Primary Vascular Tumors of Bone: A Monoinstitutional Morphologic and Molecular Analysis of 427 Cases With Emphasis on Epithelioid Variants.

Recent molecular discoveries have refined vascular bone tumor classification. To investigate the clinical relevance of these refinements, we reviewed all cases of primary vascular bone tumors treated at our Institute. On the basis of morphology, cases were assessed immunohistochemically and molecularly. A total of 427 cases of primary vascular tumor of bone with available follow-up and histologic material were retrieved and reclassified according to the most recent diagnostic criteria as follows: 289 hemangiomas, 38 epithelioid hemangiomas, 21 epithelioid hemangioendotheliomas, 2 retiform hemangioendotheliomas, 1 intraosseous papillary intralymphatic angioendothelioma, 24 pseudomyogenic hemangioendotheliomas, and 52 angiosarcomas (of these, 45 were epithelioid angiosarcomas and 7 spindle cell secondary angiosarcoma). Both epithelioid and classic hemangiomas behave as benign tumors with excellent prognosis. The distinction between cellular and conventional type of epithelioid hemangioma was not associated with a different clinical course. Conversely, epithelioid hemangioendothelioma exhibited a more aggressive clinical behavior than hemangioma, with higher rates of multifocality and distant spread. Immunohistochemical positivity for CAMTA1 or TFE3 did not have a prognostic implication. In epithelioid hemangioendothelioma, the presence of morphologic malignant features was associated with reduced disease-free (P=0.064) and overall survival (P=0.055). Pseudomyogenic hemangioendothelioma featured local aggressiveness in 5/24 patients exhibiting a clinical behavior closer to epithelioid hemangioma than epithelioid hemangioendothelioma. Last, 32/45 patients with epithelioid angiosarcoma died of disease with a median survival time of 10 months from diagnosis. In conclusion, the integration of morphologic, immunohistochemical, and molecular features allows a better stratification of primary vascular tumors of bone with significant prognostic and therapeutic implications.

Diagnostic utility of WT-1 cytoplasmic stain in variety of vascular lesions.

Vascular lesions are commonly encountered in routine pathologic practice and often pose diagnostic challenges owing to their morphologic diversity. Although WT-1 expression was reported in some vascular tumors, little is known about its staining patterns in a spectrum of vascular lesions from various locations. We examined WT-1 immunostain in 95 cases of vascular lesions including angiosarcomas (AS, 19 cases), hemangioendotheliomas (HE, 5), Kaposi's sarcomas (KS, 4), cavernous hemangiomas (CVH, 12), capillary hemangiomas (CPH, 7), pyogenic granulomas (PG, 4), lymphangiomas (LA, 4), hemangiopericytomas (HP, 5), glomus tumors (GT, 8), vascular malformation (VM, 13) and granulation tissue (GRT, 14). Strong WT-1 cytoplasmic stain was invariably observed in all cases of malignant and borderline vascular tumors including AS (19/19), KS (4/4) and HE (5/5). WT-1 was also consistently expressed in CPH (7/7), PG (4/4), and GRT (14/14), while it became weaker in VM (10/13) and often negative in CVH (2/12) and LA (0/4). WT1 stain was not demonstrated in HP (0/5) and rarely in GT (2/8). We conclude that consistent and diffuse WT-1 cytoplasmic stain in AS, HE and KS can be useful in distinguishing these tumors from poorly differentiated tumors with mimicking features. On the other hand, reliable WT-1 stain in CPH, PG and GRT may help in differential diagnosis with non-endothelial vascular tumors such as GT and HP. Recognizing the WT-1 cytoplasmic stain in a broad spectrum of benign and neoplastic tissues is critical in formulating appropriate immunohistochemical panels and avoiding misinterpretation of results.

Intravascular papillary endothelial hyperplasia: histomorphological and immunohistochemical features.

BACKGROUND: Intravascular papillary endothelial hyperplasia (IPEH) is a benign intravascular process with features mimicking other benign and malignant vascular proliferations. IPEH lesions predominate in the head-neck region and the extremities. The characteristic histomorphological feature of IPEH is a papillary structure covered with hyperplastic endothelial cells within the vascular lumen. It is critical that this clinically benign lesion should not be mistaken for well-differentiated vascular tumors. In addition to the characteristic histological features, other useful diagnostic features included the intra-luminal location of the lesion, an intimate association with the organizing thrombus, the absence of necrosis, cellular pleomorphism, and mitotic activity. In addition, immunohistochemistry may indicate the vascular origin and proliferative index. In this study, we evaluated histomorphological and immunohistochemical findings (CD31, CD34, FVIII, type IV collagen, SMA, MSA, CD105, and Ki-67 staining) of ten IPEH cases. METHODS: Ten IPEH cases were re-examined for a panel of histomorphological and immunohistochemical features. CD31, CD34, FVIII, Type IV collagen, SMA and MSA antibodies utilized for immunohistochemical analysis.The histomorphological and immunohistochemical findings were evaluated by two independent pathologists using light microscopy. RESULTS: All ten cases involved intraluminal lesions with characteristic features of IPEH. All ten cases (100%) were stained positive for CD31 and CD34. The degree of staining with FVIII, type IV collagen, SMA, and MSA was variable. CONCLUSION: In this series of specimens, CD31 and CD34 were the most sensitive markers indicating the vascular origin of the lesion. Staining for the other vascular markers (FVIII, type IV collagen, SMA and MSA) was variable. Different maturation degrees of lesions may account for the variation in immunohistochemical staining. Few previous investigations evaluated a wide range of antigen panels in IPEH sections. In our opinion, the evaluation of immune markers in a larger sample set will reveal new features in the maturity and developmental pathogenesis of vascular lesions and angiogenesis. IPEH is a benign lesion, which must be differentiated from malignant tumors such as angiosarcoma and Kaposi's sarcoma. Improved definition of IPEH lesions using immunohistochemical markers may enhance the ability to differentiate between various vascular lesions. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1381849312101856.

ß-Adrenergic receptor expression in vascular tumors.

Propranolol has recently emerged as an effective therapy for infantile hemangiomas causing regression. The ß-adrenergic receptor (AR) antagonist is thought to cause vasoconstriction by its effect on nitric oxide, block angiogenesis by its effect on vascular endothelial growth factor (VEGF), and induce apoptosis. In a prior report, we identified expression of ß2-AR (B2-AR) and its phosphorylated form (B2-ARP) in a case of infantile hemangioma that responded to propranolol treatment. We now explore the expression of ßARs on a variety of vascular lesions utilizing a tissue microarray containing 141 lesions, including infantile hemangiomas, angiosarcomas, hemangiomas, hemangioendotheliomas, and various vascular malformations. The array was immunostained for B2-AR, B2-ARP, and ß3-AR (B3-AR), and the results scored for the intensity of endothelial cell expression as negative, weak positive, or strong positive. All phases of infantile hemangiomas had strong expression of all three receptors, with the exception of only weak expression of B2-ARP in the proliferative phase infantile hemangioma. Strong expression of all three receptors was present in many hemangiomas, hemangioendotheliomas, and vascular malformations. Absent to weak expression of all three receptors was seen in glomus tumor, hobnail hemangioendothelioma, pyogenic granuloma, and reactive vascular proliferations. This is the first study to report ß-AR expression in a variety of vascular lesions. Although immunohistochemical expression of the receptors does not necessarily indicate that similar pathways of responsiveness to ß-blockade are present, it does raises the possibility that ß-blockade could potentially affect apoptosis and decrease responsiveness to VEGF. Additional study is warranted, as therapeutic options are limited for some patients with these lesions.

Occasional staining for p63 in malignant vascular tumors: a potential diagnostic pitfall.

Expression of p63, a putative marker for epithelial or myoepithelial differentiation, has been used to distinguish spindle cell carcinoma from sarcoma. The specificity of p63 for epithelial differentiation has not been thoroughly evaluated however, since p63 expression has been explored in only a handful of mesenchymal tumors. After observing unexpected immunohistochemical staining for p63 in an angiosarcoma of the breast, we evaluated a series of benign and malignant vascular tumors to determine the frequency of such a finding. Nuclear immunoreactivity to p63 was detected, at least focally, in 24% of malignant vascular tumors other than Kaposi sarcoma, which was uniformly negative. Benign vascular tumors were also negative for p63. Although p63 expression in tumors of vascular differentiation is unusual, it may be seen occasionally in some malignant vascular tumors. Thus, p63 is not entirely specific for epithelial differentiation. Since soft tissue angiosarcomas and hemangioendotheliomas sometimes express cytokeratins, the finding of nuclear p63 represents another potential pitfall in the differential diagnosis between poorly-differentiated carcinomas and vascular neoplasms.

Prox1 transcription factor as a marker for vascular tumors-evaluation of 314 vascular endothelial and 1086 nonvascular tumors.

Prox1, a transcription factor important in the regulation and maintenance of the lymphatic endothelial phenotype, is consistently expressed in lymphangiomas and Kaposi sarcoma and has also been reported in Kaposiform hemangioendothelioma. However, information on its distribution in vascular tumors, such as angiosarcoma, is limited. In this study, we examined selected normal tissues and 314 vascular endothelial and 1086 nonvascular tumors to get an insight into the biology of these tumors and on potential diagnostic use of Prox1 as an immunohistochemical marker. In adult tissues, Prox1 was essentially restricted to lymphatic endothelia, with expression in subsets of pancreatic and gastrointestinal epithelia. However, it was also detected in embryonic liver and heart. Prox1 was consistently expressed in lymphangiomas, venous hemangiomas, Kaposi sarcoma, in endothelia of spindle cell hemangioma, Kaposiform hemangioendothelioma, and retiform hemangioendothelioma, and in half of epithelioid hemangioendotheliomas. It was present in most cutaneous angiosarcomas from different sites but was less commonly expressed in deep soft tissue and visceral angiosarcomas. In contrast, Prox1 was generally absent in capillary and cavernous hemangiomas. In positive hemangiomas and angiosarcomas it was coexpressed with podoplanin, another marker of the lymphatic endothelial phenotype. There was an inverse correlation with CD34 expression. The expression in mesenchymal nonendothelial neoplasm was limited. Prox1 was detected in 5 of 27 synovial sarcomas, specifically in the epithelia of biphasic tumors. Four of 16 Ewing sarcomas and 5 of 15 paragangliomas were also positive. All melanomas and undifferentiated sarcomas were negative. Among epithelial neoplasms, Prox1 was detected in 18 of 38 colonic carcinomas and 10 of 15 cholangiocarcinomas and in a minority of pulmonary, prostatic, and endometrial adenocarcinomas. The common Prox1 expression in angiosarcoma and its rare presence in nonvascular mesenchymal tumors make this marker suitable for the diagnosis of angiosarcoma and Kaposi sarcoma. However, the presence of Prox1 in some malignant epithelial tumors necessitates caution in applying Prox1 as a marker for vascular tumors. Common Prox1 expression in angiosarcoma may reflect the lymphatic endothelial phenotype in these tumors. Its patterns of expression in hemangiomas and angiosarcoma may be diagnostically useful and offer a new parameter in the biological classification of vascular tumors.

Sphingosine-1-phosphate receptor 1 is a useful adjunct for distinguishing vascular neoplasms from morphological mimics.

Sphingosine-1-phosphate receptor 1 (S1P(1)) has been shown to play an important role in the migration, proliferation, and survival of endothelial cells. S1P(1) of vascular and lymphatic endothelial cells can be detected by immunostaining of paraffin-embedded sections using a rabbit anti-S1P(1) antibody. In this study, to distinguish vascular tumors from histologic mimics using immunohistochemical means, we evaluated the expression of S1P(1) in a range of vascular tumors. S1P(1) expression was observed in eight of eight hemangiomas, four of four lymphangiomas, four of four epithelioid hemangioendotheliomas, three of three Kaposi's sarcomas, and 15 of 15 angiosarcomas with vasoformative, spindle, epithelioid, and undifferentiated features. Conventional analysis and use of a tissue microarray of soft tissue tumors revealed three of 21 liposarcomas to have weak cytoplasmic staining and one of five squamous cell carcinomas to have membranous staining in a very limited area among 115 nonvascular tumors including histological mimics of angiosarcoma such as undifferentiated carcinoma, melanoma, and epithelioid sarcoma. The sensitivity with regards to the angiosarcoma cases was equal to, or even exceeded in undifferentiated angiosarcoma, that of CD31. Based on this study, S1P(1) may be a useful adjunct to CD31 in cases where a vascular neoplasm requires a differential diagnosis.

Intravascular B-cell lymphoma: the role of skin biopsy.

Intravascular B-cell lymphoma is a rare aggressive systemic neoplasm with cutaneous and neurological presentations, which commonly eludes the diagnosis ante mortem. First reported in 1959 as "angioendotheliomatosis proliferans" by Pfleger and Tappeiner, it is a subtype of extranodal diffuse large-B-cell lymphoma defined by an intravascular proliferation of clonal lymphocytes. We describe a case of intravascular lymphoma in a 68-year-old female who presented with altered mental status and indurated, erythematous, ecchymotic plaques with overlying telangiectasia and ulceration. The diagnosis was made by skin biopsy of an abdominal plaque revealing large hyperchromatic cells filling the lumina of several small blood vessels within the dermis and subcutis. CD20 and CD79a immunostains were strongly positive, confirming the diagnosis of intravascular large-B-cell lymphoma. On review of a previous biopsy from another institution, which was reported to be nondiagnostic, we were able to find tumor cells in the blood vessels but only very focally. The presence of a brisk, perivascular, nonneoplastic lymphocytic infiltrate may have obscured the identification of tumor cells. This case illustrates an unusual subtype of extranodal diffuse large-B-cell lymphoma, which demonstrates protean clinical presentations, requires microscopic examination for diagnosis, but can be easily overlooked on skin biopsy.

Intravascular myopericytoma.

BACKGROUND: Myopericytoma is a benign tumor composed of cells that show apparent differentiation towards putative perivascular myoid cells called myopericytes. It arises most commonly in the dermis or subcutaneous tissue of the extremities in adults. METHODS: We describe a myopericytoma that was unusual in its intravascular location. RESULTS: A 54-year-old man presented with a 10-year history of a painful slowly growing 1.5-cm nodule in the subcutaneous tissue of the thigh. Histologic examination of the excised lesion showed that is was entirely contained within the lumen of a vein. It was composed of a proliferation of myoid-appearing spindle cells, which were arranged in a striking concentric pattern around numerous blood vessels, in a manner that accentuated the vessel walls. This pattern is characteristic of myopericytoma. In some areas, fascicles of spindle cells, embedded in a myxoid stroma, bulged into the lumina of lesional vessels, reminiscent of myofibroma/myofibromatosis. Lesional spindle cells were diffusely positive for smooth muscle actin, focally positive for CD34 and were negative for desmin, cytokeratin, S100 protein, HMB-45 and CD31. CONCLUSION: This case illustrates that myopericytoma can be entirely intravascular in its location.

Intraosseous epithelioid hemangioendothelioma of the mandible: a case report with an immunohistochemical study.

Epithelioid hemangioma is the prototype of a group of vascular tumors characterized by epithelioid endothelial cells. Hemangioendothelioma of bone is a rare lesion that constitutes less than 0.5% of primary malignant skeletal tumors. We report and discuss a case of epithelioid hemangioendothelioma arising intraosseously in the anterior portion of the mandible in a 76-year-old woman. The case was treated successfully by wide resection. Radiographically, the tumor mass showed osteolysis and expansion. Histologically, the tumor showed invasive and destructive growth, although it lacked frequent mitotic figures and severe atypia. On immunohistochemical study, tumor cells exhibited characteristics of mesenchymal and endothelial origin, i.e., strong to moderate immune reactivity against vimentin, factor VIII-related antigen (F8RA), Ulex europaeus agglutinin type 1 lectin (UEA-1), and CD 34, but not against keratin, epithelial membrane antigen (EMA) or S-100 protein (S100). The proliferating cell nuclear antigen (PCNA)-positive cell index was 27.5%. These pathological findings suggested a borderline malignant potential for this tumor. Thus, clinically, wide resection with or without dissection of regional lymph nodes is recommended.

Angiosarcoma arising in a solitary schwannoma (neurilemoma) of the sciatic nerve.

Angiosarcomas rarely develop within a peripheral nerve or a peripheral nerve sheath tumor. We describe an epithelioid angiosarcoma that arose in a benign schwannoma (neurilemoma) of the right thigh in a 65-year-old man who did not have von Recklinghausen's disease. Histologically, the resected tumor was a high-grade undifferentiated sarcoma that was predominantly arranged in solid sheets or nests and composed of epithelioid cells. The endothelial origin of the tumor was suggested by Factor VIII R-ag, Ulex europaeus-I, CD34, CD31, BNH9, and vimentin immunoreactivity, along with the ultrastructural evidence of occasional Weibel-Palade bodies. In this location, epithelioid angiosarcoma should be distinguished from malignant transformation of a schwannoma with epithelioid changes. This observation stresses the importance of immunohistochemical and ultrastructural analysis in the differential diagnosis of vascular tumors with features of epithelioid sarcoma.

Immunohistochemical evaluation of vascular neoplasms.

Immunohistochemistry is of proven value in the evaluation of cutaneous vascular neoplasms. Nonetheless, the lack of sensitivity and specificity demonstrated by some endothelial markers requires that a panel of antibodies to other lineage-related determinants be applied in this context. Compared with electron microscopy, enzyme-linked antibody techniques can be applied in a cost-effective manner, with a satisfactory diagnostic result in most cases. The efficacy of these methods will likely improve as more sensitive and specific markers of endothelial differentiation are characterized. For the time being, the exclusion of non-endothelial proliferations remains an important aspect of the differential diagnosis of vascular tumors.