Metastasizing aneurysmal dermatofibroma initially diagnosed as angiosarcoma confirmed by CD63::PRKCD fusion gene detection with nanopore sequencing.

Dermatofibroma (DF) is a benign tumor that forms pedunculated lesions ranging in size from a few millimeters to 2 cm, usually affecting the extremities and trunks of young adults. Histopathologically, DF is characterized by the storiform proliferation of monomorphic fibroblast-like spindle cells. In addition to neoplastic cells, secondary elements such as foamy histiocytes, Touton-type giant cells, lymphoplasmacytes, and epidermal hyperplasia are characteristic histological features. Several histological variants, including atypical, cellular, aneurysmal, and lipidized variants, have been reported; cases with variant histologies are sometimes misdiagnosed as sarcomas. We present a case of metastasizing aneurysmal DF that was initially diagnosed as an angiosarcoma on biopsy. A 26-year-old woman was referred to our hospital with a gradually enlarging subcutaneous mass in her lower left leg. Positron emission tomography-computed tomography revealed high fluorodeoxyglucose uptake not only in the tumor but also in the left inguinal region. On biopsy, ERG and CD31-positive atypical spindle cells proliferated in slit-like spaces with extravasation, leading to the diagnosis of angiosarcoma. Histology of the wide-resection specimen was consistent with DF, and lymph node metastasis was also observed. Nanopore DNA sequencing detected CD63::PRKCD fusion and copy number gain, although CD63 was not included in the target region of adaptive sampling. This report highlights the importance of recognizing the unusual clinical, radiological, and pathological features of DF to avoid misdiagnosis, and the potential diagnostic utility of nanopore sequencer.

Etiology, pathogenesis, and management of angiosarcoma associated with implants and foreign body: Clinical cases and research updates.

Angiosarcomas are rare and highly malignant soft tissue sarcomas originating from endothelial cells lining the lymphatic or vascular system. While they predominantly emerge from (sub)cutaneous regions, occurrences have been reported throughout the body. The etiology of angiosarcoma remains elusive in most clinical cases. Nevertheless, several prognosis risk factors play a pivotal role, including chronic lymphedema, therapeutic irradiation, environmental carcinogens, familial syndromes, and the presence of foreign materials like metallic objects and biomedical implants. Despite evidence implicating retained foreign material in angiosarcoma development, understanding its prognosis and pathogenesis remains limited. The pathogenesis of angiosarcoma appears to involve a complex interplay of chronic inflammation, tissue remodeling, and genetic factors that create a conducive microenvironment for malignant transformation. Management of these sarcomas remains challenging due to their infiltrative nature owing to the high chance of metastasis and local recurrence. The primary treatment modalities currently include surgery, radiotherapy, and chemotherapy, but recent advances in targeted immunotherapy and gene therapy hold promise for more effective approaches. This comprehensive review delves into the potential etiological and pathogenic roles of foreign materials, such as metallic objects, biomedical implants, and biomaterials, in the development of angiosarcoma. Further research into the underlying molecular mechanisms could provide valuable insights for tailored management and developing novel targeted therapeutic strategies.

Proposed diagnostic and prognostic markers of primary malignant hepatic vascular neoplasms.

INTRODUCTION: Primary malignant hepatic vascular tumors with various malignant potentials include epithelioid hemangioendothelioma (EHE) and angiosarcoma (AS), which may overlap pathologically. This study aimed to compare the pathological findings of hepatic EHE with those of AS, in association with patient outcomes. METHODS: Fifty-nine histologically confirmed patients with 34 EHE and 25 AS were admitted to a tertiary hospital from 2003 to 2020. Their EHE and AS pathological features were compared. Immunohistochemistry for CD31, ERG, CAMTA-1, TFE3, P53, and Ki-67 labeling was performed on paraffin-embedded blocks. Markers, along with histological findings, were analyzed for the purposes of diagnostic and prognostic significance by multivariate analysis. RESULTS: CAMTA-1 was 91.2% positive in EHE, but negative in AS (p = < 0.001). AS was significantly correlated to an aberrant p53 expression, high Ki-67 labeling, and high mitotic activity, compared to EHE (all, p = < 0.001). EHE can be classified as low grade (LG) and high grade (HG) using the prognostic values of mitotic activity and ki-67 labeling (sensitivity = 1, specificity = 1). Low grade-EHE showed significantly better overall survival than high grade-EHE (p = 0.020). CONCLUSIONS: Immunohistochemistry for CAMTA-1, P53, and Ki-67 labeling may help distinguish EHE and AS in histologically ambiguous cases, especially small biopsied tissue. Moreover, the combination of mitotic activity and Ki-67 labeling can be a prognostic factor for EHE with various clinical features.

Clinicopathologic and molecular correlates to neoadjuvant chemotherapy-induced pathologic response in breast angiosarcoma.

Both primary and secondary breast angiosarcoma (AS) are characterized by multifocal presentation and aggressive behavior. Despite multimodality therapy, local and distant relapse rates remain high. Therefore, neoadjuvant chemotherapy (NACT) is employed to improve the R0 resection rates and survival, but its benefits remain controversial. Herein, we investigate pathologic and molecular correlates to NACT-induced histologic response in a group of 29 breast AS, 4 primary and 25 radiation-associated (RA). The two NACT regimens applied were anthracycline- and non-anthracycline-based. The pathologic response grade was defined as: I: ≤ 50%, II: 51%-90%, III: 91%-99%, and IV: 100%. An additional 45 primary AS and 102 RA-AS treated by surgery alone were included for survival comparison. The genomic landscape was analyzed in a subset of cases and compared to a cohort of AS without NACT on a paired tumor-normal targeted DNA NGS platform. All patients were females, with a median age of 31 years in primary AS and 68 years in RA-AS. All surgical margins were negative in NACT group. The NACT response was evenly divided between poor (Grades I-II; n = 15) and good responders (Grades III-IV; n = 14). Mitotic count >10/mm2 was the only factor inversely associated with pathologic response. By targeted NGS, all 10 post-NACT RA-AS demonstrated MYC amplification, while both primary AS harbored KDR mutations. TMB or other genomic alterations did not correlate with pathologic response. All four patients with Grade IV response remained free of disease. The good responders had a significantly better disease-specific survival (p = 0.04). There was no survival difference with NACT status or the NACT regimens applied. However, NACT patients with MYC-amplified tumors showed better disease-free survival (p = 0.04) compared to MYC-amplified patients without NACT. The overall survival of NACT group correlated with size >10 cm (p = 0.02), pathologic response (p = 0.04), and multifocality (p = 0.01) by univariate, while only size >10 cm (p = 0.03) remained significant by multivariate analysis.

Recurrent fever leading to the diagnosis of an angiosarcoma of the adrenal gland: a case report.

BACKGROUND: Angiosarcoma of the adrenal gland is a very rare malignant vascular neoplasm. The clinical symptoms are atypical or completely absent. Angiosarcomas of the adrenal gland are therefore often discovered incidentally, and the diagnosis is made histologically after resection. CASE PRESENTATION: A 46-year-old white Spanish male who was a previous smoker and nondrinker and was slightly overweight (92 kg, 176 cm, body mass index 29.7 kg/m2) with no relevant medical history presented to the internal medicine emergency department of our hospital with an unclear 12 cm tumor of the right adrenal gland. Prior to the computed tomography scan, he had had persistent evening fevers for 4 months and unintentional weight loss of 5 kg. The laboratory results showed anemia and an elevated C-reactive protein, but no hormone production. We performed an open adrenalectomy of the right adrenal gland. Finally, the histologic findings revealed an angiosarcoma of the adrenal gland. CONCLUSION: Even though angiosarcomas of the adrenal gland are rare, the differential diagnosis of an angiosarcoma should be considered if a malignant tumor of the adrenal gland is suspected. Treatment decisions should be made on an interdisciplinary basis and preferably in a specialized center. Owing to the rarity of angiosarcomas of the adrenal gland, it is necessary to continue to share clinical experience to gain a better understanding of this particular tumor entity.

A rare case of epithelioid angiosarcoma.

Epithelioid angiosarcoma is a rare high-grade vascular neoplasm with a poor prognosis. We present an anticoagulated 77-year-old man, with a history of popliteal/soleal vein thrombosis in the previous month, complaining of ipsilateral persistent lower limb pain and claudication. Absent popliteal/distal pulses prompted an arterial doppler ultrasound (DUS), revealing thrombosis of the distal superficial femoral artery and a popliteal mass. As the arterial wall's integrity could not be appropriately evaluated by DUS, adventitial cystic disease of the popliteal artery was suspected. Computed tomography angiography and magnetic resonance imaging findings were also suggestive. Due to refractory pain, he was submitted to a popliteal mass excision along with a femoral-posterior tibial bypass. Pathology revealed an epithelioid angiosarcoma. He was referred to a Sarcoma Center, requiring hospitalization for agitation and fever. A positron emission tomography (PET) scan revealed extensive lower limb disease persistence and distant metastases. He died on the 56th day after surgery. To our knowledge, there are only 15 cases of angiosarcoma of the popliteal artery described in the literature. Ours stands out as the first one unrelated to a popliteal aneurysm. Being a highly-aggressive tumor, an early diagnosis is challenging but essential to a successful treatment, warranting the need for suspicion of this neoplasm. An early core biopsy or surgical sample may expedite the diagnosis.

Generation of sarconoids from angiosarcoma patients as a systematic-based rational approach to treatment.

Angiosarcoma is a rare subtype of malignant neoplasm originating from vascular or lymphatic endothelial cells; its low incidence has posed significant challenges for comprehensive investigations into its pathogenic mechanisms and the development of innovative treatment modalities through in vitro and in vivo models. Recent endeavors spearheaded by patient-partnered research initiatives have aimed to elucidate the intricacies of angiosarcomas by leveraging biological omics approaches, with the overarching objective of enhancing prognostic indicators and therapeutic options for this uncommon pathology. To bridge the gap between preclinical research and translational applications, we engineered angiosarcoma-derived organoids from surgically resected primary tumors, hereafter referred to as "sarconoids," as a proof-of-concept model. A novel protocol for the establishment of these sarconoids has been developed and validated. To ensure that the sarconoids faithfully recapitulate the heterogeneity and complexities of the patients' original tumors, including transcriptomic signatures, cell-type specificity, and morphological traits, exhaustive histological and transcriptomic analyses were conducted. Subsequently, we expanded the scope of our study to include an evaluation of a sarconoid-based drug screening platform; for this purpose, a drug library (AOD IX), supplied by the National Cancer Institute's Developmental Therapeutics Program, was screened using 96-well plates. Our findings suggest that sarconoids can be reliably generated from angiosarcoma patient-derived tissues and can serve as accurate models for evaluating therapeutic responses, thereby holding far-reaching implications for translational research and clinical applications aimed at advancing our understanding and treatment of angiosarcoma.

The complete Kaposi sarcoma-associated herpesvirus genome induces early-onset, metastatic angiosarcoma in transgenic mice.

Kaposi sarcoma (KS) is the most common cancer in persons living with HIV. It is caused by KS-associated herpesvirus (KSHV). There exists no animal model for KS. Pronuclear injection of the 170,000-bp viral genome induces early-onset, aggressive angiosarcoma in transgenic mice. The tumors are histopathologically indistinguishable from human KS. As in human KS, all tumor cells express the viral latency-associated nuclear antigen (LANA). The tumors transcribe most viral genes, whereas endothelial cells in other organs only transcribe the viral latent genes. The tumor cells are of endothelial lineage and exhibit the same molecular pattern of pathway activation as KS, namely phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR, interleukin-10 (IL-10), and vascular endothelial growth factor (VEGF). The KSHV-induced tumors are more aggressive than Ha-ras-induced angiosarcomas. Overall survival is increased by prophylactic ganciclovir. Thus, whole-virus KSHV-transgenic mice represent an accurate model for KS and open the door for the genetic dissection of KS pathogenesis and evaluation of therapies, including vaccines.

Brain radiotherapy and anlotinib control primary cardiac angiosarcoma with metastases: A case report.

RATIONALE: Primary cardiac angiosarcoma (PCA) is a rare and fatal disease with a poor prognosis. Whether the survival of PCA patients can be prolonged with additional treatment following complete surgical excision is controversial. PATIENT CONCERNS: In this case study, a 52-year-old male complained of chest tightness and pain for 7 days before admission into the hospital. Subsequently, he revisited the hospital because of dizziness and headache. DIAGNOSES: Initially, the patient was diagnosed with PCA in the right atrium by thoracic computed tomography (CT). Palliative resection identified brain, lung, and liver metastases. INTERVENTION: The patient accepted multimodal combination therapy, including first-line chemotherapy and then second-line anlotinib concurrent with brain radiotherapy and immunotherapy. OUTCOME: Although anlotinib combined with brain radiotherapy controlled the growth of intracranial lesions, progression-free survival (PFS) was only 5 months, and the overall survival (OS) was only 12 months. LESSON: The treatment for metastatic PCA needs an in-depth exploration.

Pathological findings of mammary gland carcinoma and hemangiosarcoma cases in two African wild dogs (Lycaon pictus).

There are few studies on diseases affecting endangered African wild dogs. We report our findings on malignant tumors in two African wild dogs. Case 1 was a 6-year-old intact female diagnosed with inflammatory mammary carcinoma with pulmonary metastasis. Case 2 was an 11-year-old male diagnosed with primary hemangiosarcoma of the left atrial coronary sulcus with metastasis to multiple organs. Additionally, the tumor had grown through the cardiac wall, causing cardiac tamponade. The identification of disease incidence trends provides important information which will allow for the early detection and treatment of malignant tumors, and aid in the conservation of this species.

Sustained activation of the FGF1-MEK-ERK pathway inhibits proliferation, invasion and migration and enhances radiosensitivity in mouse angiosarcoma cells.

Angiosarcoma is a rare refractory soft-tissue tumor with a poor prognosis and is treated by radiotherapy. The fibroblast growth factor 1 (FGF1) mutant, with enhanced thermostability due to several substituted amino acids, inhibits angiosarcoma cell metastasis, yet the mechanism of action is unclear. This study aims to clarify the FGF1 mutant mechanism of action using ISOS-1 mouse angiosarcoma cells. The wild-type FGF1 or FGF1 mutant was added to ISOS-1 cells and cultured, evaluating cell numbers over time. The invasive and migratory capacity of ISOS-1 cells was assessed by transwell analysis. ISOS-1 cell radiosensitivity was assessed by colony formation assay after X-ray irradiation. To examine whether mitogen-activated protein kinase (MEK) inhibitor counteracts the FGF1 mutant effects, a combination of MEK inhibitor and FGF1 mutant was added to ISOS-1 cells and cultured. The FGF1 mutant was observed to inhibit ISOS-1 cell proliferation, invasion and migration by sustained FGF1 signaling activation. A MEK inhibitor suppressed the FGF1 mutant-induced inhibition of proliferation, invasion and migration of ISOS-1 cells. Furthermore, the FGF1 mutant enhanced radiosensitivity of ISOS-1 cells, but MEK inhibition suppressed the increased radiosensitivity. In addition, we found that the FGF1 mutant strongly inhibits actin polymerization, suggesting that actin cytoskeletal dynamics are closely related to ISOS-1 cell radiosensitivity. Overall, this study demonstrated that in ISOS-1 cells, the FGF1 mutant inhibits proliferation, invasion and migration while enhancing radiosensitivity through sustained activation of the MEK-mediated signaling pathway.

Synchronous Double Primary Angiosarcoma Originating from the Stomach and Rectum: A Case Report and a Literature Review.

Angiosarcomas originating from the gastrointestinal tract are rare but highly aggressive tumors with poor prognosis. These tumors can be misdiagnosed as benign and malignant gastrointestinal tract lesions. The definitive histological diagnosis of angiosarcomasis made by pathologists based on immunohistochemical analysis demonstrating cluster of differentiation 31 (CD31), factor VIII-related antigen (FVIIIRAg), erythroblast transformation specific related gene (ERG), and cluster of differentiation 34 (CD34). Angiosarcomas are treated with a single or multimodality approach that may include resection, radiotherapy, chemotherapy, and palliative care, depending on the stage of disease and the condition of the patient. No matter the treatment option, metastasis and death rates are substantially highin patients with angiosarcoma. In this context, a 59-year-old male with synchronous double primary angiosarcoma arising from the gastric and rectum who presented with the complaint of abdominal pain and distention to the outpatient clinic is presented in this case report, along with a brief literature review.

Clinical recommendations for treatment of localized angiosarcoma: A consensus paper by the Italian Sarcoma Group.

Angiosarcoma (AS) represents a rare and aggressive vascular sarcoma, posing distinct challenges in clinical management compared to other sarcomas. While the current European Society of Medical Oncology (ESMO) clinical practice guidelines for sarcoma treatment are applicable to AS, its unique aggressiveness and diverse tumor presentations necessitate dedicated and detailed clinical recommendations, which are currently lacking. Notably, considerations regarding surgical extent, radiation therapy (RT), and neoadjuvant/adjuvant chemotherapy vary significantly in localized disease, depending on each different site of onset. Indeed, AS are one of the sarcoma types most sensitive to cytotoxic chemotherapy. Despite this, uncertainties persist regarding optimal management across different clinical presentations, highlighting the need for further investigation through clinical trials. The Italian Sarcoma Group (ISG) organized a consensus meeting on April 1st, 2023, in Castel San Pietro, Italy, bringing together Italian sarcoma experts from several disciplines and patient representatives from "Sofia nel Cuore Onlus" and the ISG patient advocacy working group. The objective was to develop specific clinical recommendations for managing localized AS within the existing framework of sarcoma clinical practice guidelines, accounting for potential practice variations among ISG institutions. The aim was to try to standardize and harmonize clinical practices, or at least highlight the open questions in the local management of the disease, to define the best evidence-based practice for the optimal approach of localized AS and generate the recommendations presented herein.

Numerous multinucleated giant cells in cutaneous epithelioid angiosarcoma and pulmonary metastasis: A unique observation with potential diagnostic pitfalls.

The histopathologic diagnosis of poorly differentiated cutaneous angiosarcoma can be challenging. We report a case of cutaneous epithelioid angiosarcoma with numerous multinucleated giant cells (MGCs) developing pulmonary metastasis. A 79-year-old man presented with a red-purple plaque on the scalp. A skin biopsy revealed epithelioid cell proliferation, admixed with numerous MGCs, and background hemorrhage. Vascular spaces were focally present and lined by atypical endothelial cells, including MGCs. Immunohistochemically, tumor cells, including MGCs, were positive for CD31, D2-40, and ERG. The patient received radiation therapy and chemotherapy, after which a follow-up CT scan revealed symptomless pneumothorax and pulmonary metastases. The patient received palliative partial lung resection, and the specimen revealed histopathological and immunohistochemical features similar to the primary cutaneous lesion. Our report expands the morphologic spectrum of cutaneous epithelioid angiosarcoma. Cutaneous angiosarcoma is an aggressive neoplasm; thus, awareness of this rare manifestation is important.

Metastatic Maxillary Gingival Angiosarcoma with Aggressive Growth: A Case Report.

Angiosarcoma is a rare malignant tumor of endothelial origin. It is an aggressive neoplasm with early metastasis and poor prognosis and accounts for approximately 2% of all soft tissue sarcomas. Primary tumors arising in the oral cavity account for only 1% of all angiosarcomas. Here, we report a rare case of metastatic angiosarcoma of the gingiva originating from a primary mediastinal lesion. The patient was an 83-year-old man who presented with a maxillary interincisor tumor; it was a painless mass with rounded superficial necrosis measuring 23 mm× 17 mm on the labial side and 20 mm× 17 mm on the palatal side. The histopathological diagnosis was of an epithelioid angiosarcoma. Imaging revealed lesions in the mediastinum, lungs, liver, and skin. The primary lesion was considered a mediastinal lesion. As the tumor had spread throughout the body, palliative therapy was administered. However, the patient's general condition deteriorated rapidly, and he died 3 weeks after the first visit. Identifying oral metastatic malignancies may result in detection of malignant tumors at other sites; thus, oral and maxillofacial surgeons must maintain a heightened awareness of angiosarcoma.

Telangiectatic osteosarcoma in four dogs: Cytologic, histopathologic, cytochemical, and immunohistochemical findings.

Telangiectatic osteosarcoma is a rare variant of osteosarcoma histologically and clinically similar to hemangiosarcoma (HSA). This case series describes the imaging and cytologic features of four histologically confirmed telangiectatic osteosarcomas, including the use of cytochemical stains. Alkaline phosphatase (ALP) was applied to Wright-Giemsa-stained cytology slides, and Factor VIII immunohistochemistry was evaluated. Cytologic characteristics included atypical mesenchymal cells with evidence of acute and chronic hemorrhage. Telangiectatic osteosarcoma cases had positive ALP cytochemical staining, while control HSA cases were negative. Factor VIII immunohistochemistry was negative in telangiectatic osteosarcoma and positive in HSA. Cytologic diagnosis of telangiectatic osteosarcoma with positive ALP cytochemical staining can help differentiate this neoplasm from HSA.

Tumor-Infiltrating Mast Cells in Angiosarcoma Correlate With Immuno-Oncology Pathways and Adverse Clinical Outcomes.

Recent studies have described several molecular subtypes and deregulation of immuno-oncologic signaling pathways in angiosarcoma. Interestingly, mast cells were enriched in subsets of angiosarcoma, although their significance remains unknown. In this study, we aim to verify this observation using immunohistochemistry (H scores) and NanoString transcriptomic profiling and explore the association between mast cells with clinical and biological features. In the study cohort (N = 60), H scores showed a significant moderate correlation with NanoString mast cell scores (r = 0.525; P < .001). Both H score and NanoString mast cell scores showed a significant positive correlation (P < .05) with head and neck location, nonepithelioid morphology, and lower tumor grade. Mast cell enrichment significantly correlated with higher NanoString regulatory T-cell scores (H score, r = 0.32; P = .01; NanoString mast cell score, r = 0.27; P = .04). NanoString mast cell scores positively correlated with signaling pathways relating to antigen presentation (r = 0.264; P = .0414) and negatively correlated with apoptosis (r = -0.366; P = .0040), DNA damage repair (r = -0.348; P = .0064), and cell proliferation (r = -0.542; P < .001). Interestingly, in the metastatic setting, patients with mast cell-enriched angiosarcoma showed poorer progression-free survival (median, 0.2 vs 0.4 years; hazard ratio = 3.05; P = .0489) along with a trend toward worse overall survival (median, 0.2 vs 0.6 years; hazard ratio, 2.86; P = .0574) compared with patients with mast cell-poor angiosarcoma. In conclusion, we demonstrated the presence of mast cells in human angiosarcoma and provided initial evidence of their potential clinical and biological significance. Future research will be required to elucidate their specific roles and mechanisms, which may uncover novel avenues for therapeutic intervention.