—  SPECIALTY CONFERENCE  —

Surgical Pathology

Case 4 - Angiosarcoma in Renal Transplant Recipient Arising in Arteriovenous Fistula Previously Used for Dialysis

Cyril Fisher
Royal Marsden Hospital
London, UK





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Clinical History:
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.


Differential Diagnoses:
The differential diagnosis includes other (non-endothelial) neoplasms with epithelioid morphology, and also other endothelial neoplasms with endothelial differentiation.
  1. 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.

  2. 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.

  3. 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).

  4. Pleomorphic rhabdomyosarcoma can be composed of polygonal cells with prominent nucleoli, but they express desmin in cytoplasm and myogenin focally in nuclei, and lack endothelial antigens.

  5. Epithelioid sarcoma [28] 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. [29] Malignant rhabdoid tumor is CD34 negative also lacks INI positivity in nuclei.

  6. 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. [29] A spindle cell component is often also found peripherally.

  7. 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.

  8. Epithelioid sarcoma-like hemangioendothelioma [30, 31] 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.

  9. 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


Final Diagnosis:
Angiosarcoma in renal transplant recipient arising in arteriovenous fistula previously used for dialysis

Case Discussion:
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, [1] and endothelial proliferations. The latter include reactive angioendotheliomatosis, [2] 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 [3, 4, 5, 6, 7, 8, 9, 10] (one case was reported twice [3, 6] ). 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 grafts, [11] metal (bullet, [12] shrapnel, [13, 14] orthopedic fixation plate, [15] hip replacement prosthesis, [16] iron injection [17] ), sponge mesh, bone wax [12] and gouty tophus. [18] 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. [19] Many of these (especially in schwannoma) show epithelioid morphology, [20, 21] 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, [22] 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 chromosome.

The mechanism of angiosarcomagenesis is not known. Typically there is a latent interval of years (or decades when related to metal implantation) . [23] It is presumably related to an altered vascular environment in an immunosuppressed patient following the renal transplant. [24] Angiosarcoma arising in association with foreign material in immunocompetent individuals also sometimes arises in a focus of stasis or long-standing hematoma. [25] 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. [11] 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. [26] 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. [27] 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.

Conclusion(s):
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 aggressive.

References
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