Primary pleural angiosarcoma: Case report and literature review

Abstract

Primary pleural angiosarcoma is an exceptionally rare malignancy of pleura originating from the vascular endothelial cells. Here, we present a 70-year-old African-American female who presented with 1-month history of dyspnea on exertion, loss of appetite, and loss of weight along with left-sided pleuritic chest pain. Evaluation revealed hemorrhagic pleural effusion in the left pleural cavity. Computed tomography of the chest performed after therapeutic thoracocentesis revealed left upper lobe lung mass along with multiple nodules in right lung. Mass was biopsied at video-assisted thoracoscopy. Histopathology was consistent with high-grade angiosarcoma. Endothelial origin of the tumor cells was confirmed with positive immunohistochemical staining with CD31 antibodies. Our patient was diagnosed with primary pleural angiosarcoma metastatic to the lung. She opted for palliative care and had a rapidly declining clinical course and expired within 5 weeks of the diagnosis. Here, we present a case report and review the relevant literature.

Introduction

Angiosarcomas are uncommon malignancies of the vascular endothelial origin. It includes about 1% of all soft tissue malignancies and most commonly involves skin, soft tissue, liver, bone, breast, and spleen.¹ Primary pleural angiosarcoma (PPA) is a rare malignancy and literature is merely limited to anecdotal case reports. We performed an extensive literature search in Medline (via PubMed), Scopus, Cochrane library and Google Scholar and were able to identify 46 published cases^1–31 since the first reported case in 1943.² In this article, we describe the clinical presentation of PPA and have reviewed the literature.

Case presentation

A 70-year-old African-American woman presented to the emergency room on account of worsening of dyspnea for 1 month. At baseline, she was able to walk 1–2 blocks of streets. However, over the past 1 month, dyspnea had worsened making her short of breath at rest and limiting her from performing activities of daily living. Symptoms also included minimally productive cough and bilateral pleuritic chest pain. It was associated with progressive loss of appetite and 10 pounds of unintentional weight loss. Patient denied symptoms including orthopnea, paroxysmal nocturnal dyspnea, and swelling of lower extremities. She had history of chronic obstructive pulmonary disease with 70 pack-year history of smoking and was a social drinker denied use of illicit/narcotic drugs and asbestos or agent orange exposure. Our patient had never traveled to the tubercular endemic zone and did not have previous diagnosis or contact with tuberculosis. She did not have family history of cancer or other comorbidities. On initial evaluation, she had a respiratory rate of 28 breaths per minute and saturated 90% on room air, blood pressure of 100/70 mmHg, and a heart rate of 90 beats per minute in sinus rhythm. Examination of the chest revealed diminished expansion of the left hemithorax. Left hemithorax was dull to percussion and breath sounds were of diminished in intensity on auscultation. Trachea was pushed to the right and position of cardiac apex was difficult to localize on palpation. Heart sounds were diminished in intensity, and there was no audible murmur, bruit, rubs, or third and fourth heart sounds. Examination of the other systems including abdomen, neurology, head, neck, and extremities were essentially unremarkable.

Investigation, clinical course, and outcome

Point of care ultrasound (POCUS) revealed large left-sided pleural effusion. Laboratory parameters revealed hemoglobin of 11 g/dL, hematocrit of 42%, and white blood cell count of 11,000 cells/mcL with 74% neutrophils and 22% lymphocytes. Serum protein level was 4.8 g/dL, serum albumin was 3.5 g/dL, and serum LDH was 140 U/L. Metabolic parameters including serum creatinine of 1.1 mg/dL, blood glucose of 110 mg/dL, and other metabolic parameters were within normal limits. Coagulation parameters were remarkable with prothrombin time measuring 11 s, international normalized ratio (INR) 1.2, and d-dimer measured 0.12 µg/mL

Chest X-ray revealed a large left-sided pleural effusion pushing the mediastinum to the opposite side (Figure 1). Diagnostic thoracentesis revealed hemorrhagic pleural effusion on gross inspection. Laboratory analysis of pleural fluid revealed pH of 7.27, with 440,000 cells/mcL red blood cells and 14,000 cells/mcL white blood cells, and pleural fluid hematocrit was 31%. Pleural fluid protein was 2 g/dL, pleural fluid albumin was 1.8 g/dL, and pleural fluid LDH 100 U/L. Pleural fluid albumin is to serum albumin ratio was more than 0.5, pleural fluid LDH is to serum LDH ratio was more than 0.6, and pleural fluid LDH was more than two-third of the upper limit of serum LDH, and these findings were suggestive of exudative pleural effusion. More than hundred thousand red cells in pleural fluid were consistent with hemorrhagic pleural effusion. Patient underwent therapeutic thoracentesis and an intercostal drain was placed in the left pleural cavity given the concern for recollection. Contrast-enhanced computed tomography (CT) of the chest was performed, and it revealed a lung mass involving left upper lobe with multiple pleuroparenchymal nodules in bilateral lung parenchyma and pleurae (Figure 2). She was further evaluated with video-assisted thoracoscopy (VATS), and wedge biopsy of left pleural nodule was performed.

Figure 1.

Chest X-ray anteroposterior view showing left-sided pleural effusion.

Figure 2.

(Panel A) CT-chest with contrast axial view, showing left-sided pleural effusion, and (Panel B) CT chest coronal section performed after thoracocentisis showing left upper lobe lung mass.

Surgical specimen consisted of sections of lung with a pleural-based area of hemorrhage and necrosis with abundant fibrinous exudate. Located within the pleura and admixed with hemorrhage are scattered small islands of atypical cells containing enlarged hyperchromatic nuclei and ample eosinophilic cytoplasm. Few foci of atypical cells appear to be lining vessel-like spaces (Figure 3, Panels A and B). A panel of immunohistochemical stain was performed. It showed membranous and cytoplasmic positivity for CD31 antibody (Figure 3, Panel C) and WT1 antibody and focally positive for cytokeratin AE1/AE2. Stain for p63 was negative in atypical cells. Stain for Ki-67, a proliferation marker, showed nuclear positivity in >30% of atypical cells.

Figure 3.

Histological sections of the left lung mass: (Panel A) Section of lung with areas of hemorrhage and necrosis. (Panel B) Atypical cells with hyperchromatic nuclei surrounding vascular spaces, marked with arrows. (Panel C) Positive nuclear and cytoplasmic activity with immunohistochemical staining with CD31.

Histological appearance and distribution of the process and results of immunohistochemical stain were consistent with angiosarcoma. Positive cytokeratin staining suggested pleural origin of the cells. Pleural lesions had likely infiltrated the ipsilateral lung parenchyma and metastasized to the contralateral side. Further evaluation for staging with screening studies such as computed tomography of abdomen and pelvis, magnetic resonance imaging of the brain, and bone scan were negative. Our patient was diagnosed with primary pleural angiosarcoma metastatic to the contralateral lung. She opted for palliative care and had a rapidly declining clinical course. She passed away within 5 weeks of the diagnosis.

Discussion

Primary angiosarcoma of the chest wall and pleura is an extremely rare and aggressive malignancy. Angiosarcomas represent 1%–2% of all soft tissue tumors.^1,32 It originates from the vascular endothelial cells of small blood vessels and affects retroperitoneum, subcutaneous tissue, liver, heart, spleen, and breast.³³ Primary angiosarcoma of the pleura and chest wall is rare. We performed an extensive literature search in Medline (via PubMed), Scopus, Google Scholar, and Cochrane Library and were able to identify 46 published cases^1–31 ever reported in the literature since the first reported case in 1943² excluding the epithelioid hemangioendothelioma. Three cases^23–25 in the literature are reported in conference abstracts only, and thus, we have not included them in the literature review. Of the 46 cases identified in 28 manuscripts, we have summarized 20 cases of pleural angiosarcoma reported in the literature in English language excluding the pleuropulmonary angiosarcoma and the chest wall angiosarcomas listed in Table 1. We have performed narrative review of the inherent literature and constructed the Kaplan–Meier survival curve of the 20 cases of primary pleural angiosarcoma.

Table 1.

Cases of pleural angiosarcoma reported in English language in the literature.

Case	Age (years)/sex	Presenting feature	Metastasis at diagnosis	Treatment	Survival after diagnosis (months)	Author
1	57/F	Massive recurrent hemothorax	No	S, C, RT	10	Alexious9
2	53/M	Pleural effusion	–	–	6	Zhang11
3	62/F	Pleural effusion, ascites	–	S	<1	Zhang11
4	66/M	Pleural effusion	–	–	6	Zhang11
5	45/M	Recurrent pleural effusion	–	–	6	Zhang11
6	60/M	Bloody pleural effusion	–	–	2	Zhang11
7	34/F	Dyspnea, chest pain	No	S, C	A (5 months after surgery)	Roh12
8	57/M	Memory loss, headache	Brain	No	2	Kimura15
9	55/M	Chest pain, cough, hemoptysis	–	S	–	Pramesh20
10	39/M	Chest pain, shortness of breath	No	S, C	8	Chen17
11	61/M	Spontaneous hemothorax	Skin	–	2	Kurtz18
12	62/M	Progressive dyspnea	No	No	<1	Dainese1
13	68/M	Hoarseness	–	–	10	Miyazaki28
14	75/M	Chest pain	–	–	10	Baisi30
15	49/M	Chest pain	–	S, R, C	A (9 months after)	Kao27
16	77/M	Dyspnea	–	S	<1	Lorentziadis29
17	58/F	Dyspnea, fever	No	C	4	Quesada31
18	76/M	Cough	No	S	A (7 months after the surgery)	Zhang26
19	56/M	Chest pain, dyspnea, hemothorax	–	–	–	McCaughey4
20	70/F	Chest pain, dyspnea, weight loss	Yes	–	1	Sedhai

S: surgery; C: chemotherapy; R: radiotherapy; A: alive.

The most common presentation is pleuritic chest pain (47.5%), followed by shortness of breath (35%), hemoptysis (27.5%), cough (15%), and constitutional symptoms like weight loss (10%). Radiologic evaluation usually shows unilateral or bilateral pleural effusion (70%) and focal or diffuse pleural thickening (40%), mimicking the presentation of mesothelioma.²⁷ Mass lesions are seen in about half of the reported cases^{2–10,14,20–22,26} similar to the one observed in our patient with a left upper lobe mass. There are no distinct radiologic characteristics to differentiate from other metastatic and primary pleural tumors. The common metastatic sites reported in the literature are lymph nodes, bone, brain, liver, spleen, adrenals, skin, oral cavity, and spinal cord.^{2,3,5,15,18,19} Aozasa et al.⁵ reported adrenal as a preferential metastatic site with (n = 5).

Pleural fluid is usually hemorrhagic. Pleural fluid cytology for atypical cells was performed in seven cases^{1,8,9,13,19,20,22} and is reported positive in one case.²⁰ Most patients were diagnosed at a surgical biopsy.^{3,5,7,9,12,15,17,18,20,26,27} PPA was reported as diagnosed at autopsy in seven case reports.^{2,4,5,8,21,22} Non-invasive biopsy and surgical biopsy obtained without direct vision or non-targeted biopsy were low yield and diagnostic only in small proportion of cases.^{1,5,6,14,16,19} Biopsy was non-diagnostic in six patients.^{8,9,13,19,21,22} Thus, in setting of refractory pleural effusion, exploration of the pleural cavity with video-assisted thoracoscopy and visually targeted biopsy may aid in making the diagnosis.

Histologic characteristics of the tumor show malignant cells with epithelioid neoplasm with vasoformative nature, such as vascular spaces lined by atypical tumor cells intracytoplasmic and vasoformative spaces containing red blood cells. There are other differential diagnoses of a biphasic pleural tumor which includes mesothelioma and sarcomatoid carcinoma. Mesothelioma is characterized by more monotonous arrangement of the tumor cells with less degree of cytologic atypia. Intracytoplasmic lumen can be present in both angiosarcoma and mesothelioma, but intraluminal RBCs are not seen in mesotheliomas.²⁷ Immunohistochemical stains are important in confirming the diagnosis, and at least one positive immunohistochemical marker (CD31, CD34, Factor VIII, or FLI-1) is essential to make the diagnosis of angiosarcoma. CD31 is the most sensitive and specific immunohistochemical marker.^23,31 Epithelial markers are expressed in the epithelioid variant of angiosarcoma.²³ Positive cytokeratin^1,5,11,14,15 and immunoreactivity to CAM5.2, CK7, CK8, or CK18 are reported positive in a few case reports.^1,13,14 Cytokeratin is strongly positive in carcinoma along with mesothelioma and can be variably expressed from diffusely strong to focal and weak in distribution, thus making it less useful in the diagnosis of angiosarcoma.¹⁷ Cytokeratin is a marker of mesothelial/pleural origin of cells but cannot be used to differentiate pleural malignancies. Markers of mesothelial cells such as calretinin, CK5/6, HBME-1, and WT-1 can be useful in differentiating tumors of vascular origin from mesothelioma.

Given the rarity of PPA, etiopathology is not well studied. Case reports from Japan have studied the association with tuberculous pyothorax (n = 15).^5,15,21,24 Case reports from the Western world have reported association with asbestos exposure (n = 4)^7,10 and radiotherapy (n = 1).¹¹ Aozasa et al.⁵ in a small case series of five cases postulated 3600-fold increased risk of pleural angiosarcoma in the presence of chronic tuberculous pyothorax, although that conclusion was drawn from a small case series (n = 5). Hattori²⁵ reported that angiosarcoma associated with pyothorax manifesting as a chest wall tumor. Atanoos et al.¹⁰ reported three cases of pleural angiosarcoma, and two of the three reported cases had history of asbestos exposure and only one patient had asbestos fiber content by mineral analysis. One patient reported by Zhang et al.¹¹ had previous history of radiotherapy for ovarian carcinoma and developed simultaneous angiosarcomas in the pleura and peritoneum. Miyazaki et al.²⁸ reported angiosarcoma in setting of expanding hematoma-associated previous pneumonectomy. Our patient did not have history of tuberculous pyothorax, asbestos exposure, radiotherapy, prior thoracic surgery, or other risk factors. Thus, angiosarcoma in our patient can be described as de-novo pleural angiosarcoma.¹⁸

Treatment modalities for pleural angiosarcoma include surgery, radiotherapy, and/or chemotherapy. Surgery can be useful in the presence of localized tumor. Vascular embolization using endovascular techniques can be helpful in reducing tumor size and vascularity supporting perioperative hemostasis.^18,29 Role of chemotherapy is limited but radiotherapy can be useful in adjuvant setting. With rare exceptions, clinical course of the disease is rapidly progressive and usually fatal within few months of the diagnosis. We constructed a Kaplan–Meier curve for cases of pleural angiosarcoma (n = 20) reported in English language in the literature, as summarized in Table 1. The mean survival after the diagnosis was less than 1 year (Figure 4).

Figure 4.

Survival length of 18 cases of pleural angiosarcoma reported in English language. Most patients died within the end of a year.

Conclusion

Primary pleural angiosarcoma is an extremely rare and an aggressive malignancy. Patients usually have a rapidly declining clinical course and have a dismal prognosis with rare exceptions. Clinical and radiologic presentation can be similar to mesothelioma and use of immunohistochemical staining can aid in the diagnosis.