Successful Treatment of Extranodal Natural Killer T Cell Lymphoma Nasal Type Complicated by Severe Hemophagocytic Syndrome A Case Report

cessful Treatment of Extranodal Natural Killer T Cell Lymphoma Nasal Type Com plicated by Severe Hemophagocytic Syn drome high-grade fever, cough, chest pain and blood in phlegm. A chest computed tomography scan detected pneumonia-like features, including multiple variable nodules, ground-glass opacities and patchy infiltration, which progressed rapidly. The patient was initially diagnosed with severe pneumonia and received a combination treatment of broad-spectrum antibiotics ,however the patient’s condition continued to deteriorate. Biopsy of lung and soft tissue confirmed a diagnosis of extranodal NK/T-cell lymphoma, nasal type. Bone marrow aspiration did not show lymphoma involvement. The patient had progressive neutropenia upon presentation, with further investigations showing hepatosplenomegaly, hyperferritinemia, hypertriglyceridemia, low natural killer (NK) cell activity and increased circulating soluble IL-2 receptor. We reached a diagnosis of hemophagocytic syndrome. Chemotherapy and immunotherapy were started leading to a progressive improvement of the disease.


Introduction
Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type(ENKL), is a rare malignancy of Non-Hodgkin lymphoma characterized by an aggressive clinical course and poor prognosis [1]. It is mostly endemic to East Asia and is associated with Epstein-Barr Virus (EBV) infection [2]. Its lesions are predominantly present in the Upper Aerodigestive Tract (UADT) such as the nasal cavity, nasopharynx, paranasal sinuses or palate. Less commonly, ENKL can manifest at extra nasal locations like the lung, skin, soft tissue, gastrointestinal tract, and testis. Since the neoplasm can destroy the midline facial structures, the disease used to be known as lethal midline granuloma [3,4].The presentation of the disease at extra nasal locations is nonspecific and may mimic many other benign or malignant lesions. Patients with extra nasal presentation often have DOI: 10.26717/BJSTR.2021.38.006202 more adverse clinical features such as an advanced stage, elevated LDH and poor performance status, and the survival rate is inferior compared with the nasal sites [5][6][7]. Hemophagocytic Syndrome (HPS), also known as Hemophagocytic Lymphohistiocytosis (HLH), is highly heterogeneous and comprises primary and secondary types.
Secondary HPS is associated with a variety of underlying conditions such as infection, malignancy, and autoimmune diseases. ENKL is frequently complicated with HPS, and survival is discouraging in this circumstance [8]. However, no standard treatment has been established based on the results of randomized controlled trials because of the rarity of the disease [9]. Here, we report a case of ENKL complicated by severe Lymphoma-

Case Report
A 32-year-old non-smoking man was emergently transferred to our hospital on June 30, 2019, because of a month-long highgrade fever, cough, left-sided chest pain and blood in phlegm. Prior to this, the patient had a history of trauma to the right lower limb and the wound healed itself. About ten days later he presented to a local hospital with the above-mentioned chief complaint and a chest computed tomography scan showed multiple nodules, ground-glass opacities and patchy infiltration scattered in both lung fields. Then he had been treated as for pneumonia. However, his clinical condition did not improve. The patient was therefore admitted to our hospital for further evaluation and treatment.
There was no relevant personal or family medical history for this  The patient was HIV negative. Two sets of blood cultures, and tumor markers, including CEA,SCC, CFRA21-1,Pro-GRP, and NSE were all normal. The G test and GM test were both negative.
Antinuclear antibody, anti-ENA antibodies, and anti-neutrophil cytoplasmic antibodies were all negative. Administration of broadspectrum antibiotics did not resolve hissymptoms. Bronchoscopic examination did not give a definite diagnosis. Lung nodules increased and grew larger, and hypoxia progressed. A CT-guided transthoracic needle biopsy of the left lower lung was performed ( Figure 2). During the course of treatment, FDG PET/CT was conducted and revealed heterogeneous hypermetabolic masses in both lung fields, as well as hepatic, splenic, osseous, soft tissue on the left dorsal side and the lower margin of the right 9th rib, and multiple lymph node metastases that involved the mediastinum, porta hepatis, bilateral hilum of lung. Then we also performed a ultrasound-guided percutaneous puncture biopsy of soft tissue at the lower margin of the right 9 th rib. Immunohistochemical staining of these two specimens both yielded positive results for CD56, CD3, CD2,and the Ki-67 proliferation index was 80%;in situ hybridization for EBV-encoded early small RNAs (EBER) was also positive; however, results were negative for CD79a,CD20. findings and infiltrations can also be seen [12]. It is reported that PET-CT may act as a significant tool to assess patients with LAHS, as it is highly sensitive in detecting neoplasms of the majority of histologic subtypes of lymphoma, and also demonstrates extensive 18-fluorodeoxyglucose (FDG) uptake in tumor tissues [13]. Anyhow there is no non-invasive test specific enough to make a correct has worse clinical features and survival rate, even in cases with apparently localised disease, than nasal NK/T-cell lymphoma in extranodal NK/T cell lymphoma [14].In this report, the tumor involved multiple organs throughout the patient's body. As with the progressive disease courses and poor prognosis, effective therapeutic strategies are urgently needed. As for HPS, the patient was treated according to the R-DEP(ruxolitinib, liposomal doxorubicin,VP-16,dexamethasone) chemotherapeutic regimen, and the overall condition of the patient gradually improved during chemotherapy. Nevertheless, it was equally important to treat primary diseases as well as treating HPS [11]. Regarding ENKL, no standard treatment has been established based on the results of randomized controlled trials because of the rarity of the disease [9].
ENKL cells are associated with a high expression of P-glycoprotein, leading to multidrug resistance that is likely responsible for the poor response to conventional anthracycline-based chemotherapy [15].
P-GEMOX is a modification of the Gemcitabine, L-Asparaginase, and Oxaliplatin (GELOX) regimen in which L-asparaginase is switched to pegaspargase and was also included as a suggested treatment regimen for ENKL in the NCCN guidelines [16].  [19]. In our case the patient has already received the therapy of anti-PD1 antibody with Chidamide for more than one year, showing that this treatment is effective and safe. As randomized trials comparing different regimens have not yet been conducted and standard therapy has not yet been established for these patients, treatment should be individualized based on patient, tolerance and comorbidities.

Conclusion
At this moment, there is no recommended treatment for ENKL complicated with HPS because of the extreme rarity of this entity. It was equally important to treat primary diseases as well as treating HPS. L-asparaginase-containing regimens are the cornerstone for treating ENKL. In this modern ENKL treatment era, newer agents are being investigated for treating ENKL and prospective multicenter trials need to be performed to establish an optimal treatment for this rare and dismal disease.

Funding
There was no funding support of this work.

Disclosure
The authors declare that there is no conflict of interest.