Case Report of a Patient with Hemophagocytic Lymphohistiocytosis in Small Cell Lung Cancer

Background Hemophagocytic lymphohistiocytosis (HLH) is a rare and almost universally fatal disease in adults. Due to lack of recognition, under-diagnosis or delayed diagnosis, malignancy related HLH has a poor outcome in adults. Case Presentation A 60-year-old-female patient was admitted to our hospital with a three day history of weakness and anorexia. Physical examination revealed severe pallor without lymphadenopathy or hepatosplenomegaly. Initial blood test showed hemoglobin level of 26 g/L and platelet count of 76×10 9 /L. Later the patient experienced sustained fever with a maximum temperature of 40°C for one week without any obvious infective symptoms. Biochemical examination revealed high serum ferritin and low natural killer cell viability. The bone marrow morphology showed hemophagocytosis and inltration with metastatic small cell lung cancer (SCLC). The patient was diagnosed as hemophagocytic lymphohistiocytosis associated with SCLC and underwent chemotherapy. However, the patient progressed rapidly and died within 2 weeks. Conclusion We reported the rst HLH case with SCLC. It is critical to have an early identication of HLH in SCLC patients.


Introduction
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of severe immune activation and proin ammatory cytokine hypersecretion, result in tissues and organs damage [1].HLH may be triggered by several factors such as drugs, autoimmune diseases and infections as well as cancers in adults. Timely diagnosis may be challenging because of the rarity of HLH. Among them, malignancy-related HLH (M-HLH) is frequently miss-diagnosed with a poor outcome. The median overall survival is typically less than 2 months [2].
In this article we report a rare case of a 60-year-old female who was admitted to the department of Hematology/Oncology in The First Hospital of Tsinghua University (Beijing, China) with severe anemia, thrombocytopenia and fever for one week. Subsequently, the patient was diagnosed as small cell lung cancer (SCLC) related HLH.

Discussion
HLH is an excessive in ammatory reaction disease caused by uncontrolled proliferation of activated lymphocytes and histiocytes which secrete a large number of in ammatory cytokines, involving multiple tissues, organs and systems. HLH can be divided into primary HLH (pHLH) and secondary HLH (sHLH). pHLH mainly includes familial HLH and immunode ciency syndrome with HLH-related gene de ciency. sHLH is associated with various underlying diseases, such as infections, tumors, rheumatologic and some metabolic diseases. Malignant tumors, especially NK/T cell lymphoma, are the main causes of sHLH. Malignancy related HLH M-HLH can occur in all age groups, and is more common in adults. A large sample study showed that M-HLH accounted for 48% of adult HLH, of which 93.7% was caused by hematological malignancies [5]. Lymphoma is the most common type, followed by leukemia and Castleman's disease. M-HLH also occurred in a small number of patients with solid tumors, including embryonic cell tumors, thymoma, gastric cancer [6]. To our knowledge, this is the rst HLH case reported with SCLC.
HLH is a rare and almost universally fatal disease in adults. Due to lack of recognition, under-diagnosis or delayed diagnosis, M-HLH has a poor outcome in adults. A recent study showed that fewer than 50% adult patients with M-HLH received HLH-directed therapy 2 . M-HLH patients had high mortality rate, and majority of patients died from infection and multi-organ failure within 2-4 weeks [7]. Therefore, it is very important to make a clear diagnosis and give early treatment to control the disease timely.
At present, the HLH-2004 is the commonly used international standard criteria, which requires to meet 5 of 8 criteria to make a diagnosis of sHLH [3]. Because of atypical early symptoms and rapid progress, HLH is easily misdiagnosed. Early identi cation of HLH and assessment of underlying causes are critical to formulate optimal treatment strategies. The disease progresses rapidly and has a high mortality, so it usually requires urgent treatment to suppress excessive in ammation as soon as possible.
At present, the treatment scheme of HLH-1994 is widely used in the world. Hematopoietic stem cell transplant plays a key role in improving the long-term survival rate of pHLH [8]. For M-HLH, combined chemotherapy should be given to the corresponding tumors and timely and effective supportive treatment is essential [9]. Effective infection control and comprehensive organ support may also improve the outcome of M-HLH. With the development of HLH research, some biological targeted agents such as alemtuzumab, interferon-γ, tumor necrosis factor-α, interleukin (IL)-6, IL-1β and ruxolitinib have been assessed [10]. In the present study, we are fully aware of the diagnosis of HLH. The patient was hospitalized with persistent high fever and cytopenia. Further examination revealed elevated ferritin and lung tumor markers. Combined with chest CT scan, the diagnosis of M-HLH was strongly suspected. Given highly lethal disease with rapid progression of HLH, we treated the patient with dexamethasone quickly. At the same time, we performed the examination of NK cell activity, sCD25 as well as bone marrow biopsy to con rm HLH. As soon as the patient was con rmed as HLH association with SCLC, HLH-94 regimen was used timely. Because of the rapid progress, the patient died within two weeks. Therefore, our experience suggests SCLC related HLH has a rapid progression and high mortality. It is critical to have an early identi cation of HLH in SCLC patients. Figure 1 Chest CT revealed the right middle lobe consolidation. (arrow) Abbreviation: CT, computed tomography.

Figure 2
The morphology of bone marrow cells. Notes: The pathological result showed metastatic carcinoma of bone marrow( A arrow) and hemophagocytosis (B arrow).