Primary Pleural Hemangioendothelioma: A Case Report and Literature Review

Epithelioid hemangioendothelioma (EHE) is a rare intermediate malignant tumor originating from vascular endothelial cells. EHE can be located in variable organs, including the lung, liver, bone, soft tissue, skin, gastrointestinal tract, brain, mediastinum, spleen, breast, testis, thyroid, and heart [1]. EHE patients develop metastatic disease in 20–30% of cases. The etiology of EHE is not yet well-understood. Despite being less frequent, primary pleural hemangioendothelioma (PEH) is believed to be more aggressive than other EHE subtypes [2]. The 5-year EHE overall survival rate is >70% [3], whereas it is much less optimistic in PEH [4].

Here, we describe a 40-year-old male patient presented with right-sided chest pain diagnosed with PEH. Additionally, we discussed the relevant literature in order to advance the understanding of the symptoms and diagnosis of the disease.

In July 2020, a 40-year-old man was referred to our center, a university-affiliated respiratory hospital, complaining of right-sided chest pain accompanied by dyspnea for 1 year. He began experiencing symptoms while noticing a sharp and pleuritic pain in his right-sided chest radiating to the right neck. Besides these, he did not mention any other symptoms, such as fever or weight loss. His previous medical history was noncontributory, and he denied a history of smoking or asbestos exposure. Aside from that, he has not ever received radiotherapy. At the time of admission, our patient was hemodynamically stable, and the physical examination was unremarkable. Hematologic laboratory and blood chemical test results are demonstrated in Table 1.

He underwent an initial chest radiograph which revealed right-sided pleural effusion. Consequently, a computed tomography (CT) scan was requested, which demonstrated right-sided pleural effusion and thickening without underlying parenchymal abnormality (Fig. 1a, b). Also, the adjacent lung passively collapsed.

Echocardiography established proper cardiac function and (ejection fraction = 63%) without any structural abnormality. Also, there was no sign of pericardial effusion.

Afterward, a thoracocentesis was done. The pleural fluid analysis is given in detail in Table 2. Cytological examination of the pleural fluid was unremarkable.

To further assess the patient, a video-assisted thoracoscopic surgery (VATS) was requested, in which the following were observed: right-sided pleural thickening, visceral pleural nodularity, and massive effusion. A pleural biopsy was obtained during VATS, the results of which are as follows: microscopically, the pleural tissue composed of single cells, cords, and nests of atypical polygonal cells with round, reniform nuclei, some vesicular chromatin, and abundant pale eosinophilic vacuolated cytoplasm. Intracytoplasmic vacuoles occasionally contain an erythrocyte. In some foci, the atypical cells were surrounded by the inflammatory cells. Also, no increased mitotic activity, necrosis, or prominent pleomorphism was demonstrated (Fig. 2a). During immunohistochemistry staining, the mentioned cells showed high levels of vimentin, CD31, and CD10. A group of cells was found to react positively to CD34 and EMA, while no reaction was seen to WT1, and calretinin was negative (Fig. 2b). In addition, the proliferation index by Ki67 was up to 15%. As a result of the histopathological findings, the patient was diagnosed with PEH.

There were no findings of metastasis on CT scans of the abdomen and pelvis. A bone scan exhibited increased uptake in the right hemithorax, representing the possibility of malignancy or simply due to the previous manipulation. Also, the radiopharmaceutical agent appeared to be symmetrically taken up in both tibial cortexes, suggesting hypertrophic pulmonary osteoarthropathy (Fig. 3a, b).

Eventually, the patient was referred to oncology, where he was started on a regimen of Adriamycin and ifosfamide. The patient is currently undergoing chemotherapy and has not mentioned particular problems.

We reviewed the related literature published since 1987 (a total of 22 cases) in Table 3. According to these reports and our own, we have discussed the characteristics of this disease.

EHE is a rare vascular tumor. From the clinical perspective, the tumor behavior is between benign hemangiomas and high-grade angiosarcomas [22]. Even though EHE can arise in different body parts, it has a higher probability of developing in the liver and lung. Female individuals are generally affected by EHE more than male counterparts. The peak incidence of the disease is in the fourth and the fifth decade of life.

In contrast, PEH typically occurs more frequently in older male individuals [2]. In our analysis of the 23 cases identified in the literature, 52% of patients were male, with a mean age of 50 years. Dyspnea is shown to be the most prevalent symptom of PEH, followed by chest pain and cough, which our study was well-aligned with (overall data indicated that the most common presented symptom was dyspnea reported by 60% of patients). Also, a group of patients complained about back pain, weight loss, fatigue, and anorexia. Since some patients might be asymptomatic at diagnosis or be experiencing minor symptoms, PEH is discovered in some cases through incidental diagnosis.

Despite the lack of correlation between smoking and PEH, radiation and asbestos exposure are considered related factors. Moreover, 5CAMTA1 gene rearrangements; translocations in chromosomes 7, 14, and 22; the loss of Y chromosome; and t (1; 3) (p36; q23–25) [20] have been reported as predisposing factors for PEH. It is worth mentioning that the majority of hematological and laboratory tests are not specific.

Slight (or moderate) unilateral pleural effusion is the most common chest CT finding in PEH patients, frequently accompanied by pleural thickening. For the case reported here, chest CT showed right thoracic collapse and diffuse pleural thickening. The changes were quite similar to those reported in the other literature. Pleural effusion is more common on the right side (20). (In our review, 57% of PEH were diagnosed on the right side.)

PEH consists of relatively monomorphic epithelioid cells arranged in cords and nests within a myxohyaline stroma from the pathological perspective. Cell nuclei are eccentric, vacuolated, and similar to signet ring cells. The cytoplasm is eosinophilic, with vacuoles of varying sizes in the cytoplasm of some tumor cells. It is also notable that immunohistochemical staining is the most reliable diagnostic means to determine the origin of tumor cells. Vascular endothelial cell markers can be detected with this staining method; among them, CD31 and CD34 exhibit the highest specificity [23]. According to our literature review, CD31, CD34, and factor VIII were the most prevalent positive markers. In the case presented earlier, the immunohistochemical staining result was positive for CD31 and CD34 as well.

EHE tumors are radio- and chemoresistant [23]. Radiotherapy is reserved for the palliative therapies of cases with bone involvement, and there have not been homogeneous responses obtained from chemotherapy schemes. PEH is often presented at an advanced stage and can rarely be resected for cure [2]. Therefore, most of the patients undergo chemotherapy mainly with carboplatin and etoposide [12]. Different results from both surgical treatment and chemotherapy have been reported in different studies (showed in Table 3); however, reports are pretty conflicting, and many studies have described cases in which combination chemotherapy of carboplatin and etoposide was ineffective [12].

Metastases, mesotheliomas, sarcomas (such as angiosarcoma or Kaposi), hyperplasia, tuberculosis, and pseudopyogenic granuloma are PEH differential diagnoses [14], which physicians should consider. Despite the localized infiltration in the early stages, pleura involvement becomes more extensive as the disease progresses. As a result, neither pleuroscopy nor VATS is a reliable technique to diagnose PEH in the early stages of the disease. Even if the aforementioned methods are not diagnostic initially, it is crucial to keep an eye on suspicious cases.

The patient presented before and similar reported cases may improve the clinical understanding of PEH. Since the clinical manifestation of PEH is not specific, it is often misdiagnosed in the early stages. Consequently, we highly recommend considering PEH as a differential diagnosis for patients with pleural thickening.

We thank Ali Falsafi for his valuable help in editing this manuscript.

Written informed consent has been received from the patient. It is in the Persian language (the mother tongue of the patient). We will send it to the respectful journal if needed. The study protocol was approved by the Shahid Beheshti University of Medical Sciences Ethics Committee. The reference number is IR. SBMU.NRITLD.REC.1400.011.

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Elham Askari: she was the pathologist who presented the case and made the patient’s diagnosis and handed in the sample’s figures. Shekoofeh Yaghmaei: original draft preparation and reviewing the manuscript. Sara Haseli: she was the radiologist who did the chest CT and reported it. Mihan Pouradollah Totkaboni: she is the pathologist who approved the diagnosis on sample immunostaining. All authors read and evaluated the final manuscript.

All data analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.