The human hematopoietic progenitor cell antigen (CD34) in vascular neoplasia.

The human hematopoietic progenitor cell antigen CD34 is synthesized and expressed by early normal hematopoietic progenitor cells and by many acute leukemias. Anti-CD34 antibodies also have been reported to stain blood vessels in tissue sections, and, more recently, CD34 mRNA has been detected in vascular endothelial cells. Therefore, the authors studied the diagnostic utility of immunohistochemical CD34 antigen detection in tumors of endothelial cell derivation and compared the results with stains for von Willebrand (vW) factor. A wide variety of epithelial and mesenchymal neoplasms also were examined to assess the specificity of CD34 for vascular neoplasia. Seven cases of angiosarcoma (seven of seven), five cases of Kaposi's sarcoma (five of five), and eight cases of epithelioid hemangioendothelioma (eight of eight) were moderately to strongly positive for CD34. This reactivity was equally intense in frozen sections, alcohol-fixed tissue, and formalin-fixed specimens. In many cases, the malignant endothelial cells stained more strongly than adjacent benign endothelium. Moreover, in most cases CD34 positivity was quantitatively and qualitatively stronger than staining for vW factor. Two cases of hemangiopericytoma (two of two) were CD34 positive but stained less intensely than the angiosarcomas, Kaposi's sarcomas, or hemangioendotheliomas. Five of six cases of hemangioma also stained positively for CD34; the nonreactive tumor in this group was the only one among 28 vascular neoplasms studied that was not reactive for CD34. In comparison, 9 of the 28 vascular tumors did not stain for vW factor. Three hundred fifty-seven tumors of nonvascular derivation also were examined for CD34 antigen expression. Focal light staining was seen in one pulmonary squamous cell carcinoma; moderate to intense staining was observed in half of the epithelioid sarcomas studied (8 of 16) and in a minority of leiomyosarcomas (3 of 22). These findings indicate that CD34 is a sensitive and relatively specific marker for neoplasms of vascular origin.     

Epithelioid angiosarcoma of the intestinal tract with endothelin-1-like immunoreactivity

Two rare cases of intestinal epithelioid angiosarcoma arising in the sigmoid colon and small intestine are reported. The small intestinal tumours were located in the duodenum and upper jejunum. All tumours showed reddish-black protuberant masses with comparatively clear margins. Histology reveals solid and epithelioid growth of large polygonal cells, mimicking undifferentiated carcinoma. Vascular differentiation such as lumina containing red cells and intracytoplasmic vacuolization is noticed. Intense immunoreactivity toUlex europaeus agglutinin I and JC70 (CD31), and sporadic positive reaction to factor VIII related antigen were detected in one case but not in the other. However, both tumours have cells which show intense endothelin-1 immunoreactivity. Positive immunostaining occurred with low molecular weight keratins suggesting epithelial differentiation and suggested epithelioid angiosarcoma as a diagnosis, a specific entity within angiosarcoma. Because of their histological features, epithelioid angiosarcomas may be confused with undifferentiated carcinomas. Endothelin-1-like immunoreactivity seems to be a good marker for this type of angiosarcoma, even when the tumour cells lack usual marker substances for endothelial cells.     

Two cases of epithelioid angiosarcoma involving the thyroid and a brief review of non-Alpine epithelioid angiosarcoma of the thyroid

Epithelioid angiosarcoma involving the thyroid is a rare entity, more often described in the Alpine region. Two cases of epithelioid angiosarcoma that affected the thyroid in patients from a non-Alpine location were diagnosed during a 10-year period in our department. The first case occurred in an 89-year-old Chinese man with a history of longstanding goiter, whereas the second case involved a 74-year-old Chinese man with a history of angiosarcoma of the scalp. On histologic examination, both thyroid tumors were composed of plump epithelioid cells with vesicular chromatin and prominent nucleoli, forming vascular structures and solid sheets. Positive staining for CD31 and factor VIII-related antigen confirmed endothelial differentiation in both cases. Both patients died within 5 months following the diagnosis of thyroid disease. The relationship of the scalp angiosarcoma and thyroid disease of the second patient is unclear. A brief review of non-Alpine primary thyroid epithelioid angiosarcoma is presented.     

Cytokeratin expression in epithelioid vascular neoplasms.

Seven epithelioid and eight non-epithelioid vascular tumors were studied by the avidin-biotin-peroxidase method for the presence of endothelial- and epithelial-associated markers, using Ulex europaeus agglutinin-1 (UEA-1) lectin, and antibodies directed against factor VIII-related antigen, (FVIII-RA), vimentin, keratin, carcinoembryonic antigen, and epithelial membrane antigen. The cases included four epithelioid hemangiomas, two epithelioid hemangioendotheliomas (EHE), one epithelioid angiosarcoma (EAS), four common non-epithelioid capillary hemangiomas, and four non-epithelioid angiosarcomas. Staining for FVIII-RA, UEA-1, and vimentin were observed in all cases. The EAS showed staining for keratin in formalin-fixed, paraffin-embedded sections and in frozen sections. Staining for keratin was also observed in frozen sections of one EHE. Both keratin-positive vascular tumors were confirmed with electron microscopy. Carcinoembryonic antigen and epithelial membrane antigen stains were negative in all cases. Our results show that the epithelioid vascular tumors EHE and EAS, in addition to staining for the endothelial markers and vimentin, may also express the epithelial marker keratin. This is important since these tumors may closely resemble carcinomas by routine light microscopy. This study further underscores the importance of using a broad panel of immunohistochemical markers in the diagnostic workup of soft-tissue neoplasms.     

Langerhans cells in anaplastic Kaposi sarcoma with a paucivascular phenotype: a potential diagnostic pitfall

Anaplastic Kaposi sarcoma (AKS), a rare variant of Kaposi sarcoma, has a poorly recognized histomorphologic spectrum, including a paucivascular phenotype, that mimics a range of undifferentiated malignancies. This study, that highlights the hitherto undocumented phenomenon of S100-protein-positive Langerhans cells (SLCs) as a potential diagnostic pitfall in paucivascular AKS, involved review of nine such AKS that required diagnostic immunohistochemical (IHC) work-up. All biopsies had a predominant or exclusive spindle or epithelioid cell infiltrate. The first three tumors were diagnosed as malignant peripheral nerve sheath tumor (2) and metastatic melanoma (1), based on S100-protein immunopositivity. Biopsy of a co-existent pigmented sole lesion (patient 3) demonstrated nodular KS. Subsequent IHC investigation of these three tumors demonstrated an endothelial phenotype and HHV8 immunopositivity, confirming AKS. CD1a and langerin staining of the S100-protein-positive cells confirmed Langerhans cells as the cause of the diagnostic pitfall. Subsequently, six further paucivascular AKS with intratumoral SLCs were recognized on histomorphological and IHC appraisal. In conclusion, heightened awareness of the histomorphologic spectrum, appropriate IHC investigation, and informed appraisal thereof, are critical to the diagnosis of AKS with an undifferentiated phenotype, and the avoidance of IHC pitfalls, such as those caused by under-recognition and misinterpretation of bystander SLCs in AKS.     

L‐type amino acid transporter‐1 and CD98 expression in bone and soft tissue tumors

L‐type amino acid transporter‐1 (LAT1) is expressed in many cancers. We examined LAT1 and CD98 expression immunohistochemically in surgically resected specimens of various bone and soft tissue tumors. Out of 226 cases, 79 (35%) were LAT1⁺ and 95 (42%) were CD98⁺. In bone tumors, LAT1 was highly expressed in osteoblastoma (89%), chondrosarcoma (50%), and osteosarcoma (60%); in soft tissue tumors, LAT1 was highly expressed in rhabdomyosarcoma (80%), synovial sarcoma (63%), Ewing's sarcoma (60%), epithelioid sarcoma (100%) and angiosarcoma (100%). In malignant soft tissue tumors, LAT1 expression was associated with higher histological grade. High CD98 expression was seen in many bone tumors of intermediate and high malignancy. Among soft tissue tumors, CD98 was expressed in tendon sheath giant cell tumor and malignant peripheral nerve sheath tumor (57%), Ewing's sarcoma (50%) and undifferentiated sarcoma (64%). Some of the malignant soft tissue tumors expressed both LAT1 and CD98. This study showed that LAT1 and CD98 was expressed in many malignant and intermediate bone tumors, and some malignant soft tissue tumors.     

Recurring bone epithelioid hemangioma

Bone vascular tumors are very rare. Epithelioid types are described according to their architecture, their degree of vascular differentiation, and their cytonuclear atypia. The include epithelioid hemangioma, epithelioid hemangioendothelioma, and angiosarcoma. We report a case of L4 corpus vertebral bone epithelioid hemangioma. The patient was a 25-year-old man with a tumor that recurred twice. The lesion was characterized by a vascular lumen lined by cells with regular nuclei and inflammatory infiltrates. Capillaries were lined by prominent epithelioid endothelial cells, associated with CD31+ and cytokeratin-.     

Angiostatin receptor annexin II in vascular tumors including angiosarcoma

Inhibitors of angiogenesis, such as angiostatin, are increasingly used for targeting the tumor neovasculature and have had mixed success. Annexin II (ANX2), a 36KDa calcium and phospholipid binding protein, is a cell surface receptor for angiostatin. We hypothesized that, like normal vascular endothelium, vascular neoplasms would express ANX2, implying the potential usefulness of angiostatins in the therapy of this family of soft tissue tumors. Thirty-eight (38) vascular tumors tested included: hemangiomas - capillary [4], cavernous [6], lobular capillary [6], intramuscular hemangioma [3], spindle cell [1], and epithelioid hemangioma [4]; epithelioid hemangioendothelioma [3]; angiosarcoma [7], 4 of which were epithelioid; and angiolipomas [4]. ANX2 antibody (Zymed) was used (1/50 dilution, Ventana ES autostainer). Reactivity location (cytoplasmic, nuclear, membrane), intensity (1+/2+/3+), and quantity (focal, diffuse) was recorded. ANX2 was expressed in 97% of cases (37/38); mostly diffuse [35/37] and focal in 2 cases. Staining was strong (2+ or 3+) in 87%, and 1+ in 5/37 (14%), all benign tumors. Location was mostly cytoplasmic and membranous; no nuclear staining was seen. Both endothelium and pericytes were positive. Epithelioid angiosarcomas showed predominantly membranous staining. To our knowledge this is the first demonstration of an angiostatin receptor (ANX2) in vascular endothelial tumors including angiosarcoma. Diffuse and strong reactivity signified the absence of any down-regulation of ANX2 in both benign and malignant tumors. ANX2 reactivity may be the basis of treatment for a variety of benign tumors, especially in pediatric patients, and may offer a new and potentially less toxic therapy for angiosarcoma.     

Podoplanin is a useful diagnostic marker for epithelioid hemangioendothelioma of the liver.

Podoplanin, which is immunoreactive to D2-40 antibody, is reportedly expressed in lymphatic vessels in non-neoplastic tissues, and also in vascular and non-vascular tumors. However, its expression in non-neoplastic and neoplastic liver tissues has not been well documented. In this study, we examined podoplanin expression in specimens from 10 normal livers and 73 cases of liver tumors: hemangioma (16 cases), epithelioid hemangioendothelioma (9 cases), angiosarcoma (4 cases), angiomyolipoma (7 cases), hepatocellular carcinoma (11 cases), intrahepatic cholangiocarcinoma (11 cases), and metastatic liver cancer (15 cases). We compared levels of podoplanin and other endothelial markers (CD31, CD34, and factor VIII) in liver tumors. In the normal liver, podoplanin was expressed in lymphatic endothelium, nerve fibers, and mesothelium in the hepatic capsule, but not observed in any cells within hepatic lobules. Among liver tumors, podoplanin was specifically expressed in seven of nine cases (78%) of epithelioid hemangioendothelioma but not in other hepatic tumors. The expression of CD31, CD34, and factor VIII was observed in endothelial cells in all cases of hemangioma, epithelioid hemangioendothelioma, angiosarcoma, and angiomyolipoma with one exception, a case of epithelioid hemangioendothelioma which was without CD31 expression. Interestingly, the intensity of podoplanin expression was negatively correlated with the expression of CD34 and factor VIII. In conclusion, podoplanin would be useful as a diagnostic marker for epithelioid hemangioendothelioma in liver tumors.     

Expression of a lymphatic endothelial cell marker in benign and malignant vascular tumors

Tumors of endothelial cell origin are relatively common. Soft tissue tumors and numerous subtypes of benign and malignant vascular tumors have been described; the histogenesis of many of these tumors is uncertain, and distinguishing between benign and malignant vascular tumors, some of which express lymphatic endothelial cell markers, can be problematic. In the present study, immunophenotypic expression of a novel hyaluronan receptor (LYVE-1), which is expressed by endothelial cells of normal lymphatic vessels but not blood vessels, was determined in benign and malignant vascular tumors. It was found that, except in lymphangiomas, intramuscular hemangiomas, and Masson's hemangiomas, endothelial cells in benign blood vessel tumors (including capillary and cavernous hemangiomas, glomus tumors, pyogenic granulomas, and epithelioid hemangiomas) were negative for LYVE-1, and that all angiosarcomas and Kaposi's sarcomas were positive for LYVE-1. Expression of LYVE-1 and other lymphatic endothelial cell markers in relatively few vascular neoplasms has implications for the histogenesis of these lesions, and may prove useful in distinguishing angiosarcoma and Kaposi's sarcoma from most common benign vascular tumors.     

CD31 staining in epithelioid sarcoma

We report an unusual case of epithelioid sarcoma. The tumour occurred in the finger of a 27-year-old female. The clinical history, histology and the electron microscopy of the lesion were typical for epithelioid sarcoma. However, immunohistochemical analysis showed strong membranous CD31 staining, a finding hitherto not described. All other robust vascular markers, including factor-VIII-related antigen (FVIIIrag) were negative. The findings were compared with the available literature data, leading us to conclude that there is insufficient evidence for endothelial derivation of epithelioid sarcoma, but in the differential diagnosis with vascular tumours CD31 may stain and to rule out angiosarcoma FVIIIrag is a useful antibody.     

骨原发性上皮样血管肉瘤2例报道并文献复习

目的提高对骨原发性上皮样血管肉瘤(epithelioid angiosarcoma,EA)的认识,避免误诊。方法对2例原发于骨的EA进行临床病理、组织学及免疫组化分析,并进行文献复习。结果 2例均为男性,为骨组织内的多灶性、溶骨性病变,组织学上肿瘤主要由实性片状排列的上皮样细胞组成,瘤细胞核大,空泡状,含有明显核仁,可见细胞内空泡和血管腔样结构形成。免疫组化标记显示瘤细胞表达CD31、FⅧRAg、CK、vimentin。分别进行单纯化疗和手术治疗。1例失访,1例2个月后死亡。结论骨原发性EA是一种具有上皮样特征的高度恶性血管源性肿瘤,必须与转移癌等鉴别,CD31、CK等血管标记物对鉴别诊断具有重要的意义。     

Immunohistochemical characterization of thyroid gland angiomatoid tumors

The histogenesis of thyroid gland angiomatoid tumors, probably as a primary angiosarcoma, has been a controversy for many years. These tumors may be variants of undifferentiated (anaplastic) carcinomas. We report a thyroid gland angiomatoid carcinoma in a 61-year-old African American male. The tumor had a heterogeneous pattern with both sarcomatous and epithelioid areas. Tumor cells lined some vascular-like spaces and others had intracytoplasmic lumens containing red blood cells. The tumor cells were found to express multiple endothelial (factor VIII-related antigen, CD31, CD34, and Ulex europaeus I lectin) and epithelial (cytokeratin and epithelial membrane antigen) markers as well as thyroglobulin by immunohistochemistry. This rare presentation demonstrates the heterogeneous nature of thyroid gland angiomatoid carcinoma with both epithelial and endothelial differentiation.     

Atypical fibroxanthoma with pseudoangiomatous features: a histological and immunohistochemical mimic of cutaneous angiosarcoma

Atypical fibroxanthoma and pleomorphic dermal sarcoma may be difficult to separate from cutaneous angiosarcoma. We aim to study the morphological spectrum of pseudoangiomatous features in these tumors and the value of staining for endothelial markers CD31, CD34, FLI1, and ERG. Eleven atypical fibroxanthomas and 3 pleomorphic dermal sarcomas were identified. All tumors arose on sun-damaged skin of elderly men. Atypical fibroxanthomas were nodular and confined to the dermis, whereas pleomorphic dermal sarcoma invaded into underlying fascia. All tumors were composed of pleomorphic epithelioid and spindle cells showing blood-filled spaces and intratumoral hemorrhage. Intracytoplasmic vacuoles (n = 4), hemosiderin deposition (n = 2), and keloidal stromal change (n = 1) were also noted. Immunohistochemically, CD31 was expressed in 43% of cases, FLI1 in 79% and smooth muscle actin in 50%. Staining for CD34, ERG, S100, HMB-45, desmin, p63 and cytokeratins was negative. Follow up (median, 43.1 months; range 1-100), available for 10 patients, showed no adverse outcome. Pseudoangiomatous features and aberrant expression of CD31 and FLI1 in atypical fibroxanthoma and pleomorphic dermal sarcoma may lead to an erroneous diagnosis of cutaneous angiosarcoma. Negativity for CD34 and ERG, in particular, is a reliable differentiating feature in this setting.     

Primary epithelioid angiosarcoma of bone: a case report with immunohistochemical study

Primary malignant vascular tumors of the bone are exceedingly rare and represent <1% of primary malignant bone tumors. Angiosarcoma is a malignant mesenchymal neoplasm in which the neoplastic cells demonstrate endothelial differentiation. Epithelioid angiosarcoma (EA) is a rare variant of angiosarcoma that is characterized by large cells with an epithelioid morphology. EA is an aggressive tumor with poor prognosis. Here, we present a case of a 62-year-old man who had primary EA of the left tibia. He was treated with amputation and chemotherapy. After 1 month of chemotherapy, he developed pleural effusion and died.     

Cutaneous epithelioid angiosarcoma: a clinicopathological study of four cases

Four cases of cutaneous epithelioid angiosarcoma are described together with the potential diagnostic trap of mistaking these tumours for poorly differentiated carcinoma or malignant melanoma. The immunophenotypic profile using four endothelial markers showed positive staining in all cases for factor VIII related antigen in a predominantly paranuclear dot-like fashion and for CD31 (JC70); in three cases for CD34 (QB-END/10) and in two cases with UEA-1. All four cases were cytokeratin (CAM 5.2 and AE1/AE3) negative in contrast to the positive staining reported at non-cutaneous sites. Aberrant S-100 protein expression was seen in one case. In two cases subsequent recurrences showed better differentiation than the original tumour. Electronmicroscopy confirmed the absence of non-endothelial lines of differentiation but failed to reveal Weibel-Palade bodies.     

Matrix metalloproteinase-1 expression in splenic angiosarcoma metastasizing to the serous membrane

Angiosarcoma involving the serous membrane may mimic mesothelioma; therefore, the term “pseudomesotheliomatous angiosarcoma” has been suggested for this entity. However, the pathogenesis of pseudomesotheliomatous angiosarcoma remains unclear. Here, we report an autopsy case of splenic angiosarcoma, which systemically metastasized to the serous membrane of both the peritoneum and pleura, closely resembling a mesothelioma. The spindle-shaped tumor cells exhibited marked invasion of the lymphatic vessels and invaded the serous membrane causing thickening of the fibrous tissues like desmoplastic mesothelioma. In the present case, immunohistochemical staining showed that the tumor expressed not only the endothelial cell markers, such as CD31, vascular endothelial growth factor receptor 3, and podoplanin (D2-40), but also matrix metalloproteinase-1 (also known as collagenase-1), which is known to increase the invasiveness of mesothelioma cells. MMP-1 expression was not observed in the other cases of angiosarcoma, examined. This tumor might systemically metastasize to the serous membrane via the lymphatic route and might generate the fibrous stroma aided by the matrix metalloproteinase-1.     

Intravascular (”intimal”) epithelioid angiosarcoma: clinicopathological and immunohistochemical analysis of three cases

Angiosarcomas are rare malignant mesenchymal tumours, characterized morphologically by anastomosing vascular channels lined by atypical and proliferative active endothelial cells. An epithelioid cytomorphology of tumour cells is often seen focally in angiosarcoma, whereas purely epithelioid angiosarcomas are rare. Although angiosarcomas show a vascular differentiation they are almost never confined to pre-existing blood vessels. We describe three cases of intravascular epithelioid angiosarcoma arising in the carotid artery of a 60-year-old man, in the infrarenal part of the abdominal aorta and both renal arteries of a 69-year-old woman, and in the abdominal aorta of a 68-year-old man. In all cases malignant tumour tissue was found incidentally after disobliteration of thrombosed vessels. Histologically, purely epithelioid angiosarcoma composed of solid sheets of epithelioid tumour cells was seen; immunohistochemistry confirmed the endothelial differentiation of neoplastic cells. The reported cases show that angiosarcoma can occasionally arise within a pre-existing vessel. Received: 18 May 1999 / Accepted: 8 June 1999     

Sphingosine-1-phosphate receptor-1 (S1P1) is expressed by lymphocytes,dendritic cells,and endothelium and modulated during inflammatory bowel disease

The sphingosine-1-phosphate receptor-1 (S1P₁) agonist ozanimod ameliorates ulcerative colitis, yet its mechanism of action is unknown. Here, we examine the cell subsets that express S1P₁ in intestine using S1P₁-eGFP mice, the regulation of S1P₁ expression in lymphocytes after administration of dextran sulfate sodium (DSS), after colitis induced by transfer of CD4⁺CD45RB^hi cells, and by crossing a mouse with TNF-driven ileitis with S1P₁-eGFP mice. We then assayed the expression of enzymes that regulate intestinal S1P levels, and the effect of FTY720 on lymphocyte behavior and S1P₁ expression. We found that not only T and B cells express S1P₁, but also dendritic (DC) and endothelial cells. Furthermore, chronic but not acute inflammatory signals increased S1P₁ expression, while the enzymes that control tissue S1P levels in mice and humans with inflammatory bowel disease (IBD) were uniformly dysregulated, favoring synthesis over degradation. Finally, we observed that FTY720 reduced T-cell velocity and induced S1P₁ degradation and retention of Naïve but not effector T cells. Our data demonstrate that chronic inflammation modulates S1P₁ expression and tissue S1P levels and suggests that the anti-inflammatory properties of S1PR agonists might not be solely due to their lymphopenic effects, but also due to potential effects on DC migration and vascular barrier function.     

Malignant epithelioid vascular tumors of the pleura: report of a series and literature review

Primary malignant vascular tumors of the pleura are rare. The significance and difficulty of distinction between pleural epithelioid hemangioendothelioma (EHE) and angiosarcoma have not yet been addressed. A new series of pleural angiosarcoma is reported, and the relevant literature is reviewed. Five cases were identified from files of the authors' institutions and personal consultation cases (J.J.B.). Twenty-six cases of primary malignant vascular tumors of the pleura were identified in the literature. In a total of 31 cases, 22 were from the West and 9 from Japan. Patients were 22 to 79 years old (average, 57), and the male/female ratio was 9:1. Prior chronic pyothorax was identified only in cases reported from Japan. History of exposure to radiation or asbestos was noted in a few Western cases. The most common presentation was pleural thickening and effusion. Almost all of the patients died of disease shortly after diagnosis. A spectrum of histology ranging from characteristic high-grade epithelioid to relatively low-grade EHE-like features was observed in our cases and can be found in previous reports. Most cases showed variable spotty cytokeratin immunoreactivity. Endothelial markers (factor 8, CD34, or CD31) were invariably positive. Pleural angiosarcomas are often epithelioid and can be easily mistaken for mesothelioma or carcinoma clinically and histologically. Awareness of this rare tumor should prompt the use of endothelial markers when faced with a questionable mesothelioma. When cytokeratin is negative, or focal with strong vimentin reactivity, a vascular tumor should be suspected and confirmed with vascular markers. Because of their invariably aggressive behavior, all epithelioid vascular tumors of the pleura should be considered highly malignant regardless of the presence of EHE-like histological features.