Epithelioid hemangioma of bone harboring FOS and FOSB gene rearrangements: A clinicopathologic and molecular study

The diagnosis of epithelioid hemangioma (EH) remains challenging due to its rarity, worrisome histologic features, and locally aggressive clinical and radiographic presentation. Especially in the bone, EH can be misdiagnosed as a malignant vascular neoplasm due its lytic, often destructive or multifocal growth, as well as atypical morphology. The discovery of recurrent FOS and FOSB gene fusions in the pathogenesis of most EH has strengthened its stand‐alone classification, distinct from other malignant epithelioid vascular lesions, such as epithelioid hemangioendothelioma or angiosarcoma. In this study we investigate a group of molecularly confirmed skeletal EH by the presence of FOS or FOSB gene rearrangements to better define its clinical and pathologic characteristics within a homogenous molecular subset. The cohort included 38 patients (25 males, 13 females), with a mean age at diagnosis of 38 years (range, 4‐75). Regional, multifocal presentation was noted in 10 cases. Only six cases were correctly recognized as EH by the referring institutions, while most were misdiagnosed as other vascular tumors. Of the 17 patients with follow‐up data available, five patients (29%) developed local recurrence after marginal en bloc excision (n = 3) or curettage (n = 2). Local recurrence‐free survival rates were 84% at 3 years and 38% at 5 years. No metastasis or disease‐related death was identified. Imaging studies exhibited no specific features, showing cortical bone destruction and soft‐tissue extension in 14 (38%) cases. FOS gene rearrangements were detected in 28 (74%) of cases, while FOSB rearrangements in 10 (26%) cases. Our results highlight the significant challenges encountered in establishing a correct diagnosis exclusive of the molecular testing, mainly due to its overlap to other malignant epithelioid vascular tumors. Skeletal EH emerges as a genetically defined locally aggressive vascular neoplasm, with a high rate of local recurrence, but lacking the propensity for distant spread.     

骨上皮样血管内皮瘤临床病理学观察

目的 探讨骨上皮样血管内皮瘤的临床病理特征和诊断。方法 对3例骨上皮样血管内皮瘤进行临床资料分析、光镜观察和免疫组织化学检测，并结合文献进行讨论。结果 3例病变部位均为下肢。最常见的临床症状是局部疼痛。X线表现为溶骨性骨破坏，1例伴有病理性骨折。组织形态学特征是上皮样瘤细胞形成较原始的小血管腔，呈巢状、索状、不规则形分布于有黏液样变或透明变性的间质中，肿瘤组织内或边缘散布成熟的骨小梁组织。3例肿瘤均表达vimentin、FⅧRAg和CD34。随访结果2例未见肿瘤复发，1例失访。结论 原发于骨的上皮样血管内皮瘤是较少见中间型血管源性肿瘤，其组织形态学要与骨上皮样血管瘤、上皮样血管肉瘤和转移性癌等鉴别。     

Primary kaposiform hemangioendothelioma of a long bone: two cases in unusual locations with long-term follow up

Kaposiform hemangioendothelioma (KHE) is a rare vascular neoplasm of low malignant potential that mainly affects infants and adolescents. The tumor almost exclusively occurs in somatic soft tissue or the retroperitoneum. We report herein two cases of primary KHE occurring in a long bone without cutaneous changes with long-term follow up in young patients. The patients were a 9-year-old girl and 5-year-old boy presenting with lytic lesions of the femur and humerus, respectively, without cutaneous lesions. Histologically, the neoplasms were comprised of nodules of spindle- to oval-shaped cells growing in an infiltrative fashion. The neoplastic cells formed poorly canalized or slit-like blood vessels alternating with solid spindle areas. Immunohistochemical studies showed that the tumor cells expressed CD31, CD34 and Fli1, but not HHV8, LNA-1 or GLUT1. D2-40 stained the neoplastic spindle cells and lymphatic channels adjacent to vascular lobules. The girl remains well with 15 years and 6 months follow up after a second complete excision. The boy has no signs of recurrence or metastasis nearly 5 years after local complete excision. To our best knowledge, this is the first report in the English literature of primary long bone occurrences of KHE without cutaneous changes with long-term follow up.     

Vascular tumors of bone: A study of 17 cases other than ordinary hemangioma,with an evaluation of the relationship of hemangioendothelioma of bone to epithelioid hemangioma,epithelioid hemangioendothelioma,and high-grade angiosarcoma

Cases filed as vascular tumor of bone other than ordinary hemangioma were reviewed. They were included in the study if there was adequate histologic material and clinical information, clear evidence of bone origin, and at least 5 years follow-up. The study group comprised 17 cases, of which 13 were categorized as hemangioendothelioma of bone, 1 as epithelioid hemangioendothelioma, and 3 as high-grade angiosarcoma. Hemangioendothelioma of bone had growth patterns varying from vasoformative to solid, but well-formed vessels were present in at least some area in all cases. The cells generally had a rounded, epithelioid character, regular nuclei, and relatively few mitotic figures; occasional features included spindle cells and scattered enlarged, hyperchromatic or pleomorphic nuclei. Lymphoplasmacytic and eosinophilic inflammatory infiltrate ranged from prominent to slight or absent, and myxoid or hyaline stroma was never more than focal. Epithelioid hemangioma could not be separated from hemangioendothelioma of bone. The single epithelioid hemangioendothelioma for the most part had cords of relatively uniform epithelioid cells in a prominent myxoid stroma but focally demonstrated an angiosarcoma-like appearance, with irregular vascular spaces and marked nuclear pleomorphism. The high-grade angiosarcomas exhibited predominantly irregular vasoformation combined with solid areas, diffuse nuclear hyperchromatism and pleomorphism, and, in 2 cases, numerous mitotic figures (the third case had only a small biopsy and a postradiation amputation specimen). Of the hemangioendotheliomas of bone, 7 were unicentric and 6 were regionally multicentric either concurrently or sequentially. Three patients had intraosseous local recurrence, 2 had discontinuous regional skin or soft tissue involvement (including the popliteal artery in 1), and 1 had a solitary lung metastasis, but none died of tumor. The patient with epithelioid hemangioendothelioma had multicentric tumors in widely separated bones and died with liver and lung metastases. Two of the high-grade angiosarcomas were unicentric, and the third was regionally multicentric, with a popliteal artery-soft tissue component as well. All 3 of these patients died with metastases in various sites.     

骨卡波西样血管内皮瘤临床病理特点

目的 探讨骨卡波西样血管内皮瘤（KHE）的临床病理特点、鉴别诊断及生物学特征。方法 对2例发生于儿童长骨的KHE进行组织病理学、免疫表型和电镜观察,结合临床资料进行分析并复习相关文献。结果 2例患儿临床以肢体持续性隐痛为主,1例伴局部皮温升高,病程较长（发病1年余就诊）,影像学示局限性骨密度减低或蜂窝状骨质破坏。临床未见血小板减少及低纤维蛋白血症（Kabasach-Merritt syndrome,卡梅综合征）。光镜下肿瘤呈多结节状或小叶状分布,浸润性生长,见特征性的肾小球样结构。部分瘤细胞梭形,呈束状排列并形成裂隙状血管腔,肾小球样结构区瘤细胞多为上皮样,见空泡形成及胞质内脂褐素沉积,部分区域见明显的毛细血管瘤样结构。免疫表型：瘤细胞呈CD31、CD34和Fli-1强阳性表达、SMA灶性阳性,GLUT1、CKpan和FⅧRAg均为阴性,Ki-67有少量散在阳性表达。结论 KHE是一种罕见的好发于儿童的潜在恶性肿瘤,诊断主要靠病理组织学及免疫组化确诊,须与幼年性毛细血管瘤、卡波西肉瘤、丛状血管瘤、梭形细胞血管内皮瘤等鉴别,病变切除干净是治疗KHE的最佳手段。     

Epithelioid hemangioendothelioma of bone and soft tissue: A fine-needle aspiration biopsy study with histologic and immunohistochemical confirmation

We retrospectively reviewed two fine-needle aspiration biopsy (FNAB) specimens from two patients with histologically confirmed epithelioid hemangioendothelioma (EH). Both patients were men, ages 79 and 39 years; their primary tumors arose in the soft tissues of the mediastinum and within the proximal tibia, respectively. The former patient had symptoms of superior vena cava syndrome; multicentric intraosseous lesions involved the proximal tibia of the latter patient. All cytologic smears were hypercellular and composed of mostly disassociated single cells and small aggregates of ovoid to polygonal-shaped epithelioid cells. Nuclei were variable, ranging from ovoid and reniform to round and polylobated and surrounded by an abundant amount of dense cytoplasm. Binucleated epithelioid neoplastic cells were frequent. Nuclear pleomorphism ranged from slight to moderate, and small solitary to multiple nucleoli were identified within the majority of tumor cells. Rare neoplastic cells with a single, sharply demarcated intracytoplasmic vacuole and intranuclear cytoplasmic pseudoinclusions were observed in the smears of one tumor. Metachromatic stromal fragments, probably representing hyalinized chondromyxoid stroma, were seen in the other tumor. Neither case was recognized initially on FNAB as EH. Immunohistochemically, sections from the surgical biopsy specimens of both cases showed diffuse and strong immunopositivity for the endothelial marker CD31. Although the cytomorphology of EH appears distinct, clinicoradiologic correlation is essential, and immunohistochemistry may be helpful to avoid misdiagnoses. Diag. Cytopathol. 1998;19:38–43. © 1998 Wiley-Liss, Inc.     

Unique vascular tumor primary arising in the liver and exhibiting histopathological features consistent with so‐called polymorphous hemangioendothelioma

Reported herein is an unusual vascular tumor primary arising in the liver and exhibiting unique histopathological features. A 47‐year‐old woman underwent left hepatectomy because of a large hepatic mass. On histology the tumor had a composite pattern, consisting of angiomatous, retiform and solid areas, formed by oval to cuboidal to spindle cells, that expressed only endothelial markers (CD31 and factor VIII‐related antigen). These findings led to the diagnosis of a low‐grade vascular neoplasm with morphological features consistent with so‐called polymorphous hemangioendothelioma. The tumor was completely resected. At 24 month follow up the patient was alive, without evidence of disease. Polymorphous hemangioendothelioma is a rare vascular neoplasm, with borderline malignant potential, which usually occurs in lymph nodes and, rarely, at extranodal sites. Its classification as an entity has been questioned recently. The unusual morphological features of the present case, which do not fit neatly with any other recognized hemangioendothelioma subtype, indicate that the family of vascular tumors is broader than currently accepted. In addition the present case widens the spectrum of primary vascular tumors arising in the liver.     

骨上皮样血管内皮细胞瘤9例诊治分析

目的 探讨骨上皮样血管内皮细胞瘤(B-EHE)的诊断、治疗方法。方法 回顾性分析2002年2月—2015年9月解放军东部战区总医院骨科收治的9例B-EHE患者的临床资料。其中男6例、女3例,年龄15~64岁。术前X线及CT检查均表现为溶骨性改变,1例MRI可见周围软组织受累,1例出现肺部转移灶。3例选择病灶刮除、植骨内固定;1例腰椎病灶选择肿瘤切除椎板减压内固定;3例近关节病灶选择肿瘤切除假体置换,其中1例术后化疗;1例多发病灶伴肺转移选择活检确诊后化疗治疗;1例病理性骨折伴出血选择行截肢术后综合治疗。结果 9例中失访1例,其余随访时间8～72个月。现7例存活。3例行病灶刮除植骨内固定,2例局部复发,二次手术后治愈。1例腰椎肿瘤切除减压固定,术后恢复良好。3例行肿瘤切除假体置换术,1例失访;2例术后治愈,关节功能良好,其中1例术后辅助化疗,未出现局部复发和病灶转移。1例多发病灶伴肺部转移行化疗,肺部无进展,局部无进展。1例行截肢术后综合治疗者,肿瘤复发迁延性出血,最终因器官衰竭死亡。结论 B-EHE为低-中度恶性肿瘤,术前影像学无特异性,诊断困难,主要依靠术后病理结果诊断。治疗首选边界切除,辅以化疗或放疗,可降低局部复发率和远处转移。     

CLTC‐ALK fusion as a primary event in congenital blastic plasmacytoid dendritic cell neoplasm

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a subtype of acute myeloid leukemia, affecting mainly the elderly. It is thought to be derived from plasmacytoid dendritic cell precursors, which frequently present as cutaneous lesions. We have made a detailed analysis of an infant with BPDCN, who manifested with hemophagocytic lymphohistiocytosis. The peripheral blood leukocytes revealed the t(2;17;8)(p23;q23;p23) translocation and a CLTC‐ALK fusion gene, which have never been reported in BPDCN or in any myeloid malignancies thus far. Neonatal blood spots on the patient's Guthrie card were analyzed for the presence of the CLTC‐ALK fusion gene, identifying the in utero origin of the leukemic cell. Although the leukemic cells were positive for CD4, CD56, CD123, and CD303, indicating a plasmacytoid dendritic cell phenotype, detailed analysis of the lineage distribution of CLTC‐ALK revealed that part of monocytes, neutrophils, and T cells possessed the fusion gene and were involved in the leukemic clone. These results indicated that leukemic cells with CLTC‐ALK originated in a multipotent hematopoietic progenitor in utero. This is the first report of the CLTC‐ALK fusion gene being associated with a myeloid malignancy, which may give us an important clue to the origin of this rare neoplasm. © 2013 Wiley Periodicals, Inc.     

A novel low‐grade nasopharyngeal adenocarcinoma characterized by a GOLGB1‐BRAF fusion gene

Nasopharyngeal adenocarcinoma is a rare malignancy that is classified into conventional/surface‐ and salivary‐types. Herein we report the case of a 52‐year‐old male who presented with a right nasopharyngeal mass and right‐sided hearing loss. Diagnostic imaging revealed a circumscribed 1.7 cm mass centred in the right antero‐lateral aspect of the nasopharynx. A biopsy showed a gland‐forming neoplasm that was in continuity with the surface epithelium. The tumor exhibited a nested to micro‐papillary architecture, with mild cytologic atypia. Immunohistochemistry demonstrated diffuse staining for CK7, SOX10, and p16; the abluminal layer was highlighted by CK5 and p63, while the luminal cells expressed CD117. The tumor was not amenable to subclassification and was diagnosed as a low‐grade nasopharyngeal adenocarcinoma, not otherwise specified (NOS). Subsequent RNA sequencing was performed which identified a novel GOLGB1‐BRAF fusion product. Based on its unique morphology and molecular findings, this is presumed to represent a novel subtype of nasopharyngeal adenocarcinoma. In addition to being of diagnostic relevance, this fusion may ultimately represent a potential therapeutic target.     

A case of pulmonary malignant epithelioid hemangioendothelioma misdiagnosed as adenocarcinoma by fine needle aspiration cytology

Malignant epithelioid hemangioendothelioma (MEHE) is a rare vascular tumor with a biological behavior that lies between those of classical epithelioid hemangioendothelioma and angiosarcoma. Furthermore, MEHE is rarely diagnosed by fine needle aspiration cytology. The authors describe the cytological features of MEHE in a 41-year-old man who presented with increasing dyspnea over a period of 1 month before admission. Computed tomography of the chest showed a 3 cm poorly defined mass in the right lower lobe. Fine needle aspiration cytology demonstrated cellular smears of loosely cohesive clusters of epithelioid cells with numerous intracytoplasmic lumens in a necrotic background. Cellular features included fine chromatin and vesicular or slightly hyperchromatic nuclei with inconspicuous nucleoli and intranuclear inclusions. Nuclear membranes were relatively irregular with indentation. Mean N/C ratio was not increased, presumably due to a moderate amount of cytoplasm. The histologic examination displayed epithelioid and spindle cell proliferation with necrosis accompanying a classical epithelioid hemangioendotheliomatous area. The immunohistochemical evaluation was confirmatory and showed immunoreactivity for vascular markers. The authors also reviewed FNAB findings of epithelioid angiosarcoma, primary adenocarcinoma, and bronchioloalveolar carcinoma of the lung to identify cytomorphologic differences by literature bases. MEHE of the lung is difficult to diagnose cytologically because of its rarity and its cytomorphologic similarities with other malignant epithelial and mesenchymal tumors. However, it may be possible to distinguish it from other entities when the possibility of this unusual vascular neoplasm is suspected and ancillary studies are supportive.     

Morphologic changes and altered gene expression in an epithelioid hemangioendothelioma during a ten-year course of disease

Epithelioid hemangioendothelioma (EHE) is a rare low-grade malignant vascular neoplasm with unpredictable prognosis. We report on a patient suffering from a vascular neoplasm with primary manifestation in the skeleton and subsequent development of lesions of EHE in the spleen, liver and lung. Based on the assumption that involvement of visceral organs was due to metastatic spread, changes in clinical behavior, morphology, and proliferation index suggest malignant progression of the tumor. Analyzing the expression of genes known to be involved in the pathogenesis of vascular tumors, we found that the appearance of less differentiated tumor was paralleled by an accumulation of TP53 and murine double minute-2 (MDM-2) protein, decreased caveolin-1 (CAV-1) expression, and increased vascular endothelial growth factor (VEGF) expression. Mutations of the von-Hippel-Lindau-tumor-suppressor-gene (VHL) were excluded as mechanism of VEGF upregulation. Therefore, we propose that the expression of TP53, MDM-2, CAV-1 and VEGF as a marker of biologic behavior be verified in a larger case study of EHE.