YAP1-TFE3-fused hemangioendothelioma: a multi-institutional clinicopathologic study of 24 genetically-confirmed cases.

YAP1-TFE3-fused hemangioendothelioma is an extremely rare malignant vascular tumor. We present the largest multi-institutional clinicopathologic study of YAP1-TFE3-fused hemangioendothelioma to date. The 24 cases of YAP1-TFE3-fused hemangioendothelioma showed a female predominance (17 female, 7 male) across a wide age range (20-78 years old, median 44). Tumors were most commonly located in soft tissue (50%), followed by bone (29%), lung (13%), and liver (8%), ranging from 3 to 115 mm in size (median 40 mm). About two-thirds presented with multifocal disease, including 7 cases with distant organ metastasis. Histopathologically, we describe three dominant architectural patterns: solid sheets of coalescing nests, pseudoalveolar and (pseudo)vasoformative pattern, and discohesive strands and clusters of cells set in a myxoid to myxohyaline stroma. These patterns were present in variable proportions across different tumors and often coexisted within the same tumor. The dominant cytomorphology (88%) was large epithelioid cells with abundant, glassy eosinophilic to vacuolated cytoplasm, prominent nucleoli and well-demarcated cell borders. Multinucleated or binucleated cells, prominent admixed erythrocytic and lymphocytic infiltrates, and intratumoral fat were frequently present. Immunohistochemically, ERG, CD31, and TFE3 were consistently expressed, while expression of CD34 (83%) and cytokeratin AE1/AE3 (20%) was variable. CAMTA1 was negative in all but one case. All cases were confirmed by molecular testing to harbor YAP1-TFE3 gene fusions: majority with YAP1 exon 1 fused to TFE3 exon 4 (88%), or less commonly, TFE3 exon 6 (12%). Most patients (88%) were treated with primary surgical resection. Over a follow-up period of 4-360 months (median 36 months) in 17 cases, 35% of patients remained alive without disease, and 47% survived many years with stable, albeit multifocal and/or metastatic disease. Five-year progression-free survival probability was 88%. We propose categorizing YAP1-TFE3-fused hemangioendothelioma as a distinct disease entity given its unique clinical and histopathologic characteristics in comparison to conventional epithelioid hemangioendothelioma.

Kaposiform Hemangioendothelioma: clinicopathological characteristics of 8 cases of a rare vascular tumor and review of literature.

BACKGROUND: Kaposiform Hemangioendothelioma (KHE) is a rare vascular tumor of intermediate malignant potential which shows locally aggressive growth but only rarely metastasizes. It is mostly considered to be a tumor of pediatric population but its occurrence in the adults is not uncommon as once considered. Histologically, KHE can mimic other soft tissue neoplasms of different behaviors (e.g. Kaposi Sarcoma, hemangioma) and establishing the correct diagnosis is important for appropriate treatment. Herein, we describe the clinicopathological features of 8 cases of KHE which will be helpful in making their diagnosis. METHODS: We reviewed pathology reports, microscopy glass slides and obtained follow up information about 8 cases of KHE which were diagnosed at our institution from January 2008 till June 2020. Immunohistochemical stain for HHV8 was also performed. RESULTS: Age ranged from 7 months to 25 years. Seven patients were less than 20 years of age and one patient was 25 years old. Equal gender distribution was observed. Extremities were the most common sites of involvement, followed by head and neck, pancreas and ischiorectal region. 2 cases were resection specimen and all others were incisional biopsies. The largest tumor size was 5.5 cm in one of the resections. The incisional/fragmented tissues were all less than 5 cm in aggregate. Most cases showed predominance of nodular growth and a minor component of spindle cell population along with lymphangiomatosis like vascular channels, with evidence of microthrombi in 2 cases. Few multinucleated giant cells were observed in 2 cases. None of the cases exhibited significant nuclear atypia or mitotic activity. One of the cases arising in dermis showed underlying bone involvement. HHV8 was negative in 7/7 cases. CONCLUSIONS: KHE can also involve adult population and it should always be considered in the differential diagnoses of a vascular lesion. Presence of multinucleated giant cells is a rare finding. Knowledge about histological features and potential mimics is helpful in avoiding misdiagnosis.

Primary pseudomyogenic hemangioendothelioma of bone: case report and review of the literature.

Pseudomyogenic hemangioendothelioma (PMH) represents a multicentric recently characterized tumor type, generally presenting in young adults, of postulated vascular origin and intermediate malignancy. This entity tends to arise in the deep-seated dermal-subcutaneous locations, preferentially limited to one anatomic site, and may extend secondary to bone. PMH restricted to the skeletal system is rare. To our knowledge, only 19 cases with description of both histologic and clinical findings have been reported to date. We report the clinicopathological features of a further intraosseous PMH occurring in a 46-year-old woman involving the right patella. Histologic examination showed an infiltrating growth composed of sheets and fascicles of spindled to epithelioid large cells, with ample eosinophilic cytoplasm, large vesicular nuclei and prominent nucleoli, sometimes resembling rhabdomyoblastic tumor cells, without morphologic signs of vascular differentiation. At immunohistochemical examination, neoplastic cells stained diffusely for AE1/AE3 keratins, vimentin, ERG, FLI-1, INI-1, FOSB with only focal CD31 expression.The morphologic clues leading to the correct diagnosis of intraosseous PMH have been correlated with the data of the literature, and a special emphasis has been given to the differential diagnosis with other neoplasms, particularly epithelioid sarcoma, in order to avoid unnecessary radical surgery and to optimise possible treatment protocols.

[Pseudomyogenic hemangioendothelioma in the upper limb: A case report and literature review]. / Hemangioendotelioma pseudomiogénico en miembro superior: descripción de un caso y revisión de la literatura.

Pseudomyogenic hemangioendothelioma, also called epithelioid sarcoma-like hemangioendothelioma, is a rare, vascular neoplasm usually with indolent behaviour. It was introduced in the latest World Health Organization (WHO) Classification of Tumours of Soft Tissue. We report a case of a 45 year-old patient presenting with a localized, palpable and slightly painful lesion in the left arm. Histologically it consisted of fascicles of spindle and epithelioid cells with ample eosinophilic cytoplasm, without nuclear pleomorphism or significant mitotic activity. Tumour cells showed diffuse expression for cytokeratin AE1/AE3, CD31 and FLI1, intact expression for INI1 and negativity for CD34. We describe the clinical, histological, molecular and immunohistochemical features of pseudomyogenic hemangioendothelioma and review the pertinent literature.

Differentiating Intralymphatic Histiocytosis, Intravascular Histiocytosis, and Subtypes of Reactive Angioendotheliomatosis: Review of Clinical and Histologic Features of All Cases Reported to Date.

Reactive angioendotheliomatosis (REA) is a rare benign angioproliferative condition of the skin, which has been noted to occur in patients with a variety of underlying systemic diseases. Histopathologically, this condition is characterized by vascular proliferation, and endothelial cell hyperplasia within the lumina and around dermal vessels, without significant cellular atypia. Since the first case of RAE was reported in 1958, multiple histologic patterns of benign cutaneous vascular proliferations with similar clinical presentations to RAE have been described in the literature and have been proposed as subtypes of the originally described condition. Among these entities are diffuse dermal angiomatosis (DDA), acroangiodermatitis, glomeruloid angioendotheliomatosis, and angiomatosis associated with cryoproteins. It has also been proposed that another entity, characterized by the benign proliferation of histiocytes within the lumina of cutaneous vessels, is a subtype of RAE. Histiocytosis within dermal vessels, in conjunction with skin pathology, was first reported in 1994. Based on the appearance of involved vessels, it was initially believed that the histiocytic proliferations were within the lumina of capillaries. Hence, the term intravascular histiocytosis was introduced to describe this histologic finding. However, subsequent introduction of an immunohistochemical (IHC) marker specific for lymphatic vessels demonstrated that most cases of cutaneous histiocyte proliferation are intralymphatic, rather than truly intravascular. However, there have also been reports of IHC-confirmed cases of true intravascular (intracapillary) histiocytosis. In this study, clinical and histologic data from all of the cases of RAE and IHC-confirmed cases of intravascular histiocytosis and intralymphatic histiocytosis reported in the literature to date are examined. Through comparison of the frequency with which key clinical and histologic features present in cases of each group, the authors provide improved clarity of the similarities and differences between these 3 entities.

Diagnostic utility of FOSB immunohistochemistry in pseudomyogenic hemangioendothelioma and its histological mimics.

BACKGROUND: Pseudomyogenic hemangioendothelioma (PHE) is an unusual vascular tumor of intermediate malignancy that rarely metastasizes and tends to arise in the lower limbs of young adults and children. Histologically, PHE shows fascicular proliferation of eosinophilic spindle cells and/or epithelioid cells showing "pseudomyogenic" morphology. Immunohistochemically, PHE is usually positive for vimentin, cytokeratin, CD31 and ERG. METHOD: We examined FOSB immunohistochemistry (IHC) in 27 cases consisting of 4 PHE and its histologic mimics including 6 epithelioid hemangioendotheliomas (EHE), 8 angiosarcomas (AS), 4 Kaposi sarcomas (KS) and 5 epithelioid sarcomas (ES). In addition, we performed IHC of CAMTA1 which has recently been established as a useful marker of EHE. We elucidated the diagnostic utility of FOSB IHC in the differential diagnosis of PHE and its histological mimics and also examined the usefulness of FOSB and CAMTA1 IHC combination in the differential diagnosis of the tumors. RESULTS: IHC revealed diffuse and strong FOSB expression in all PHE cases, while the other tumor types demonstrated limited, weak or no FOSB expression. All EHE cases exhibited diffuse and moderate to strong expression of CAMTA1. All tumor types except for EHE showed limited, weak or no CAMTA1 reactivity. CONCLUSIONS: Diffuse and strong FOSB expression was specific for PHE in the current series and FOSB IHC is an effective tool for differentiating between PHE and its histological mimics. Moreover, the combination of FOSB and CAMTA1 IHC is useful for distinguishing PHE from EHE.

Successful Everolimus Treatment of Kaposiform Hemangioendothelioma With Kasabach-Merritt Phenomenon: Clinical Efficacy and Adverse Effects of mTOR Inhibitor Therapy.

Kasabach-Merritt phenomenon (KMP) is a life-threatening consumptive coagulopathy associated with underlying kaposiform hemangioendothelioma (KHE) in infancy. We describe the case of a 3-month-old girl with KHE complicated by KMP who responded dramatically to treatment with everolimus, a mechanistic target of rapamycin (mTOR) inhibitor. Immunohistochemical expression of mTOR was found in the KHE biopsy specimens, which may explain the improvement of KMP and reduction in KHE tumor size with mTOR inhibitor treatment. This effective use of everolimus may shed light on the emerging role of mTOR signaling in the development and pathogenesis of KHE and KMP.

Primary Pseudomyogenic Hemangioendothelioma of Bone.

Pseudomyogenic hemangioendothelioma (PMH) is a well-recognized neoplasm that usually arises in the soft tissue; concurrent bone involvement occurs in 24% of cases. PMH of bone without soft tissue involvement is rare. We describe the clinicopathologic findings of 10 such cases, the largest series reported to date. The study included 9 male and 1 female patient; their ages ranged from 12 to 74 years (mean 36.7 y). All patients had multiple tumors with a distinct regional distribution: 45% restricted to the lower extremity; 25% to the spine and pelvis; and 15% to the upper extremity. On imaging studies the tumors were well circumscribed and lytic. The neoplasms were composed of spindled cells arranged in intersecting fascicles with scattered epithelioid cells; epithelioid cells predominated in 3 cases. The neoplastic cells contained abundant densely eosinophilic cytoplasm and vesicular nuclei. There was limited cytologic atypia and necrosis, few mitoses (0 to 2/10 high-power fields), and inconspicuous stroma. Unique findings included abundant intratumoral reactive woven bone and hemorrhage with numerous osteoclast-like giant cells. Immunohistochemically, most tumors were positive for keratin, ERG, and CD31; CD34 was negative. The balanced t(7:19)(q22;13) translocation was documented in 3 cases. Follow-up is limited, but no patient developed documented visceral dissemination, and all have stable or progressive osseous disease. PMH exclusively involving bone is rare. It is multicentric, often involves the lower extremity, and has unusual morphology. The differential diagnosis includes epithelioid vascular neoplasms, giant cell tumor, bone forming neoplasms, and metastatic carcinoma. Because of its rarity, unusual presentation, and morphology, accurate diagnosis can be challenging.

Kaposiform hemangioendothelioma complicated by Kasabach-Merritt phenomenon: ultrastructural observation and immunohistochemistry staining reveal the trapping of blood components.

Kaposiform hemangioendothelioma (KHE), a borderline tumor of endothelial origin, is associated with Kasabach-Merritt phenomenon, characterized by profound thrombocytopenia and consumptive coagulopathy resulting from the localized intravascular coagulation (LIC) in the tumor. Previous studies have suggested that the trapping of blood components, including platelets, may underlie the LIC in KHE. However, more evidence is needed to support this hypothesis. In this study, one case of a Chinese infant with a KHE in the left arm was complicated by Kasabach-Merritt phenomenon. The tumor was partially resected and the sample was used for ultrastructural observation and immunohistochemistry staining of Glut-1. Ultrastructural observation found the trapping of erythrocytes, platelets, macrophages, and lymphocytes in the slit-like channels of the tumor nodules, and phagocytic vesicles in the cytoplasm of neoplastic cells. Immunohistochemistry staining further showed numerous Glut-1(+) erythrocytes in the channels. In conclusion, our results provided compelling morphological evidence of the trapping of blood components in KHE, which may interpret the LIC in the tumor and subsequent consumptive coagulopathy.

Composite hemangioendothelioma and its classification as a low-grade malignancy.

Hemangioendotheliomas are vascular neoplasms occupying a spectrum of biological potential ranging from benign to low-grade malignancy. Composite hemangioendothelioma (CH) is one of the less commonly encountered variants exhibiting a mixture of elements of other hemangioendothelioma subtypes, such as epithelioid, retiform, and spindle cell. Some authors have identified areas histopathologically equivalent to angiosarcoma within CH, raising the question of the true nature of this neoplasm. Although CH recurs locally, there are only 3 reported cases which metastasized. To date, 26 cases (including the present case) have been described in the literature. Herein, we describe a unique case of CH arising in the background of previous radiation therapy and long-standing lymphedema (classically associated with the development of angiosarcoma-Stewart-Treves syndrome) that harbored higher grade areas but behaved as a low-grade malignant neoplasm. This, in conjunction with the many reported cases of CH-harboring angiosarcoma-like areas, and the occasional association with a history of lymphedema, raises the question of whether this variant of hemangioendothelioma may actually be an angiosarcoma that behaves prognostically better than the conventional type. After careful study of the natural disease progression of the current case and review of the literature, we discuss justification for the continued classification of CH as a low-grade malignancy.

Pseudomyogenic hemangioendothelioma: report of an additional case with aggressive clinical course.

: Pseudomyogenic hemangioendothelioma is a recently described vascular tumor that occurs predominantly in the distal extremities of young adults. Because of multifocal presentation, epithelioid morphology, and strong cytokeratin expression, the tumor was frequently misdiagnosed as epithelioid sarcoma. However, substantial immunohistochemical studies revealed an endothelial nature. It has been currently considered a tumor of intermediate malignancy with frequent local recurrence but low risk of distant metastasis. In this report, we describe a case of pseudomyogenic hemangioendothelioma occurring in a 22-year-old man who presented with multifocal disease in the lower extremity and developed bilateral pulmonary metastases within a short period.

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.

Diagnostic implications of oral intravascular papillary endothelial hyperplasia.

This study examined the clinical, histological, and immunohistochemical features as well as the differential diagnoses of oral intravascular papillary endothelial hyperplasia (IPEH) to aid clinicians and pathologists in its diagnosis. Clinical features of five oral IPEH cases were obtained from medical records, and all histopathological diagnoses were reviewed. Immunohistochemical reactions, including anti-CD-34, laminin, vimentin, estrogen receptor alpha, and Ki-67, were assessed. Microscopically, a reactive proliferation of vascular cells composed of small papillary structures with hypocellular and hyalinized cores arising in an organized thrombus was seen. CD-34, vimentin, and laminin staining were strongly positive, while estrogen receptor alpha was negative in all cases. A low percentage of cells were positive for Ki-67 in four of five lesions, but one case was strongly positive. A diagnosis of angiosarcoma was investigated and rejected. IPEH presents specific microscopic characteristics that along with clinical data lead to an accurate diagnosis. The general dentist, the first to participate in the diagnostic process, must share the responsibility for diagnosis with the pathologist, and they must work together to determine the correct diagnosis and management. Oral lesions of IPEH are uncommon. Their main significance is that they show a microscopic resemblance to angiosarcoma. Thus, clinicians should have more information regarding this benign entity. Finally, we suggest that in recurrent cases exhibiting strong immunolabeling of proliferative markers the possibility of angiosarcoma should be investigated.

Expression of prox1, lymphatic endothelial nuclear transcription factor, in Kaposiform hemangioendothelioma and tufted angioma.

Kaposiform hemangioendothelioma (KHE) and tufted angioma (TA) are rare tumors mainly occurring in early childhood. Our recent results showed that ectopic overexpression of human Prox1 gene, a lymphatic endothelial nuclear transcription factor, promoted an aggressive behavior in 2 murine models of KHE. This dramatic Prox1-induced phenotype prompted us to investigate immunohistochemical staining pattern of Prox1, podoplanin (D2-40), LYVE-1, and Prox1/CD34 as well as double immunofluorescent staining pattern of LYVE-1/CD31 in KHE and TA, compared with other pediatric vascular tumors. For this purpose, we examined 75 vascular lesions: KHE (n=18), TA (n=13), infantile hemangioma (n=13), pyogenic granuloma (n=18), and granulation tissue (n=13). Overall, KHE and TA shared an identical endothelial immunophenotype: the neoplastic spindle cells were Prox1, podoplanin, LYVE-1, CD31, and CD34, whereas endothelial cells within glomeruloid foci were Prox1, podoplanin, LYVE-1, CD31, and CD34. The lesional cells of all infantile hemangiomas and pyogenic granulomas were negative for Prox1 in the presence of positive internal control. These findings provide immunophenotypic evidence to support a preexisting notion that KHE and TA are closely related, if not identical. Overall, our results show, for the first time, that Prox1 is an immunohistochemical biomarker helpful in confirming the diagnosis of KHE/TA and in distinguishing it from infantile hemangioma and pyogenic granuloma.

Endothelial neoplasms of the lungs.

In the period of 20 years, the author had an opportunity to observe 14 cases of endothelial neoplasms of the lungs. The group consisted of eight women and six men, differing in age from 18 to 75 years. These cases presented as two subsets: low grade malignancy epithelioid hemangioendothelioma (PEH) (12 cases--eight women and four men, aged between 18 and 75 years) and highly malignant endotheliosarcoma seen in two men, 28 and 47 years old. The patients with epithelioid hemangioendothelioma reported to hospitals mainly because routine chest X-ray examinations accidentally revealed nodular lesions involving both lungs. Histological examination of the material collected from the bronchi and sputum was negative for neoplasm. The patients were suspected of suffering from tuberculosis or sarcoidosis and in some cases therapy was even initiated. Correct diagnoses were established based on histological examinations of material from the lesions taken during thoracotomy or thoracoscopy. In these cases, the course of the disease was slow and the patients were in a good condition for many years. In one case (a 27-year old woman), the diagnosis was possible after autopsy. The morphological appearance of these tumors is very characteristic. In case of any doubts, we can perform immunohistochemical examinations using endothelial markers, mainly CD34, possibly CD31 or factor VIII. Highly malignant endothelial sarcomas were seen in two men with a poor clinical status; one of them died shortly after histological diagnosis had been established based on material taken during a thoracotomy. In the second case, the diagnosis was possible on autopsy The prognosis for patients with these highly malignant tumors is highly unfavorable.

Knockdown of endothelial NOS by lentivirus-mediated short hairpin RNA in hemangioendothelioma cells increases proliferation and tumor formation.

Endothelial nitric oxide synthase (ecNOS) derived nitric oxide (NO) is a key contributor to the angiogenic process. By augmenting angiogenesis NO could potentially promote tumor progression. The object of this study was to determine how knockdown of ecNOS affects endothelial NO production and the angiogenic response in endothelial cells. EOMA cells derived from a spontaneously arising murine hemangioendothelioma were genetically manipulated to stably express siRNA targeting ecNOS. Knockdown of ecNOS in different stably transfected EOMA cell lines was demonstrated by quantitative RT-PCR, Western blot and ecNOS specific ELISA. An EOMA cell line with near complete knockdown of ecNOS exhibited dramatically altered morphology and changes in the expression of mRNAs encoding proteins involved in angiogenesis. This cell line exhibited a 4-fold increase in proliferation in vitro, altered tube formation in matrigel and formed tumors in mice more rapidly than the parental cells. In contrast, a cell line in which ecNOS protein levels were reduced only 5-fold did not show changes in proliferation rate, tube formation or tumor growth. These results suggest that ecNOS derived nitric oxide reduces the growth of hemangioendothelioma derived tumors, and underscore the importance of careful consideration of the tumor type when selecting modulation of nitric oxide signaling as a treatment strategy.

Haemangioendothelioma on the conjunctiva of the upper eyelid.

A 62-year-old man visited the authors' clinic complaining of a mass on the palpebral conjunctiva of the right upper eyelid. The 2.0 cm x 1.2 cm sized, red and painless mass underwent incision and biopsy for histopathological examination. The mass was confirmed to be Kaposiform haemangioendothelioma characterized by densely packed spindle cells. These cells were positive to vimentin, CD31 and factor VIII-related antigen by immunohistochemical stain. The mass was completely resolved by oral steroid therapy and has not recurred through the presentation. Kaposiform haemangioendothelioma generally occurs in infant and adolescent periods and is characterized by rapid progression and invasion to adjacent tissue. Herein, an unusual case of Kaposiform haemangioendothelioma affecting the conjunctiva of the upper eyelid on a middle-aged man is reported.

Multifocal kaposiform haemangioendothelioma.

Kaposiform haemangioendothelioma (KHE) is a rare, locally aggressive vascular spindle cell proliferation, with resemblance to Kaposi's sarcoma. This tumour usually occurs in skin and retroperitoneum of infants and young children and is often complicated by the Kasabach-Merritt phenomenon (KMP). A 3-year-old boy presented with a right submandibular swelling due to lymphadenopathies, a violaceous skin lesion at the left commissure of the lips and an ill-defined lesion in the right thyroid lobe. There were some signs of KMP. Histological examination revealed a typical infiltrative multilobular spindle cell proliferation with slit-like vascular spaces in these three localisations. Immunohistochemical stains showed positivity for CD34 and CD31 and many alpha-smooth muscle actin-positive spindle cells around the vascular spaces. There was no Herpes virus type 8 expression. The presented case is unique in two ways. First, thyroid involvement of KHE has never been described in the literature until now. Secondly, and most remarkably, the multifocal presentation in three anatomically distinct and separated localisations is extremely unusual.