Angiosarcoma is a rare tumor that accounts for less than 2% of all soft tissue sarcomas (1). It is highly malignant and prone to recurrence and metastasis. These tumors can occur in any part of the body and at any age (2). Angiosarcoma is insidious in the initial stage, and its clinical manifestations lack specificity (3). The common imaging manifestations of pulmonary angiosarcoma are multiple peripheral pulmonary nodules, and diagnosis is based on histopathology and immunohistochemistry (4, 5). Immunohistochemical staining analysis is positive for the expression of tumor endothelial cell markers (CD31 and CD34) (6).

Angiosarcoma has a high mortality rate and lacks typical and specific signs and symptoms, which pose as challenges for its diagnosis and treatment by clinicians. Herein, we report the rare cause of pulmonary nodules in an elderly man. The patient had a persistent cough and hemoptysis. Owing to the non-specificity of clinical features, his condition was misdiagnosed as vasculitis and Wegener’s granuloma successively. To determine the cause, he underwent a biopsy several times. Eventually, the cause was confirmed following the resection and biopsy of a neoplasm beside the left submandibular gland, whose immunohistochemical staining suggested CD31 and CD34 positivity, indicating metastatic angiosarcoma. We discuss this case including its clinical features, diagnosis, and treatment. We also discuss the lessons we learned and the challenges experienced. It can play a certain warming role in clinical work and provide evidence for clinicians and radiologists who lack knowledge about it, to diagnose this rare entity.

A 73-year-old nonsmoker male developed a dry cough without an obvious cause about in July, 2019. He had no other symptoms and physical examination did not reveal any significant findings. He had no personal or family history. There were no findings in the laboratory examinations and imaging examinations, Chest computed tomography (CT) scan was performed using a 64-slice spiral CT (Brilliance 64, Philips Healthcare, The Netherlands) on Aug 1, 2019 ( Figure 1A ). Cough medications were ineffective. In December 2019, dark-red blood was noticed in his sputum. There was no significant improvement with traditional Chinese medicines. Subsequently, the patient developed fever, with an elevated white blood cell count (11.0×10⁹/L, 82.6% neutrophils), C-reactive protein (CRP) of 92 mg/L, and erythrocyte sedimentation rate (ESR) of 95 mm/h. CT scan of the chest showed scattered high-density nodular shadows of different sizes with clear borders in both lungs on January 10, 2020. The diameter of the largest nodule was approximately 1.5 ×1.6 cm. Some of the nodules were surrounded by ground-glass shadow ( Figure 1B ). ¹⁸F-fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography (¹⁸FDG-PET/CT) showed that multiple solid nodules of different sizes were diffused in both lungs, with a maximum standardized uptake values (SUV) of 4.29 ( Figure 2 ). He was administered intravenous moxifloxacin (400 mg daily) and linezolid (600 mg every 12 h) in the clinic.

When the patient was admitted to the hospital, his temperature, respiration, blood pressure, and heart rate were normal. His chest was clear, and his abdomen was soft, with no guarding or rigidity. Purpuric rashes were scattered on both calves at 0.1–1 cm, without fading under pressure, and without breaking of the skin. His blood tests indicated a white blood cell count of 9.9 × 10⁹/L, with 87% neutrophils, and hemoglobin levels of 86 g/L. He had a slightly reduced CRP level of 69 g/L, reduced ESR of 65 mm/h, and rheumatoid factor of 33.5 IU/mL. His other laboratory data, including anti-endothelial cell antibody, anti-neutrophil cytoplasm autoantibodies, and antinuclear antibody were unremarkable. He was advised to undergo a lung biopsy, however, he refused. While he accepted a skin biopsy, the area of purpuric rash on the left calf was removed using a scalpel, which revealed vasculitis. When the sputum culture and next-generation sequencing suggested Mycobacterium chelonae, antibiotics, posaconazole (300 mg daily) and methylprednisolone (40 mg daily) were given. However, cough and blood sputum persisted. The CT was used for the patient follow-up, and the imaging revealed worse findings than the previous one, on February 17, 2020 ( Figure 1C ).

He agreed to undergo a CT-guided percutaneous core needle biopsy of the nodule in the upper lobe of the right lung at 120 kVp tube voltage (Philips Healthcare, The Netherlands), and the pathology suggested organized pneumonia. Experienced physicians in the departments of respiratory diseases, hematology, rheumatology, infectious diseases and radiology participated in multidisciplinary discussions, and systemic vasculitis was first considered for which hormone therapy (methylprednisolone 80 mg every 12h) was recommended. During the treatment period, a soft, mobile, non-tender mass was detected beside his left submandibular gland, with the diameter of 1.7 ×1.3 cm using ultrasound scan (Logic 9, GE Healthcare, Horton, Norway). When magnetic resonance imaging (MRI) scan was performed using a 3.0 T scanner (Achieva, Philips Healthcare, The Netherlands) with a neck matrix coil, the lesion demonstrated heterogeneous hyper-intensity on axial and coronary fat-suppressed T2-weighted images, as well as on the axial diffusion weighted image. Axial T1-weighted image showed slight hypo-intensity around the left submandibular gland ( Figure 3 ). It was considered a benign lesion based on a stomatology consultation.

Since hemoptysis did not relieved obviously, the patient was advised to undergo a biopsy again. A bronchoscopic lung biopsy was performed using endobronchial ultrasound-guide sheath, which pathology suggested chronic inflammation. However, he had a severe hemoptysis. Re-examination by CT scan showed that there was an obvious halo sign around the focus, which indicated a lesion combined with bleeding ( Figure 1D ) and pulmonary auscultation showed bilateral rales. Although antibiotics and hormone therapy were administered for more than a month, the lung lesions still progressed. Multiple experts from our hospital and Shanghai Ruijin Hospital, including those from departments of respiratory diseases, rheumatology, infectious diseases, radiology, and pathology after repeated discussions, concluded on February 24, 2020 that Wegener’s granuloma could not be excluded. Therefore, methylprednisolone 1000 mg was administered intravenously every day for 3 days with other treatments including immunoglobulin and thymosin to boost the immune system of the patient. Owing to the deterioration in symptoms and CT imaging ( Figure 1E ), experts of the above departments from Peking Union Medical College Hospital also participated in the multidisciplinary discuss of the patient online. They concluded that angiosarcoma should be considered as the cause of hemoptysis, and a thoracoscopic lung biopsy was proposed for the lung lesion. However, the hemoptysis worsened, accompanied by aggravated chest tightness and oxygen saturation of 90% (SpO₂), and the patient could not tolerate the surgery.

After multidisciplinary discussions, his family members agreed to a repeated biopsy to clarify the cause. When the patient’s respiratory failure improved, following the opinions of experts in respiratory diseases, radiology, oncology, thoracic surgery and pathology departments, the surgeon separated the neoplasm and removed it completely beside the left submandibular gland under local anesthesia. The histopathology of surgical tissue sections showed that it was a metastatic tumor, and immunohistochemical analysis revealed CD31 and CD34 expression ( Figure 4 ), which confirmed the diagnosis of metastatic angiosarcoma. Thus, the cause of hemoptysis and pulmonary nodules was finally identified as angiosarcoma. Anlotinib (12 mg every day) was administered, and next-generation sequencing was performed, which showed that no effective targeted drugs. The expression of PD-L1 was 70%. Pembrolizumab 200 mg (an immune checkpoint inhibitor that targets the PD-1 receptor of lymphocytes) was administered intravenously. After 2 weeks of treatment, the pulmonary lesions showed that pleural effusion decreased, and pulmonary lesions partially resolved ( Figure 1F ). However, hemoptysis did not improve significantly and respiratory failure was detected. Various treatments did not terminate the disease progression; with the gradual development of multiple serosal cavity effusions, liver failure, heart failure, and disseminated intravascular coagulation, the patient eventually died less than a month after diagnosis.

Angiosarcoma lacks typical and specific signs and symptoms. The diagnosis depends on immunohistochemistry, which requires repeated biopsies of multiple sites in highly suspected cases. The present case provides evidence of a rare cause of pulmonary nodules and hemoptysis and play a certain warning role in the diagnosis and treatment of similar diseases. It also contributes to the existing knowledge in the subject and will aid clinicians and radiologists in diagnosing this rare entity.

The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.

Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

PW was a major contributor in writing the manuscript. LX and YY were main physicians for the patient, and proofread and revised the manuscript. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.