Basic histological feature of IPEH is the formation of papillary structures lined by hyperplastic endothelial cells in the vascular lumen [1–5, 11]. Frequently, IPEH has a close association with thrombus. Several reports have proposed that there is a special variation in the organization procedure of thrombus [1, 3, 4, 12], however, the basis for the development of the lesion in thrombus has not been determined. The developmental procedure of the lesion takes place in several steps .
Normally older trombi tend to become organized. This refers to ingrowth of endothelial cells, smooth muscle cells, and fibroblasts into the fibrin-rich thrombus. In time, capillary channels are formed, which may anastomose to create conduits from one and of the thrombus to the other, reestablishing to some extent the continuity of the original lumen. This recanalization may eventually convert the thrombus into a vascularised mass of connective tissue, which is incorporated as a subendothelial swelling of the vessel wall. With time and contraction of the mesenchimal cells, only a fibrous lump may remain to mark the original thrombus site .
Similar to thrombus organization and recanalization, the developmental pathogenesis of IPEH lesion formation occurs in several steps . Embedment of endothelial cells within the thrombus characterizes early stage lesions. Subsequently, the proliferating endothelial cells segregate the collagenase-digested thrombus into irregular clumps from which papillary structures will develop. In the final stage, papillae combine and form anastomosing vascular structures.
Some investigators have proposed that the developing thrombus serves as a matrix for the ingrowth of papillary structures . Ultrastructurally, these papillary structures closely resemble granulation tissue, suggesting a reparative origin . In addition, endothelium-lining cells appear to originate in histiocytes and the exuberant endothelial proliferation involves an autocrine loop of endothelial secretions including basic fibroblast growth factor . Reports of occasional cases that did not involve thrombosis in addition to reports of the presence of a lymphatic counterpart have led some authors to support Masson’s original theory that IPEH is a benign tumor marked by primary endothelial proliferation and secondary thrombus formation .
IPEH is a benign behavioral vascular lesion that must be accurately differentiated from malignant angiosarcoma and other vascular tumours [1–5, 20]. Correct diagnosis consists of careful histomorphological examination in conjunction with IHC staining.
Monoclonal antibodies directed against CD34 and CD31 have yielded insights into the nature of vascular tumors. These antigens are not endothelial cell specific, but they are widely expressed by vascular endothelium, particularly under pathological conditions .
CD34 is a cell surface protein that is expressed by human hematopoietic cells of both the myeloid and lymphoid lineage, as well as endothelial cells. CD34 may regulate the early events of blood cell differentiation and modulate adhesion in both endothelial cells and hematopoietic progenitor cells .
CD31 is a trans-membrane glycoprotein expressed by platelets, monocytes, granulocytes, B-cells, certain subsets of leukocytes, and endothelial cells .
We observed CD31 and CD34 staining in all 10 cases (100%). In our opinion both CD31 and CD34 stain IPEH endothelium with high intensity and are highly effective in establishing the vascular root of the lesion. In our study CD31 and CD34 labeled all maturity levels of lesions. They stained diffuse strongly the immature endothelium which covers multiple small papillary structures (lining endothelial cells), and also mature well formed vessels,
Factor VIII-related antigen (FVIII) is a protein that is synthesized by endothelial cells and is an excellent marker of endothelial differentiation .
Tosios et al. have described the presence of FVIII-related antigen in the final stages of IPEH organization , and the presence of FVIII-related antigen is strong evidence of IPEH.
Flope et al. observed that well differentiated capillaries strongly express factor VIII, but is not expressed in the endothelial cells lining small slit-like, sieve-like vascular spaces and spindle-shaped tumor cells. Jones et al., Mentzel et al. and Wilken et al. have reported similar observations [21, 24–26].
In our study 6 cases (60%) exhibited FVIII staining, similar to the findings of Albrecht and Kahn . In their study, Albrecht and Kahn presented maturity-dependent variation in FVIII staining of IPEH lesions. FVIII positive staining was seen only in mature lesions.
In addition to endothelial cells, IPEH lesions consist of basal membrane and pericytes associated with vascular proliferation and immune markers. Effective identification of these components using IHC may improve IPEH diagnosis. Multiple reports have established the use of a panel of immune markers to demonstrate the vascular root of IPEH [4, 5, 12, 21, 27]. We evaluated Type 4 collagen, SMA, and MSA staining in addition to the established endothelial-specific markers in this study, observing variation in staining intensity in many of the cases examined. This variability may be related to the stage of IPEH lesion development.
Soares et al. has described Collagen type IV staining in the basement membrane of the endothelial vessel wall, and cells surrounding the vessel wall express SMA .
We also examined the immune marker CD105. CD105 (endoglin) is a membrane-bound homodimer expressed in angiogenic endothelial cells that has recently been associated with tumor angiogenesis. CD105 has an important role in angiogenesis and is essential for the proliferation of endothelial cells during the active phase of angiogenesis. Endothelial cells are the principal source of CD105, however other cells types including vascular smooth muscle cells, fibroblasts, and macrophages express CD105 to a lesser extent . The expression of CD105 is a prominent feature of newly formed blood vessels, but is minimally expressed in fully formed vessels. The expression of CD105 in blood vessels surrounding IPEH lesions suggests a potential role for CD015 in tumor angiogenesis. Non-neoplastic tissues with increased angiogenic activity, such as the developing embryo and during wound remodeling, can also express limited amounts of CD105 [28–33].
Soares et al.  found that proliferative endothelial cells are negative for CD105 in IPEH tissues, suggesting that IPEH differs from the reactive processes occurring in pyogenic granulomas in which all cells are positive for CD105 expression. IPEH tissues are unlikely to be comprised of proliferative angiogenic tissues.
We investigated whether this new endothelial marker, CD105, was not present in 10 cases of IPEH. None of the tissues evaluated demonstrated significant CD105 staining, consistent with the work done by Soares et al. .
Few previous studies of IPEH immunohistochemical staining have utilized a wide panel of immune markers. In our opinion, the evaluation of novel immune markers, primarily FVIII, in a wider series will enhance our understanding of vascular lesions and angiogenesis.
In conclusion, IPEH is a benign behavioral vascular lesion that must be accurately differentiated from malignant angiosarcoma through careful histomorphological examination in conjunction with immunohistochemical staining.
CD31 and CD34 are the most effective markers for identification of the vascular root, whereas FVIII, Type 4 collagen, SMA and MSA staining vary widely between individual cases.