Primary Diagnosis of Epithelioid Hemangioendothelioma in Pleural Effusion Based on Cytologic Features and Vascular Marker Immunocytochemical Staining.

INTRODUCTION

Epithelioid hemangioendothelioma (EHE) is a rarely encountered vascular neoplasm of intermediate malignancy affecting less than one per million.[1] Owing to its epithelioid features, it mimics carcinoma, melanoma, mesothelioma, and sarcomas with epithelioid morphology.[234] Pettinato and colleagues[5] were the first to describe the cytologic features of EHE in soft tissue aspiration samples. Since then, few case reports and series studies ascertained these features. Yet, distinction of EHE from its mimickers seems challenging in cytologic material, in which the histoarchitectural features couldn't be assessed.[234] Due to its non-specific features, EHE poses a diagnostic pitfall in pleural effusion (PE) especially in case of limited cytology material and in absence of prior biopsy diagnosis,[4] particularly that the cytomorphology of EHE in PE has not been well characterized in literature.[3] Here, we characterize the distinctive cytologic features of EHE in a patient initially presented with pleural effusion (PE) with an overview of the literature yield in this regard.

CASE PRESENTATION

A 41-year-old male patient presented with progressive dyspnea and history of recurrent hemoptysis during the past 5 years for which he has done a fiberoptic bronchoscopy that revealed nodular mucosa in both lung bronchial trees suggestive of vascular lesion, however no data were available concerning bronchoscopic biopsy. Radiologic assessment revealed bilateral PE that was massive on the left side. Approximately 2000 cc of thick turbid yellowish-white fluid were drained through left-sided pleural tube and sent for cytopathologic analysis. Four smears and two cell blocks-stained with hematoxylin and eosin (H&E) were prepared.

On microscopic examination, smears were formed entirely of blood elements. Cell blocks revealed low/mild cellularity with myxo-hyaline background. Tumor cells were arranged individually in cohesive clusters with knobby borders laying within vascular-like spaces in admixture with blood elements, rosette-like pseudo-glandular arrangements, and morules of overlapping cells. The cells imparted epithelioid morphology with moderately abundant eosinophilic cytoplasm, round/ovoid nuclei with raisinoid nuclear contours, inconspicuous nucleoli, and mild pleomorphism but no mitoses. Intracytoplasmic vacuoles and lumina mimicking signet ring cells were frequently observed with occasional nuclear grooves, but no intracytoplasmic erythrocytes. Scattered plasmacytoid cells with eccentric nuclei were present. Immunohistochemistry (IHC) for vascular markers revealed positivity for CD31 and CD34 [Figure 1]. Cytokeratin (CK) 7, CK20, EMA, calretinin, TTF-1, and Napsin A were all negative. Thus, a cytologic diagnosis of EHE was signed out with a recommendation for biopsy. Days later, biopsy was done and reviewed with the cytology and IHC results. After being signed with the same diagnosis, the patient has been transferred to the Medical Oncology and Radiotherapy Department.

Figure 1

Cytologic features of epithelioid hemangioendothelioma in pleural effusion. Tumor cells seen individually and in cohesive clusters with knobby borders (a and b, H and E x100; c‑e, H and E x400). Rosette‑like formation (b, H and E x100); intracellular lumina; vacuolization (c and d [white arrow]; H and E x400); raisinoid nuclear contours; occasional nuclear grooves [black arrow] (d, H and E x400); and morules (e, H and E x400). Myxo‑hyaline background (f, H and E x100). Tumor cells show membranous immunoreactivity for CD31 and CD34 (g and h respectively, diaminobenzidine x200)

DISCUSSION

EHE is a vascular neoplasm composed of cords and nests of epithelioid endothelial cells within myxo-hyaline stroma. Most cases are characterized by WWTR1-CAMTA1 gene fusion, while YAP1-TFE3 fusion occur in a small subset that shows well-formed vessels lined by paler cells. EHE involves somatic soft tissue, lung, and liver of adults, but any organ or age can be affected. Presenting symptoms depends on the involved anatomical site/s but visceral EHEs are often multifocal and metastasizing with variable prognosis. Risk factors for worse outcome include: male sex, weight loss, anemia, pulmonary symptoms, PE/invasion, and metastasis (liver, pleura, and lymph nodes). The reported 5-year survival of patients with PE is 2% while that of patients without PE is 73%.[6]

In agreement with the limited handful case studies describing EHE in effusion cytology,[234] cytologic diagnosis clues include: variable cellularity (scanty to highly cellular); myxo-hyaline background; single cells; knobby bordered (frayed edges) or pseudo-glandular clusters; epithelioid to plasmacytoid or occasionally spindle tumor cells; round to ovoid (somewhat eccentric) nuclei with occasional inclusions or grooves and raisinoid nuclear membranes; variably conspicuous nucleoli; variable cytoplasm from medium to abundant and from relatively dense to vacuolated; intracytoplasmic vacuoles that forms signet-ring like appearance (probably represents primitive lumen formation by a single cell). Clear-cut intracytoplasmic lumina are frequently detected but intracytoplasmic erythrocytes are not frequently seen in cytologic material and seems non-specific for EHE.[4] Most EHE tissue biopsies show minimal atypia and pleomorphism, low mitotic count and infrequent necrosis,[6] and these findings apply to cytology as well.

For distinction of EHE from other pleural malignancies, immunoreactivity for vascular markers: CD31 (specific vascular marker), CD34 (sensitive, not very specific), FLI-1, and ERG are often helpful to establish the tumor's vascular nature, however, there may be substantial variability in the degree of staining for a given marker. Keratins (CK7, 8, 18, pan-keratin) are expressed in around 40% of cases, but EMA and Calretinin expression is unusual. Except for a single study,[6] CAMTA1 immunostaining, has not been widely utilized in effusion cytology.[346] In distinction from epithelioid angiosarcoma (EAS), high degree nuclear pleomorphism, elongated nuclei, and overt nucleolar prominence may favor EAS, while the presence of nuclear grooves and intracellular lumina favors EHE.[3]

In conclusion, configuring cytologic diagnostic clues for EHE in PE seems of utmost importance as PE carries the risk for poor outcome in EHE patients. Inclusion of this entity in the differential diagnoses of malignant PE and application of immunocytochemistry would be obliging to reach accurate diagnosis.

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Conflicts of interest

There are no conflicts of interest.