This study aimed to determine the clinical characteristics and etiologies of HisPE. We found that HisPE was not uncommon (9.0%) among patients with PE, and > 50% of exudative HisPE cases were caused by malignancy (50.7%). The major malignancies were lung cancer, breast cancer, and stomach cancer. Thus, physicians must consider the possibility of underlying cancer if they encounter HisPE.
In a previous study on the cellular content of pleural fluid from patients with normal pleura who were undergoing thoracoscopy for hyperhidrosis, approximately 75% of the cells in the pleural fluid were macrophages, belonging to histiocytes . That is, histiocytes comprised a considerable proportion of normal pleural fluid. However, the characteristics and etiologies of patients with HisPE due to pathologic conditions have not been studied. In the present study, we defined HisPE as when histiocytes comprised 50% or more of the pleural fluid WBCs. In our clinical experience, we have found that HisPE is not uncommon, and felt that it is associated with malignant PE. We presumed that pleural metastasis of cancer would trigger immune responses and induce reactive histiocytic proliferation . Thus, we started this study because of this insightful experience.
Previous studies investigating HisPE consist of only case reports. One such report observed proliferating histiocytes in the pleural fluid with no palpable lymphadenopathy or organomegaly; this was an atypical case of Rosai-Dorfman disease (also known as sinus histiocytosis with massive lymphadenopathy), which involves the over-production of non-Langerhans sinus histiocytes . Another case report described histiocytic proliferation mimicking metastatic signet ring cell adenocarcinoma and highlighted the importance of differentiation between histiocytic proliferation and signet ring cell carcinoma . There was also a report of histiocytic sarcoma presenting with HisPE. In this case report, a patient presented with anterior mediastinal tumor accompanied by HisPE, and the cause of the mass was histiocytic sarcoma .
The term “histiocytes” was originally used to describe the large cells commonly found in the lymph nodes and spleen that were morphologically nonspecific. Currently, histiocytes are considered to be tissue macrophages that are differentiated from the monocyte lineage, including alveolar macrophages in the lung, Kupffer cells in the liver, Langerhans cells in the skin, and dendritic cells in the germinal centers of lymph nodes . These cells (histiocytes) play an important role in antigen presentation, phagocytosis, and removal of pathogens and cellular debris, and can be found anywhere on the human body including the PE [15, 16].
There are two situations in which histiocytes could increase: reactive and neoplastic histiocytic proliferation . Neoplastic proliferation refers to the clonal proliferation of histiocytes, such as acute/chronic myelomonocytic leukemia, acute monocytic leukemia, and histiocytic sarcoma . Reactive proliferation is caused by inflammatory responses secondary to infection, autoimmune diseases, or malignancies. Granuloma is a representative reactive proliferation, wherein histiocytes fuse to form giant cells . Severe inflammation may cause hemophagocytic lymphohistiocytosis via hypercytokinemia .
The causative mechanism of reactive histiocytosis is poorly understood. It is presumed that histiocytes, which are antigen-presenting cells, are likely increased by antigenic or microbial stimuli . In the current study, histiocytes were primarily increased in those with PE caused by malignant tumors (50.7% of all exudative HisPE). The mechanism of histiocytosis in malignant PE seems to be associated with the immune response to cancer (cancer cells as antigens) .
Further, in our study, lung cancer was the most common cause of malignant PE (41.2%), followed by breast cancer (15.7%) and stomach cancer (10.8%). It is reported that lung cancer, breast cancer, and lymphoma account for most cases of malignant PE [2, 17]. However, it is rather interesting that stomach cancer was the third most common cause in our study. This is thought to be due to the higher incidence of stomach cancer in South Korea than in other countries . In addition, it is known that malignant PE can occur in all types of lung cancer, but adenocarcinoma is the most common cause [19, 20]. The present study confirmed that adenocarcinoma is the most common cause (81.0%) of lung cancer-induced malignant PE.
Aside from malignancy, in the present study, HisPE occurred in patients with parapneumonic effusion (4.5%) and tuberculous pleurisy (4.5%). These diseases must be differentiated by using a variety of clinical situations. However, our findings provide some insights. In parapneumonic effusion, neutrophils were the second most common WBCs after histiocytes, whereas in tuberculous pleurisy, the most common cell type was lymphocytes. In tuberculous pleurisy, a prominent rise in ADA was also observed. These findings could aid discrimination of the causative disease of HisPE. Moreover, there were multiple cases of PE due to heart failure, liver cirrhosis, or renal diseases (11.9%). However, since we only applied Light's criteria, approximately 25% of transudative PE could have been misclassified as exudative PE . Further consideration of the serum-pleural fluid protein gradient as well as Light's criteria would have significantly reduced the proportion of PE due to heart failure, liver cirrhosis, or renal diseases.
This study has some limitations. First, this was a retrospective study. Second, it was conducted at a single center and the sample was small. It is necessary to confirm whether the HisPE characteristics identified herein can be replicated through prospective studies involving a large number of PE patients. In addition, further studies are needed to determine the mechanism by which histiocytes reactively increase in PE.