Angiosarcoma is a malignant vascular neoplasm. It comprises less than 1% among all primary soft tissue sarcomas with poor prognosis [1]. It is more common in elderly patients. Common primary sites include skin and soft tissue, followed by visceral organs. Angiosarcoma has a high propensity to spread hematogenously and metastasize [2]. Lung is the most common site for metastases, and other rarer sites for metastases include liver, bone, and lymph nodes. Bone marrow involvement by angiosarcoma is uncommon, and rarely documented [3]. Only a few case reports have been published regarding marrow involvement by angiosarcoma [3],[4],[5],[6]. It can compromise the hematopoietic function of bone marrow resulting in marrow failure. For instance, leukoerythroblastic changes or cytopenia may be noted. The diagnosis requires bone marrow aspiration and/or biopsy. Here, we report a case of angiosarcoma on the scalp with bone marrow metastasis.

The patient was an 80-year-old man presented with a 1 cm pigmented lesion on the scalp and a 4 cm pigmented lesion on the temporal region respectively in 2015. Excision for the 1 cm scalp lesion and biopsy for the 4 cm temporal lesion were performed. Both lesions were diagnosed as angiosarcoma. Resection margin for the scalp angiosarcoma was clear by 1 mm. He refused surgery for the temporal angiosarcoma.

Since then, he had disease progression with new lesion at the right temporal region, and increase in size of the left temporal lesion. He only agreed for palliative radiotherapy and two courses of chemotherapy (paclitaxel). He also had repeated episodes of bleeding from tumor. In November 2018, he was found to have thrombocytopenia (platelet count 20 × 10⁹/dL) as well as anemia (Hb level 7.4 g/dL). Upon further questioning, he also complained of occasional epistaxis and tarry stool. He was given platelet transfusion but thrombocytopenia persisted. He was then arranged for bone marrow biopsy in February 2019 to work up for persistent thrombocytopenia.

The slides of scalp lesion and temporal lesion were reviewed (Figure 1), and the diagnosis of angiosarcoma was confirmed. Sections showed an ulcerated tumor comprising anastomosing and angulated vascular channels dissecting between dermal collagen bundles. The lining endothelium featured enlarged and pleomorphic hyperchromatic nuclei. Occasional mitotic figures were noted in those tumor cells. The cells were immunoreactive toward various endothelial markers including CD31, Factor VIII and CD34.

Blood tests and peripheral blood smear

Before the bone marrow biopsy, peripheral blood smear showed mild anisocytosis. White cell count (Table 1) was at the upper limit of normal. A moderate thrombocytopenia (33 × 10⁹/L) was present (Table 1). There were no significant dysplastic features or abnormal cells seen. Prothrombin time (PT) and partial thromboplastin time (aPTT) were normal.

Microscopic examination

The bone marrow aspirate and biopsy were reviewed. The bone marrow aspirate contained granules which are mildly hypercellular for the patient’s age. There were no abnormal cells or infiltrates identified. Iron stain did not reveal any iron stores. There were no ring sideroblasts detected. The clot section was a particulate.

The trephine biopsy showed marrow space with stromal hemorrhage and areas with dilated sinuses. Some slit-like vascular channels lined by atypical endothelial cells with enlarged, pleomorphic and hyperchromatic nuclei were also noted. Extravasated red cells were also seen (Figure 2).

In the remaining uninvolved areas, trilineage hematopoiesis was present.

Immunohistochemical studies were performed. The atypical endothelial cells lining the slit-like spaces and dilated sinuses were strongly positive for endothelial markers, namely CD34, CD31, and ERG (Figure 3, Figure 4, Figure 5).

Progress

Patient received further palliative radiotherapy to the scalp and temporal region. He also had occasional blood transfusion to alleviate his anemic symptoms. In May 2019, three months after the bone marrow biopsy, the patient eventually succumbed.

This case illustrates two points for discussion: (1) Persistence thrombocytopenia and its clinical implications. (2) Histopathological differential diagnosis of metastatic angiosarcoma at bone marrow.

Persistent thrombocytopenia in a patient with angiosarcoma can be attributed to chemotherapy or other drugs related thrombocytopenia. For example, high dose systemic rIL-2 may result in peripheral destruction of platelets, leading to thrombocytopenia [7],[8]. So clinicians should review the drug history and investigate for drug related thrombocytopenia. After stopping the causative agent, one should expect the platelet count to return to normal.

Another possible cause for persistent thrombocytopenia is Kasabach-Meritt syndrome. It is a life-threatening complication characterized by profound thrombocytopenia and consumption coagulopathy [9]. It occurs more commonly in Kaposiform hemangioendothelioma and tufted angioma. However, rarely it can also occur in angiosarcoma as well [10],[11].

Bone marrow metastasis, as in this case, is another important differential diagnosis. Among the patients with persistent anemia and thrombocytopenia, bleeding from the tumor and treatment related side effects may not account for the persistence of thrombocytopenia. The persistence of anemia and thrombocytopenia despite repeated transfusion were unusual, and a bone marrow examination was therefore performed a few months after the initial discovery of thrombocytopenia and anemia.

Although angiosarcoma has a high propensity to metastasize [12],[13], bone marrow metastasis is rare [14]. A high level of suspicion helps to achieve the diagnosis. Clinicians should have this diagnosis in mind when there is unexplained anemia and/or thrombocytopenia, especially when drug causes have already been excluded. A bone marrow exam will be appropriate to exclude/confirm the diagnosis of bone marrow metastasis [15],[16].

For pathologists, it is usually not too difficult in diagnosing metastatic angiosarcoma when the appropriate clinical history is provided by the referring clinicians. The histological features of angiosarcoma in bone marrow is the same as elsewhere in the body, featuring proliferation of slit like vascular channels lined by malignant cells with pleomorphic hyperchromatic nuclei. The background marrow tissue would also be destroyed.

However, it will become more challenging for pathologists if there is no known history of angiosarcoma. One may easily dismiss those vascular channels as reactive changes, especially when there is only a small focus. Other vascular lesions, such as hemangioma or Kaposi sarcoma, do not have such infiltrating pattern therefore can be differentiated. As a pathologist, one should always have a high index of suspicion when seeing atypical vascular channels and/or proliferation [5],[17].

Most angiosarcomas show positive staining by vascular markers, including ERG, CD31, and CD34. CD31 is more sensitive compared to CD34. ERG is a nuclear stain which allows easier interpretation compare to CD31 and CD34, which show cytoplasmic and membranous staining.

The incidence of bone marrow involvement by angiosarcoma is very rare, with only a few case reports available. The clinical presentation of anemia and thrombocytopenia should raise suspicion of marrow failure. Bone marrow aspiration and biopsy are necessary to confirm the diagnosis.