Pseudomyogenic hemangioendothelioma (PMHE), a rare vascular neoplasm, was first described in 1992 asa fibroma-like variant of epithelioid sarcoma, and would be termed as epithelioid sarcoma-like hemangioendothelioma a decade later due to its significant histologic overlap with epithelioid sarcoma and diffuse cytokeratin expression. PHME is currently defined as a distinct, potentially intermediate malignant, rarely metastasizing neoplasm with vascular/endothelial differentiation. It is characterized by young age (typically less than 40 years old), extremity location (approximately ~80%), and t(7:19) SERPINE1::FOSB fusion as the most common molecular alteration. Herein, we report a case of a 59-year-old male presenting with multifocal lesions, including in the right temporalis muscle, right frontoparietal calvarium, right pterygoid muscles, and right mandibular condyle. Histologic examination of the right temporal lesion revealed a multinodular biphasic lesion composed of sheets and fascicles of elongated spindle and epithelioid cells infiltrating into the adjacent skeletal muscle. Admixed abundant neutrophilic infiltration is noted; however, areas of necrosis, increased mitosis, nuclear atypia, or rhabdomyoblast-like cells are absent. Immunohistochemical (IHC) staining showed that the tumor cells were diffusely and strongly positive for FOSB, pan-cytokeratin (AE1/AE3), CD31, and ERG. Molecular testing demonstrated a t(9:19) EGFL7::FOSB fusion mRNA. This constellation of morphological, IHC and molecular findings was consistent with a diagnosis of PMHE. This is the first reported case of multifocal PMHE with EGFL7::FOSB fusion in the head and neck area of a patient aged more than 50 years old. Since the differential diagnoses for PMHE includes high-grade malignancies with aggressive clinical behavior, coupled with the rare reports of PMHE in the head and neck region, awareness of this tumor in the head and neck region will avoid the misdiagnosis and overtreatment of this entity.

Pseudomyogenic hemangioendothelioma (PMH), also known as epithelioid sarcoma-like hemangioendothelioma, is a rare epithelioid vascular neoplasm predominantly affecting young adult males at an average age of approximately 30 years. This tumor is rare; therefore, detailed information regarding this tumor is still lacking. Here, we report a case of a man in his 20s presenting with left foot pain for about one year. Imaging showed a 2-cm ovoid, cortically based lesion with a lytic defect of the cortex at the fifth metatarsal proximal shaft. Histologically, the lesion presented as an infiltrating proliferation of distinctly myoid-appearing spindled cells with eosinophilic cytoplasm and mildly atypical vesicular nuclei. Scant mitoses were identified with no areas of necrosis. Tumor cells exhibited strong, diffuse cytokeratin expression as well as CD31 and ERG. CD34 was positive in a few tumor cells, and integrase interactor 1 (INI1) retained nuclear expression. No reactivity for S100, desmin, smooth muscle actin (SMA), epithelial membrane antigen (EMA), and CD1a was present. Over half of the patients with PMH develop multifocal lesions, often involving several tissue planes; however, distant metastasis is very infrequent. This patient underwent curettage and internal fixation of the left fifth metatarsal and had no evidence of recurrence or distant metastasis after seven years of follow-up. Our case contributes to the growing knowledge of PMH and sheds light on the prognosis of these lesions.

Pseudomyogenic hemangioendothelioma (PMH) can be a challenge for diagnosis and might be confused with other tumors, such as epithelioid sarcoma. Here we present a case and a systematic review of the literature to identify and discuss PMH treatment in primary bone involvement. A 25-year-old woman was referred for bone pain (10/10) in the left lower limb. Magnetic resonance imaging (MRI) showed multiple bone lesions (left femur, tibia, patella, ankle, and foot) with well-defined borders without signs of local aggressiveness. Positron Emission Tomography-Computed Tomography (PET-CT) showed multiple metabolic musculoskeletal lesions in the left lower limb. A CT scan-guided biopsy was performed. Histological and immunohistochemical findings confirmed the diagnosis of PMH. After treatment with intravenous pamidronate (90 mg/monthly), the patient had clinical improvement, mild pain 2/10 without the use of non-steroidal anti-inflammatory drugs or opiates. Follow-up was assessed by MRI and PET-CT. PET-CT showed metabolic resolution of most of the bone and muscular lesions and a significant improvement of the femoral lesion. MRI showed that the lesions in the left femur, tibia, and foot had a marked decrease in size without intravenous post-contrast enhancement and smaller lesions had disappeared. After a 3-year follow-up, PET-CT showed no metabolically active images. Literature review identified 31 records including 58 clinical cases of PMH with primary bone involvement and treatment description for qualitative analysis. Most lesions (69%) were treated by local excision or curettage. In addition, amputations were performed in a significant percentage of cases (20.7%). In the last years, mTOR inhibitors (n = 7) and anti-resorptive treatments (n = 4) were considered as alternative treatment options, especially in multifocal lesions.

Pseudomyogenic hemangioendothelioma rarely arises in bone. WWTR1-FOSB fusion gene is rarely reported in PMHE of bone. Currently, fusion genes can be used as diagnostic markers in PMHE; however, their prognostic and therapeutic significance is unclear.

Chromosomal translocations are prevalent among soft tissue tumors, including those of the vasculature such as pseudomyogenic hemangioendothelioma (PHE). PHE shows endothelial cell (EC) features and has a tumor-specific t(7;19)(q22;q13) SERPINE1-FOSB translocation, but is difficult to study as no primary tumor cell lines have yet been derived. Here, we engineer the PHE chromosomal translocation into human induced pluripotent stem cells (hiPSCs) using CRISPR/Cas9 and differentiate these into ECs (hiPSC-ECs) to address this. Comparison of parental with PHE hiPSC-ECs shows (1) elevated expression of FOSB, (2) higher proliferation and more tube formation but lower endothelial barrier function, (3) invasive growth and abnormal vessel formation in mice after transplantation, and (4) specific transcriptome alterations reflecting PHE and indicating PI3K-Akt and MAPK signaling pathways as possible therapeutic targets. The modified hiPSC-ECs thus recapitulate functional features of PHE and demonstrate how these translocation models can be used to understand tumorigenic mechanisms and identify therapeutic targets.

Pseudomyogenic (epithelioid sarcoma-like) hemangioendothelioma (PMHE) is a relatively newly described vascular neoplasm, characterized by distinct clinicopathological and molecular features, with no report on its cytomorphological features on smears, till date. A 17-year-old male presented with multiple nodules on his left upper limb. Radiologic imaging disclosed multiple lesions involving the soft tissues, skin, and bones of his left upper limb. Biopsy of one of the lesions on his left ring finger revealed a cellular tumor comprising plump spindle and epithelioid cells, containing moderate to abundant, eosinophilic cytoplasm; mild nuclear atypia, vesicular nuclear chromatin, discernible nucleoli, infrequent mitotic figures, and interspersed neutrophils. Immunohistochemically, tumor cells were positive for AE1/AE3, CD31, and FLI-1, while negative for CD34 and desmin. INI1/SMARCB1 was retained. MIB1/Ki67 highlighted nearly 3% tumor cells (low). Diagnosis of a PMHE was offered. A simultaneous fine needle aspiration cytology smears of the lesions in his left forearm and ipsilateral axillary region revealed spindle and some polygonal shaped cells, arranged in tight and loose clusters, as well as scattered singly, containing abundant cytoplasm with tapering cell membranes, at places; vesicular nuclear chromatin and characteristic intercellular fibrillary stromal material. The present case constitutes the first report on cytomorphological features of a PMHE, diagnosed on cytology, including its differential diagnoses, immunohistochemical features with molecular updates.

Pseudomyogenic hemangioendothelioma, an uncommon mesenchymal neoplasm composed of plump spindled and/or epithelioid endothelial cells, may present multicentrically and tends to locally recur but rarely metastasizes. Morphologic resemblance to epithelioid sarcoma and other spindle cell neoplasms may result in diagnostic confusion. Molecular characterization of pseudomyogenic hemangioendothelioma has revealed these neoplasms often harbor a rearrangement of the FOSB gene with SERPINE1 or ACTB as recurrent fusion gene partners. Herein, a case of a fibular pseudomyogenic hemangioendothelioma with minimal extension into the adjacent soft tissue arising in a 17 year-old male is presented. The neoplasm exhibited sheets of epithelioid cells with abundant eosinophilic cytoplasm and variably eccentric nuclei. RNA sequencing revealed a novel CLTC-FOSB fusion transcript that was subsequently confirmed by direct sequencing of reverse transcription-polymerase chain reaction products demonstrating an in-frame fusion between exon 17 of the clathrin heavy chain (CLTC) gene and exon 2 of the FOSB (FosB proto-oncogene, AP-1 transcription factor subunit) gene. CLTC-FOSB fusion has not been described in a neoplasm before.

We present here our experience with 24 cases of pseudomyogenic hemangioendothelioma (PMHE) to further delineate its clinicopathological spectrum. There were 18 males and 6 females with a median age of 28 years (range 10~64 years). Most patients presented with erythematous nodules or papules, with or without pain. The majority (63%) occurred in the lower extremities, whereas a minority involved the trunk (25%), upper extremities (8%), and head and neck (4%). Six cases (25%) had a primary bone origin. With physical and radiological examinations, 16 cases (67%) manifested as multifocal disease, involving multiple tissue planes or different bones within the anatomic region. Six cases (25%) involved skin, soft tissue, and bone simultaneously. Histologically, all cases showed features consistent with a PMHE characterized by loose fascicles or sheets of plump spindled to epithelioid cells harboring brightly eosinophilic cytoplasm and vesicular nuclei. In addition, five cases (21%) contained a prominent myxoid matrix, and one case displayed perineural and intravascular invasion. The follow-up information available in 18 patients revealed local recurrence in 4 patients (22%) and persistent disease in 8 patients (44%), respectively. One patient developed bilateral pulmonary metastases which showed significant remission after systemic chemotherapy. None of the patients died of the disease. As the clinical appearance of PMHE can be deceptive, a radiological examination is essential in identifying an insidious multifocal disease. Although PMHE has a predilection for the distal extremities of young males, this rare tumor type could also occur in unusual sites and affect middle-aged adults of both genders. The striking myoid appearance in association with myxoid stromal change may represent a potential diagnostic pitfall. Biologically, PMHE has an indolent clinical behavior, albeit metastatic disease may occur in rare instance.

BACKGROUND: Pseudomyogenic hemangioendothelioma (PMHE) is a rare endothelial neoplasm that involves the bones in only 14% of all cases. The optimal treatment strategy has not been established. We herein report a case of primary PMHE in which denosumab treatment showed activity in both imaging studies and the clinical outcome.
METHODS: A 20-year-old woman presented with worsening pain in her left ankle. Imaging studies showed multifocal fluorodeoxyglucose (FDG)-avid [maximum standardized uptake value (SUVmax), 15.95] osteolytic lesions in the bones of her left lower extremity. While waiting for the definitive pathologic diagnosis of PMHE, denosumab, a human immunoglobulin G2 monoclonal antibody against RANKL, was initiated to treat progressive bone absorption after curettage of one of the lesions. Denosumab induced osteosclerosis around the lesions and pain relief and was discontinued 4 years after its initiation. Although all of the multifocal lesions remained, they all became less FDG-avid (SUVmax, 2.6), and the patient developed no signs of new lesions or distant metastasis.
CONCLUSIONS: Denosumab plays a certain role in prevention of bone destruction by PMHE through suppression of osteoclast-like giant cells and would be an excellent treatment for bone absorption by PMHE of bone.

Pseudomyogenic hemangioendothelioma (PMH) of bone is a very rare tumor and frequently presents at multiple locations. PMH is difficult to diagnose by imaging and histopathologic features. Various and partially discordant imaging findings have been reported in case reports and small case series. We report a case of a 63-year-old man with PMH isolated to the sacrum, presenting with chronic intermittent buttock pain that was incidentally identified on imaging for acute pancreatitis. We believe that learning about PMH of bone will help to include this disease in the differential diagnosis of lytic lesions of the sacrum. Becoming aware of the various and sometimes discordant imaging findings of this rare entity is important and helpful for radiologists, pathologists, and orthopedic surgeons.