Infantile hemangioma is a proliferation of LYVE-1-negative blood endothelial cells without lymphatic competence

Abstract

Infantile hemangiomas are common benign vascular tumors that exhibit a characteristic history of rapid proliferation in the first year of life and slow spontaneous involution during early childhood. The causative pathogenic event responsible for the abnormal endothelial proliferation remains elusive. The recent discovery of an immature phenotype of proliferating hemangioma endothelial cells due to the exclusive expression of the lymphatic endothelial hyaluronan receptor LYVE-1 led to the proposal that infantile hemangiomas are the result of a primary defect in endothelial cell maturation. To test this hypothesis, we looked for the expression of the lymphatic endothelial cell-specific markers LYVE-1, Prox-1, podoplanin and D2-40 in b4 integrin-negative proliferating and b4 integrin-positive involuting infantile hemangiomas. As b4 integrin proved to be a suitable marker for staging infantile hemangiomas, we used it in combination with clinical and histological criteria to objectively determine the proliferative and involutional phases. In immunohistochemical and immunofluorescent stains, hemangioma vessels were negative for all lymphatic endothelial cell-specific markers tested during both proliferation and involution. LYVE-1 immunoreactivity, however, was found in the dense network of perivascular HLA-DR-positive cells with dendritic cell morphology that are supposed to play a role in hemangiogenesis by releasing pro-and antiangiogenic factors. Notably, this LYVE-1 staining failed to correlate with the growth status of infantile hemangiomas. Our results do not support the notion that LYVE-1 expression was restricted to the proliferative phase and downregulated during involution. Thus, LYVE-1 does not seem to be a reliable marker for proliferating infantile hemangiomas. We conclude that the suggested intrinsic defect in endothelial cell maturation is unlikely the cause for the post-natal rapid growth in infantile hemangiomas. In addition, the lack of lymphatic endothelial cell-specific markers implies that infantile hemangiomas are tumors of blood vessels without lymphatic competence.

Solitary hepatic lymphangioma: Report of a case

“…The radiologic-pathologic correlation between lymphangioma and hemangioma is summarized in Table 2. 2,13,[19][20][21][22][23][24][25][26][27] Ultrasonography fi ndings, contrast enhancement patterns on multiphasic CT and MR images, gross fi ndings, and immunohistochemical examination are very important for distinguishing lymphangioma from hemangioma. In particular, Prox-1 was found to be very helpful for making a defi nitive diagnosis in the present case.…”

Characterization of Anti-podoplanin Monoclonal Antibodies: Critical Epitopes for Neutralizing the Interaction Between Podoplanin and CLEC-2

“…(15,17) Several studies have discussed the difference between D2-40 and AB3, and the results have been controversial. (17)(18)(19)(20)(21)(22)(23) In this study, we identified the epitope of these anti-podoplanin antibodies using ELISA, Western blot, and flow cytometry in an attempt to clarify the differences between these monoclonal antibodies. We first produced six different podoplanin-Fc chimeras and synthesized 21 peptides (Table 2).…”

Value of Podoplanin as an Immunohistochemical Marker in Tumor Diagnosis

“…46,47 Because of its high specificity for lymphatic endothelium, podoplanin has proved to be a useful immunohistochemical marker when investigating the relationship between lymphatic vascular density and lymph node metastasis [48][49][50][51] in determining lymphatic invasion by tumors, [52][53][54][55] as well as in the demonstration of lymphatic endothelial differentiation in both benign and malignant vascular tumors. 47 These include PROX1, 64 52,63,65,66 and vascular growth factor receptor-3 (VEGFR-3). 47 These include PROX1, 64 52,63,65,66 and vascular growth factor receptor-3 (VEGFR-3).…”