiently distinctive to allow diagnosis from angiosarcoma. However,
there is a spectrum of appearances and more malignant examples, with nuclear pleomorphism, mitoses and
necrosis can resemble epithelioid angiosarcoma.
- Epithelioid sarcoma-like hemangioendothelioma
is a rare
entity with an indolent course that affects mainly extremities in young adults and does not usually
exceed 3.5 cm in diameter. It forms sheets and nodules of spindle cells with eosinophilic cytoplasm,
sometimes manifesting intracytoplasmic vacuolation. Mitotic activity is low and necrosis is absent.
The tumor is immunoreactive for CK, CD31, and FLI1 but not CD34.
- Epithelioid hemangioma (angiolymphoid hyperplasia with eosinophilia) is a
localized lesion that involves skin or subcutaneous tissue, in head and neck, distal extremities and
other sites. There is often a central vessel surrounded by smaller vessels, lined by plump endothelial
cells with abundant cytoplasm that is occasionally vacuolated. The cells can form sheets and there can
be mitoses and nucleolation, but the proliferation index is low. In addition, there is an inflammatory
component comprising lymphocytes (including lymphoid follicle formation), plasma cells and,
characteristically, eosinophils. This is more marked in early lesions. Endothelial antigens are
expressed, but cytokeratins are usually negative
Angiosarcoma in renal transplant recipient arising in arteriovenous fistula previously used for dialysis
Patients who are immunosuppressed, for whatever reason, are prone to develop various malignant
neoplasms. Among these are squamous cell carcinoma, post-transplantation lymphoproliferative disorders,
EBV-associated smooth muscle tumors,  and endothelial proliferations. The latter include
reactive angioendotheliomatosis,  Kaposi sarcoma and angiosarcoma.
Angiosarcoma arising at any site in immunosuppressed renal transplant recipients is rare, with fewer
than 20 reports. Examples have arisen in skin, abdominal wall, periureteric soft tissue, and in a Dacron
aortic prosthetic graft. A distinct clinicopathologic subset comprises angiosarcoma in a nonfunctioning
arteriovenous fistula, of which there are 7 previously reported examples
was reported twice
). All reported cases have been in males. The time interval between
transplantation and development of the angiosarcoma varies between two and ten years, and is usually more
than five years. The presence of satellite nodules and the (at least focal) epithelioid morphology are
typical. It is not clear where the tumor originates though it usually involves the occluded vessels.
Angiosarcoma can also arise in relation to foreign material, in the course of other neoplasms, or in
malformations. The material in the former has included plastic (Dacron) vascular
orthopedic fixation plate,  hip
replacement prosthesis, 
iron injection 
), sponge mesh, bone
wax  and
gouty tophus.  Angiosarcoma can also rarely arise in nerve sheath tumors including
schwannoma and malignant peripheral nerve sheath tumor (usually in the course of NF1), as well as in
examples of hemangioma and AV malformation. 
Many of these (especially in schwannoma) show
which is the most frequent pattern in angiosarcoma arising in
all these situation. It is also common in spontaneously-occurring angiosarcoma of soft tissue, being
found in 70% of cases in a series of 80 soft tissue angiosarcomas,  but it is relatively rare
in cutaneous angiosarcoma.
Epithelioid angiosarcoma is composed of sheets of relatively uniform polygonal cells with prominent
central nucleoli and moderate amounts of eosinophilic cytoplasm, rarely with rhabdoid cytomorphology.
There is usually mitotic activity, hemorrhage and necrosis. Foci of vascular channel formation and of
spindling can be seen. Immunohistochemistry shows positivity for CD31, FLI-1 and INI-1 is positive in
nuclei, and more variably for CD34 and FVIIIRAg (which is less sensitive). D2-40 can be positive in
tumors with lymphatic endothelial differentiation. A variable proportion of epithelioid angiosarcomas
express cytokeratins, usually focally, and in some cases EMA, but S100 protein is negative. There are no
specific genetic findings; a variety of complex changes have been described including loss of Y
The mechanism of angiosarcomagenesis is not known. Typically there is a latent interval of years (or
decades when related to metal implantation)
.  It is presumably related to an altered
vascular environment in an immunosuppressed patient following the renal transplant. 
Angiosarcoma arising in association with foreign material in immunocompetent individuals also sometimes
arises in a focus of stasis or long-standing hematoma.  Smooth-surfaced, large intact
portions of foreign material seem to be more tumorigenic than roughened, perforated or smaller ones, and
the formation of a dense fibrous capsule following inflammatory response has been associated with
angiosarcoma in some cases.  In arteriovenous fistulae, the aberrant flow through a fistula
can also have significant effects on tumorigenesis in the background of immunosuppression. It has been
shown that shear forces and oscillatory flow up-regulate certain growth factors, such as vascular
adhesion molecules which can have pro-migratory and proliferative effects on local endothelial
cells.  Experimental evidence on animal models also suggests that the potent growth pathway
orchestrated by NFKappaB is activated by abnormal flow dynamics, resulting in proliferative changes in
vascular endothelium.  The sudden variation in flow from the venous to the arterial limb in
AV fistulae certainly provides the exact deviant forces that are required for the molecular changes that
stimulate tumour genesis and establishment.
Review of the Literature/Treatment Options:
Epithelioid angiosarcoma is a high grade
sarcoma which infiltrates locally and metastasizes to lymph nodes, lung, bone and other soft tissue
sites. Reported cases arising in the clinical setting described here have developed local recurrences
and pulmonary metastases. Initial treatment often includes amputation, and reported cases have developed
local recurrences. However, our patient remains free of disease one year after amputation.
This is a rare example of angiosarcoma at the site of a disused AV shunt in an
immunosuppressed patient. Reported cases so far have all been in males. This tumor is usually very
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